Singh Et Al-2021-Cochrane Database of Systematic Reviews

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Cochrane Database of Systematic Reviews

Chloroquine or hydroxychloroquine for prevention and treatment of
COVID-19 (Review)
Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T
Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T.

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.
Cochrane Database of Systematic Reviews 2021, Issue 2. Art. No.: CD013587.
DOI: 10.1002/14651858.CD013587.pub2.
www.cochranelibrary.com

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review)
Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on
behalf of The Cochrane Collaboration.
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Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 3
SUMMARY OF FINDINGS.............................................................................................................................................................................. 5
BACKGROUND.............................................................................................................................................................................................. 9
OBJECTIVES.................................................................................................................................................................................................. 11
METHODS..................................................................................................................................................................................................... 12
Figure 1.................................................................................................................................................................................................. 13
RESULTS........................................................................................................................................................................................................ 15
Figure 2.................................................................................................................................................................................................. 19
DISCUSSION.................................................................................................................................................................................................. 23
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 25
ACKNOWLEDGEMENTS................................................................................................................................................................................ 26
REFERENCES................................................................................................................................................................................................ 27
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 34
DATA AND ANALYSES.................................................................................................................................................................................... 66
Analysis 1.1. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 1: Death due to any 67
cause......................................................................................................................................................................................................
Analysis 1.2. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 2: Death due to any 67
cause (sensitivity analysis)...................................................................................................................................................................
Analysis 1.3. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 3: Negative PCR for 68
SARS-CoV-2 on respiratory samples at day 14 from enrolment........................................................................................................
Analysis 1.4. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 4: Negative PCR for 68
SARS-CoV-2 on respiratory samples at day 7 from enrolment..........................................................................................................
Analysis 1.5. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 5: Proportion admitted 68
to hospital (if receiving ambulatory treatment).................................................................................................................................
Analysis 1.6. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 6: Progression to 69
mechanical ventilation.........................................................................................................................................................................
Analysis 1.7. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 7: Length of hospital 69
admission (in days)...............................................................................................................................................................................
Analysis 1.8. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 8: Time to clinical 69
improvement.........................................................................................................................................................................................
Analysis 1.9. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 9: Time to negative 70
PCR for SARS-CoV-2 on respiratory samples.......................................................................................................................................
Analysis 1.10. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment, Outcome 10: Participants with 70
any adverse events...............................................................................................................................................................................
serious adverse events.........................................................................................................................................................................
prolongation of QT-interval on electrocardiogram.............................................................................................................................
Analysis 2.1. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome 1: Negative PCR for SARS-CoV-2 on respiratory 72
samples at day 7 from enrolment.......................................................................................................................................................
Analysis 2.2. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome 2: Negative PCR for SARS-CoV-2 on respiratory 72
samples at day 14 from enrolment.....................................................................................................................................................
Analysis 2.3. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome 3: Discharge from hospital at day 14 from 73
enrolment..............................................................................................................................................................................................
Analysis 2.4. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome 4: Clinical improvement at day 10 from 73
enrolment..............................................................................................................................................................................................
Analysis 2.5. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome 5: Total adverse events.................................. 73
Analysis 2.6. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome 6: Serious adverse events.............................. 74
Analysis 3.1. Comparison 3: HCQ + azithromycin versus standard care for treatment, Outcome 1: Death due to any cause......... 74
Analysis 3.2. Comparison 3: HCQ + azithromycin versus standard care for treatment, Outcome 2: Progression to mechanical 75
ventilation..............................................................................................................................................................................................
Analysis 3.3. Comparison 3: HCQ + azithromycin versus standard care for treatment, Outcome 3: Length of hospital stay in days... 75
Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) i
Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane
Collaboration.
Informed decisions.

Analysis 3.4. Comparison 3: HCQ + azithromycin versus standard care for treatment, Outcome 4: Participants with any adverse 75
events.....................................................................................................................................................................................................
Analysis 3.5. Comparison 3: HCQ + azithromycin versus standard care for treatment, Outcome 5: Participants with serious 76
adverse events......................................................................................................................................................................................
Analysis 3.6. Comparison 3: HCQ + azithromycin versus standard care for treatment, Outcome 6: Participants with prolongation 76
of QT-interval on electrocardiogram...................................................................................................................................................
Analysis 4.1. Comparison 4: HCQ versus febuxostat for treatment, Outcome 1: Death due to any cause....................................... 77
Analysis 4.2. Comparison 4: HCQ versus febuxostat for treatment, Outcome 2: Admission to hospital.......................................... 77
Analysis 5.1. Comparison 5: HCQ versus placebo for postexposure prophylaxis, Outcome 1: Development of confirmed COVID-19 78
at 14 days from enrolment...................................................................................................................................................................
Analysis 5.2. Comparison 5: HCQ versus placebo for postexposure prophylaxis, Outcome 2: Patients hospitalized due to 78
COVID-19................................................................................................................................................................................................
Analysis 5.3. Comparison 5: HCQ versus placebo for postexposure prophylaxis, Outcome 3: Participants with any adverse 78
events.....................................................................................................................................................................................................
Analysis 5.4. Comparison 5: HCQ versus placebo for postexposure prophylaxis, Outcome 4: Participants with serious adverse 79
events.....................................................................................................................................................................................................
ADDITIONAL TABLES.................................................................................................................................................................................... 79
APPENDICES................................................................................................................................................................................................. 89
HISTORY........................................................................................................................................................................................................ 91
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 91
DECLARATIONS OF INTEREST..................................................................................................................................................................... 91
SOURCES OF SUPPORT............................................................................................................................................................................... 91
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 92
INDEX TERMS............................................................................................................................................................................................... 92
Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) ii

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[Intervention Review]
Chloroquine or hydroxychloroquine for prevention and treatment of

COVID-19
Bhagteshwar Singh1,2,3, Hannah Ryan4, Tamara Kredo5, Marty Chaplin6, Tom Fletcher6
1Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. 2Tropical and Infectious Diseases
Unit, Royal Liverpool University Hospital, Liverpool, UK. 3Department of Infectious Diseases, Christian Medical College, Vellore, India.
4Department of Clinical Pharmacology, Royal Liverpool University Hospital, Liverpool, UK. 5Cochrane South Africa, South African Medical
Research Council, Cape Town, South Africa. 6Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
Contact address: Bhagteshwar Singh, bsingh@liverpool.ac.uk.
Editorial group: Cochrane Infectious Diseases Group.

Publication status and date: New, published in Issue 2, 2021.
Citation: Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T. Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.
Cochrane Database of Systematic Reviews 2021, Issue 2. Art. No.: CD013587. DOI: 10.1002/14651858.CD013587.pub2.
Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The
Cochrane Collaboration. This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial Licence,
which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for
commercial purposes.
ABSTRACT
Background
The coronavirus disease 2019 (COVID-19) pandemic has resulted in substantial mortality. Some specialists proposed chloroquine (CQ) and
hydroxychloroquine (HCQ) for treating or preventing the disease. The efficacy and safety of these drugs have been assessed in randomized
controlled trials.
Objectives
To evaluate the effects of chloroquine (CQ) or hydroxychloroquine (HCQ) for
1) treating people with COVID-19 on death and time to clearance of the virus;
2) preventing infection in people at risk of SARS-CoV-2 exposure;
3) preventing infection in people exposed to SARS-CoV-2.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Current Controlled Trials (www.controlled-
trials.com), and the COVID-19-specific resources www.covid-nma.com and covid-19.cochrane.org, for studies of any publication status and
in any language. We performed all searches up to 15 September 2020. We contacted researchers to identify unpublished and ongoing
studies.
Selection criteria
We included randomized controlled trials (RCTs) testing chloroquine or hydroxychloroquine in people with COVID-19, people at risk of
COVID-19 exposure, and people exposed to COVID-19.
Adverse events (any, serious, and QT-interval prolongation on electrocardiogram) were also extracted.
Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 1

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Data collection and analysis

Two review authors independently assessed eligibility of search results, extracted data from the included studies, and assessed risk of bias
using the Cochrane ‘Risk of bias’ tool. We contacted study authors for clarification and additional data for some studies. We used risk ratios
(RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs). We performed
meta-analysis using a random-effects model for outcomes where pooling of effect estimates was appropriate.
Main results
1. Treatment of COVID-19 disease
We included 12 trials involving 8569 participants, all of whom were adults. Studies were from China (4); Brazil, Egypt, Iran, Spain, Taiwan, the
UK, and North America (each 1 study); and a global study in 30 countries (1 study). Nine were in hospitalized patients, and three from
ambulatory care. Disease severity, prevalence of comorbidities, and use of co-interventions varied substantially between trials. We found
potential risks of bias across all domains for several trials.
Nine trials compared HCQ with standard care (7779 participants), and one compared HCQ with placebo (491 participants); dosing schedules
varied. HCQ makes little or no difference to death due to any cause (RR 1.09, 95% CI 0.99 to 1.19; 8208 participants; 9 trials; high-certainty
evidence). A sensitivity analysis using modified intention-to-treat results from three trials did not influence the pooled effect estimate.
HCQ may make little or no difference to the proportion of people having negative PCR for SARS-CoV-2 on respiratory samples at day 14 from
enrolment (RR 1.00, 95% CI 0.91 to 1.10; 213 participants; 3 trials; low-certainty evidence). HCQ probably results in little to no difference in
progression to mechanical ventilation (RR 1.11, 95% CI 0.91 to 1.37; 4521 participants; 3 trials; moderate-certainty evidence). HCQ probably
results in an almost three-fold increased risk of adverse events (RR 2.90, 95% CI 1.49 to 5.64; 1394 participants; 6 trials; moderate-certainty
evidence), but may make little or no difference to the risk of serious adverse events (RR 0.82, 95% CI 0.37 to 1.79; 1004 participants; 6
trials; low-certainty evidence). We are very uncertain about the effect of HCQ on time to clinical improvement or risk of prolongation of QT-
interval on electrocardiogram (very low-certainty evidence).
One trial (22 participants) randomized patients to CQ versus lopinavir/ritonavir, a drug with unknown efficacy against SARS-CoV-2, and did
not report any difference for clinical recovery or adverse events.
One trial compared HCQ combined with azithromycin against standard care (444 participants). This trial did not detect a difference in
death, requirement for mechanical ventilation, length of hospital admission, or serious adverse events. A higher risk of adverse events was
reported in the HCQ-and-azithromycin arm; this included QT-interval prolongation, when measured.
One trial compared HCQ with febuxostat, another drug with unknown efficacy against SARS-CoV-2 (60 participants). There was no
difference detected in risk of hospitalization or change in computed tomography (CT) scan appearance of the lungs; no deaths were
reported.
2. Preventing COVID-19 disease in people at risk of exposure to SARS-CoV-2
Ongoing trials are yet to report results for this objective.
3. Preventing COVID-19 disease in people who have been exposed to SARS-CoV-2
One trial (821 participants) compared HCQ with placebo as a prophylactic agent in the USA (around 90% of participants) and Canada.
Asymptomatic adults (66% healthcare workers; mean age 40 years; 73% without comorbidity) with a history of exposure to people with
confirmed COVID-19 were recruited. We are very uncertain about the effect of HCQ on the primary outcomes, for which few events
were reported: 20/821 (2.4%) developed confirmed COVID-19 at 14 days from enrolment, and 2/821 (0.2%) were hospitalized due to
COVID-19 (very low-certainty evidence). HCQ probably increases the risk of adverse events compared with placebo (RR 2.39, 95% CI 1.83 to
3.11; 700 participants; 1 trial; moderate-certainty evidence). HCQ may result in little or no difference in serious adverse events (no RR: no
participants experienced serious adverse events; low-certainty evidence).
One cluster-randomized trial (2525 participants) compared HCQ with standard care for the prevention of COVID-19 in people with a history
of exposure to SARS-CoV-2 in Spain. Most participants were working or residing in nursing homes; mean age was 49 years. There was no
difference in the risk of symptomatic confirmed COVID-19 or production of antibodies to SARS-CoV-2 between the two study arms.
Authors' conclusions
HCQ for people infected with COVID-19 has little or no effect on the risk of death and probably no effect on progression to mechanical
ventilation. Adverse events are tripled compared to placebo, but very few serious adverse events were found. No further trials of
hydroxychloroquine or chloroquine for treatment should be carried out.
These results make it less likely that the drug is effective in protecting people from infection, although this is not excluded entirely. It is
probably sensible to complete trials examining prevention of infection, and ensure these are carried out to a high standard to provide
unambiguous results.

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Informed decisions.

PLAIN LANGUAGE SUMMARY
Is chloroquine or hydroxychloroquine useful in treating people with COVID-19, or in preventing infection in people who have been
exposed to the virus?
What is the aim of this review?
COVID-19 is an infectious respiratory disease caused by a coronavirus called SARS-CoV-2. If the infection becomes severe, people may need
intensive care and support in hospital, including mechanical ventilation.
Drugs used for other diseases were tried out in COVID-19, and this included chloroquine, used for malaria; and hydroxychloroquine used
for rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus. We sought evidence of the effects of these drugs
in treating people ill with the disease; in preventing the disease in people at risk of getting the disease, such as health workers; and
people exposed to the virus developing the disease.
Key messages
Hydroxychloroquine does not reduce deaths from COVID-19, and probably does not reduce the number of people needing mechanical
ventilation.
Hydroxychloroquine caused more unwanted effects than a placebo treatment, though it did not appear to increase the number of serious
unwanted effects.
We do not think new studies of hydroxychloroquine should be started for treatment of COVID-19.
What was studied in the review?
We searched for studies that looked at giving chloroquine and hydroxychloroquine to people with COVID-19; people at risk of being exposed
to the virus; and people who have been exposed to the virus.
We found 14 relevant studies: 12 studies of chloroquine or hydroxychloroquine used to treat COVID-19 in 8569 adults; two studies of
hydroxychloroquine to stop COVID-19 in 3346 adults who had been exposed to the virus but had no symptoms of infection. We did not find
any completed studies of these medicines to stop COVID-19 in people who were at risk of exposure to the virus; studies are still under way.
The studies took place in China, Brazil, Egypt, Iran, Taiwan, North America, and Europe; one study was worldwide. Some studies were partly
funded by pharmaceutical companies that manufacture hydroxychloroquine.
What are the main results of our review?
Treating COVID-19
Compared with usual care or placebo, hydroxychloroquine:
· clearly did not affect how many people died (of any cause; 9 studies in 8208 people);
· probably did not affect how many people needed mechanical ventilation (3 studies; 4521 people);
· may not affect how many people still tested positive for the virus after 14 days (3 studies; 213 people).
We are uncertain whether hydroxychloroquine affected the number of people whose symptoms improved after 28 days.
Compared with other antiviral treatment (lopinavir plus ritonavir), chloroquine made little or no difference to the time taken for symptoms
to improve (1 study; 22 people).
Compared with usual care in one study in 444 people, hydroxychloroquine given with azithromycin (an antibiotic) made no difference to:
· how many people died;
· how many needed mechanical ventilation; or
· time spent in hospital.
Compared with febuxostat (a medicine to treat gout), hydroxychloroquine made no difference to how many people were admitted to
hospital or to changes seen on scans of people's lungs; no deaths were reported (1 study; 60 people).
Preventing COVID-19 in people exposed to it

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We are uncertain whether hydroxychloroquine affected how many people developed COVID-19, or how many people were admitted to
hospital with COVID-19, compared with those receiving a placebo treatment (1 study; 821 people).
Compared with usual care, hydroxychloroquine made no difference to the risk of developing COVID-19, or antibodies to the virus, in people
exposed to it (1 study; 2525 people).
Unwanted effects
When used for treating COVID-19, compared with usual care or placebo, hydroxychloroquine:
· probably increases the risk of mild unwanted effects (6 studies; 1394 people);
· may not increase the risk of serious harmful effects (6 studies; 1004 people).
When given along with azithromycin, hydroxychloroquine increased the risk of any unwanted effects, but made no difference to the risk
of serious unwanted effects (1 study; 444 people).
Compared with lopinavir plus ritonavir, chloroquine made little or no difference to the risk of unwanted effects (1 study; 22 people).
When used for preventing COVID-19, hydroxychloroquine probably causes more unwanted effects than placebo, but may not increase the
risk of serious, harmful unwanted effects (1 study; 700 people).
How confident are we in our results?
We are confident about our results for how many people died and moderately confident about how many needed mechanical ventilation.
We are moderately confident about the unwanted effects of hydroxychloroquine treatment, but less confident about our results for serious
unwanted effects; these results might change with further evidence.
How up-to-date is this review?
We included evidence published up to 15 September 2020.

Collaboration.
Collaboration.
SUMMARY OF FINDINGS

Summary of findings 1. Hydroxychloroquine (HCQ) compared to standard care or placebo for the treatment of people with COVID-19
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Patients or population: adults with mild to severe COVID-19
Settings: hospital inpatients and ambulatory care in the community
Intervention: HCQ
Better health.
Informed decisions.
Trusted evidence.
Comparison: standard care or placebo (no HCQ)
Outcomes Anticipated absolute effects* Relative effect № of partici- Certainty of Comments

(95% CI) (95% CI) pants (studies) the evidence
(GRADE)
Risk with stan- Risk with HCQ
dard care or
placebo
Death due to any 18 per 100 19 per 100 RR 1.09 8208 ⨁⨁⨁⨁ HCQ results in little or no difference to death due
cause (18 to 21) (0.99 to 1.19) (9 RCTs)a HIGH b,c to any cause.
Negative PCR for 83 per 100 83 per 100 RR 1.00 213 ⨁⨁◯◯ HCQ may make little or no difference to propor-
SARS-CoV-2 on respi- (76 to 91) (0.91 to 1.10) (3 RCTs)e LOW f,g tion of people having negative PCR for SARS-
ratory samples at day CoV-2 on respiratory samples at day 14 from en-
14 from enrolmentd rolment.
Progression to me- 8 per 100 9 per 100 RR 1.11 4521 ⨁⨁⨁◯ HCQ probably results in little to no difference in
chanical ventilation (7 to 11) (0.91 to 1.37) (3 RCTs)h MODERATE i,j progression to mechanical ventilation.
Time to clinical im- 28 per 100 28 per 100 (18 HR 1.01 119 ⨁◯◯◯ We are uncertain whether HCQ increases or de-
provement to 44) (0.59 to 1.74) (1 RCT)k VERY LOW f,l,m creases the proportion of people with clinical im-
provement at day 28 from enrolment.

Participants with any 16 per 100 46 per 100 RR 2.90 1394 ⨁⨁⨁◯ HCQ probably increases the risk of developing
adverse events (24 to 90) (1.49 to 5.64) (6 RCTs)n MODERATE o,p adverse events.
Participants with se- 36 per 1000 30 per 1000 RR 0.82 1004 ⨁⨁◯◯ HCQ may result in little or no difference to risk of
rious adverse events (13 to 64) (0.37 to 1.79) (6 RCTs)q LOW r serious adverse events.
Participants with 2 per 100 17 per 100 RR 8.47 147 ⨁◯◯◯ The evidence is very uncertain about the effect of
prolongation of QT- (2 to 100) (1.14 to 63.03) (1 RCT)s VERY LOW t,u,v HCQ on prolongation of QT-interval on ECG.
interval on ECG
5

Collaboration.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI).
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CI: confidence interval; ECG: electrocardiogram; HCQ: hydroxychloroquine; HR: hazard ratio; PCR: polymerase chain reaction RCT: randomized controlled trial; RR: risk ra-
tio.
GRADE Working Group grades of evidence

High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
Better health.
Informed decisions.
Trusted evidence.
substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
a Abd-Elsalam 2020; Cavalcanti 2020; Chen 2020a; Chen 2020c; Horby 2020; Mitjà 2020a; Pan 2020; Skipper 2020; Tang 2020. Of these, no participants died in Chen 2020a; Chen
2020c; Mitjà 2020a; Tang 2020.
bNot downgraded for risk of bias, as most of the evidence comes from Horby 2020 and Pan 2020, which have low risk of bias for this outcome.
cNot downgraded for indirectness, but it is noted that the population in the largest trial, Horby 2020, was mostly severely/critically unwell.
dThis was selected as the most relevant of three related outcomes reported by trials in this review. Analyses for the other outcomes (time to negative PCR for SARS-CoV-2 on
respiratory samples; negative PCR for SARS-CoV-2 at day 7 from enrolment) did not demonstrate an important benefit/harm.
e Chen 2020a; Chen 2020c; Tang 2020.
fDowngraded by one level for serious indirectness: almost all people had mild or moderate COVID-19; all were hospitalized; and all were from one region.
gNot downgraded for imprecision: narrow confidence interval, not including appreciable benefit nor harm. The sample size has approximately 80% power to detect an absolute
difference of 13%, or 90% power to detect an absolute difference of 15%, in this outcome for the group receiving HCQ versus those receiving standard care.
h Cavalcanti 2020; Horby 2020; Tang 2020.
iNot downgraded for indirectness: the three trials all recruited participants admitted to hospital.
jDowngraded by one level for serious imprecision: lower confidence interval bound represents no benefit nor harm from HCQ, whereas the upper bound suggests appreciable
harm.
k Tang 2020.
lDowngraded by one level for serious risk of bias: unclear risk of attrition and reporting bias, and high risk of other bias.
mDowngraded by one level for serious imprecision: lower confidence interval bound represents appreciable harm from HCQ, whereas the upper bound suggests no appreciable
benefit.
n Cavalcanti 2020; Chen 2020a; Chen 2020b; Mitjà 2020a; Skipper 2020; Tang 2020.

oDowngraded by one level for serious risk of bias: all trials except Skipper 2020 were open-label. Chen 2020a had a high risk of selection and reporting bias; Chen 2020b a high risk
of performance, detection, and reporting bias and unclear risk of selection bias; Mitjà 2020a a high risk of performance, detection, attrition, and reporting bias for this outcome,
and unclear risk of selection bias; Skipper 2020 a high risk of reporting bias and unclear risk of attrition bias; and Tang 2020 an unclear risk of attrition and reporting bias. We
deemed Skipper 2020, Mitjà 2020a, and Tang 2020 as at high risk of other bias.
pNot downgraded for inconsistency: despite high statistical heterogeneity (I2 = 87%), all of the effect estimates were above a risk ratio of 1, with only one trial having a confidence
interval that crossed 1.
q Cavalcanti 2020; Chen 2020a; Chen 2020b; Chen 2020c; Skipper 2020; Tang 2020.
rDowngraded by two levels for very serious imprecision: low number of events, and lower confidence interval bound represents appreciable harm from HCQ, whereas the upper
bound includes appreciable benefit.
s Cavalcanti 2020.
6

Collaboration.
tDowngraded by one level for risk of bias: Cavalcanti 2020 was unblinded, which could have led to detection bias, meaning more participants with QT prolongation were identified
in the HCQ group.
uDowngraded by one level for indirectness: Cavalcanti 2020 included only hospitalized patients, and excluded participants with severe disease, in whom problems with drug
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interactions and cardiac arrhythmia are more likely.
vDowngraded by one level for imprecision: Cavalcanti 2020 had a low event rate for this outcome, and a small sample size leading to a very broad confidence interval.

Summary of findings 2. Hydroxychloroquine (HCQ) compared to placebo for the prevention of COVID-19 in people who have been exposed to SARS-
CoV-2
Better health.
Informed decisions.
Trusted evidence.
Patients or population: people who have been exposed to SARS-CoV-2
Settings: community
Intervention: HCQ
Comparison: placebo
Outcomes Anticipated absolute effects* Relative effect № of partici- Certainty of Comments

(95% CI) (95% CI) pants (studies) the evidence
(GRADE)
Risk with Risk with HCQ
placebo
Development of con- 2 per 100 2 per 100 RR 1.20 821 ⨁◯◯◯ The evidence is very uncertain about the effect of
firmed COVID-19 at HCQ on development of confirmed COVID-19 at
14 days from enrol- (1 to 6) (0.50 to 2.87) (1 RCT) VERY LOW a,b 14 days from enrolment.
ment
Hospitalized due to 2 per 1000 2 per 1000 RR 0.98 821 ⨁◯◯◯ The evidence is very uncertain about the effect
COVID-19c of HCQ on risk of being hospitalized due to COV-
(0 to 31) (0.06 to 15.66) (1 RCT) VERY LOW a,b ID-19.
Participants with any 17 per 100 41 per 100 RR 2.39 700 ⨁⨁⨁◯ HCQ probably increases the risk of adverse

adverse events events when compared with placebo.
(31 to 53) (1.83 to 3.11) (1 RCT) MODERATE a
Participants with se- 0 per 1000 0 per 1000 Not estimable 700 ⨁⨁◯◯ HCQ may result in little or no difference in seri-
rious adverse events ous adverse events when compared with place-
(0 to 0) (1 RCT) LOW a,d bo.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention
(and its 95% CI).
CI: confidence interval; HCQ: hydroxychloroquine; RCT: randomized controlled trial; RR: risk ratio.
7

Collaboration.
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
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substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aDowngraded by one level for serious indirectness: one trial, limited to North America; few older and comorbid participants, possibly due to social media-based recruitment and
internet-based data collection (Boulware 2020).
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Trusted evidence.
bDowngraded by two levels for very serious imprecision: confidence interval around effect estimate includes appreciable benefit and appreciable harm.
cThis outcome, as reported by Boulware 2020, was closest to our predefined outcome of 'disease severity of participants who develop COVID-19, as defined by study authors'.
dDowngraded by one level for imprecision: no events in either group, therefore risk ratio is not estimable. The optimal information size to be confident that this is a true reflection
of risk of serious adverse events would be larger than the total number of participants in this trial. Risk difference = 0% (95% CI −1% to 1%).


8

Informed decisions.

BACKGROUND Transmission is common in, though not limited to, households

(Pung 2020). Self-isolation, quarantine, and travel restrictions can
Description of the condition limit community transmission (Kraemer 2020), but prevention
measures within households can be more challenging. Healthcare
Coronavirus disease 2019 (COVID-19) is a viral infection transmitted
workers are at high risk of being infected. Data from Italy show that
by respiratory droplet spread. It is caused by severe acute
20% of frontline healthcare workers responding to the pandemic
respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19
have developed COVID-19 (Lancet 2020). There were widespread
commonly presents as a mild respiratory tract illness, with fever
shortages of personal protective equipment (Lewis 2020). With
and cough the most commonly reported symptoms; however, in
established community transmission in many countries, healthcare
some people this progresses to cause a life-threatening respiratory
workers are also at risk outside of health facilities. Despite
syndrome (Guan 2020).
vaccine roll-out having commenced in some countries, achieving
SARS-CoV-2 is a novel coronavirus that has caused a pandemic target coverage will take several months, and will not eliminate
since December 2019. Over 27 million people have been diagnosed symptomatic infections in the near future. Consequently, there is
with COVID-19, and as of 7 September 2020 over 890,000 people great interest in using existing drugs as treatment for or prevention
have died (JHU 2020). The World Health Organization (WHO) of COVID-19.
declared COVID-19 a public health emergency of international
Several potential antivirals have been suggested for use in
concern on 30 January 2020, and a pandemic on 11 March 2020
treating people with COVID-19. Remdesivir, a drug trialled for
(WHO 2020a).
Ebola virus disease and Middle East respiratory syndrome
National data from China and Italy describe severe disease in
(MERS), showed promising results in vitro (Wang 2020b).
14% to 20% of people with COVID-19, and a further 2% to 5%
An early trial showed no benefit on time to clinical
are reported to have critical illness (ISS 2020; Wu 2020). Early
improvement, mortality, or clearance of the virus from the
mortality estimates ranged from around 2% to 12%, though this
respiratory tract (Wang 2020c). Subsequently, two randomized
has varied considerably between countries and as the pandemic
trials have reported a beneficial effect of remdesivir on measures
has progressed (ISS 2020; Wu 2020). Severe disease is characterized
of clinical improvement in patients hospitalized with COVID-19,
by hypoxia, and progressive acute respiratory distress syndrome
but no significant effect on mortality (Beigel 2020; Spinner 2020).
appears to be the driver for mortality, although patients can
Other experimental antivirals being studied include the influenza
experience a syndrome with clinical and laboratory features of
treatments umifenovir (Arbidol), Deng 2020, and favipiravir,
severe systemic inflammation, termed a “cytokine storm” (Guan
Cai 2020, and the antiretroviral protease inhibitor combination
2020; Mehta 2020).
lopinavir/ritonavir (Cao 2020). Of the many other options being
At the other end of the spectrum, asymptomatic infection is not
investigated, corticosteroids are now recommended by WHO for
uncommon; national Italian data describe this in approximately
patients with COVID-19 requiring oxygen or higher respiratory
10% of all people with a confirmed COVID-19 diagnosis (ISS
support therapy (WHO 2020d), having been reported to reduce
2020). More recently, wide-ranging longer-term morbidity has been
mortality in this population in a systematic review (REACT 2020).
described in the absence of a severe initial illness (Greenhalgh
Other options that have yet to show benefit in randomized trials
2020).
are tocilizumab (Stone 2020), convalescent plasma (Agarwal 2020),
Transmission is by direct contact with people with the and camostat mesylate (Hoffman 2020). Several studies have
infection, indirectly via contact with respiratory secretions on used novel methods to assess whether existing drugs can be
objects and surfaces, or from droplets generated by sneezing and repurposed for COVID-19 treatment (Chandel 2020; Zhou 2020).
coughing (WHO 2020b). Concerns have been raised about airborne
transmission: viability of SARS-CoV-2 has been demonstrated for at
Description of the intervention
least three hours when suspended in an aerosol (van Doremalen Chloroquine (CQ) and hydroxychloroquine (HCQ) are 4-
2020). The amount of virus found in the respiratory tract appears to aminoquinoline compounds, derivatives of quinine, and have been
be higher in people with severe versus those with mild disease, with used as antimalarial drugs since the 1940s (Ben-Zvi 2012). HCQ
shedding of virus in the nasopharynx occurring for up to 25 days is an analogue of CQ in which one of the N-ethyl substituents of
in people with severe disease (Liu 2020a). The virus has also been CQ is β-hydroxylated. HCQ and CQ have similar pharmacokinetic
found in stools, with one study reporting live virus in non-diarrhoeal properties, with high oral bioavailability and tissue penetrance,
stool, thus raising concerns about faecal-oral transmission (Wang partial hepatic metabolism, and high volumes of distribution as
2020a). they diffuse into adipose tissue (Ben-Zvi 2012).
Multiple episodes of transmission by pre-symptomatic or
asymptomatic people have been described (Bai 2020; Rothe 2020). Both drugs have been used widely and for many years for the
treatment and prevention of malaria (although they are now largely
The main method for diagnosis of COVID-19 is by polymerase ineffective against falciparum malaria) and in the treatment of
chain reaction (PCR) of respiratory tract samples, mostly from rheumatological conditions, such as systemic lupus erythematosus
the nasopharynx or oropharynx. However, some guidelines advise and rheumatoid arthritis (Fiehn 2020; Steinhardt 2011).
nasal swabs (CDC 2020), and some evidence suggests lower
respiratory samples, such as sputum, may have higher sensitivity The mechanism of action in malaria is thought to result from
(Wang 2020a). Serological tests are being used for detecting inhibition of the biocrystallization of hemozoin, causing cytotoxic
antibodies to SARS-CoV-2 for confirmation of past infection, accumulation of heme (Schrezenmeier 2020). For rheumatological
although there are concerns regarding the evidence for their conditions, the mechanism of action is not fully delineated, but
accuracy and value in certain populations and clinical situations appears to arise from multiple effects. As weak bases, both CQ
(Deeks 2020). and HCQ accumulate in the acidic environment within lysosomes,

Collaboration.
Informed decisions.

and thus interfere with lysosomal activity and autophagy, which medicines that may be of benefit is of high importance. Despite
in turn may inhibit major histocompatibility complex (MHC) the small number of published studies, some governments have
class II expression and antigen presentation, inhibiting immune recommended using HCQ as prophylaxis for healthcare workers,
activation (Schrezenmeier 2020). CQ and HCQ also interfere with and some prominent political figures have asserted that CQ or HCQ
Toll-like receptor (TLR) signalling, again via changes to local should be used as a first-line treatment for COVID-19. Sadly, there
pH but also through direct binding to nucleic acids. TLR signal have already been instances of significant harm where individuals
pathways stimulate cytokine production, and CQ and HCQ have have misinterpreted news stories about the use of CQ and suffered
been demonstrated to inhibit production of various cytokines toxicity as a result (CNN 2020).
including interleukin (IL)-1, IL-6, tumour necrosis factor (TNF), and
interferon gamma (IFNγ) by mononuclear cells (van den Borne CQ and HCQ for treatment of COVID-19
1997). Earlier national guidelines, mostly in February to April
2020, recommended CQ or HCQ for the treatment of individuals
CQ and HCQ have well-described adverse effect profiles.
with COVID-19. Belgian guidelines recommended HCQ for severe
Common adverse effects include gastrointestinal upset and
disease, and advised that it be considered for mild-moderate
headache (Ben-Zvi 2012). Several adverse effects are associated
disease (WIV-ISP 2020). Chinese guidelines advised consideration
with chronic therapy, such as QT-interval prolongation on
of CQ in all hospitalized patients, although later iterations have
electrocardiogram, other cardiac arrhythmia, and retinopathy
expressed caution regarding dosing and special patient groups
(Fiehn 2020). CQ is generally less tolerable than HCQ, and can cause
(Wong 2020). Italian guidelines recommended early use of CQ
acute poisoning at a lower dose, as has been seen in reports from
or HCQ, or lopinavir/ritonavir (Brescia-COVID Group 2020). More
the USA and Nigeria of members of the public taking CQ without a
recently, concerns about adverse effects have led to removal
prescription (CNN 2020; Owens 2020).
of recommendations to use CQ and HCQ from several national
There are two types of CQ salts: CQ phosphate and CQ sulphate. guidelines, alongside which the US Food and Drug Administration
Most dosing recommendations for CQ refer to the salt rather than revoked their initial emergency use authorization provided for use
the base compound. Usual doses for CQ are 250 mg to 500 mg CQ of CQ and HCQ in the treatment of COVID-19 (FDA 2020), and the
phosphate (155 mg to 310 mg CQ base) per dose, or CQ sulphate 200 UK Medicines and Healthcare products Regulatory Agency enforced
mg (150 mg CQ base), with weekly dosing for malaria prophylaxis, suspension of recruitment to trial arms using CQ or HCQ as an
and daily dosing for treatment of malaria and rheumatological intervention (Robinson 2020).
conditions. HCQ is given at a dose of 400 mg weekly for malaria
Initial observational studies reported efficacy of CQ and HCQ. A
prophylaxis, and 200 mg to 400 mg daily for rheumatological
widely publicized small, non-randomized study from Marseille,
disease (Ben-Zvi 2012).
France, reported that HCQ was associated with earlier negative
How the intervention might work PCR for SARS-CoV-2 among 20 patients given HCQ compared
to those who had refused to take HCQ or who had presented
Some researchers have suggested that both CQ and HCQ could be to other hospitals (Gautret 2020a). Subgroup analyses reported
clinically effective against COVID-19. Studies have reported in vitro quicker clearance of the virus for six participants who had
activity against SARS-CoV-2 (Liu 2020b; Wang 2020b; Yao 2020), and azithromycin in combination with HCQ versus those who received
pharmacokinetic modelling suggests efficacy of a few postulated neither drug (Gautret 2020a). There has been widespread
dosing regimens for treatment (Yao 2020). criticism of the methods, reporting, and conclusions of this study
(Machiels 2020). The same group then published two observational
Liu 2020b reported that CQ and HCQ appear to inhibit transport single-arm cohorts of patients treated with HCQ plus azithromycin,
of SARS-CoV-2 virions from early endosomes to endolysosomes in reporting benefit of the combination (Gautret 2020b; Million 2020).
Vero E6 cells, which may be a requirement for release of the viral Soon after this, another research group from France reported much
genome and subsequent viral replication. Wang 2020b performed poorer clinical and virological outcomes in 11 hospitalized patients
a "time-to-addition" assay using Vero E6 cells and found that CQ treated with both drugs (Molina 2020). A quasi-experimental
appeared to both inhibit entry of SARS-CoV-2 into cells and inhibit study of patients admitted with moderate COVID-19 in four French
viral replication after cell entry. The authors of both studies also hospitals reported no difference in efficacy outcomes, but reported
speculate that CQ and HCQ could impact on disease severity in early discontinuation of HCQ in 9 of 84 participants due to
COVID-19 through modulating the excess cytokine release that abnormalities on electrocardiography (Mahévas 2020).
appears to contribute to life-threatening forms of the disease (Liu
2020b; Wang 2020b). More recently, a number of larger non-randomized studies have
reported beneficial effects of HCQ. A retrospective cohort study
Why it is important to do this review in Michigan, USA compared four groups of a total of 2541
Given the pace of the pandemic, and the extraordinary impact on patients hospitalized with confirmed COVID-19 according to
public health and society in many countries, there is high demand physician-directed treatment assignment: 1202 received HCQ; 147
for effective prevention and treatment interventions for COVID-19. azithromycin alone; 783 HCQ with azithromycin; and 409 received
CQ and HCQ are inexpensive drugs that are registered in most neither drug (Arshad 2020). A significant reduction in mortality
countries, and are included on the WHO essential medicines list was reported when HCQ was received (hazard ratio (HR) 0.49,
(WHO 2019). They can be delivered orally, and both drugs have well- 95% confidence interval (CI) 0.29 to 0.83). Differences in baseline
described safety profiles in adults and children. Given the uncertain characteristics suggested underlying confounding, although an
effects of antiviral drugs for treatment of COVID-19, or the underpowered propensity-matching analysis reported persistence
effectiveness of the newly developed vaccines, identifying existing of the reported mortality benefit (Arshad 2020). The quantity
of missing data and early patient exclusions were not reported
Collaboration.
Informed decisions.

(Arshad 2020). Another study retrospectively comparing 4542 in northern Brazil was stopped early by the independent safety
patients in Belgian hospitals reported lower risk of death in the monitoring board due to higher death and cardiac serious adverse
group who received HCQ as per national guidance (804/4542, events, including QT-interval prolongation on electrocardiogram,
17.7%) versus 3533 patients who did not receive HCQ (957/3533, in the group receiving higher-dose CQ (Borba 2020). An article
27.1%) (Catteau 2020). After adjusting for multiple covariates, published in The Lancet reporting higher incidence of death and
this difference was found to be statistically significant (adjusted serious adverse events in patients receiving CQ or HCQ with or
HR 0.68, 95% CI 0.62 to 0.76) (Catteau 2020). Of note, nearly 50% without a macrolide drug (azithromycin or clarithromycin), as
of patients screened for eligibility were excluded, though some of documented in a large international surgical registry. The Lancet
these patients were found to have similar baseline characteristics later retracted this when the data and analysis were questioned,
to those included in the analysis (Catteau 2020). though regulatory authorities and trial steering groups had already
decided to stop trials or trial arms investigating CQ and HCQ (Mehra
At the time of writing the protocol for this review, China had 2020).
reported two small randomized trials of HCQ, with mixed results
(Chen 2020a; Chen 2020b). Several trials have since been reported At the time of development of the protocol for this review, other
and are included in this review. systematic reviews had already been produced. Due to the intense
interest in finding a therapeutic that is safe and effective for
CQ and HCQ for preventing COVID-19 COVID-19, many review papers have been published over the
Despite no human data on prophylaxis early in the pandemic, the last six months. Reviews published early in the outbreak relied
Indian Council of Medical Research (ICMR) recommended HCQ as on pre-clinical data, expert commentary, and small, mostly non-
pre-exposure prophylaxis for frontline healthcare workers having randomized studies. A systematic review of CQ for the treatment of
“high-risk” contact with patients with suspected or confirmed COVID-19, which searched PubMed and Embase up to 1 March 2020,
COVID-19, and postexposure prophylaxis for household and identified no published studies other than the aforementioned
healthcare worker contacts of patients with confirmed COVID-19 letter (Gao 2020), though 23 clinical trials of CQ or HCQ were
(ICMR 2020). The background section of this recommendation found on registries (Cortegiani 2020). Another systematic review
referred to in vivo evidence for efficacy of HCQ for the treatment of CQ and HCQ for treating COVID-19, published as a preprint on
of COVID-19, and inferred prophylactic efficacy from therapeutic 30 March 2020, concluded: “There is theoretical, experimental,
efficacy (ICMR 2020). Concerns have been raised by multiple groups preclinical and clinical evidence of the effectiveness of chloroquine
regarding this approach (Rathi 2020). in patients affected with COVID-19” (Kapoor 2020). A further review
included one non-randomized study and one randomized trial,
Since then, two comparative studies have reported the effect of use and concluded: "Without further evidence, HCQ is not appropriate
of CQ or HCQ for prophylaxis of COVID-19, one of which is a for patients with COVID-19 in primary care" (McCormack 2020). A
randomized trial (Boulware 2020), and the other a case-control systematic review of antimalarials (CQ and HCQ) for the treatment
study conducted by the ICMR (Chatterjee 2020). The former is of COVID-19 was produced by the Epistemonikos Working Group,
included in this review. The case-control study involved a telephone which synthesized the results of two small randomized trials and
survey of healthcare workers tested for SARS-CoV-2 when found low- to very low-certainty evidence regarding efficacy and
suspected of having symptomatic COVID-19: the 378 cases (172 harms (Epistemonikos 2020).
of whom took HCQ) had a positive PCR test for SARS-CoV-2,
whilst 373 controls (193 of whom used HCQ) had a negative test We propose that, in this context, a systematic review of randomized
(Chatterjee 2020). Whilst use of HCQ versus no use of HCQ was controlled trials using standard Cochrane methods that provides
not found to be significantly associated with confirmed COVID-19, summary estimates of effects for both treatment and prophylactic
a dose-response effect was reported, with lower odds of positive use of CQ and HCQ, with an appraisal of the certainty of the
PCR the higher the number of weekly doses reported to have evidence using the GRADE approach, is important for the general
been taken: for four or five maintenance doses of HCQ after an public, clinicians, and policymakers. We plan to update this review
initial loading dose, the adjusted odds ratio using multivariate in an expedited fashion as new data become available from the
regression analysis was 0.44 (95% CI 0.22 to 0.88) (Chatterjee 2020). trials that are currently in progress on prevention.
Reported side effects were uncommon. Methods were reported
incompletely, such as the sampling approach for cases and controls
OBJECTIVES
from the database of 21,402 healthcare workers, of whom 1073 has To evaluate the effects of chloroquine (CQ) or hydroxychloroquine
a positive PCR test (Chatterjee 2020). The target sample size was (HCQ) as:
not met, though this was calculated for HCQ prophylaxis as a binary
exposure variable, rather than the duration-based groups used in 1. an antiviral treatment on death and time to clearance of the virus
the eventual analysis (Chatterjee 2020). Several trials exploring from clinical samples in people with COVID-19;
the use of CQ or HCQ for prophylaxis of COVID-19 are ongoing 2. a prophylactic treatment on prevention of COVID-19 in people at
(Cortegiani 2020). risk of SARS-CoV-2 exposure;
Adverse events have been a particular concern with CQ and HCQ. 3. a prophylactic treatment on prevention of COVID-19 in people
Studies using data from pharmacovigilance databases prior to the who have been exposed to SARS-CoV-2.
use of these drugs, and azithromycin, have suggested caution
regarding even short-term use due to their association with cardiac
adverse effects (Nguyen 2020; Singh 2020). A randomized trial
comparing higher-dose CQ (41 participants) versus lower-dose CQ
(40 participants) in patients hospitalized with severe COVID-19

Collaboration.
Informed decisions.

METHODS Secondary outcomes
• Development of COVID-19 in household contacts of the recipient

Criteria for considering studies for this review of the prophylaxis
Types of studies • Disease severity of participants who develop COVID-19, as
defined by study authors
Randomized controlled trials (RCTs).
Adverse events (relating to objectives 1, 2, and 3)
Types of participants
• All adverse events
Objective 1. People who have COVID-19, as defined by study
authors. • All serious adverse events attributed to study drug (i.e. serious
adverse effects)
Objective 2. People who are at risk of SARS-CoV-2 exposure, as • QT-interval prolongation
defined by study authors.
Search methods for identification of studies
Objective 3. People who have been exposed to SARS-CoV-2, as
defined by study authors. We attempted to identify all relevant trials regardless of language
or publication status (published, unpublished, in press, and in
Types of interventions progress) up to 15 September 2020.
Intervention Electronic searches
Chloroquine (CQ) or hydroxychloroquine (HCQ) given by any route We searched the following databases on 15 September 2020 using
of administration and dose used alone or in combination with other the search terms and strategy described in Appendix 1:
treatments. the Cochrane Central Register of Controlled Trials (CENTRAL),
published in the Cochrane Library, up to Issue 9 of 12, September
Control
2020; MEDLINE (PubMed) (1966 to 15 September 2020); and
No treatment, supportive treatment, or other experimental Embase (1974 to 15 September 2020). We also searched Current
antiviral treatment (i.e. any other treatment that does not contain Controlled Trials (www.controlled-trials.com) and the World
CQ or HCQ). Health Organization International Clinical Trials Registry Platform
(www.who.int/clinical-trials-registry-platform) using 'chloroquine',
Types of outcome measures 'hydroxychloroquine', 'coronavirus', and 'COVID-19' as search terms
Objective 1. For treatment of COVID-19 disease on 15 September 2020. We also searched COVID-specific resources
COVID-NMA (www.covid-nma.com) and the Cochrane COVID-19
Primary outcomes Study Register (covid-19.cochrane.org/), which are updated daily
• Death with lists of ongoing and published trials, using 'chloroquine' and
'hydroxychloroquine' on 15 September 2020.
• Time to negative PCR for SARS-CoV-2 on respiratory samples
Searching other resources
Secondary outcomes
• Number of participants admitted to hospital (if receiving We contacted researchers in the field to identify any unpublished
ambulatory treatment) or ongoing studies.
• Number of participants requiring mechanical ventilation Data collection and analysis
• Length of hospital admission
Two review authors (BS and HR, MC, or TK) independently
• Time to clinical improvement, as defined by study authors
conducted each step of study selection and data extraction. Any
• Duration of mechanical ventilation postenrolment in survivors disagreements were resolved through discussion.
of COVID-19
Selection of studies
Objectives 2 and 3. For prevention of COVID-19 disease in people
at risk of exposure/who have been exposed to SARS-CoV-2 Two review authors (BS and HR or MC) independently screened
the search results using Covidence (Covidence), and retrieved the
Primary outcomes full-text articles of all potentially relevant trials. We examined each
• Development of confirmed COVID-19, as defined by study trial report to ensure that we included multiple publications from
authors the same trial only once. We planned to contact trial authors for
• Production of antibodies to SARS-CoV-2 clarification if eligibility of a trial was unclear. Any disagreements
were resolved through discussion. We listed the excluded studies
and the reasons for their exclusion in the 'Characteristics of
excluded studies' table. The study selection process is illustrated in
a PRISMA diagram (Figure 1).


Collaboration.
Informed decisions.

Figure 1. Study flow diagram.

Data extraction and management measures. Any disagreements were resolved through discussion.
We contacted the corresponding trial author in the case of unclear
Two review authors (BS and HR, MC, or TK) used a piloted data
or missing data.
extraction form to extract data on participant characteristics,
diagnostic criteria, disease severity, comorbidity, CQ or HCQ
dose and administration, other treatments given, and outcome
Collaboration.
Informed decisions.

For dichotomous outcomes, we recorded the number of We did not anticipate that any cross-over trials for treatment of
participants that experienced the event and the number of COVID-19 would meet our inclusion criteria, as cross-over trials are
participants randomized to each treatment group. We recorded used to evaluate interventions that have a temporary effect in the
the number of participants analysed in each treatment/ treatment of stable, chronic conditions.
prophylaxis arm, and used the discrepancy between the figures to
calculate the number of participants lost to follow-up, which would We also thought it unlikely that cross-over trials would have been
allow us to perform sensitivity analyses to investigate the effect of conducted for the prevention of COVID-19, due to the long half-
missing data if necessary. For continuous outcomes, we planned life of CQ/HCQ, meaning that a long wash-out period would be
to extract means for the outcome in each group; we also recorded required. It is also unknown whether the effects of receiving CQ or
medians for narrative comparisons where means were unavailable. HCQ in the first period of the trial may have an irreversible effect
that would subsequently impact outcomes in the second period
Assessment of risk of bias in included studies of the trial. If we identified cross-over trials for the prevention of
COVID-19, we would include data from the first period of the trial
Two review authors (BS and HR, MC, or TK) assessed the
only. We would carefully consider whether studies that reported
methodological quality of studies using the Cochrane 'Risk of bias'
data only for the first period of a cross-over trial were at risk of bias,
tool, and reported the results in a 'Risk of bias' figure (Higgins 2011).
and whether the omission of studies that did not report data from
We classified each 'Risk of bias' domain as either at high, low, or
the first period of the trial (i.e. only a paired analysis was reported)
unclear risk of bias (Higgins 2011). We assessed the risk of bias
would lead to bias at the meta-analysis level.
associated with blinding for each outcome separately and used
these judgements in the GRADE assessment, but made an overall Dealing with missing data
judgement in the 'Risk of bias' assessment for each study based
on the primary outcome as stated by the study authors. For other The primary analysis for efficacy outcomes was an available-
domains we assessed the risk of bias for the trial as a whole. We case analysis where the denominator is the number of patients
planned to attempt to contact the trial authors if information was completing follow-up to the point of outcome assessment, where
not specified or was unclear. Any disagreements were resolved by possible. Where this was not possible, we performed an intention-
discussion between the review authors. to-treat analysis, with investigation of the effects of missing
data. For safety outcomes, we planned to include all participants
Measures of treatment effect receiving at least one dose of the intervention drug or placebo.
We presented dichotomous outcomes as risk ratios (RR) with We planned to carry out sensitivity analyses to explore the impact
95% confidence intervals (CIs). We reported continuous outcomes of missing data on the primary outcomes. For dichotomous
as mean differences (MD) with 95% CIs if the outcomes were outcomes, we planned to vary the event rate within the missing
measured in the same way across all included trials. If included patients from intervention and control groups within plausible
trials measured continuous outcomes in different ways, we would limits. For continuous data, we planned to also perform sensitivity
use the standardized mean difference (SMD) and 95% CI as the analyses using the methods described by Ebrahim 2013 and
effect measure. If using the SMD, we would re-express the SMD in Ebrahim 2014.
the units of one or more of the specific measurement instruments
used in the original studies, to aid interpretation. We presented Assessment of heterogeneity
time-to-event outcomes as hazard ratios (HRs) and 95% CIs.
We assessed heterogeneity by visually inspecting the forest plots
Unit of analysis issues to determine closeness of point estimates with each other and
overlap of CIs. We used the Chi2 test with a P value of 0.10 to
We did not anticipate that any cluster-randomized studies
indicate statistical significance, and the I2 statistic to measure
would meet our inclusion criteria. In the case that cluster-
heterogeneity. We used the following ranges outlined in the
randomized studies did meet our inclusion criteria, we
Cochrane Handbook for Systematic Reviews of Interventions to
would ensure appropriate analysis adjusting for the effect of cluster
interpret the I2 statistic (Higgins 2019):
randomization was carried out before including effects estimates
in a meta-analysis. If available, we planned to extract adjusted • 0% to 40%: might not be important;
measures of effect from the trial reports. If only unadjusted data
• 30% to 60%: may represent moderate heterogeneity;
were available, we would adjust these data ourselves using the
intracluster correlation coefficient (ICC). If the ICC was not reported, • 50% to 90%: may represent substantial heterogeneity;
we would contact the study authors to obtain it, or borrow an • 75% to 100%: considerable heterogeneity.
ICC value from a similar study, or estimate the ICC. If the ICC was
estimated, we would perform sensitivity analyses to investigate the We also considered the magnitude and direction of effects, and the
robustness of our analyses. strength of evidence for heterogeneity (e.g. P value from the Chi2
test), when determining the importance of the observed I2 value.
If we identified multi-arm trials, we would either select relevant
arms for inclusion in our analyses, or if more than two arms were Assessment of reporting biases
relevant to this review, we would either combine intervention We planned to construct a funnel plot to investigate any potential
arms so that there was one comparison, or split the control group reporting bias if 10 or more studies were included for a given
between multiple comparisons so that participants are not double- outcome.
counted in meta-analysis.

Collaboration.
Informed decisions.

Data synthesis RESULTS

We analysed the data using Review Manager Web (RevMan Web
Description of studies
2019). We performed all meta-analyses using random-effects
models. Where a meta-analysis was not appropriate due to Results of the search
important clinical or methodological heterogeneity, or if study
Our searches identified 953 records, 93 of which were excluded as
results differed to the extent that combining them in a pooled
duplicate records. Of the remaining 860 records, we excluded 603
analysis would not make sense, we summarized data in tables.
based on the assessment of titles and abstracts. We retrieved 257
Subgroup analysis and investigation of heterogeneity full-text publications to assess for inclusion. The screening process
is illustrated in a flow diagram in Figure 1.
We planned to investigate heterogeneity by performing the
following subgroup analyses for people with COVID-19. Ongoing studies
• Disease severity at presentation From our search on 15 September 2020 and reviewing the COVID-
NMA website, we identified 122 ongoing trials registered for
• Time in the illness when treatment started (< 7 days, and ≥ 7
treatment or prevention of COVID-19. Due to the pressures of the
days after symptoms started)
pandemic and fluctuating interest in CQ and HCQ, many trials
• Comorbidity, such as cardiovascular disease, diabetes, and have been suspended or terminated, or had significant changes
immunosuppression in protocol. We have therefore presented a summary of those
• Age ongoing trials that are reported to be recruiting actively, or that
• Sex have completed recruitment but are yet to publish, and have a
• Admitted to hospital versus receiving ambulatory/outpatient target recruitment of 500 or more participants, in tables (Table
treatment 1 for 22 ongoing treatment trials; Table 2 for 15 ongoing prevention
• CQ or HCQ dosing regimen trials). Up-to-date lists of ongoing trials can be found at www.covid-
nma.com, updated daily.
We planned to investigate heterogeneity by performing the
following subgroup analyses for people exposed to SARS-CoV-2 or Included studies
at risk of exposure to SARS-CoV-2. We included 14 RCTs with a total of 11,915 participants. Further
details of the trials are provided in subsections for each of the
• Healthcare workers review's objectives. A summary description is provided in Table 3,
• Household contacts with more details in the Characteristics of included studies section.
• Laboratory staff
• Age Objective 1. For treatment of COVID-19 disease
• Comorbidity, such as cardiovascular disease, diabetes, and We included 12 RCTs (8569 participants) assessing treatment of
immunosuppression patients diagnosed with COVID-19.
Sensitivity analysis Trial size
To explore the possible effect of losses to follow-up on the effect Trial size varied widely, from 22 participants in Huang 2020 to 4716
estimates for the primary outcomes, we planned to perform participants in Horby 2020. Five trials recruited fewer than 100
sensitivity analyses. For dichotomous outcomes, we planned to participants each (Chen 2020a; Chen 2020b; Chen 2020c; Davoodi
vary the event rate within the missing patients from intervention 2020; Huang 2020).
and control groups within plausible limits. For continuous data,
Geographical location and time period
we planned to perform sensitivity analyses using the methods
described by Ebrahim 2013 and Ebrahim 2014. Four trials were conducted in China, early in the pandemic; all
completed recruitment in February 2020 (Chen 2020a; Chen 2020b;
Summary of findings and assessment of the certainty of the Huang 2020; Tang 2020). The other trials recruited from March
evidence until May or June 2020: in Brazil (Cavalcanti 2020); Egypt (Abd-
We summarized the results of the analysis in 'Summary of findings' Elsalam 2020); Iran (Davoodi 2020); Spain (Mitjà 2020a); Taiwan
tables, and presented the summary effects estimates for the (Chen 2020c); the UK (Horby 2020); the USA and Canada (Skipper
primary outcomes and other important outcomes with illustrative 2020; around 90% of participants were in the USA); and one trial
comparative risks. We used the GRADE framework to evaluate recruited participants in 30 countries globally (Pan 2020).
the certainty of evidence for each outcome, as developed by
Participants
the GRADE Working Group and described in the Cochrane Handbook
for Systematic Reviews of Interventions (Higgins 2019). None of the trials recruited children. The protocol of one trial was
modified on 9 May 2020 to allow recruitment of children, but none
of the participants in the study arms included in this review (i.e. HCQ
and standard care) were children (Horby 2020). The average age in
most trials was between 40 and 50 years old, except for Horby 2020,
in which the mean age of participants was around 65 years in both
arms, and Pan 2020, with a median somewhere between 50 and 69
years old.

Collaboration.
Informed decisions.

Nine trials recruited hospitalized patients (Abd-Elsalam 2020; Cavalcanti 2020; Chen 2020a; Chen 2020b; Chen 2020c; Huang
Cavalcanti 2020; Chen 2020a; Chen 2020b; Chen 2020c; Horby 2020; Mitjà 2020a; Tang 2020). Whilst not excluding pregnant
2020; Huang 2020; Pan 2020; Tang 2020), whilst the other women from their trials, Horby 2020 and Pan 2020 did not
three trials were focused on ambulatory care and only included report how many pregnant women were included, and Skipper
outpatients (Davoodi 2020; Mitjà 2020a; Skipper 2020). 2020 recruited none. Only Skipper 2020 reported recruitment
of people with immunosuppression other than due to HIV (3
Overall, 7347/8569 (85.7%) participants had COVID-19 confirmed of 491 total participants); across all trials, 26 participants were
by SARS-CoV-2 PCR on clinical samples. Six trials recruited reported to have HIV.
participants only if they had a positive PCR (Chen 2020a; Chen
2020b; Chen 2020c; Huang 2020; Mitjà 2020a; Tang 2020). In three of Two trials provided a breakdown of contact history: 238/293 (81%)
the remaining six trials, the majority of participants had a positive had healthcare exposure history and 2% were household
PCR: 504/665 (75.8%; Cavalcanti 2020), 4234/4716 (89.8%; Horby contacts in Mitjà 2020a; 51% of participants in Skipper 2020 were
2020), and 1850/1853 (> 99%; Pan 2020). Skipper 2020 reported healthcare workers, whilst 29% had household exposure to
169/491 (34.4%) to have positive PCR testing, though the test result someone with COVID-19.
was pending for 48/491 (9.8%), and not available or not done for
204/491 (41.5%) (Skipper 2020). Abd-Elsalam 2020 and Davoodi Time from onset of symptoms to enrolment varied widely between
2020 did not report number of participants with positive PCR test trials. The outpatient trials reporting this information enrolled very
results. soon after symptom onset, with medians of between one and
two days in Skipper 2020 and three days in Mitjà 2020a. Three
Where severity of COVID-19 disease at enrolment was not of the hospital-based trials recruited on average between six
reported using author label or defined criteria equivalent to and nine days from onset (Cavalcanti 2020; Chen 2020a; Horby
asymptomatic, mild, moderate, severe or critical, this was inferred 2020). Tang 2020 enrolled at a mean of 16 to 17 days from
using classification as described by WHO guidance (WHO 2020c). onset, which contributed to the change in timing of their primary
Of the 1800 participants (9 trials) amenable to classification, 100 outcome, from negative SARS-CoV-2 PCR at 28 days to 10 days from
(6%) were asymptomatic, 1183 (66%) had mild disease, 506 (28%) enrolment. Huang 2020 recruited relatively early from onset, but
moderate disease, and 11 (0.6%) severe disease. Participants in this appeared to be earlier for the CQ arm (median 2.5 days) than
Horby 2020 were classified according to receipt of oxygen or other for the lopinavir/ritonavir arm (6.5 days). Abd-Elsalam 2020, Chen
respiratory support: 1112/4716 (24%) were not receiving oxygen or 2020b, Chen 2020c, Davoodi 2020, and Pan 2020 did not report time
ventilation at enrolment (who would be labelled as asymptomatic from symptom onset to enrolment.
or mild); 2811/4716 (60%) received oxygen (who could have
moderate, severe or critical disease, depending on oxygen needs); Interventions and comparators
and 793/4716 (17%) received invasive ventilation (who would Four comparisons are reported for Objective 1 (see Effects of
be classified as having critical disease). Participant disease interventions), as follows.
severity was reported similarly by Pan 2020: 686/1853 (37%)
were not receiving oxygen at enrolment; 1000/1853 (54%) were 1. HCQ versus standard care without HCQ, or placebo
receiving oxygen or other respiratory support but not invasive Ten trials were included in this comparison (Abd-Elsalam 2020;
ventilation; 167/1853 (9%) were receiving invasive ventilation. Cavalcanti 2020; Chen 2020a; Chen 2020b; Chen 2020c; Horby
Where reported, hypertension was usually the most common 2020; Mitjà 2020a; Pan 2020; Skipper 2020; Tang 2020). Nine trials
comorbidity, though its prevalence varied widely: from 6% of compared HCQ to standard of care, and one trial, Skipper 2020,
participants in Tang 2020 and 11% in Skipper 2020, to 27% compared HCQ to placebo (folic acid). Two trials were multi-
in Chen 2020a and 39% in Cavalcanti 2020. The next most common arm trials: Horby 2020 allocated to five arms in a 2:1:1:1:1 ratio
comorbidity was usually diabetes mellitus, though its prevalence (the control arm (standard care) was twice the size of each
varied from < 10% (Chen 2020a; Huang 2020; Skipper 2020), to intervention arm), and Pan 2020 randomized to one of five arms in
19% in Cavalcanti 2020, 21% in Pan 2020, and 27% in Davoodi a 1:1:1:1:1 ratio, of which HCQ was one arm. Horby 2020 and Pan
2020 and Horby 2020. In three of the five trials reporting chronic 2020 are ongoing adaptive trials that have each dropped the HCQ
heart and lung disease (including asthma), prevalence for each arm.
was < 15% of participants (Cavalcanti 2020; Mitjà 2020a; Skipper 2. CQ versus lopinavir/ritonavir
2020); Horby 2020 reported 26% of participants to have heart
disease and 22% chronic lung disease; Pan 2020 reported 21% of One trial was included in this comparison (Huang 2020).
participants to have cardiac disease and 12% chronic lung disease
3. HCQ + azithromycin versus standard care
or asthma. Other reported comorbidities were present in < 5% of
participants, such as cancer and chronic renal or liver disease. Two One trial was included in this comparison, in which participants
of the three outpatient-treatment trials reported proportions of were randomized 1:1:1 to receive HCQ, HCQ and azithromycin, or
participants with no known comorbidities: 47% for Mitjà 2020a standard of care without HCQ or azithromycin (Cavalcanti 2020).
and 31% for Skipper 2020. The third outpatient-treatment trial
reported 28% of participants to have diabetes mellitus, and 1 4. HCQ versus febuxostat
of 54 participants had underlying lung disease (Davoodi 2020). One trial was included in this comparison (Davoodi 2020). In this
Two trials did not report comorbid conditions for their participants trial, febuxostat was the experimental drug of interest, and HCQ was
(Chen 2020b; Chen 2020c). the comparator.
Special patient populations were not commonly recruited.
Most trials excluded pregnant women (Abd-Elsalam 2020;
Collaboration.
Informed decisions.

Dosing regimens for HCQ varied widely, and are summarized PCR-based outcomes varied amongst the included trials. Three
in Table 4. To highlight the heterogeneity of regimens between the trials reported time to negative PCR (Abd-Elsalam 2020; Chen
trials, the loading daily dose on day 1 for participants in Horby 2020a; Huang 2020); four trials reported negative PCR at specified
2020 and Pan 2020 (2000 mg) was equivalent to the total cumulative time points: 7 days (Chen 2020a; Tang 2020); 10 days (Huang 2020;
dose given to participants in Chen 2020a, Chen 2020b, and Davoodi Tang 2020); and 14 days from enrolment (Chen 2020c; Huang 2020;
2020. Tang 2020); and the primary outcome in one trial was reduction in
'viral load' (amount of virus per swab sample) at day 3 and day 7
Huang 2020 administered 500 mg of CQ twice daily for 10 days to after enrolment (Mitjà 2020a).
participants in the CQ arm, without a loading dose on day one, for
a cumulative total dose of 10,000 mg. Regarding our secondary outcomes, the following information was
reported.
Co-interventions
The pharmacological co-interventions reported per arm in the • Number of participants admitted to hospital (if receiving
treatment trials for comparison 1 (HCQ versus standard care ambulatory treatment): this was reported by the three
without HCQ or placebo) are shown in Table 5. Considerable outpatient-based trials (Davoodi 2020; Mitjà 2020a; Skipper
variability in reporting was observed. The following are of particular 2020).
note regarding co-interventions. • Number of participants requiring mechanical ventilation: three
trials reported this outcome (Cavalcanti 2020; Horby 2020; Tang
• Cavalcanti 2020 reported that fewer than 10% of participants did 2020).
not receive concurrent treatment with an antiviral, antibiotic, or • Length of hospital admission: this was reported as a mean
corticosteroid. However, corticosteroids were rarely given (13 of by Abd-Elsalam 2020 and Cavalcanti 2020; the authors of Tang
448 participants). 2020 provided this upon request. Horby 2020 reported a
• All participants in Chen 2020a received nebulized interferon- median, but without interquartile range, and no mean. Huang
alpha, and the majority (22/30) received umifenovir (Arbidol). 2020 provided a Kaplan-Meier chart, but no mean; however,
Both are postulated anti-SARS-CoV-2 drugs. proportion discharged by day 14 from enrolment was reported.
• Horby 2020 reported that a minority of participants received • Time to clinical improvement was reported as survival data
concurrent corticosteroids (dexamethasone) (< 10%) and only by Tang 2020. For the remaining trials, either a mean
azithromycin (< 20%). (Abd-Elsalam 2020) or median (Chen 2020a; Mitjà 2020a) was
• Participants initially enrolled into the HCQ arm of Mitjà reported, and/or the definitions of time to clinical improvement
2020a received cobicistat-boosted darunavir with HCQ as a were not comparable (Chen 2020a; Chen 2020b).
planned combination, which was stopped when its activity • Duration of mechanical ventilation postenrolment in survivors
against SARS-CoV-2 was called into question. of COVID-19 was not reported by any trials.
• Skipper 2020 reported subgroup analyses for self-reported use
of zinc and vitamin C; this was common, with ~25% and ~50% of Five of the 12 included trials did not report the number of
participants reporting their use, respectively. participants experiencing any adverse events (Abd-Elsalam 2020;
Chen 2020c; Davoodi 2020; Horby 2020; Pan 2020). Five, with
There did not appear to be a difference in receipt of some overlap (Abd-Elsalam 2020; Davoodi 2020; Horby 2020; Pan
pharmacological co-interventions between trial arms, where this 2020; Skipper 2020), did not report the number of participants
information was reported. No trials reported concurrent use of experiencing serious adverse events, with Skipper 2020 stating: “No
remdesivir. serious adverse events attributable to the study drug occurred”. The
remaining trials reported events without attribution to a particular
Follow-up drug.
One trial measured all outcomes up to six days (Chen 2020b); six Additionally, Skipper 2020 used the change in symptoms over
trials followed participants up until 14 to 15 days (Cavalcanti 2020; 14 days from enrolment as their primary outcome. This differed
Chen 2020a; Chen 2020c; Davoodi 2020; Huang 2020; Skipper 2020); significantly from our predefined outcomes, and was not
and four trials completed data collection at 28 days from enrolment comparable with the outcomes of other trials.
(Abd-Elsalam 2020; Horby 2020; Mitjà 2020a; Tang 2020). Pan
2020 followed participants up to discharge from hospital. Two Objective 2. For prevention of COVID-19 disease in people at risk
trials used telephone follow-up in place of or in addition to in- of exposure to SARS-CoV-2
person outcome assessment (Cavalcanti 2020; Mitjà 2020a); one
trial employed online surveys for enrolment and all follow-up No eligible trials were identified for this objective.
(Skipper 2020).
Objective 3. For prevention of COVID-19 disease in people who
Outcome measures have been exposed to SARS-CoV-2
Our predefined primary outcomes were death and time to negative We included two trials for this objective: one with double-
PCR for SARS-CoV-2 on respiratory samples. Ten trials reported blind individual randomization to HCQ or placebo that enrolled
death (Abd-Elsalam 2020; Cavalcanti 2020; Chen 2020a; Chen 821 participants (Boulware 2020), and one open-label cluster-RCT
2020c; Davoodi 2020; Horby 2020; Mitjà 2020a; Pan 2020; Skipper comparing HCQ with standard care that enrolled 2525 participants
2020; Tang 2020). (Mitjà 2020b).

Collaboration.
Informed decisions.

Geographical location and time period The comparator in Boulware 2020 was placebo in the form
Boulware 2020 was based in the USA and Canada, and recruited of unmarked folic acid tablets, which closely resembled HCQ
from 17 March to 6 May 2020. Mitjà 2020b recruited in Spain tablets, to be taken on the same schedule as HCQ. Mitjà 2020b used
between 17 March and 28 April 2020. neither placebo nor an active comparator.
Follow-up
Participants
Both trials only recruited asymptomatic people with a history of In Boulware 2020, follow-up was conducted using online surveys
exposure to people with laboratory-confirmed COVID-19 (Boulware exclusively, with the final survey to be completed four to six weeks
2020; Mitjà 2020b). after enrolment. Mitjà 2020b used a combined approach of in-
person visits to the participant's home on days 1 and 14, and
In Boulware 2020, exposure history was most commonly in telephone interviews on days 3, 7, and 28.
a healthcare setting (545/821, 66%), followed by household
Outcome measures
contact (245/821, 30%). The corresponding figures for Mitjà
2020b were 12% for healthcare workers and 28% household Our primary outcome of development of COVID-19 was assessed at
exposure; additionally, 49% worked and 13% lived in a nursing 14 days in both trials. In Boulware 2020, the definition of COVID-19
home. Exposure was deemed to be high risk (neither eye protection was expanded beyond confirmed (i.e. by PCR for SARS-CoV-2) to
nor a surgical mask/respirator was worn) in 88% of participants, include probable COVID-19 due to difficulty accessing PCR testing,
with 60% in Boulware 2020 wearing no personal protective whereas in Mitjà 2020b development of COVID-19 required both
equipment. Participants were enrolled at a median of three days symptoms and a positive PCR test. Our second primary outcome,
after exposure in Boulware 2020 and four days after exposure in production of antibodies to SARS-CoV-2, was assessed by Mitjà
Mitjà 2020b. 2020b at 14 days.
Children were excluded. Median age was 41 years in the HCQ arm A variety of secondary outcomes were measured, including
and 40 years in the placebo arm in Boulware 2020; mean age was hospitalization due to COVID-19, which partly addressed our
49 years in both the HCQ and standard care arms in Mitjà 2020b. outcome of disease severity in participants developing COVID-19
(Boulware 2020; Mitjà 2020b). Onward transmission to household
Most participants did not have comorbidities associated with contacts from index participants was not assessed.
increased risk of severe acute COVID-19. In Boulware 2020, 12%
had hypertension, 8% chronic respiratory disease (mostly asthma), Adverse events were assessed through self-reporting by
3% diabetes, and < 1% reported each of heart disease, kidney participants using an online survey in Boulware 2020, and through
disease, and cancer; 73% reported no pre-existing conditions. Mitjà telephone and in-person visits in Mitjà 2020b. QT prolongation was
2020b reported underlying cardiovascular disease in 13% of not assessed due to lack of in-person assessment (which would be
participants, respiratory disease in 4%, metabolic disease in necessary for electrocardiography to be performed) in Boulware
8%, and some nervous system disease in 15%. HIV and non- 2020; there was one in-person assessment in Mitjà 2020b, but at the
HIV immunosuppression were reported in 1/821 and 4/821 participant's home, where electrocardiography may not have been
participants, respectively (Boulware 2020). Whilst pregnant women practical.
were not excluded, their representation in the participants was
not reported (Boulware 2020). Mitjà 2020b did not report on Excluded studies
participants with HIV or other immunosuppression, nor whether We excluded 791 articles (see Figure 1), 88 of which were at the
pregnant women were included. full-text stage (see the Characteristics of excluded studies section),
Interventions and comparators
for the following reasons: 35 were not RCTs; 16 lacked a control
group without CQ or HCQ; one did not include mention of CQ or
The HCQ dosing regimen in Boulware 2020 was the same as in HCQ; 32 duplicates were found, which had not been apparent at
Skipper 2020: 1400 mg (800 mg, then 600 mg 6 to 8 hours later) first screening; and four were excluded for other reasons.
on day 1, followed by 600 mg once daily for a further four days,
translating to a cumulative total of 3800 mg over five days. Mitjà Risk of bias in included studies
2020b used the same HCQ dosing as in the paired treatment
See Characteristics of included studies, which includes a 'Risk of
trial Mitjà 2020a: 800 mg on day 1, followed by 400 mg once daily
bias' table for each included trial. The results of the 'Risk of bias'
for a further six days, for a total of 3200 mg over seven days.
assessments across all included trials are summarized in Figure 2.


Collaboration.
Informed decisions.

Figure 2. Risk of bias summary: review authors' judgements about each 'Risk of bias' item for each included trial.
Blinding of participants and personnel (performance bias): All outcomes

Blinding of outcome assessment (detection bias): All outcomes
Incomplete outcome data (attrition bias): All outcomes
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Selective reporting (reporting bias)

Other bias
Abd-Elsalam 2020 + - + + ? -
Boulware 2020 + + + + + ?
Cavalcanti 2020 + + ? + + -
Chen 2020a - ? + + + -
Chen 2020b + ? - - + -
Chen 2020c + ? + + - -
Davoodi 2020 ? + - + - -
Horby 2020 + + + + + +
Huang 2020 - ? + + + -
Mitjà 2020a + ? + + - - -
Mitjà 2020b ? ? - - + - -
Pan 2020 + ? + + + ?
Skipper 2020 + + + + ? - -
Tang 2020 + + + + ? ? -

Collaboration.
Informed decisions.

Allocation Incomplete outcome data

We judged that 10 out of the 14 included trials were at We assessed eight trials as at low risk of bias for incomplete
low risk of bias (Abd-Elsalam 2020; Boulware 2020; Cavalcanti outcome data (Boulware 2020; Cavalcanti 2020; Chen 2020a;
2020; Chen 2020b; Chen 2020c; Horby 2020; Mitjà 2020a; Pan Chen 2020b; Horby 2020; Huang 2020; Mitjà 2020b; Pan 2020).
2020; Skipper 2020; Tang 2020), two were at unclear risk of Three trials were at unclear risk of bias for this domain: Abd-
bias (Davoodi 2020; Mitjà 2020b), and two were at high risk Elsalam 2020 did not report on losses to follow-up or missing
of bias for random sequence generation (Chen 2020a; Huang data; Skipper 2020 had significant losses to follow-up that were
2020). The description of the method of randomisation was balanced between each group, but no explanations for losses were
inadequate in Davoodi 2020 and Mitjà 2020b. Chen 2020a had 15 provided; and Tang 2020 had significant loss to follow-up beyond
participants in each arm, and Huang 2020 had a notable imbalance 21 days of follow-up. We assessed Mitjà 2020a as at high risk of
between treatment arms raising concerns about the integrity of bias for incomplete outcome data: 60 participants were excluded
the randomisation process; neither trial explicitly described the from the intention-to-treat (ITT) analysis due to negative baseline
method of randomisation. SARS-CoV-2 swab, missing reverse transcription polymerase chain
reaction (RT-PCR) at all follow-up visits, or consent withdrawal,
We assessed six trials as at low risk of bias for allocation and a further 23 participants had protocol deviations including
concealment (Boulware 2020; Cavalcanti 2020; Davoodi 2020; eight participants lost to follow-up. We judged Chen 2020c as at
Horby 2020; Skipper 2020; Tang 2020), and seven trials as at unclear high risk of attrition bias, as the authors reported loss to follow-
risk of bias due to lack of clear reporting of the method of allocation up of ~10% (3/33), and missing participants were imputed as having
concealment (Chen 2020a; Chen 2020b; Chen 2020c; Huang 2020; negative results, which could have impacted on the results as the
Mitjà 2020a; Mitjà 2020b; Pan 2020). We judged Abd-Elsalam 2020 to sample size was small. We judged Davoodi 2020 as at high risk of
be at high risk of bias for allocation concealment, as the method bias as there were no outcome data for 10% (6/60), which could
used was not reported, and there were more participants with have impacted the results due to the small sample size.
comorbidity (obesity and smoking history) in the intervention arm,
although there was not a statistically significant difference in these Selective reporting
characteristics between the treatment arms.
We assessed Horby 2020 as at low risk of bias for selective reporting.
Blinding Three trials were at unclear risk of bias for this domain: Boulware
2020 changed the primary outcome from confirmed COVID-19 cases
We assessed the risk of bias associated with blinding for each to probable due to a problem with access to testing; Pan 2020 was
outcome separately (details are provided in the 'Risk of bias' table accessed as a preprint at the time of writing of this review, which
for each trial), but made our overall judgement for each trial based did not include all outcome data, and referencing one change
on the primary outcome as stated by the trial authors. between protocol and trial report that was not explained; Tang
2020 changed their primary outcome and gave justification for
We assessed 10 trials as at low risk of performance bias (blinding
this, but did not report the secondary outcomes. Ten trials were
of participants and personnel) (Abd-Elsalam 2020; Boulware 2020;
at high risk of bias for selective reporting (Abd-Elsalam 2020;
Chen 2020a; Chen 2020c; Horby 2020; Huang 2020; Mitjà 2020a;
Cavalcanti 2020; Chen 2020a; Chen 2020b; Chen 2020c; Davoodi
Pan 2020; Skipper 2020; Tang 2020). We judged Cavalcanti 2020 to
2020; Huang 2020; Mitjà 2020a; Mitjà 2020b; Skipper 2020), all of
be at unclear risk of bias, as it was not blinded, and the primary
which reported outcomes that deviated from those stated in the
outcome consisted of an ordinal scale ranking clinical improvement
protocol (described in Characteristics of included studies).
or deterioration. We judged Chen 2020b to be at high risk of
bias because although the authors stated that the researchers Other potential sources of bias
and patients were unaware of treatment assignments, no placebo
was used and the methods of blinding were not described, We identified other potential sources of bias in four trials. Skipper
and the primary outcome was based on patient-reported clinical 2020 and Tang 2020 were at high risk of bias as they were
recovery. We judged Davoodi 2020 to be at high risk of bias as it terminated early, which could have introduced bias as both trials
was an open-label trial, and the primary outcome of hospitalization had a time-updating variable as the primary outcome. Mitjà
could have been influenced by clinicians knowing the treatment 2020a was also at high risk of other bias: a small number of
allocation. Similarly, we judged Mitjà 2020b to be at high risk of bias participants were randomized who were in fact not eligible for the
as it was an open-label trial, and the primary outcome involved a trial, but these participants were kept as part of the ITT population.
subjective assessment of symptoms.
Mitjà 2020b was a cluster-randomized trial, and so was assessed
We assessed 11 trials as at low risk of detection bias (blinding for risk of bias against five further domains specific to cluster-
of outcome assessment) (Abd-Elsalam 2020; Boulware 2020; randomized trials. We judged the trial to be at low risk for four out of
Cavalcanti 2020; Chen 2020a; Chen 2020c; Davoodi 2020; Horby five domains (see Characteristics of included studies), and at high
2020; Huang 2020; Mitjà 2020a; Pan 2020; Skipper 2020; Tang risk of bias for comparability with individually randomized trials:
2020). We judged Chen 2020b and Mitjà 2020b to be at high risk contamination was possible due to the open-label design, and
of detection bias, as the outcome assessors were not blinded to the intervention would be expected to work best when given
treatment allocation, and the primary outcomes of time to clinical to all contacts of a case rather than some being randomized to
improvement and development of symptoms are likely to have the intervention and some randomized to no intervention, which
been subjectively assessed. would preclude comparability with an individually randomized
trial.

Collaboration.
Informed decisions.

Effects of interventions and included potential important harm (RR 0.41, 95% CI 0.13 to
1.27; 465 participants; 1 RCT; Analysis 1.5).
See: Summary of findings 1 Hydroxychloroquine (HCQ) compared
to standard care or placebo for the treatment of people with Three trials reported results for people hospitalized with COVID-19
COVID-19; Summary of findings 2 Hydroxychloroquine (HCQ) going on to require mechanical ventilation (Cavalcanti 2020;
compared to placebo for the prevention of COVID-19 in people who Horby 2020; Tang 2020). No significant difference was found
have been exposed to SARS-CoV-2 in participants progressing to mechanical ventilation when
comparing HCQ to no HCQ (RR 1.11, 95% CI 0.91 to 1.37; 4521
See Summary of findings 1 for Objective 1, Comparison 1, participants; 3 RCTs; Analysis 1.6).
and Summary of findings 2 for Objective 3.
Three trials reported mean length of hospital admission (Abd-
Due to inability to extract data disaggregated for subgroups on Elsalam 2020; Cavalcanti 2020; Tang 2020). We noted that early in
outcomes predefined in the review protocol, we did not perform the pandemic suitability for discharge was often driven by infection
subgroup analyses. Furthermore, heterogeneity in most analyses prevention and control considerations, and therefore might not
was minimal. have been a good reflection of the efficacy of HCQ. Accordingly, we
decided not to include results from Tang 2020 in the analysis
Objective 1. For treatment of COVID-19 disease
for this outcome, as participants remained in hospital until they
Comparison 1: HCQ versus standard care without HCQ or placebo were deemed no longer infectious. Pooled length of admission
in Abd-Elsalam 2020 and Cavalcanti 2020 did not differ between
Ten trials of treatment of people with COVID-19 compared HCQ
participants who received HCQ and those who did not (mean
to standard care or placebo (8270 participants; Abd-Elsalam
difference (MD) 0.15 days shorter with HCQ, 95% CI 0.75 shorter
2020; Cavalcanti 2020; Chen 2020a; Chen 2020b; Chen 2020c;
to 0.45 longer; 642 participants; 2 RCTs; Analysis 1.7).
Horby 2020; Mitjà 2020a; Pan 2020; Skipper 2020; Tang 2020).
The arm randomizing participants to a combination of HCQ Time to clinical improvement (for symptomatic patients) and
with azithromycin in Cavalcanti 2020 was not included in this time to negative PCR for SARS-CoV-2 on respiratory samples
comparison, but is included in Comparison 3 below. were reported as hazard ratios (HRs) and corresponding 95%
CIs by Tang 2020. No significant difference was found for time to
Nine of the 10 trials reported death due to any cause (Abd-
clinical improvement (HR 1.01, 95% CI 0.59 to 1.74; 119 participants;
Elsalam 2020; Cavalcanti 2020; Chen 2020a; Chen 2020c; Horby
1 RCT; Analysis 1.8) or time to negative PCR for SARS-CoV-2 on
2020; Mitjà 2020a; Pan 2020; Skipper 2020; Tang 2020). Meta-
respiratory samples (HR 0.85, 95% CI 0.58 to 1.23; 150 participants;
analysis using ITT results for each trial found little or no difference
1 RCT; Analysis 1.9).
between HCQ and standard care without HCQ or placebo in all-
cause death (risk ratio (RR) 1.09, 95% confidence interval (CI) 0.99 to Duration of mechanical ventilation postenrolment in survivors of
1.19; 8208 participants; 9 RCTs; Analysis 1.1). Sensitivity analysis COVID-19 was not reported by any trials.
performed using modified ITT results as reported by three trials
revealed no difference in the pooled effect estimate (RR 1.09, 95% Six trials reported number of participants with any adverse
CI 0.99 to 1.19; 8043 participants; 9 RCTs; Analysis 1.2) (Cavalcanti events (Cavalcanti 2020; Chen 2020a; Chen 2020b; Mitjà 2020a;
2020; Mitjà 2020a; Skipper 2020). Skipper 2020; Tang 2020). Meta-analysis revealed a higher risk of
adverse events in participants receiving HCQ versus those receiving
Our predefined outcome involving tests for SARS-CoV-2, time to standard care or placebo (RR 2.90, 95% CI 1.49 to 5.64; 1394
negative PCR for SARS-CoV-2 on respiratory samples, was reported participants; 6 RCTs; Analysis 1.10). Adverse events reported in the
as a median by Chen 2020a and Chen 2020c, and as a mean by Abd- six trials are summarized in Table 6.
Elsalam 2020 and Tang 2020; all trials reported no significant
difference between the arm that received HCQ and the arm that did Meta-analysis of six trials that reported the number of participants
not. Two of the trials reported the related outcome of negative experiencing serious adverse events showed no significant
PCR for SARS-CoV-2 at day 7 after enrolment as dichotomous difference between participants receiving HCQ and those receiving
outcomes (Chen 2020a; Tang 2020), and three trials reported standard care (RR 0.82, 95% CI 0.37 to 1.79; 1004 participants;
negative PCR at day 14 (Chen 2020a; Chen 2020c; Tang 2020). 6 RCTs; Analysis 1.11) (Cavalcanti 2020; Chen 2020a; Chen 2020b;
We deemed the latter (i.e. negative PCR at day 14) to be more Chen 2020c; Mitjà 2020a; Tang 2020). It was not possible to
important based on the current understanding of COVID-19, so this disaggregate data for specific serious adverse events for each trial,
is displayed in Summary of findings 1 . No significant difference nor was it possible to disaggregate data for serious adverse events
between HCQ and standard care without HCQ was revealed in attributed to the intervention drug for each trial.
meta-analysis of either negative PCR at day 14 (RR 1.00, 95% CI
0.91 to 1.10; 213 participants; 3 RCTs; Analysis 1.3) or negative Our predefined specific adverse event, prolongation of the QT-
PCR at day 7 (RR 0.86, 95% CI 0.68 to 1.09; 180 participants; 2 interval on electrocardiogram (ECG), was reported by one trial
RCTs; Analysis 1.4) after enrolment. (Cavalcanti 2020). Risk of QT-interval prolongation increased in
participants receiving HCQ (without azithromycin) versus those
Of the two trials assessing ambulatory treatment of people with receiving standard care or azithromycin (RR 8.47, 95% CI 1.14 to
COVID-19, only Skipper 2020 was included in the analysis of risk 63.03; 147 participants; 1 RCT; Analysis 1.12). Fewer than half of
of admission to hospital; Mitjà 2020a did not report denominators participants had an ECG performed within seven days of enrolment;
disaggregated for allocation to HCQ versus standard care without this appeared to be higher in those receiving HCQ (89/199,
HCQ. In Skipper 2020, though the risk ratio may suggest an 44.7%) than in those receiving standard care (58/177, 32.8%).
important benefit from HCQ, the confidence intervals were wide,

Collaboration.
Informed decisions.

Comparison 2: CQ versus lopinavir/ritonavir (LPV/r) Length of hospital admission was similar between groups (MD 0.50
days longer with HCQ + azithromycin, 95% CI 0.81 days shorter to
One trial (22 participants) reported this comparison (Huang 2020).
1.81 days longer; 444 participants; 1 RCT; Analysis 3.3).
Due to the comparison not having been predefined, and this being
a single small trial with high risk of selection and reporting bias, Time to clinical improvement was not reported.
reporting few of our predefined outcomes, a separate 'Summary of
findings' table is not provided. Adverse events were experienced by a higher proportion of
participants who received at least one dose of HCQ + azithromycin
Death was not reported as an outcome (Huang 2020). versus participants receiving neither HCQ nor azithromycin
(RR 1.74, 95% CI 1.27 to 2.38; 416 participants; 1 RCT; Analysis 3.4).
Time to negative PCR for SARS-CoV-2 on respiratory samples was
Serious adverse events did not differ significantly between study
not reported, but the proportion with negative PCR ranged from
arms (RR 1.85, 95% CI 0.36 to 9.43; 416 participants; 1 RCT; Analysis
appreciable benefit to appreciable harm between arms at day 7
3.5).
from enrolment (RR 1.20, 95% CI 0.64 to 2.25; 22 participants; 1
RCT; Analysis 2.1) and day 14 from enrolment (RR 1.08, 95% CI 0.85 When assessed, QT-interval prolongation on ECG was
to 1.36; 22 participants; 1 RCT; Analysis 2.2). more common amongst participants receiving HCQ +
azithromycin (17/116) versus those receiving neither drug (1/58)
Number of participants admitted to hospital (if receiving
(RR 8.50, 95% CI 1.16 to 62.31; 174 participants; 1 RCT; Analysis 3.6).
ambulatory treatment) was not relevant for this hospital inpatient-
Performance of ECG within seven days of enrolment appeared to be
based trial.
more frequent in the HCQ + azithromycin arm (116/239, 48.5%) than
Number of participants requiring mechanical ventilation after in the standard care arm (58/177, 32.8%).
enrolment was not reported (Huang 2020).
Comparison 4: HCQ versus febuxostat
We were unable to extract length of hospital admission as a mean, One trial (60 participants) reported this comparison (Davoodi 2020).
but visual inspection of the Kaplan-Meier chart appeared to show A separate 'Summary of findings' table is not provided.
a median time to discharge of around 11 days for the CQ arm, and
around 14 days for the LPV/r arm (Huang 2020). The number of No deaths were reported in either study arm (Davoodi 2020).
participants discharged by day 14 from enrolment was reported to
be 10/10 in the CQ arm versus 6/12 in the LPV/r arm (RR 1.91, 95% Three participants in each arm (of 25 in the HCQ arm and 29 in
CI 1.09 to 3.34; 22 participants; 1 RCT; Analysis 2.3). the febuxostat arm) required hospitalization during the 14 days
of follow-up (RR 1.16, 95% CI 0.26 to 5.24; 54 participants; 1
Time to clinical improvement was not reported as a mean or RCT; Analysis 4.2).
median (Huang 2020). However, clinical recovery at day 10 was
reported as showing no significant difference between study arms Number of participants requiring mechanical ventilation was not
(RR 1.37, 95% CI 0.78 to 2.42; 22 participants; 1 RCT; Analysis 2.4). reported explicitly, but the authors reported: “All
hospitalised patients … did not require ICU care" (Davoodi 2020).
There was no difference in the number of participants
experiencing adverse events between study arms (RR 1.08, 95% Length of hospital admission was not reported precisely, but
CI 0.78 to 1.50; 22 participants; 1 RCT; Analysis 2.5); QT-interval authors reported: “All
prolongation was not specifically reported. No serious adverse hospitalised patients were released from hospitals between 1 and
events were reported in either arm (Huang 2020). 7 days of hospitalization” (Davoodi 2020).
Comparison 3: HCQ + azithromycin versus standard care Time to clinical improvement was not reported in a way that fit with
our planned data extraction or analysis.
One trial (444 participants) reported this comparison (Cavalcanti
2020). Due to the comparison not having been predefined, Duration of mechanical ventilation was not reported.
and this trial having a high risk of reporting bias and unclear risk of
performance and detection bias, a separate 'Summary of findings' Reduction in involvement of the lungs on CT scan between days
table is not provided. 1 and 14 was reported to be no different between the HCQ and
febuxostat arms.
Death was reported as showing no difference between study arms
(RR 0.52, 95% CI 0.13 to 2.07; 444 participants; 1 RCT; Analysis 3.1). Adverse events were not reported.
Time to negative PCR for SARS-CoV-2 was not reported, and as Objective 2. Preventing COVID-19 disease in people at risk of
this was a trial of hospitalized patients, neither was number of exposure to SARS-CoV-2
participants admitted to hospital (Cavalcanti 2020). No eligible trials provided outcome results for this objective.
The number of participants requiring mechanical ventilation did Objective 3. Preventing COVID-19 disease in people who have
not differ between study arms (RR 1.61, 95% CI 0.82 to 3.15; been exposed to SARS-CoV-2
444 participants; 1 RCT; Analysis 3.2). Duration of mechanical
ventilation was not reported (Cavalcanti 2020). We deemed the effect of HCQ on the prevention of COVID-19 to be
susceptible to differences in administration to an individual, versus
a cluster of individuals all in contact with one index person. We

Collaboration.
Informed decisions.

therefore did not pool results from the individually-randomized the pharmacovigilance consultants employed by the trial (Mitjà
RCT, Boulware 2020, with those from the cluster-RCT (Mitjà 2020b). 2020b). QT-interval prolongation was not measured in this trial.
Comparison 5: HCQ versus placebo by individual randomization DISCUSSION

One trial (821 participants) reported this comparison (Boulware
Summary of main results
2020). See Summary of findings 2.
Treating COVID-19 disease
Development of confirmed COVID-19 at 14 days from enrolment
was not found to differ significantly between the two arms (RR 1.20, Ten trials compared HCQ versus standard care without HCQ, or
95% CI 0.50 to 2.87; 821 participants; 1 RCT; Analysis 5.1). placebo (see Summary of findings 1). HCQ makes little or no
difference to death due to any cause, compared with no HCQ (high-
Production of antibodies to SARS-CoV-2 and development of certainty evidence). HCQ may make little or no difference to the
COVID-19 in household contacts of the recipient of the prophylaxis likelihood of a negative PCR for SARS-CoV-2 on respiratory samples
were not reported (Boulware 2020). at day 14 from enrolment (low-certainty evidence). HCQ probably
results in little to no difference in progression to mechanical
For our predefined outcome of disease severity of participants ventilation (moderate-certainty evidence). We are very uncertain
who develop COVID-19, we extracted data for participants about the effect of HCQ on time to clinical improvement when
hospitalized due to COVID-19; this did not differ significantly compared to standard care without HCQ or placebo (very low-
between those receiving HCQ and those receiving placebo (RR 0.98, certainty evidence). HCQ probably results in an increased risk of
95% CI 0.06 to 15.66; 821 participants; 1 RCT; Analysis 5.2). developing adverse events (moderate-certainty evidence), but may
make little or no difference to the risk of serious adverse events
Participants receiving at least one dose of HCQ had an increased (low-certainty evidence). We are very uncertain about the effect
risk of adverse events compared to those not receiving HCQ of HCQ on prolongation of QT-interval on ECG when compared
(RR 2.39, 95% CI 1.83 to 3.11; 700 participants; 1 RCT; Analysis with standard care without HCQ, or placebo (very low-certainty
5.3). No serious adverse events were reported in either arm. QT- evidence).
interval prolongation on ECG was not reported, but follow-up
was performed remotely using an online survey, so ECG was not We have drawn no conclusions from small single-trial comparisons
performed as part of the trial (Boulware 2020). of CQ versus lopinavir/ritonavir; HCQ and azithromycin versus
standard care; and HCQ versus febuxostat.
Comparison 6: HCQ versus standard care by
cluster randomization Objective 2. For prevention of COVID-19 disease in people at
One trial (2525 participants) reported this comparison (Mitjà risk of exposure to SARS-CoV-2
2020b). Due to the cluster-RCT design and appropriate analysis by No eligible studies were identified for this objective.
the trial authors, adjusted risk ratios have been taken from the
report. Objective 3. For prevention of COVID-19 disease in people who
have been exposed to SARS-CoV-2
Development of symptomatic confirmed COVID-19 at 14 days
from enrolment was not found to differ significantly between One individually randomized trial compared HCQ with placebo
participants randomized to HCQ (64/1116; 5.7%) and those (see Summary of findings 2). We are very uncertain about the
allocated to standard care (74/1198; 6.2%) (adjusted RR 0.89, 95% effect of HCQ on the development of confirmed COVID-19 at
CI 0.54 to 1.46; 2314 participants; 1 RCT; Mitjà 2020b). 14 days from enrolment and the risk of hospitalization due to
COVID-19, compared with placebo (very low-certainty evidence).
Production of antibodies to SARS-CoV-2 at 14 days was reported HCQ probably increases the risk of adverse events, compared with
in 137/958 (14.3%) of the participants in HCQ clusters and 91/1042 placebo (moderate-certainty evidence). HCQ may result in little or
(8.7%) in clusters not receiving HCQ (adjusted RR 1.6, 95% CI 0.96 to no difference in serious adverse events, compared with placebo,
2.69; 2000 participants; 1 RCT; Mitjà 2020b). though no participants in the trial experienced any events (low-
certainty evidence).
Development of COVID-19 in household contacts of the recipient of
the prophylaxis was not reported by either trial. A cluster-randomized trial compared HCQ with no intervention
for postexposure prevention of COVID-19. The results of this trial
Disease severity of participants who developed COVID-19 was not could not be combined with those of the individually randomized
reported. Five participants in the HCQ clusters (with a denominator RCT. There was no difference in the risk of symptomatic confirmed
of 1197, which is unexplained in its deviation from the randomized COVID-19 or production of antibodies to SARS-CoV-2 between study
total of 1225) and 8/1300 in the standard care clusters died (Mitjà arms.
2020b). Causes of death were not reported.
Overall completeness and applicability of evidence
Adverse events were reported in 671/1197 (56%) participants in the
HCQ clusters versus 77/1300 (6%) participants in the clusters not Objective 1. For treatment of COVID-19 disease
receiving HCQ; a relative effect estimate was not reported (Mitjà The 12 included trials were conducted in Brazil, Canada, China,
2020b). Serious adverse events were reported, but it was not clear Egypt, Iran, Spain, Taiwan, the UK, and the USA. The largest
whether they were reported as number of events or number of trial, contributing the majority of participants (4716/8569, 55%),
participants, and did not match the intensity grading reported by was based in the UK. It is as yet uncertain whether geographical

Collaboration.
Informed decisions.

differences may impact on the efficacy or safety of interventions for Objective 3. For preventing COVID-19 disease in people who
the treatment of COVID-19. have been exposed to SARS-CoV-2
None of the trials included children or pregnant women, so the One of the two trials included in this objective was conducted in
evidence cannot be applied to these populations. Most participants the USA and Canada; the other in Spain. Most participants were
(86%) had COVID-19 confirmed by positive RT-PCR for SARS- healthcare or nursing home workers and had no comorbidities;
CoV-2. Nine of the 12 trials recruited hospitalized patients, average age was between 40 and 50 years. Consequently, the
with the three ambulatory treatment trials contributing only findings may have limited applicability of the evidence to older
844/8569 (10%) of participants in the review, potentially people with multi-morbidity, household contacts, and possibly
affecting applicability of the findings to outpatient settings. to lower-income settings. Additionally, as the assessment for the
development of COVID-19 was based on the presence of symptoms,
Severity of disease varied between trials. Whilst not all participants and no outcomes assessed infection or disease in household
could be classified according to WHO severity grading, 3139/8569 or other contacts of the person with exposure to SARS-CoV-2,
(37%) of participants did not require oxygen or other respiratory no evidence was available for the effect of HCQ on the risk of
support at enrolment; 5230/8569 (63%) were receiving oxygen or asymptomatic infection or onward transmission.
higher respiratory support. The two largest trials (Horby 2020;
Pan 2020), which mostly included participants requiring oxygen or Certainty of the evidence
higher respiratory support, contributed the majority of participants We used the GRADE approach to assess the certainty of the
to the meta-analysis of the outcome death due to any cause for evidence, employing GRADEpro GDT software (GRADEpro GDT). The
the comparison of HCQ versus standard care or placebo. Data GRADE assessment with explanatory footnotes is outlined in
for participants with any or serious adverse events could not Summary of findings 1 and Summary of findings 2.
be extracted from these trials. This means that evidence for
the outcome of death was based on a population with more For Objective 1 - treatment of COVID-19, we included nine RCTs and
severe disease. For adverse events outcomes, the meta-analysed assessed seven outcomes. We graded the effect estimate for death
population was less severely unwell, and so this effects estimate as high certainty, implying that treatment with HCQ results in no
should be interpreted with this in mind as the baseline risk of difference to death from any cause in people with COVID-19. We
adverse events in more severely unwell patients is likely to be graded the effect estimate for negative SARS-CoV-2 PCR at 14
higher. These trials were designed to assess the efficacy of HCQ, and days as low certainty, that is HCQ may make no difference to the
may not be of sufficient power to detect any but the most common proportion of people who have a negative SARS-CoV-2 swab at 14
adverse events. days; the certainty of the evidence was downgraded by one level for
serious risk of bias, as both trials in this analysis were at high risk of
HCQ and CQ have similar pharmacological actions, but only one bias across several domains; and one level for serious indirectness,
study used CQ, to which 10 participants were allocated, and so we as almost all participants had mild or moderate COVID-19, all were
could not draw conclusions about the efficacy and safety of CQ hospitalized, and all were from one country (Chen 2020a; Tang
for the treatment of COVID-19. This is likely due to the increased 2020). We graded the effect estimate for progression to mechanical
rate of adverse effects seen with CQ compared with HCQ in other ventilation as moderate certainty, implying that HCQ probably has
conditions. no effect on progression to mechanical ventilation in people with
COVID-19; the certainty of the evidence was downgraded by one
Only one trial included an arm with a combination of HCQ and
level for serious imprecision, as the lower bound of the confidence
azithromycin (217 participants), and so few conclusions can be
interval around the estimate represents no benefit nor harm from
drawn about the efficacy or safety of this combination treatment.
HCQ, whereas the upper bound suggests appreciable harm. For
Dosing of HCQ varied considerably between trials (see Table 4). The time to clinical improvement, we graded the estimate of effect
two largest trials used relatively high total cumulative doses, and so as very low certainty, that is we do not know what effect HCQ
it is unlikely that a lack of efficacy for the primary outcome of death has on this outcome. Data for this outcome came from a single
is due to underdosing. As the data for adverse events were drawn trial (Tang 2020); we downgraded the certainty of the evidence for
from the trials using lower doses, it is possible that this meta- serious risk of bias, serious indirectness (all hospitalized patients
analysis underestimates dose-dependent adverse events. with mild-moderate COVID-19 in one centre in China), and serious
imprecision (confidence interval extends from appreciable benefit
Pharmacological co-interventions also varied considerably to appreciable harm).
between studies (see Table 5), and reporting was at times
incomplete. Co-interventions were mostly balanced between For adverse effects in people with COVID-19 treated with HCQ, we
intervention arms across the studies, and are unlikely to have graded the effects estimate for participants with any adverse events
impacted on the summary effects estimates for the primary as moderate certainty, meaning that HCQ probably increases the
outcome. risk of developing adverse events. We downgraded the certainty
of the evidence by one level for serious risk of bias, as all trials
Objective 2. For preventing COVID-19 disease in people at risk contributing to this analysis had high or unclear risk of bias
of exposure to SARS-CoV-2 across various domains, and all but one trial were open-label. We
graded the effects estimate for participants with serious adverse
No eligible studies were identified for this objective. events as low certainty, downgrading by two levels for very serious
imprecision, as the confidence intervals ranged from appreciable
benefit to appreciable harm; overall the rate of serious adverse
events was low. We graded the effects estimate for participants

Collaboration.
Informed decisions.

who developed prolonged QT interval on ECG as very low certainty; CI 0.97 to 1.24). The authors concluded that HCQ is not effective
data for this outcome came from one trial, and the certainty of the for COVID-19, and that further research is not needed. Elavarasi
evidence was downgraded for risk of bias, as the trial was open- 2020, published in September 2020, is a systematic review of
label; indirectness, as severe COVID patients were excluded; and RCTs, case series, and cohort studies with a comparator arm
imprecision, as the low event rate and small sample size led to a including 12 non-randomized studies and 3 RCTs. Meta-analysis
broad confidence interval. of the included studies revealed no difference in mortality with
HCQ use (RR 0.98 95% CI 0.66 to 1.46), leading the authors to
We found no studies addressing Objective 2 - prevention of conclude that the available evidence does not support the use of
COVID-19 disease in people at risk of exposure to SARS-CoV-2. HCQ and that further RCTs are required. Hernandez 2020, published
in August 2020, is a living systematic review which includes 3
For Objective 3 - prevention of COVID-19 in people who have been
RCTs, 8 cohort studies, and 3 case series. No meta-analysis was
exposed to SARS-CoV-2, we included one RCT and graded four
conducted due to high heterogeneity between studies; the authors
outcomes (Boulware 2020). We graded the effects estimate for
concluded that the evidence on the benefits and harms of HCQ
development of COVID-19 at 14 days from enrolment as very low
for COVID-19 is weak and conflicting. Zang 2020, published in
certainty, implying that we do not know whether HCQ prevents
September 2020, includes 3 RCTs, 2 prospective observational
COVID-19 in people exposed to SARS-CoV-2. We downgraded the
studies, and 2 retrospective observational studies. In participants
certainty of the evidence by one level for serious indirectness, as
treated with HCQ compared with standard therapy, meta-analysis
data for this outcome came from a single trial in North America
suggested increased mortality with HCQ (RR 1.92, 95% CI 1.26
with few older or comorbid participants; and by two levels for
to 2.93), although the authors identified significant unexplained
very serious imprecision, as the confidence interval around the
heterogeneity and problems with study quality, and concluded that
effects estimate included appreciable benefit and appreciable
better RCTs are urgently needed. All these systematic reviews cite
harm. We graded the effect estimate for participants hospitalized
the three Chinese RCTs included in this review (Chen 2020a; Chen
due to COVID-19 as very low certainty, again downgrading by one
2020b; Tang 2020). Few systematic reviews have used GRADE to
level for serious indirectness and by two levels for very serious
assess the certainty of the evidence.
imprecision. We graded the effects estimate for participants with
any adverse events as moderate certainty, implying that HCQ There are fewer studies and fewer reviews examining CQ and HCQ
probably increases the risk of adverse events when compared with as prophylaxis for COVID-19 (Objectives 2 and 3). Shah 2020 is a
placebo; the certainty of the evidence was downgraded by one systematic review of the evidence for HCQ in preventing COVID-19,
level for serious indirectness, as described above. We graded the which was published in March 2020. Due to the lack of studies at
effects estimate for participants with serious adverse events as low that time, the authors included only two pre-clinical studies and
certainty, meaning that HCQ may result in no difference to the risk three commentaries, concluding that although evidence from pre-
of developing serious adverse events compared with placebo; the clinical studies is promising, there was no evidence to support the
certainty of the evidence was downgraded by one level for serious efficacy of CQ or HCQ in preventing COVID-19.
indirectness and one level for serious imprecision.
National and international guideline recommendations for the use
Potential biases in the review process of CQ and HCQ have changed over the course of the pandemic. The
US National Institutes of Health published updated guidance on 27
We took measures to limit bias in the review process by following
August 2020 recommending against the use of CQ or HCQ for the
the procedures outlined in the Cochrane Handbook for Systematic
treatment of COVID-19 in hospitalized patients, and against the use
Reviews of Interventions (Higgins 2019). The Cochrane Infectious
of CQ or HCQ in non-hospitalized patients except in the context of
Diseases Group (CIDG) Information Specialist conducted the
a clinical trial (NIH 2020). In May 2020, WHO recommended that CQ
literature search using a variety of general and COVID-19 specific
and HCQ not be administered to COVID-19 patients outside of the
resources, and included preprints. In addition, we also checked
context of a clinical trial (WHO 2020c).
the COVID-NMA website at www.covid-nma.com/ for further studies
at regular intervals. We did not make a funnel plot, as fewer than
AUTHORS' CONCLUSIONS
10 studies were included per comparison. Two review authors
independently examined the search results, assessed studies for Implications for practice
eligibility, and extracted data, in order to minimize bias in study
selection and data extraction. Hydroxychloroquine for treatment
Agreements and disagreements with other studies or Hydroxychloroquine (HCQ) has no clinical benefit in treating
reviews COVID-19 in hospitalized patients, with moderate- to high-certainty
evidence from several randomized trials, and a probable increase
Several systematic reviews have been published examining in adverse events associated with its use.
the treatment of COVID-19 with HCQ/CQ, all of which have
included RCTs and non-randomized studies. For the most part Evidence for prevention of hospital admission in outpatients with
their conclusions match ours regarding the finding of HCQ COVID-19 is very uncertain. However, given the lack of benefit in
showing no benefit for mortality from COVID-19, but with less hospitalized patients, and limited available evidence suggesting
precision. Fiolet 2020, published in August 2020, describes results little or no effect on clearance of the virus from the respiratory tract,
from 29 studies including 3 RCTs, but studies with no mortality benefit from treatment of outpatients appears unlikely.
were excluded. In participants treated with HCQ versus comparator
group for the outcome of death, the RR was 0.83 (95% CI 0.65 to Hydroxychloroquine for pre- or post-exposure prophylaxis
1.06); excluding non-randomized studies, the RR was 1.09 (95%

Collaboration.
Informed decisions.

The lack of any demonstrable clinical benefit in the treatment of ACKNOWLEDGEMENTS

COVID-19 makes it less likely the drug will prevent the illness in
those who are exposed, but this effect is not excluded. The Academic Editor is Dr Hellen Gelband.
No trials of the use of HCQ for prophylaxis of COVID-19 in those at We thank Vittoria Lutje, the Cochrane Infectious Diseases Group
risk of exposure to SARS-CoV-2 were identified. (CIDG) Information Specialist, for designing the search strategy.
We also thank Paul Garner (CIDG Co-ordinating Editor) for
Evidence that HCQ is effective as prophylaxis for COVID-19 in his contributions to this review.
people exposed to SARS-CoV-2 is limited. However, HCQ probably
increases adverse events, although there does not appear to be a MC is supported by the Research, Evidence and Development
difference between comparison groups for serious adverse events. Initiative (READ-It) project, and TK is partly supported by READ-It
(project number 300342-104). The CIDG editorial base is funded by
Implications for research UK aid from the UK government for the benefit of low- and middle-
income countries (project number 300342-104). READ-It (project
No further trials in hospital inpatients are justified.
number 300342-104) is funded by UK aid from the UK government;
The evidence is less certain for ambulatory treatment of people however, the views expressed do not necessarily reflect the UK
with mild COVID-19, and for prevention of COVID-19 in people with, government’s official policies.
or at risk of, exposure to SARS-CoV-2.
BS receives support from the Medical Research Council (MRC), UK
If other reasons are identified that suggest the drugs may (project number MR/V033441/1) and from the UK National Institute
have benefit in prevention despite no effect in treatment, then for Health Research (NIHR) through its Global Health Research
researchers should ensure that trials are adequately powered, Group on Brain Infections (No. 17/63/110). The views expressed in
prioritize inclusion of people at risk for severe COVID-19, and this review do not necessarily reflect UK government policy.
include risk of asymptomatic infection and onward transmission as
We thank the peer reviewers: Dr Marie Stolbrink (protocol stage);
outcome measures.
and Dr Joseph Okebe, Dr S Gould, Dr Alice V Easton, and consumer
peer reviewer Jenny Negus (review stage) for their constructive
comments. We also thank Dr Kerry Dwan, Cochrane Statistical
Editor for input, and Cochrane copy editor Lisa Winer.

Collaboration.
Informed decisions.

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centre, randomized, controlled trial. www.medrxiv.org/ Brown R. Hydroxychloroquine and “off-label” utilization in the
treatment of oral conditions. Oral Surgery, Oral Medicine, Oral

Collaboration.
Informed decisions.

Pathology and Oral Radiology 2020;129(6):643-4. [DOI: 10.1016/ Ferner 2020 {published data only}
j.oooo.2020.03.047] Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in
Covid-19. BMJ 2020;369:m1432. [DOI: 10.1136/bmj.m1432]
ChiCTR2000029542 {published data only}
ChiCTR2000029542. Study for the efficacy of chloroquine Gao 2020 {published data only}
in patients with novel coronavirus pneumonia (COVID-19). Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate
www.chictr.org.cn/showprojen.aspx?proj=48968 (first received 3 has shown apparent efficacy in treatment of COVID-19
February 2020). [ChiCTR2000029542] associated pneumonia in clinical studies. Bioscience Trends
2020;14(1):72-3. [DOI: 10.5582/bst.2020.01047]
ChiCTR2000029609. A prospective, open-label, multiple-center Gendrot 2020 {published data only}
study for the efficacy of chloroquine phosphate in patients with Gendrot M, Javelle E, Clerc A, Savini H, Pradines B. Chloroquine
novel coronavirus pneumonia (COVID-19). www.chictr.org.cn/ as a prophylactic agent against COVID-19? International Journal
showprojen.aspx?proj=49145 (first received 6 February 2020). of Antimicrobial Agents 2020;55(6):105980. [DOI: 10.1016/
[ChiCTR2000029609] j.ijantimicag.2020.105980]
ChiCTR2000029898 {published data only} Heldwein 2020 {published data only}
ChiCTR2000029898. Evaluation the efficacy and safety Heldwein FL, Calado A. Does hydroxychloroquine prevent the
of hydroxychloroquine sulfate in comparison with transmission of COVID-19? Annals of the Rheumatic Diseases
phosphate chloroquine in severe patients with novel 2020;79(6):e60. [DOI: 10.1136/annrheumdis-2020-217501]
coronavirus pneumonia (COVID-19): a randomized,
open-label, parallel, controlled trial. www.chictr.org.cn/ Lee 2020 {published data only}
showprojen.aspx?proj=49482 (first received 16 February 2020). Lee SH, Son H, Peck KR. Can post-exposure prophylaxis
[ChiCTR2000029898] for COVID-19 be considered as an outbreak response
strategy in long-term care hospitals? International Journal
of Antimicrobial Agents 2020;55(6):105988. [DOI: 10.1016/
ChiCTR2000029899. Evaluation the efficacy and safety of j.ijantimicag.2020.105988]
hydroxychloroquine sulfate in comparison with phosphate
chloroquine in mild and commen (sic) patients with Lofgren 2020 {published data only}
novel coronavirus pneumonia (COVID-19): a randomized, Lofgren SM, Nicol MR, Bangdiwala AS, Pastick KA, Okafor EC,
open-label, parallel, controlled trial. www.chictr.org.cn/ Skipper CP, et al. Safety of hydroxychloroquine among
showprojen.aspx?proj=49536 (first received 16 February 2020). outpatient clinical trial participants for COVID-19. medRxiv
[ChiCTR2000029899] [preprint] 22 July 2020. [DOI: 10.1101/2020.07.16.20155531]
Colson 2020a {published data only} Nau 2020 {published data only}
Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 Nau JY. Coronavirus epidemic and chloroquine controversy.
novel coronavirus SARS-CoV-2. International Journal of Revue Medicale Suisse 2020;685:510-1.
Antimicrobial Agents 2020;55(3):105923. [DOI: 10.1016/
j.ijantimicag.2020.105923] NCT04304053 {published data only}
Colson 2020b {published data only} NCT04304053. Treatment of COVID-19 cases and
chemoprophylaxis of contacts as prevention (HCQ4COV19).
Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine clinicaltrials.gov/ct2/show/NCT04304053 (first received 11
and hydroxychloroquine as available weapons to fight March 2020). [NCT04304053]
COVID-19. International Journal of Antimicrobial Agents
2020;55(4):105932. [DOI: 10.1016/j.ijantimicag.2020.105932] NCT04321278 {published data only}
EUCTR2020-000890-25-FR {published data only} NCT04321278. Safety and efficacy of hydroxychloroquine
associated with azithromycin in SARS-CoV-2 virus (Coalition
EUCTR2020-000890-25-FR. Hydroxychloroquine as a treatment Covid-19 Brasil II). clinicaltrials.gov/show/NCT04321278 (first
for coronavirus disease COVID-19. www.clinicaltrialsregister.eu/ received 25 March 2020). [NCT04321278]
ctr-search/search?query=EUCTR2020-000890-25-FR (first
received 10 March 2020). [EUCTR2020-000890-25-FR] NCT04321993 {published data only}
EUCTR2020-001421-31-ES {published data only} NCT04321993. Treatment of moderate to severe coronavirus
disease (COVID-19) in hospitalized patients. clinicaltrials.gov/
EUCTR2020-001421-31-ES. Clinical trial randomized, show/NCT04321993 (first received 26 March 2020).
unblinded and controled for evaluation of efficacy [NCT04321993]
and safety of hydroxychloroquine chemoprophylaxis
against SARS-CoV-2 (COVID-19) infection in healthcare NCT04323527 {published data only}
professionals. www.clinicaltrialsregister.eu/ctr-search/search? NCT04323527. Chloroquine diphosphate for the treatment of
query=EUCTR2020-001421-31-ES++ (first received 7 April 2020). severe acute respiratory syndrome secondary to SARS-CoV2
[EUCTR2020-001421-31-ES] (CloroCOVID19). clinicaltrials.gov/ct2/show/NCT04323527 (first
received 26 March 2020). [NCT04323527]
Collaboration.
Informed decisions.

NCT04326725 {published data only} NCT04344457 {published data only}

NCT04326725. Proflaxis using hydroxychloroquine plus NCT04344457. Evaluate the efficacy and safety of oral
vitamins-zinc during COVID-19 pandemia. clinicaltrials.gov/ hydroxychloroquine, indomethacin and zithromax in subjects
show/NCT04326725 (first received 30 March 2020). with mild symptoms of COVID-19. clinicaltrials.gov/ct2/show/
[NCT04326725] NCT04344457 (first received 14 April 2020). [NCT04344457]

NCT04329572. Efficacy and safety of hydroxychloroquine NCT04345419. A real-life experience on treatment of patients
and azithromycin for the treatment of hospitalized patients with COVID 19. clinicaltrials.gov/show/NCT04345419 (first
with moderate to severe COVID-19. clinicaltrials.gov/show/ received 14 April 2020). [NCT04345419]
NCT04329572 (first received 1 April 2020). [NCT04329572]
NCT04345653 {published data only}
NCT04329611 {published data only} NCT04345653. Hydroxychloroquine as chemoprevention for
NCT04329611. ALBERTA HOPE COVID-19 for the prevention COVID-19 for high risk healthcare workers. clinicaltrials.gov/
of severe COVID19 disease. clinicaltrials.gov/ct2/show/ show/NCT04345653 (first received 14 April 2020).
NCT04329611 (first received 1 April 2020). [NCT04329611] [NCT04345653]

NCT04332094. Clinical trial of combined use of NCT04346147. Clinical trial to evaluate efficacy of 3 types
hydroxychloroquine, azithromycin, and tocilizumab for the of treatment in patients with pneumonia by COVID-19
treatment of COVID-19 (TOCOVID). clinicaltrials.gov/show/ (Covid-19HUF). clinicaltrials.gov/ct2/show/NCT04346147 (first
NCT04332094 (first received 2 April 2020). [NCT04332094] received 15 April 2020). [NCT04346147]

NCT04333225. Hydroxychloroquine in the prevention of NCT04347798. IMPACT: IMPact of Antimalarials on Covid-19
COVID-19 infection in healthcare workers. clinicaltrials.gov/ Infections in RAPPORT (IMPACT). clinicaltrials.gov/ct2/show/
show/NCT04333225 (first received 3 April 2020). [NCT04333225] NCT04347798 (first received 15 April 2020). [NCT04347798]

NCT04334512. A study of quintuple therapy to treat COVID-19 NCT04348474. Efficacy and safety of hydroxychloroquine and
infection. clinicaltrials.gov/show/NCT04334512 (first received 6 azithromycin for the treatment of ambulatory patients with
April 2020). [NCT04334512] mild COVID-19. clinicaltrials.gov/ct2/show/NCT04348474 (first
received 16 April 2020). [NCT04348474]
NCT04335084. A study of hydroxychloroquine, vitamin C, NCT04350281 {published data only}
vitamin D, and zinc for the prevention of COVID-19 infection NCT04350281. Double therapy with IFN-beta 1b and
(HELPCOVID-19). clinicaltrials.gov/show/NCT04335084 (first hydroxychloroquine. clinicaltrials.gov/show/NCT04350281 (first
received 6 April 2020). [NCT04335084] received 17 April 2020). [NCT04350281]

NCT04341493. Hydroxychloroquine vs nitazoxanide in patients NCT04350450. Hydroxychloroquine treatment of healthcare
with COVID-19. clinicaltrials.gov/show/NCT04341493 (first workers with COVID19 illness at Montefiore. clinicaltrials.gov/
received 10 April 2020). [NCT04341493] show/NCT04350450 (first received 17 April 2020).
[NCT04350450]
NCT04341727. Hydroxychloroquine, hydroxychloroquine, NCT04351620 {published data only}
azithromycin in the treatment of SARS CoV-2 infection (WU352). NCT04351620. High-dose hydroxychloroquine for the
clinicaltrials.gov/show/NCT04341727 (first received 10 April treatment of ambulatory patients with mild COVID-19.
2020). [NCT04341727] clinicaltrials.gov/show/NCT04351620 (first received 17 April
2020). [NCT04351620]
NCT04343092. Efficacy of ivermectin as add on therapy in NCT04351919 {published data only}
COVID-19 patients. clinicaltrials.gov/show/NCT04343092 (first NCT04351919. Assessment of efficacy and safety of HCQ
received 13 April 2020). [NCT04343092] and antibiotics administrated to patients COVID19(+).
clinicaltrials.gov/show/NCT04351919 (first received 17 April
NCT04343677 {published data only} 2020). [NCT04351919]
NCT04343677. Military COVID-19 hydroxychloroquine pre-
exposure and post-exposure prophylaxis study. Unable to NCT04354870 {published data only}
access - removed from clinicaltrials.gov website. [NCT04343677] NCT04354870. COVID-19 PrEP HCW HCQ Study.
clinicaltrials.gov/ct2/show/NCT04354870 (first received 21 April
2020). [NCT04354870]
Collaboration.
Informed decisions.

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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Abd-Elsalam 2020
Study characteristics

Collaboration.
Informed decisions.

Abd-Elsalam 2020 (Continued)
Methods Open-label trial comparing HCQ with standard care without HCQ for the treatment of COVID-19. No
placebo was used. Follow up for 4 weeks from enrolment.
Participants Setting: 3 tertiary hospitals in Egypt.
Number of participants: 194 total, 97 allocated to HCQ; 97 allocated to standard care
Inclusion criteria: "all patients admitted with SARS-CoV-2 infection". Note that no criteria for diagnosis
were reported.
Exclusion criteria: "allergy or contraindication to HCQ, pregnant and lactating females, and patients
with cardiac problem (chronic heart failure or prolonged QT interval on ECG)".
Age: HCQ arm: Mean 40.35 ± SD 18.65 years; standard care arm: Mean 41.09 ± SD 20.07 years.
Sex: HCQ arm: female:male 41:56; standard care arm: female:male 39:58.
Method of diagnosis: not reported.
Clinical presentation: not reported.
COVID-19 disease severity at diagnosis: “The patients were randomized equally between the two
groups regarding the disease severity”.
Time from symptom onset to enrolment: not reported.
Comorbidities:
1. Obesity: HCQ 40/97 (41%); standard care 35/97 (36%)

2. Morbid obesity: HCQ 21/97 (22%); standard care 24/97 (25%)
3. Smoking: HCQ 35/97 (36%); standard care 25/97 (26%)
4. Liver disease: HCQ 0/97; standard care 2/97 (2%)
5. Renal impairment: HCQ 2/97 (2%); standard care 4/97 (4%)
6. "Comorbidities": HCQ 15/97 (15%); standard care 12/97 (12%)
Place of care: inpatients in hospital.
Interventions HCQ group received 400 mg twice daily on day 1, then 200 mg twice daily up to 15 days.
Control group received standard care, without HCQ.
Outcomes Primary endpoint in the report was “percentage of recovery”. This was used for a retrospective power
calculation.
On ClinicalTrials.gov (clinicaltrials.gov/ct2/show/NCT04353336), primary outcomes were:
• number of patients with cure or death;

• number of patients with virological cure.
Note that the only primary outcome on the original registry entry (17 April 2020) was number of pa-
tients with virological cure. No secondary outcomes in registry entry.
Notes Dates of recruitment: March 2020 to June 2020.
Funding and sponsorship: not reported.
Risk of bias
Bias Authors' judgement Support for judgement

Collaboration.
Informed decisions.

Abd-Elsalam 2020 (Continued)
Random sequence genera- Low risk “Computerized random number generator using simple randomization with
tion (selection bias) an equal allocation ratio. During randomization, the proportional allocation of
each clinical stratum was equalized in both groups.” Appropriate method.
Allocation concealment High risk Not reported. Noted more comorbidity, obesity, smoking in HCQ group (al-
(selection bias) though not statistically significant) – this group may have had more risk for
more severe disease. Bias in favour of control.
Blinding of participants Low risk Low for death.

and personnel (perfor-
mance bias) High for length of admission and time to clinical improvement.
All outcomes
No blinding: open-label. Unlikely to influence mortality, but could affect length
of admission (clinician’s decision on this, if a clinical vs protocol/virological de-
cision) and time to clinical improvement.
Blinding of outcome as- Low risk Low for death.

sessment (detection bias)
All outcomes High for length of admission and time to clinical improvement.
No blinding: open-label. Unlikely to influence mortality, but could affect length

of admission and time to clinical improvement.
Incomplete outcome data Unclear risk No report of loss to follow-up, or missing data. No plan reported for imputa-
(attrition bias) tion for missing data. No trial flow diagram.
All outcomes
Selective reporting (re- High risk No detailed protocol provided with the report or found online. 1 outcome (vi-
porting bias) rological response) in registry record not reported in trial report. Other out-
comes (e.g. time to clinical improvement) reported in trial report but not reg-
istry record.

Boulware 2020
Methods Double-blind RCT comparing outcomes in people receiving HCQ as post-exposure prophylaxis vs those
receiving placebo.
Follow-up involved sending participants surveys by email – completed online on REDCap: at days 1, 5,

10, and 14; then at 4 to 6 weeks. “Participants who did not respond to follow-up surveys received text
messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes. When these
methods were unsuccessful, the emergency contact provided by the enrollee was contacted to deter-
mine the participant’s illness and vital status. When all communication methods were exhausted, Inter-
net searches for obituaries were performed to ascertain vital status.”
Participants Setting: community; recruitment via social media.
Number of participants: 821 total: 414 allocated to HCQ; 407 allocated to placebo.
Inclusion criteria: "known exposure (by participant report) to a person with laboratory-confirmed COV-
ID-19, whether as a household contact, a health care worker, or a person with other occupational expo-
sures”. Recruited < 3 days after presumptive-case exposure (17 March); then updated to < 4 days after
confirmed-case exposure (23 March). Exposure was defined as < 6-feet distance, for > 10 minutes, with-
out full personal protection. This was subdivided into high risk (no mask and no eye protection) and
moderate risk (wearing a mask but no eye protection).

Collaboration.
Informed decisions.

Boulware 2020 (Continued)
Exclusion criteria: < 18 years old; hospitalized; symptoms of COVID-19; PCR positive for SARS-CoV-2;
others listed in appendix, such as certain medical conditions and co-medications.
Age: HCQ arm: median 41 years (interquartile range: 33 to 51); placebo arm: median 40 years (interquar-
tile range: 32 to 50).
Sex: HCQ arm female:male 218:196; placebo arm female:male 206:201.
Types of participant: HCQ arm: 275 healthcare workers, 125 household contacts, 14 exposure not re-
ported; placebo arm: 270 healthcare workers, 120 household contacts, 17 exposure not reported.
Definition of development of COVID-19: confirmed: by PCR; probable: “presence of cough, shortness of

breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia,
headache, sore throat, and new olfactory and taste disorders”; possible: “presence of one or more com-
patible symptoms, which could include diarrhoea”. Probable and possible were defined by 4 blinded
physicians.
Comorbidities: HCQ arm (total 414) vs placebo arm (total 407): 4 vs 2 cardiac disease; 51 vs 48 hyper-
tension; 12 vs 16 diabetes mellitus; 1 vs 0 HIV; 2 vs 2 other immunosuppression; 31 vs 31 asthma; 3 vs 0
other chronic lung disease; 1 vs 2 cancer/malignancy; 0 vs 3 chronic kidney disease.
Interventions HCQ “800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for
4 more days for a total course of 5 days (19 tablets total).” Oral; could split doses if developed gastroin-
testinal upset.
Placebo = folate tablets; taken as per the HCQ schedule.
Outcomes Primary – at day 14 from enrolment: development of confirmed or probable COVID-19 (see Participants
for definitions).
Secondary: hospitalization for COVID-19 or death; PCR-confirmed SARS-CoV-2 infection; COVID-19

symptoms; discontinuation of the trial intervention - from any cause; “severity of symptoms (if any) at
days 5 and 14 according to a visual analogue scale (scores ranged from 0 [no symptoms] to 10 [severe
symptoms]).”
Adverse events: directed questioning for common side effects along with open-ended free text.
The authors stated regarding losses to follow-up:
Of the 821 participants who underwent randomization, 96 did not complete the day 14 follow-up sur-
vey, of whom 8 formally withdrew from the trial (4 in each group). Investigators confirmed the vital sta-
tus and lack of infection in 19 participants (10 in the hydroxychloroquine group and 9 in the control
group); 17 completed some follow-up surveys without symptoms before being lost to follow-up (13 in
the hydroxychloroquine group and 4 in the control group). A total of 52 participants never completed
any surveys after enrolment and did not respond to investigators e-mails, text messages, or telephone
calls (23 in the hydroxychloroquine group and 29 in the control group).
Notes Dates of recruitment: 17 March to 6 May 2020
Sponsors/funders: “Supported by David Baszucki and Jan Ellison Baszucki, the Alliance of Minnesota
Chinese Organizations, the Minnesota Chinese Chamber of Commerce, and the University of Minneso-
ta.”
Risk of bias
Random sequence genera- Low risk Permuted-block sequence – variably sized blocks, stratified by country
tion (selection bias)
Allocation concealment Low risk “Randomization will be recorded on an electronic log by the pharmacy. Study
(selection bias) investigators and subjects will be blinded.”

Collaboration.
Informed decisions.

Boulware 2020 (Continued)
Blinding of participants Low risk Blinded participants and investigators – pharmacies that packaged drug were
and personnel (perfor- separate and drug was sent by FedEx. A minority of participants knew what
mance bias) their allocation was for HCQ and placebo.
All outcomes
Blinding of outcome as- Low risk Outcome assessors not in pharmacies, and blinded from allocation sequence.
sessment (detection bias) Outcomes assessed by online survey, then analysed by outcome assessors – so
All outcomes reduced opportunity for outcome data collection to be biased.
Incomplete outcome data Low risk Reasonably low attrition (10% to 11%); similar between groups; similar char-
(attrition bias) acteristics of those lost to follow-up in each group; sensitivity analysis includ-
All outcomes ing these as having events found no difference in primary outcome.
Selective reporting (re- Unclear risk There was a change in the primary outcome, from confirmed COVID-19, to in-
porting bias) clude probable/possible cases. Confirmed also reported separately. Justified
by lack of access to confirmatory testing.

Cavalcanti 2020
Methods 3-arm RCT comparing HCQ with HCQ plus azithromycin and a control group receiving standard care for
treatment of COVID-19. Participants, clinicians, and outcome assessors in hospital were not blinded,
but researchers continuing post-discharge follow-up were. No placebo was used. Follow up to 15 days
post-randomization.
Participants Setting: 55 hospitals in Brazil, mostly Southeast Brazil.
Number of participants: HCQ+AZ 217 (172 in modified ITT); HCQ alone 221 (159 in modified ITT); no
HCQ/AZ 227 (173 in modified ITT).
Inclusion criteria: Hospitalized patients aged 18 or older with suspected or confirmed COVID-19 with
symptom onset fewer that 14 days.
Confirmed COVID-19 was defined as RT-PCR positive from nose and throat swabs. Suspected COVID-19
was defined according to the Brazilian Ministry of Health criteria: patients with fever and at least 1 res-
piratory sign or symptom (cough, shortness of breath, nasal congestion, sore throat, peripheral oxygen
saturation < 95%, cyanosis, dyspnoea); those from an endemic region or travelling from an endemic re-
gion in the last 14 days; or those in contact in the last 14 days with someone with a suspected or con-
firmed COVID-19 diagnosis.
Exclusion criteria:
1. Need for oxygen supplementation > 4 L/min via nasal cannula or ≥ 40% via Venturi mask.
2. Need for oxygen supplementation via high-flow nasal cannula.
3. Need for non-invasive ventilation.
4. Need for invasive mechanical ventilation.
5. Previous use of chloroquine, hydroxychloroquine, azithromycin, or any other macrolide for more than
24 hours before enrolment.
6. History of severe ventricular cardiac arrhythmia or electrocardiogram with QTc ≥ 480 ms.
7. History of liver cirrhosis.
8. Chronic renal failure (eGFR < 30 mL/min/1.73 m2).
9. Known retinopathy or macular degeneration.
10.History of pancreatitis.
11.Less than 18 years of age.
12.Known allergy to chloroquine or hydroxychloroquine.

Collaboration.
Informed decisions.

Cavalcanti 2020 (Continued)
13.Known allergy to azithromycin.
14.Pregnancy or breastfeeding.
Age (years): HCQ+AZ: Mean 49.5 ± 13.4 SD; HCQ alone: Mean 50.1 ± 13.5 SD; no HCQ/AZ: Mean 50.5 ± 14.7
SD.
Sex: HCQ+AZ: female:male 94:123; HCQ alone: female:male 79:142; no HCQ/AZ: female:male 106:123.
COVID-19 disease severity at presentation: Asymptomatic and severe patients excluded; HCQ+AZ: mild:
125/217 (58%); moderate 92/217 (42%); HCQ alone: mild 132/221 (60%); moderate 89/221 (40%); no
HCQ/AZ: mild 130/227 (57%); moderate 97/227 (43%).
Time from symptom onset to randomization: HCQ+AZ: median 7 [IQR 5-9] days; HCQ alone: median 7
[IQR 5-8] days; no HCQ/AZ: median 7 [IQR 4-9] days.
Comorbidities:
1. Heart failure: HCQ+AZ 4/217; HCQ alone 3/221; No HCQ/AZ 3/227

2. Hypertension: HCQ+AZ 81/217; HCQ alone 94/221; No HCQ 83/227
3. Diabetes mellitus: HCQ+AZ 40/217; HCQ alone 47/221; No HCQ/AZ 40/227
4. HIV/AIDS: HCQ+AZ 1/217; HCQ alone 0/221; No HCQ/AZ 3/227
5. Chronic airways disease (asthma or COPD): HCQ+AZ 20/217; HCQ alone 13/221; No HCQ/AZ 19/227
6. Smoking history: HCQ+AZ 17/217; HCQ alone 12/221; No HCQ/AZ 15/227
7. Obesity: HCQ+AZ 29/217; HCQ alone 37/221; No HCQ/AZ 37/227
8. Cancer: HCQ+AZ 7/217; HCQ alone 4/221; No HCQ/AZ 8/227
9. Chronic renal disease: HCQ+AZ 2/217; HCQ alone 1/221; No HCQ/AZ 2/227
Interventions HCQ group received hydroxychloroquine 400 mg orally twice daily for 7 days.
HCQ plus azithromycin group received hydroxychloroquine 400 mg orally twice daily and azithromycin
500 mg orally once daily for 7 days.
Control group received standard care.
Outcomes Primary outcome: clinical status on a 7-point ordinal scale at day 15.
1 - indicated not hospitalized with no limitations on activities;
2 - not hospitalized but with limitations on activities;
3 - hospitalized and not receiving supplemental oxygen;
4 - hospitalized and receiving supplemental oxygen;
5 - hospitalized and receiving oxygen supplementation administered by a high-flow nasal cannula or

non-invasive ventilation;
6 - hospitalized and receiving mechanical ventilation;
7 - death.
Secondary outcomes:
• Clinical status at 7 days on 6-point ordinal scale (points 1 and 2 above combined).
• Receipt of oxygen via high-flow nasal cannula or non-invasive ventilation.
• Indication for intubation within 15 days.
• Duration of hospital stay.
• In-hospital death.

Collaboration.
Informed decisions.

Cavalcanti 2020 (Continued)
• Thromboembolic complications.
• Acute kidney injury.
• Number of days alive and free from respiratory support up to 15 days.
Notes Dates of recruitment: first patient randomized 29 March 2020; the last patient underwent randomiza-
tion on 17 May 2020; follow-up was completed on 2 June 2020.
Funding and sponsorship: the trial was funded by the hospitals and research institutes participating
in Coalition Covid-19 Brazil. EMS Pharma provided additional funding and logistic support for the trial
and also donated and supplied the trial drugs. EMS Pharma had no role in the conduct of the trial, the
analysis, or the decision to submit the manuscript for publication.
Risk of bias
Random sequence genera- Low risk “Randomization was performed in blocks of six and was stratified according
tion (selection bias) to the use or nonuse of supplemental oxygen at the time of randomization.
Randomization was performed centrally by means of an electronic case-report
form system (RedCap) as described in the Supplementary Appendix.”
However, 1 instance of “duplicate randomization” is reported, without further

explanation.
Allocation concealment Low risk “The trial statistician, not involved with patient enrolment or care, generated
(selection bias) the randomization table in R software (R Core Team, 2019) and implemented
in the RedCap. The study treatment was revealed to investigators only after
patients were registered in the RedCap, ensuring proper concealment of the
allocation sequence.”
Blinding of participants Unclear risk Unclear for primary outcome

mance bias) Low for mortality
All outcomes
Unclear for safety outcomes
No blinding of participants and personnel. Some participants in the control

group were given study drugs (12%), and decisions to discharge and institute
respiratory support may have been influenced. The effect of this is unclear for
all outcomes except mortality.
Blinding of outcome as- Low risk Low for primary outcome

All outcomes Low for mortality
Unclear for safety outcomes
Assessors of the primary outcome were blinded, and the ordinal scale mea-
surement was sufficiently objective. Secondary outcomes were also measured
in a predefined objective way, which would minimize risk of bias.
Incomplete outcome data Low risk Low attrition for all outcomes, so lack of imputation for missing values was not
(attrition bias) a problem.
All outcomes
Selective reporting (re- High risk Changes in outcome and analysis approach described, but they occurred after
porting bias) start of participant recruitment, and without adequate explanation provided.
However, sensitivity analysis, ITT approach, and mITT approach do not show a
difference in results.

Collaboration.
Informed decisions.


Chen 2020a
Methods RCT investigating treatment with HCQ vs standard care without HCQ. No blinding or placebo used.
Follow-up: “On the 0th, 3rd, 5th and 7th day of enrolment, the subjects' vital signs, clinical symptoms,
laboratory test results, and adverse events recorded. The study was followed up for 2 weeks.” It was im-
plied that all of this occurred in hospital.
Participants Setting: Shanghai Public Health Clinical Center, Shanghai, China.
Number of participants: 30 randomized: 15 assigned to receive HCQ ("HCQ arm"); 15 assigned to stan-
dard care without HCQ ("standard care arm").
Inclusion criteria:
1. Age ≥ 18 years old

2. Confirmed COVID-19 according to Chinese national guidelines
3. Signed informed consent
Exclusion criteria:
1. Allergy to chloroquine/hydroxychloroquine
2. Pregnancy
3. "Combined heart, lung, kidney, brain, blood, etc. - patients with serious diseases of important organs
and dysfunction"
4. "Retinal diseases, hearing loss or hearing loss"
5. "Serious patients with neurological or psychiatric disorders"
6. "Researchers believe that they cannot complete the study as required or are not suitable to participate
in the research"
Age: HCQ arm: mean 50.5 ± 3.8; standard care arm: mean 46.7 ± 3.6.
Method of diagnosis: not reported; inferred that all had positive RT-PCR on “pharyngeal swabs, spu-
tum, or lower respiratory tract secretions”, as clearance of SARS-CoV-2 from these was the primary out-
come.
Clinical presentation: all 30 participants assumed to have lower respiratory tract disease, due to abnor-
mality on CT chest scan being present for all at baseline.
COVID-19 disease severity at presentation: all 30 participants assumed to have moderate severity, due
to abnormality on CT chest scan prompting classification as moderate severity in the Chinese diagnosis
and treatment guidelines, and exclusion of individuals with severe disease.
Time from symptom onset to enrolment (mean ± standard deviation): HCQ arm: 6.6 ± 3.9 days; stan-
dard care arm: 5.9 ± 4.1 days.
Comorbidities: hypertension in 5/15 HCQ arm participants vs 3/15 standard care; diabetes mellitus in
1/15 HCQ arm participants vs 1/15 standard care.
Place of care: all participants were cared for in hospital.
Interventions HCQ arm: HCQ 400 mg once daily for 5 days. Additionally, all had nebulized interferon alpha; 12/15 had
umifenovir (Arbidol).
Standard care arm: no HCQ; all had nebulized interferon alpha; 10/15 had umifenovir (Arbidol).
2 participants received lopinavir/ritonavir, but it is not reported which group they were in.

Collaboration.
Informed decisions.

Chen 2020a (Continued)
Outcomes Primary: "virological clearance of pharyngeal swabs, sputum, or lower respiratory tract secretions on
day 7 or death"
Secondary: "occurrence of serious adverse drug events within 2 weeks or the subject’s condition
turned severe and critical"
Notes Dates of recruitment: 6 February to 25 February 2020
Sponsors/funders: “Shanghai Science and Technology Commission (20431900103); First-class univer-

sity and first-class discipline construction project of Fudan University (IDF162005) Zhejiang Universi-
ty New Coronavirus Pneumonia Emergency Scientific Research Project (2020XGZX030); Shanghai Pub-
lic Health Clinical Center New Coronavirus '2019-nCoV' scientific research project special project in the
hospital (2020YJKY01); Shanghai key specialty infectious disease project (shslczdzk01102); Haishi 'Med-
ical Garden New Star' Medical Talent Project (2019-72)”
Risk of bias
Random sequence genera- High risk No details reported, but an identical group size with such a small number of
tion (selection bias) participants is suspicious for poorly performing randomization process.
Allocation concealment Unclear risk No details reported.

(selection bias)
Blinding of participants Low risk No blinding, but performance bias unlikely.

mance bias)
All outcomes
Blinding of outcome as- Low risk No blinding, but unlikely to have influenced outcome assessment.
All outcomes
Incomplete outcome data Low risk Data are complete on the primary outcome.
(attrition bias)
All outcomes
Selective reporting (re- High risk The publicly available protocol (clinicaltrials.gov/ct2/show/NCT04261517) re-
porting bias) ports different outcome measures, except for virological clearance at 7 days,
without providing justification.

Chen 2020b
Methods RCT comparing outcomes in participants receiving HCQ vs those not receiving HCQ. Reported to be
double-blind, but no placebo given, and no details reported of methods used to blind participants and
investigators from knowledge of treatment allocation.
Follow-up: clinical assessment of body temperature and cough 3 times a day, until 6 days from enrol-
ment, “or severe adverse reactions appeared”.
Participants Setting: Renmin Hospital of Wuhan University, Wuhan, Hubei province, China (tertiary referral hospi-
tal).

Collaboration.
Informed decisions.

Chen 2020b (Continued)
Number of participants: 62 total: 31 received HCQ ("HCQ arm"); 31 did not receive HCQ ("standard care
arm").
Inclusion criteria: “1. Age ≥ 18 years; 2. Laboratory (RT-PCR) positive of SARS-CoV-2; 3. Chest CT with
pneumonia; 4. SaO2/SPO2 ratio > 93% or PaO2/FiO2 ratio > 300 mmHg under the condition in the hos-
pital room (mild illness); 5. Willing to receive a random assignment to any designated treatment group
and not participating in another study at the same time.”
Exclusion criteria: “1. Severe and critical illness patients or participating in the trial does not meet the
patient's maximum benefit or does not meet any criteria for safe follow-up in the protocol after a doc-
tor’s evaluation; 2. Retinopathy and other retinal diseases; 3. Conduction block and other arrhythmias;
4. Severe liver disease (e.g., Child-Pugh score ≥ C or AST> twice the upper limit); 5. Pregnant or breast-
feeding; 6. Severe renal failure [eGFR ≤ 30 mL/min/1.73m2] or receiving renal replacement therapy; 7.
Possibility of being transferred to another hospital within 72 hours; 8. Received any trial treatment for
COVID-19 within 30 days before this research.”
Age: HCQ arm: mean 44.1 (SD 16.1) years; standard care arm: mean 45.2 (SD 14.7) years.
Method of diagnosis: positive PCR for SARS-CoV-2; specimen type not reported.
Clinical presentation: all had lower respiratory tract disease, as evidenced by pneumonia on chest CT
scan.
COVID-19 disease severity at presentation: all mild.
Comorbidities: not reported.
Interventions HCQ arm: HCQ 200 mg orally twice daily for 5 days.
Standard care arm: no HCQ.
“All received the standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and im-
munoglobulin, with or without corticosteroids)”; no further details reported.
Outcomes Time to clinical recovery: “defined as the return of body temperature and cough relief, maintained for
more than 72 h. Normalization and mitigation criteria included the following: a. Body temperature
≤36.6 °C on the surface, ≤ 37.2 °C under the armpit and mouth or ≤ 37.8 °C in the rectum and tympanic
membrane; b. Cough from patients’ reports, slight or no cough was in the asymptomatic range.” Mea-
sured in 39 patients with fever at enrolment and 37 patients with cough at enrolment.
“For radiological changes, the chest CT results in one day before (Day 0) and one day after (Day 6) the
study for evaluation. Pulmonary recovery is defined as three levels: exacerbated, unchanged, and im-
proved, moderately improved when less than 50 % of pneumonia were absorbed, and more than 50 %
means significantly improved.”
Adverse events (all patients).
Notes Dates of recruitment: 4 February to 28 February 2020
Sponsors/funders: “Funding: This study was supported by the Epidemiological Study of COVID-19

Pneumonia to Science and Technology Department of Hubei Province (2020FCA005).”
This study was available as a preprint ahead of publication at the time of completion of this review.
Risk of bias

Collaboration.
Informed decisions.

Chen 2020b (Continued)
Random sequence genera- Low risk “Randomization was performed through a computer-generated list stratified
tion (selection bias) by site.” Note only 1 hospital site is reported.
Allocation concealment Unclear risk No information reported.

(selection bias)
Blinding of participants High risk Reported as double-blinded: “Neither the research performers nor the pa-
and personnel (perfor- tients were aware of the treatment assignments.”
mance bias)
All outcomes However, oral tablets given, and no placebo given, and no methods describing
blinding of the prescribing clinician, nor what the patients were told about the
tablets they were given.
Blinding of outcome as- High risk Due to the nature of the primary outcome (time to clinical improvement), out-
sessment (detection bias) come assessment could have been influenced by lack of blinding, therefore
All outcomes with no details about blinding methods and no placebo, judged as high risk of
bias.
Incomplete outcome data Low risk Data reported for all participants.
(attrition bias)
All outcomes
Selective reporting (re- High risk Outcomes listed on the trial registry record differ from the reported outcomes,
porting bias) with no predefined methods for the primary outcome reported.

Chen 2020c
Methods Open-label RCT comparing HCQ with standard care without HCQ. No placebo used. Followed up to 14
days.
Participants Setting: 11 public hospitals in northern, central, and southern Taiwan.
Inclusion criteria: “Enrolled patients were aged 20–79 y and confirmed positive for SARS-CoV-2 infec-
tion by real-time reverse transcription polymerase chain reaction (rRT-PCR).”
Exclusion criteria: "Participants presenting with severe illness were excluded from this study. The fol-
lowing patients were excluded from the trial: (a) documented history of hypersensitivity to quinine de-
rivatives; (b) retinal disease; (c) hearing loss; (d) severe neurological or mental illness; (e) pancreati-
tis; (f) lung disease; (g) liver disease (ALT/AST > 3× the normal upper limit); (h) kidney disease (eGFR <
30 mL/min/1.73 m2 according to MDRD or CKD-EPI); (i) haematological disease; (j) ECG screening with
long QT syndrome or QTcF interval > 450 msec for males and > 470 msec for females at screening; (k)
known HIV infection; (l) active hepatitis B or C without concurrent treatment (positive for hepatitis B
[HBsAg and HBeAg] or hepatitis C ribonucleic acid [RNA] titer > 800,000 IU/mL); (m) G6PD; (n) psychi-
atric disorders and alcohol/substance dependence/abuse that may jeopardize patient safety; and (o)
pregnant or breast-feeding women... Patients who had undetected virus within 2-days of hospitaliza-
tion were excluded.”
Age: HCQ arm: mean 33 (SD 12) years; standard care arm: mean 32.8 (SD 8.3) years.
Sex: HCQ arm female:male 10:11; standard care arm female:male 4:8.
Clinical presentation: not reported specifically, but at least 2/21 in the HCQ arm and 2/12 in the stan-
dard care arm had some infiltration of the lungs on imaging of the chest.

Collaboration.
Informed decisions.

Chen 2020c (Continued)
COVID-19 disease severity at presentation: HCQ arm: 19/21 mild, 2/21 moderate; standard care
arm: 10/12 mild, 2/12 moderate.
Comorbidities: not reported.
Place of care: all hospitalized.
Interventions HCQ: 400 mg orally twice daily on day 1, then 200 mg twice daily on days 2 to 7.
Standard care: all participants with moderate disease had “(1) ceftriaxone 2 g daily for 7 days +/-
azithromycin 500 mg on day 1 and 250 mg on days 2–5; or (2) levofloxacin 750 mg daily for 5 d; or (3)
levofloxacin 500 mg daily; or (4) moxifloxacin 400 mg daily for 7–14 days for subjects allergic to ceftriax-
one or azithromycin or according to physician discretion.”
Outcomes Primary: “time to negative rRT-PCR assessments from randomization up to 14 days.”
Secondary:
• negative PCR for SARS-CoV-2 on hospital day 14

• “resolution of clinical symptoms (time to clinical recovery)”
• discharge by day 14
• mortality
“HCQ safety and tolerability were also evaluated.”
Notes Dates of recruitment: 1 April to 31 May 2020.
Sponsors/funders: “The authors thank the Hospital and Social Welfare Organizations Administration
Commission, Ministry of Health and Welfare for their research grant. This funding source played no role
in study design or conduction, data collection, analysis or interpretation, writing of the manuscript, or
decision to submit it for publication. The authors also thank Taiwan Biotech Co. Ltd. for their donation
of investigational products, the National Health Research Institutes, Taiwan Centers for Disease Con-
trol, Taiwan Food and Drug Administration, Center for Drug Evaluation, Taiwan for their technical assis-
tance”
A retrospective study was also conducted, reviewing records of patients preceding the trial. Its results
are not extracted here.
Risk of bias
Random sequence genera- Low risk “randomly assigned by an interactive web response system in a 2:1 ratio to re-
tion (selection bias) ceive either HCQ plus standard of care (SOC) or SOC alone. They were stratified
by mild or moderate illnesses within 4 days of diagnosis.”
Allocation concealment Unclear risk No allocation sequence concealment reported.

(selection bias)
Blinding of participants Low risk Low for time to negative PCR, negative PCR on day 14, and mortality.
mance bias) High for discharge by day 14 and adverse events.
All outcomes
Unclear for time to clinical recovery.
No blinding. Unlikely effect on time to negative PCR, negative PCR on day 14,
or mortality. High risk of bias for discharge and adverse events. Unclear risk of
bias for time to clinical recovery – no methods reported for how this was deter-
mined.

Collaboration.
Informed decisions.

Chen 2020c (Continued)
Blinding of outcome as- Low risk Low for time to negative PCR, negative PCR on day 14, and mortality.
All outcomes High for discharge by day 14, time to clinical recovery and adverse events.
No blinding. Unlikely effect on time to negative PCR, negative PCR on day 14,
or mortality. High risk of bias for discharge by day 14, adverse events, and time
to clinical recovery.
Incomplete outcome data High risk Attrition of ~10% (3/33) before first dose of HCQ (1/21 HCQ arm; 2/12 standard
(attrition bias) of care arm), with no reason or characteristics reported. Imputation of PCR re-
All outcomes sults not available as negative results, with no sensitivity analysis, nor report-
ing of how much missing data there were for each outcome. With such a small
sample size, effect may be influenced by this degree of missing data.
Selective reporting (re- High risk No trial protocol is available. Clinical efficacy outcomes were not reported in
porting bias) the trial registry entry (clinicaltrials.gov/ct2/show/record/NCT04384380); only
virological outcomes (time to negative PCR = primary) and adverse events list-
ed.

Davoodi 2020
Methods Open-label RCT comparing HCQ with febuxostat. No placebo.
Followed up to 14 days.
Participants Setting: outpatients at Mostafavian Fever Clinic in Sari, Iran.
Number of participants: 54 total: 25 received HCQ; 29 received febuxostat.
Inclusion criteria: “1; chest CT finding compatible with COVID-19 infection along with other symptoms
of coronavirus infection. Bilateral and peripheral ground-glass and consolidative pulmonary opacities
were the hallmarks of CT findings. 2; any symptoms of respiratory tract involvement including cough,
dyspnoea or tachypnoea along with a history of contact with a known case of COVID-19. 3; creatinine
clearance greater than 60 mL/min.”
Exclusion criteria: “1; Suspicious patients for COVID-19 pneumonia who had severe underlying diseases
such as cardiovascular, lung and kidney diseases, 2; patients with severe pneumonia needing hospital-
isation, 3; patient who were unable to take oral medications and 4; concurrent use of azathioprine, di-
danosine, mercaptopurine or pegloticase (due to drug interaction with febuxostat).”
Age: HCQ arm: mean 57.3 (standard error 2.2) years; febuxostat arm: mean 58 (standard error 1.47)
years.
Sex: HCQ arm female:male 9:16; febuxostat arm female:male 13:16.
Method of diagnosis: based on CT scan and symptoms, as in inclusion criteria above.
Clinical presentation: not specifically reported, but all had some lung abnormalities on CT chest scan.
COVID-19 disease severity at presentation: presumed to all have moderate disease based on WHO clas-
sification: all had pneumonia on CT.
Comorbidities: 7/25 in the HCQ arm and 8/29 in the febuxostat arm had diabetes mellitus; 1/25 in the
HCQ arm and 0/29 in the febuxostat arm had underlying lung disease.
Place of care: ambulatory care.

Collaboration.
Informed decisions.

Davoodi 2020 (Continued)
Interventions HCQ: 200 mg orally twice daily for 5 days.
Febuxostat: 80 mg orally once daily for 5 days.
“All patients were taken acetaminophen [paracetamol] 325 mg, as needed, for controlling the fever.”
No other co-interventions reported.
Outcomes Primary: need for hospitalization.
Secondary:
• “clinical improvements (eg, resolution of fever, cough and dyspnoea)”; and

• “improvement of CT findings”
at day 14 after initiation of the treatment.
Notes Dates of recruitment: 16 March to 10 April 2020.
Sponsors/funders: “This study was supported by a grant from Mazandaran University of Medical

Science, Sari, Iran (ID#7294).”
Febuxostat was the intervention drug of interest for this trial; HCQ was an active comparator.
Risk of bias
Random sequence genera- Unclear risk No description beyond “randomised using the balance block method”.
Allocation concealment Low risk "The patient receives the medication (intervention or comparison) in sealed
(selection bias) envelopes that are coded. The coding is done by a project colleague and the
physician, assessor and patient are blind.”
Blinding of participants High risk High for hospitalization (primary) and clinical improvement
mance bias) Low for improvement of CT scan
All outcomes
Reported as open-label, but also states: “Both patients and physician did not
know the contents of tables [tablets].”
No measures for blinding described, and the interventions had different fre-
quencies of administration.
If assumed to be open-label, hospitalization and clinical improvement would

be at high risk of performance bias. Improvement of CT scan findings would be
at low risk of performance bias.
Blinding of outcome as- Low risk Low for hospitalization (primary) and improvement of CT scan
All outcomes High for clinical improvement
Reported as open-label, but also states: “Both patients and physician did not
know the contents of tables [tablets].”
No measures for blinding described, and the interventions had different fre-
quencies of administration.
If assumed to be open-label, clinical improvement would be at high risk of de-

tection bias. Hospitalization and improvement of CT scan findings would be at
low risk of detection bias.

Collaboration.
Informed decisions.

Davoodi 2020 (Continued)
Incomplete outcome data High risk No outcome data used for 5/30 participants randomized to HCQ arm and 1/30
(attrition bias) to febuxostat arm. Reasons provided, but neither baseline characteristics nor
All outcomes outcomes reported, and no imputation performed for these participants. With
small total trial numbers, and possibility of some participants not having re-
mained in trial due to poor outcomes, we judged this domain as high risk.
Selective reporting (re- High risk In registry record, outcomes: CT scan findings (primary), fever, lymphocyte
porting bias) count, CRP.
In report: hospitalization (primary), “clinical improvements (eg, resolution of

fever, cough and dyspnoea)”, “improvement of CT findings”.
No reason given for change in outcomes, especially primary outcome.

Horby 2020
Methods Adaptive factorial design RCT (RECOVERY) comparing a HCQ with standard of care (SOC) in patients
hospitalized with COVID-19. The RECOVERY trial evaluated several treatments, of which only HCQ was
relevant for this review. Centralized web-based randomization was done. There was no blinding of par-
ticipants or personnel.
Follow-up: Data were collected at time of death, discharge, or 28 days after randomization. Data were
available for 98% of participants for the 28-day follow-up.
Participants Setting: UK National Health Service (NHS) hospitals - secondary and tertiary facilities (176 in total)
Number of participants: 4674 total: 1542 received HCQ; 3132 received SOC
Inclusion criteria: hospitalized AND SARS-CoV-2 infection (clinically suspected or laboratory confirmed)

AND without a medical history that might, in the opinion of the attending clinician, put the patient at
significant risk if he/she were to participate in the trial.
Exclusion criteria: only those 18 years and above were eligible, until 9 May after which children were in-
cluded. Exclusions included those with known prolonged electrocardiograph QTc interval. Co-adminis-
tration with medications that prolong the QT interval was not an absolute contraindication, but attend-
ing clinicians were advised to check the QT interval by performing an electrocardiogram.
Method of diagnosis: clinically suspected or laboratory confirmed were included. Clinical suspicion

was suspected when a patient presented with (i) typical symptoms (e.g. influenza-like illness with fever
and muscle pain, or respiratory illness with cough and shortness of breath); and (ii) compatible chest X-
ray findings (consolidation or ground-glass shadowing); and (iii) alternative causes have been consid-
ered unlikely or excluded (e.g. heart failure, influenza). Method of laboratory testing not specifically de-
scribed, but antibody testing not used in most UK hospitals.
HCQ: positive "SARS-COV-2 test": 1393 (89%); negative 153 (10%); unknown 15 (1%). SOC: positive
"SARS-COV-2 test": 2841 (90%); negative 291 (9%); unknown 23 (1%).
A small number of children (age < 18 years old) presented with atypical features, including a hyperin-
flammatory state and evidence of single or multi-organ dysfunction. Some did not have significant lung
involvement.
Clinical presentation: not specifically reported, but 77% (HCQ) vs 76% (SOC) were receiving oxygen or
invasive ventilation at enrolment.

Collaboration.
Informed decisions.

Horby 2020 (Continued)
COVID-19 disease severity at presentation:
HCQ: no oxygen received 362 (23%); received oxygen: 938 (60%); invasive ventilation 261 (17%).
SOC: no oxygen received 750 (24%); received oxygen: 1873 (59%); invasive ventilation 532 (17%).
Time from symptom onset to enrolment: HCQ: median 9 days (IQR 5 to 14); SOC: median 9 days (IQR 5
to 13); this is presumed to be time from symptom onset to randomization, not to hospital presentation.
Comorbidities:
1. cardiac disease (such as coronary artery disease or heart failure): HCQ: 422 (27%) and SOC: 789 (25%);
2. diabetes mellitus: HCQ: 427 (27%) and SOC: 856 (27%);
3. HIV: HCQ: 8 and SOC: 13;
4. chronic airways disease (asthma, COPD): HCQ: 334 (21%) and SOC: 712 (23%);
5. severe liver disease: HCQ: 18 (1%) and SOC: 46 (1%);
6. severe kidney impairment: HCQ: 111 (7%) and SOC: 261 (8%);
7. tuberculosis: HCQ: 4 and SOC: 9.
Interventions Oral formulation of HCQ given at dosage of 800 mg at 0 and 6 hours, then 400 mg at 12 hours from first
dose and every 12 hourly for 10 days.
Outcomes Primary outcome: all-cause mortality at 28 days after randomization.
Secondary outcomes:
• duration of hospital stay

• need for (and duration of) ventilation
• composite endpoint of death or need for mechanical ventilation/ECMO
• need for renal replacement therapy
• new major cardiac arrhythmias
Regarding major new cardiac arrhythmia, data were collected for 698 (44.7%) patients in the HCQ arm
and 1357 (43.0%) in the SOC arm; supraventricular tachycardia was observed in 6.9% HCQ participants
vs 5.9% SOC; ventricular tachycardia or fibrillation in 0.9% HCQ vs 0.7% SOC; and atrioventricular block
requiring intervention in 0.1% HCQ vs 0.1% SOC. No other data regarding adverse events provided.
Notes Dates of recruitment: 25 March to 5 June 2020
Sponsors/funders: Nuffield Department of Population Health at University of Oxford. The RECOVERY

trial is supported by a grant to the University of Oxford from UK Research and Innovation/National In-
stitute for Health Research (NIHR) (Grant reference: MC_PC_19056) and by core funding provided by
NIHR Oxford Biomedical Research Centre, Wellcome, the Bill and Melinda Gates Foundation, the De-
partment for International Development, Health Data Research UK, the Medical Research Council Pop-
ulation Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections,
and NIHR Clinical Trials Unit Support Funding.
This study was available as a preprint ahead of publication at the time of completion of this review.
Risk of bias
Random sequence genera- Low risk “central web-based randomisation service (without stratification or minimisa-
tion (selection bias) tion)”
Allocation concealment Low risk Handled centrally, so unlikely.

(selection bias)

Collaboration.
Informed decisions.

Horby 2020 (Continued)
Blinding of participants Low risk No blinding used.
mance bias) Clinicians could decide eligibility for each arm of the trial on an individual ba-
All outcomes sis, which could lead to systematic bias in comparability of the 2 groups; how-
ever, due to the comparison for each intervention being with controls who
were eligible for that intervention, and this is pre-randomization, it is unlikely
to lead to a high risk of bias.
Blinding of outcome as- Low risk Low for death and invasive ventilation
All outcomes Unclear for discharge
Unlikely to influence mortality or need for invasive ventilation, but unclear ef-
fect on discharge decision.
Incomplete outcome data Low risk Follow-up data available for 98% of participants.
(attrition bias)
All outcomes
Selective reporting (re- Low risk Low for all outcomes, except unclear for time to discharge and adverse events.
porting bias)
Reported outcomes decided a priori. Insufficient detail of time to discharge
and adverse events. However, this is a preprint, so further details may become
available.

Huang 2020
Methods RCT comparing outcomes in participants receiving CQ with those receiving lopinavir/ritonavir (LPV/r).
Blinding not reported.
Participants had daily clinical data collection and nasopharyngeal swab PCR for SARS-CoV-2. They had
follow-up CT chest scans (unclear frequency). Outcomes were reported to be measured up to 14 days.
Participants Setting: Fifth Affiliated Hospital of Sun Yat-sen University in Zhuhai, China.
Number of participants: 22 total: 10 received CQ; 12 received LPV/r.
Inclusion criteria: age ≥ 18 years old; hospitalized; positive PCR for SARS-CoV-2.
Exclusion criteria: “1. Pregnant woman patients; 2. Documented allergic history to Chloroquine; 3. Doc-
umented history of hematological system diseases; 4. Documented history of chronic liver and kidney
diseases; 5. Documented history of cardiac arrhythmia or chronic heart diseases; 6. Documented histo-
ry of retina or hearing dysfunction; 7. Documented history of mental illnesses; 8. Use of digitalis due to
the previous disease.”
Age: CQ arm: median 41.5 (IQR 33.8 to 50.0) years; LPV/r arm: median 53.0 (IQR 41.8 to 63.5) years.
Sex: CQ arm female:male 3:7; LPV/r arm female:male 6:6.
Clinical presentation: not reported specifically, but at least 8/10 in the CQ arm and 11/12 in the LPV/r
arm had some abnormalities on CT chest scan.
COVID-19 disease severity at presentation: CQ arm: 7/10 moderate, 3/10 severe; LPV/r arm: 7/12 moder-
ate, 5/12 severe.

Collaboration.
Informed decisions.

Huang 2020 (Continued)
Time from symptom onset to enrolment: CQ arm: median 2.5 (IQR 2 to 3.75) days; LPV/r arm: medi-
an 6.5 (4.75 to 8.5) days.
Comorbidities: 1/10 in the CQ arm and 3/12 in the LPV/r arm had hypertension; 0 in the CQ arm and
1/12 in the LPV/r arm had history of stroke/cerebrovascular disease; 1/10 in the CQ arm and 1/12 in the
LPV/r arm had diabetes mellitus; 2/10 in the CQ arm and 0 in the LPV/r had a history of smoking.
Place of care: all inpatients in hospital.
Interventions CQ: 500 mg orally twice daily for 10 days.
LPV/r: 400/100 mg orally twice daily for 10 days.
No other co-interventions reported.
Outcomes Primary outcome: time to conversion of SARS-CoV-2 PCR on nasal and pharyngeal swab samples from
positive to negative, and proportion (reported as "rate") negative at day 10 and day 14.
Secondary outcomes: “rate of hospital discharge at Day 14, clinical recovery at day 10, CT scan im-
provement at Day 10 and 14, and the frequency of adverse events. The criteria of clinical recovery
were: no fever, axilla temperature ≤36.6°C or oral temperature ≤37.2°C or rectal/tympanic temperature
≤37.8°C; respiratory rate ≤24/minute on room air; oxygen saturation >94% on room air; mild or absent
of cough (the scale of cough is classified as severe, moderate, mild, absent). The criteria of hospital dis-
charge were: the temperature returned to normal for more than 3 days; the respiratory symptoms im-
proved significantly; the pulmonary imaging showed that the inflammation was obviously absorbed;
and the detection of respiratory pathogenic nucleic acid was negative twice in a row (the sampling time
is at least 1 day apart). The criteria of CT scan improvement were: exudation or consolidation of the le-
sion absorbed; the lesion area was gradually narrowed; and there might be residual linear fibrosis.”
Notes Dates of recruitment: 27 January to 15 February 2020.
Sponsors/funders: not reported.
Risk of bias
Random sequence genera- High risk No information about method of randomization in trial report, however base-
tion (selection bias) line differences seem significant for duration of symptoms prior to hospital ad-
mission, age, baseline severity, and baseline radiographic characteristics. The
trial registry protocol states that the study is non-randomized.
Allocation concealment Unclear risk No information reported.

(selection bias)
Blinding of participants Low risk No blinding, but low risk of performance bias.
mance bias)
All outcomes
Blinding of outcome as- Low risk No blinding, and little detail on assessment of outcome, so although possi-
sessment (detection bias) ble, it is unlikely that interpretation of the result may have been influenced by
All outcomes knowledge of treatment received.
Incomplete outcome data Low risk Complete data for all participants.
(attrition bias)
All outcomes
Selective reporting (re- High risk Protocol on the trials registry (ChiCTR2000029542) lists different outcomes
porting bias) from protocol in the article supplement.

Collaboration.
Informed decisions.


Mitjà 2020a
Methods RCT evaluating early treatment of mild COVID-19 with HCQ compared to standard of care (SOC)
Follow up: on day 1, patients were visited at home for baseline assessment and participant enrolment.
Outbreak field teams verified the selection criteria for eligibility, obtained patients’ signed informed
consent, assessed specific symptoms associated with COVID-19, and collected relevant epidemiologi-
cal information from a structured interview. Disease progression, safety, and self-reported treatment
compliance were monitored by the Clinical Trials Unit of Hospital Germans Trias Pujol at days 3 and 7
(home visits), 14 and 28 (telephone reviews).
Participants Setting: participants identified via an electronic registry of the Epidemiological Surveillance Emergency
Service of Catalonia (SUVEC) of the National Department of Health, from 3 health administrative re-
gions in Catalonia, Spain. They were managed at home, not hospitalized.
Number of participants: 293 total: 136 allocated to HCQ; 157 allocated to standard of care.
Inclusion criteria: adult patients aged 18 years or more were eligible if they had mild symptoms of COV-
ID-19 (i.e. fever, acute cough, shortness of breath, sudden olfactory or gustatory loss, or influenza-like
illness) for less than 5 days before enrolment, were non-hospitalized, and had a positive PCR test for
SARS-CoV-2 in the baseline nasopharyngeal swab.
Exclusion criteria: moderate-to-severe COVID-19 disease (e.g. required hospitalization), any condition

that might preclude following the study procedures safely (e.g. mental disability), known allergy or
hypersensitivity to study drugs, known retinal and severe liver or renal diseases, history of cardiac ar-
rhythmia, known QT prolongation or other diseases that could be exacerbated by study drugs (e.g. pso-
riasis), active treatment with medications that are contraindicated with study drugs, or known HIV in-
fection. Females who were pregnant (verbally declared or positive pregnancy test) or breastfeeding
were also excluded.
Age: HCQ arm: mean 41.6 years (SD 12.4); control arm: mean 41.7 years (SD 12.6).
Sex: HCQ arm female:male 98:38; standard of care arm female:male 103:54.
Types of participant: HCQ arm: 106 healthcare workers, 4 household contacts, 8 nursing home workers,
18 exposure not reported; control arm: 132 healthcare workers, 1 household contacts, 8 nursing home
workers, 16 exposure not reported.
Severity on presentation: not reported.
Time from symptom onset to presentation: all < 5 days by definition; however, note that 4 reported > 5
days symptoms, but duration not reported.
Definition of development of COVID-19: positive PCR on nasopharyngeal swab
Comorbidities:
1. cardiac disease (such as coronary artery disease or heart failure): HCQ: 20 (14.7%) and SOC: 15 (9.6%);
2. chronic airways disease (asthma, COPD): HCQ: 7 (5%) and SOC: 10 (6%);
3. metabolic disease: HCQ: 9 (6.6%) and SOC: 11 (9%);
4. nervous system disease: HCQ: 19 (14%) and SOC: 21 (13.4%);
5. any co-existing disease: HCQ: 71 (52.2%) and SOC: 85 (54.1%).
Care setting: home-based care
Interventions Intervention group received oral dose of HCQ 800 mg on day 1, followed by 400 mg daily for a further
6 days (total duration of treatment 7 days).
Comparator group received standard of care.

Collaboration.
Informed decisions.

Mitjà 2020a (Continued)
Outcomes Primary: reduction of viral RNA load in nasopharyngeal swabs at days 3 and 7 after start of treatment.
Secondary: clinical progression measured by a simplified version of the WHO progression scale (1, not
hospitalized with or without resumption of normal activities; 2, hospitalized, requiring supplemental
oxygen; 3, hospitalized, requiring invasive mechanical ventilation; and 4, death); time from randomiza-
tion to complete resolution of symptoms within the 28-day follow-up period.
Resolution of symptoms was assessed sequentially using a symptoms questionnaire designed to gath-
er information on the type of symptom and last day experienced; complete resolution was considered
when no COVID-19-related symptoms were reported.
Safety outcomes: adverse events occurring during treatment, serious adverse events, adverse events of
special interest (i.e. cardiac), and premature discontinuation of therapy.
Notes Recruitment: 17 March to 26 May 2020
Sponsor/ funding: mainly supported by the crowdfunding campaign JoEmCorono (www.yomecoro-

no.com/) with the contribution of over 72,000 citizens and corporations. The study also received finan-
cial support from Laboratorios Rubió, Laboratorios Gebro Pharma, Zurich Seguros, SYNLAB Barcelona,
and Generalitat de Catalunya. Laboratorios Rubió also contributed to the study with the required doses
of hydroxychloroquine (Dolquine).
Risk of bias
Random sequence genera- Low risk “Participants were randomized (1:1) using a computer-generated ran-
tion (selection bias) dom-number list”
Allocation concealment Unclear risk Insufficient detail provided.

(selection bias)
Blinding of participants Low risk Low for viral load reduction at 3 days and 7 days.
mance bias) High for admission to hospital, time to clinical improvement, and adverse
All outcomes events.
“Laboratory technicians were unaware of participants’ treatment allocation,

treatment response, and previous PCR results at all time points.”
None for participants or investigators (i.e. open-label).
Outcomes not affected by lack of blinding: viral load reduction at 3 days and 7
days.
Outcomes prone to lack of blinding: admission to hospital and adverse events.
Blinding of outcome as- Low risk Low for viral load reduction at 3 days and 7 days.
All outcomes High for admission to hospital, time to clinical improvement, and adverse
events.
“Laboratory technicians were unaware of participants’ treatment allocation,

treatment response, and previous PCR results at all time points.”
None for participants or investigators (i.e. open-label).
Outcomes not affected by lack of blinding: viral load reduction at 3 days and 7
days.
Outcomes prone to lack of blinding: admission to hospital and adverse events.

Collaboration.
Informed decisions.

Mitjà 2020a (Continued)
Incomplete outcome data High risk Low attrition numbers labelled as "lost to follow up", and 2 further participants
(attrition bias) withdrew consent without explanation. Denominators very unclear (e.g. 291 vs
All outcomes 293).
Selective reporting (re- High risk Reported to be a secondary trial within this combined postexposure prophy-
porting bias) laxis and treatment trial (clinicaltrials.gov/ct2/show/NCT04304053). Not re-
ported clearly in article how many participants were contacts vs index cases.
Virological clearance at 3 days reported in ClinicalTrials.gov registry record,
but not reported in trial report. Also ClinicalTrials.gov record does not report
the ordinal outcome scale used in the report (which is not standard e.g. WHO).
Other bias High risk A small number of participants were randomized who were in fact not eligi-
ble for the trial; however, these participants were kept in the ITT population,
which could have introduced bias.

Mitjà 2020b
Methods Open-label cluster-randomized trial comparing HCQ with standard care when given to individuals with
a history of exposure to SARS-CoV-2, for prevention of COVID-19.
Follow-up was up to day 28, using in-person visits to the participant's home on days 1 and 14, and tele-
phone interviews on days 3, 7, and 28.
Participants Setting: community; “screened using the electronic registry of the Epidemiological Surveillance Emer-
gency Service of Catalonia (SUVEC) of the Department of Health. During the COVID-19 outbreak in Cat-
alonia, a public health ordinance required all patients who tested positive for COVID-19 in any of the
designated diagnostic laboratories to be notified to the SUVEC.”
Number of participants: 2525 total: 1225 allocated to HCQ; 1300 allocated to standard care. (Note
that baseline characteristics and efficacy outcomes use a modified ITT population as their denomina-
tor: 1116 HCQ; 1198 standard care. Adverse events are reported for all randomized participants: 1225
HCQ; 1300 standard care.)
Inclusion criteria: “adult individuals ≥ 18 years of age with a recent history of close contact exposure
to a PCR confirmed COVID-19 case (i.e., > 15 minutes within two meters, up to seven days before en-
rolment) and absence of COVID-19-like symptoms on the two weeks preceding enrolment, as either a
healthcare worker, a household contact, a nursing home worker or a nursing home resident.”
Exclusion criteria: symptoms or signs of COVID-19 at baseline assessment; “all eligibility criteria are list-
ed in the Supplementary Appendix.” (No appendix was available with the preprint publication.)
Gender: HCQ arm F:M 813:303; standard care arm F:M 875:323.
Types of participant: HCQ arm: 131 (12%) healthcare workers; 302 (27%) household contacts; 550 (49%)
nursing home workers; 133 (12%) nursing home residents. Standard care arm: 130 (11%) healthcare
workers; 338 (28%) household contacts; 584 (49%) nursing home workers; 160 (13%) nursing home res-
idents. (Note that the denominator for the standard care arm is 1212 rather than 1198.)
Definition of development of COVID-19: "confirmed COVID-19 episode, defined as symptomatic ill-

ness (at least one of the following symptoms: fever, cough, difficulty breathing, myalgia, headache,
sore throat, new olfactory and taste disorder(s), or diarrhoea) and a positive SARS-CoV-2 RT-PCR test";
“SARS-CoV-2 infection, defined as either the RT-PCR detection of SARS-CoV-2 in a nasopharyngeal spec-
imen or the presence of any of the aforementioned symptoms compatible with COVID-19”.
Comorbidities:

Collaboration.
Informed decisions.

Mitjà 2020b (Continued)
1. cardiovascular disease: HCQ: 130 (11.6%) and standard care: 178 (14.9%);
2. respiratory disease: HCQ: 64 (5.7%) and standard care: 47 (3.9%);
3. metabolic disease: HCQ: 99 (8.9%) and standard care: 94 (7.8%);
4. nervous system disease: HCQ: 170 (15.2%) and standard care: 170 (14.2%).
Interventions HCQ: 800 mg orally on day 1, followed by 400 mg once daily for 6 days. Total 7 days.
Standard care: no treatment.
Co-interventions not reported.
Outcomes Primary outcome: “confirmed COVID-19 episode, defined as symptomatic illness (at least one of the
following symptoms: fever, cough, difficulty breathing, myalgia, headache, sore throat, new olfactory
and taste disorder(s), or diarrhoea) and a positive SARS-CoV-2 RT-PCR test. The primary outcome was
assessed in all asymptomatic individuals, irrespective of the PCR result; in a post hoc analysis, we ex-
plored the outcome in individuals with positive and negative PCR separately. Time-to-event was de-
fined as the number of days from the date of randomization/exposure to the confirmed date of the on-
set of symptomatic illness.”
Secondary efficacy outcomes:
• “incidence of SARS-CoV-2 infection, defined as either the RT-PCR detection of SARS-CoV-2 in a na-
sopharyngeal specimen or the presence of any of the aforementioned symptoms compatible with
COVID-19”
• “serological positivity (IgM/IgG) of contacts at day 14”
Safety outcomes: “frequency and severity of adverse events (AE), serious AE (SAE), and AE of special in-
terest (e.g., cardiac) up to 28 days from treatment start. Causality was assessed by an external panel of
pharmacovigilance consultants.” (Note that this included death and hospitalization.)
Notes Recruitment: 17 March to 28 April 2020.
Sponsor/funding: "mainly supported by the crowdfunding campaign JoEmCorono (https://www.y-

omecorono.com/) with the contribution of over 72,000 citizens and corporations. The study also re-
ceived financial support from Laboratorios Rubió, Gebro Pharma, Zurich Seguros, SYNLAB Barcelona,
and Generalitat de Catalunya. Laboratorios Rubió also contributed to the study with the required doses
of hydroxychloroquine (Dolquine®).”
Note that LR and GP are pharmaceutical companies. No mention of their involvement in the study, or
lack thereof.
Risk of bias
Random sequence genera- Unclear risk “Randomization was performed remotely by a member of the study team not
tion (selection bias) involved in participants’ enrollment.”
No description of sequence generation method.
Allocation concealment Unclear risk “Randomization was performed remotely by a member of the study team not
(selection bias) involved in participants’ enrollment… The allocation was revealed to partici-
pants after providing written consent on day 1 (baseline).”
Blinding of participants High risk High for symptomatic confirmed COVID-19 (primary outcome) and adverse
and personnel (perfor- events.
mance bias)
All outcomes Low for antibody positivity.
Open-label study. Due to symptoms being required to define primary out-

come, this would be at high risk of bias due to lack of blinding, as would safe-

Collaboration.
Informed decisions.

Mitjà 2020b (Continued)
ty outcomes. Antibody positivity at day 14 would not be influenced by knowl-
edge of group allocation.
Blinding of outcome as- High risk High for symptomatic confirmed COVID-19 (primary outcome); composite
sessment (detection bias) symptoms without PCR positivity OR PCR-positive asymptomatic COVID-19;
All outcomes and adverse events.
Low for antibody positivity and death.
No blinding. As above, due to symptoms being required to define primary out-

come, this would be at high risk of bias due to lack of blinding, as would safe-
ty outcomes. Antibody positivity at day 14/death would not be influenced by
knowledge of group allocation.
Incomplete outcome data Low risk Low for efficacy outcomes.

(attrition bias)
All outcomes Unclear for adverse events.
Exclusions from "intention-to-treat (ITT)" (assessed as modified ITT; prima-

ry analysis) were < 10%; reasons were reported, and loss to follow-up was <
5%. Numbers seemed to be balanced between the 2 treatment arms. Compar-
ison of characteristics between those included vs excluded not presented in
preprint. This applies to all efficacy outcomes. There was no imputation for
missing data.
The safety sample included all randomized participants, so there was low risk
of bias for the outcomes of adverse events and death. < 3% of participants ei-
ther did not receive HCQ in the HCQ arm or started HCQ in the control arm.
However, denominators were unclear: 1197 vs 1225 in the intervention arm.
Selective reporting (re- High risk Both of the outcomes currently specified in the trial registry entry (clinicaltrial-
porting bias) s.gov/ct2/show/NCT04304053) were included in the report.
However, disease in contacts of contacts was also specified and is not report-
ed, with no reason provided.
Other bias High risk Additional domains for cluster-RCTs:
Recruitment bias: low risk. Appears unlikely, as the rings (clusters) were ran-
domized first, and then the contacts were told their allocation.
Baseline imbalance: low risk. No stratified or pair-matched randomization.

Baseline characteristics not disaggregated by cluster. But many clusters, so
unlikely to lead to baseline imbalance.
Loss of clusters: low risk. No clusters lost.
Incorrect analysis: low risk. The analysis accounted for clustering.
Comparability with individually randomized trials: high risk. Contamination-

possible, as this was an open-label study, and people within clusters may en-
courage differential adherence to intervention. However, reported adherence
was > 95%. This intervention would be expected to work best when given to
all contacts of a case rather than some being randomized to the intervention
and some randomized to no intervention, which would preclude comparabili-
ty with an individually randomized trial.


Collaboration.
Informed decisions.

Pan 2020
Methods Adaptive open-label RCT comparing multiple different experimental pharmaceutical interventions vs
standard care. Participants in treatment arms were compared only with those eligible for that treat-
ment but that were randomized to standard care. No placebo used.
Followed up to hospital discharge.
Participants Setting: hospitals in 30 countries in all 6 WHO regions; ~60% of participants recruited in Africa/Asia.
Number of participants: 1853 total: 947 received HCQ; 906 received standard care.
Inclusion criteria: hospitalized adults (> 18 years old) with confirmed COVID-19, receiving any treatment
other than the study drugs, with no contraindications to any study drug, and no transfer planned with-
in the subsequent 72 hours.
Exclusion criteria: "1. Any of the available study drugs are contra-indicated (e.g. because of patient
characteristics, chronic liver or heart disease, or some concurrent medication).
2. Declined to participate in the study."
Note that an initial exclusion criterion was pregnancy, but this was removed early in the trial.
Age: HCQ arm: 335 participants (< 50 years), 410 (50 to 69 years), 202 (≥ 70 years); standard care arm:
317 participants (< 50 years), 396 (50 to 69 years), 193 (≥ 70 years).
Method of diagnosis: not reported, but presumed PCR positivity due to "confirmed" inclusion criterion
and WHO-sponsored study.
COVID-19 disease severity at presentation: HCQ: 862/947 moderate or severe (of whom 517 were re-
ceiving oxygen at randomization), 85 critical; standard care: 824/906 moderate or severe (of whom 483
were receiving oxygen at randomization), 82 critical.
Comorbidities:
1. cardiac disease: HCQ: 193/947 and standard care: 194/906;

2. diabetes mellitus: HCQ: 199/947 and standard care: 194/906;
3. chronic lung disease: HCQ: 62/947 and standard care: 66/906;
4. chronic liver disease: HCQ: 15/947 and standard care: 14/947;
5. asthma: HCQ: 41/947 and standard care: 46/906.
Interventions HCQ: 800 mg orally at 0 and 6 hours, then 400 mg twice daily from 12 hours onwards, for a total of 10
days.
Standard care: any drugs that were not part of the study.
Co-interventions not reported.
Outcomes Primary: all-cause death in hospital.
Secondary:
• Initiation of ventilation (initial on protocol as on 16 October 2020: “Time to first receiving ventilation
(or intensive care)”).
• Time to discharge from hospital.

Collaboration.
Informed decisions.

Pan 2020 (Continued)
Notes Dates of recruitment: 22 March to 4 October 2020 for whole report, from which data were extracted;
HCQ arm stopped on 18 June 2020.
Sponsors/funders: drugs donated by drug companies; WHO and national governments shared sponsor-

ship.
Details of the trial results were taken from a preprint publication.
Risk of bias
Random sequence genera- Low risk Centralized computer generated.

Allocation concealment Unclear risk Not reported.

(selection bias)
Blinding of participants Low risk No blinding, but unlikely to lead to performance bias for death.
mance bias)
All outcomes
Blinding of outcome as- Low risk No blinding, but unlikely to affect outcome assessment for death.
All outcomes
Incomplete outcome data Low risk Near-complete data for death outcome.
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Preprint with not all outcomes reported, and 1 changed between protocol and
porting bias) report with no reason provided (www.isrctn.com/ISRCTN83971151, accessed
16 October 2020).

Skipper 2020
Methods RCT comparing outcomes in people receiving HCQ for prophylaxis vs those receiving placebo for pre-
vention of COVID-19.
Follow-up: participants were sent surveys by email on days 1 (medication start date), 3, 5 (medication
stop date), 10, and 14 to assess medication adherence, adverse effects, presence and severity of COV-
ID-19 symptoms, COVID-19 test results, and hospitalization status. If participants were hospitalized, fol-
low-up continued to assess outcomes.
Participants Setting: community; recruitment via social media campaign.
Number of participants: 491 total: 244 allocated to HCQ; 247 allocated to placebo.
Inclusion criteria: non-hospitalized adults who were required to have 4 or fewer days of symptoms and
either PCR-confirmed SARS-CoV-2 infection or compatible symptoms after a high-risk exposure to a
person with PCR-confirmed COVID-19 within the past 14 days. High-risk exposure was defined as an im-
mediate household contact or a close occupational exposure to someone with COVID-19 (e.g. health-
care worker or first responder). Healthcare workers who had COVID-19-compatible symptoms and
high-risk exposure but whose contact had PCR results pending were enrolled after symptom review by

Collaboration.
Informed decisions.

Skipper 2020 (Continued)
an infectious diseases physician. All of these participants met the COVID-19 case definition of the US
Council of State and Territorial Epidemiologists.
Exclusion criteria: age < 18 years old, current hospitalization, HCQ allergy, retinal disease, known glu-
cose-6 phosphate dehydrogenase deficiency, known chronic kidney disease (stage 4 or 5 or receiving
dialysis), known porphyria, weight less than 40 kg, receiving chemotherapy, current use of HCQ, CQ,
current use of cardiac arrhythmia medicines of: flecainide; amiodarone; digoxin; procainamide; or so-
talol. In Canada, additional exclusions mandated by regulatory authorities were: pregnancy, breast-
feeding; severe diarrhoea or vomiting; known cirrhosis with encephalopathy or ascites; known pro-
longed cardiac QT interval, ventricular arrhythmia, or history of sudden cardiac death; or QT-prolong-
ing medicines. On 20 April 2020, additional US exclusions were added for weight less than 50 kg, struc-
tural or ischaemic heart disease, personal or family history of cardiac QT prolongation, and QT-pro-
longing medications. Concomitant QT-prolonging medications included current use of: antimicro-
bials: azithromycin clarithromycin, erythromycin, ciprofloxacin, levofloxacin, moxifloxacin, ketocona-
zole, itraconazole, or mefloquine; antidepressants: amitriptyline, citalopram, desipramine, escitalo-
pram, imipramine, doxepin, fluoxetine, bupropion (Wellbutrin), or venlafaxine; antipsychotic or mood
stabilizers: haloperidol, droperidol, lithium, quetiapine, thioridazine, ziprasidone, methadone, suma-
triptan, zolmitriptan. The prohibition of azithromycin and other QT-prolonging medicines was at the re-
quest of the US Food and Drug Administration as potentially unsafe in an outpatient clinical trial.
Age: HCQ arm: median 41 years (IQR 33 to 49); placebo arm: median 39 years (IQR 31 to 50).
Sex: HCQ arm female:male 136:123; placebo arm female:male 130:115.
Types of participant: HCQ arm: 132 healthcare workers, 59 household contacts; placebo arm: 128
healthcare workers, 82 household contacts.
Disease severity: not specifically reported, but it appeared that most were mild at presentation. 47
were asymptomatic in the HCQ arm, and 52 were asymptomatic in the placebo arm. All were < 7 days
from onset of symptoms.
Definition of development of COVID-19: confirmed SARS-CoV-2 by PCR or meeting the case definition

of the US Council of State and Territorial Epidemiologists: in outpatient or telehealth settings at least
2 of the following symptoms: fever (measured or subjective), chills, rigors, myalgia, headache, sore
throat, new olfactory and taste disorder(s), OR at least 1 of the following symptoms: cough, shortness
of breath, or difficulty breathing OR severe respiratory illness with at least 1 of the following: clinical or
radiographic evidence of pneumonia, or acute respiratory distress syndrome (ARDS) AND no alterna-
tive more likely diagnosis.
Comorbidities:
1. cardiac disease (such as coronary artery disease or heart failure): HCQ: 4 (1.6%) and placebo: 2 (0.8%);
2. hypertension: HCQ: 23 (10.8%) and placebo: 23 (10.9%);
3. diabetes mellitus: HCQ: 8 (3.8%) and placebo: 7 (3.3%);
4. HIV: HCQ: 1 and placebo: 0;
5. chronic airways disease (asthma, COPD): HCQ: 30 (12.3%) and placebo: 21 (8.5%);
6. chronic liver disease: HCQ: 1 and placebo: 1.
Interventions Intervention: oral dosing of HCQ: 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then
600 mg (3 tablets) once daily for 4 more days (5 days in total).
Placebo: folic acid in the USA and lactose in Canada - unlabelled placebo tablets.
Outcomes Primary outcomes: initial outcome was the ordinal outcome by day 14 of not hospitalized, hospitalized,
or intensive care unit stay or death; however, this was amended on 24 April when fewer patients were
hospitalized than anticipated. The primary outcome was therefore change in symptom severity over 14
days as longitudinally measured on a 10-point visual analogue scale.
Secondary outcomes: incidence of death and hospitalization, incidence of study medicine withdrawal.
Notes Dates of recruitment: 22 March to 6 May with follow-up for all outcomes until 15 June 2020.

Collaboration.
Informed decisions.

Sponsors/funders: Steve Kirsch, Jan and David Baszucki, the Minnesota Chinese Chamber of Com-
merce, the Alliance of Minnesota Chinese Organizations, and the University of Minnesota Founda-
tion. Canadian funding was received from various sources. In Quebec, funds were received from the
Clinical Practice Assessment Unit of the McGill University Health Centre and the McGill Interdiscipli-
nary Initiative in Infection and Immunity's Emergency COVID-19 Research Funding. In Manitoba, re-
search support was received from the Manitoba Medical Service Foundation and Research Manitoba.
Purolator Canada provided in-kind courier support for the participating Canadian sites. Apotex Canada
and Rising Pharmaceuticals in the USA provided a donation of some of the hydroxychloroquine tablets
used.
Risk of bias
Random sequence genera- Low risk “The trial statistician generated a permuted block randomization sequence
tion (selection bias) using differently sized blocks in a 1:1 allocation, stratified by country. A sepa-
rate randomization stratum also existed for persons who were initially asymp-
tomatic at the time of informed consent but became symptomatic before re-
ceiving the study medication on day 1.”
Appropriate method; adequate description.
Allocation concealment Low risk “The research pharmacies held this list, and statisticians verified that the ran-
(selection bias) domization sequence was followed.”
Appropriate; blinding maintained for investigators and participants.
Blinding of participants Low risk Appropriate method: the tablets were unmarked.
mance bias)
All outcomes
Blinding of outcome as- Low risk Outcomes were self-assessed by participants.

All outcomes “We assessed the efficacy of study medicine masking on day 14. Of the 194
participants who completed day-14 surveys in the intervention group, 49% (n
= 94) correctly identified that they had received hydroxychloroquine, 7% (n =
14) believed that they had received placebo, and 44% (n = 86) were unsure. Of
the 182 who completed day-14 surveys in the placebo group, 30% (n = 54) cor-
rectly guessed placebo, 25% (n = 46) incorrectly guessed hydroxychloroquine,
42% (n = 76) were unsure of their randomization assignment, and 3% (n = 6)
did not respond. Thus, masking was generally effective, with adverse effects
markedly differing between groups.”
Incomplete outcome data Unclear risk Unclear for all outcomes.

(attrition bias)
All outcomes The primary outcome was self-reported by participants, therefore it relied on
follow-up data responses. There was significant attrition from enrolment to
availability of follow-up data (14%), with similar percentages in each group,
but unknown reasons for loss to follow-up.
Imputation for missing data in participants who were asymptomatic at base-

line or who were hospitalized or died could have mitigated the effect of this,
but the number for whom this occurred is not reported.
Sensitivity analyses only included different denominators (or used a median

in place of mean), rather than imputing data for all missing participants, for
the primary outcome of change in severity – only for absolute severity: “An
additional sensitivity analysis was performed using overall symptom sever-
ity scores (rather than change in scores) and which included the 68 partici-
pants with no follow-up symptom data. We generated 1000 estimates from

Collaboration.
Informed decisions.

simple random samples of n=400, and derived a mean difference of -0.17 over-
all symptom severity with a corresponding 95%CI of -0.39 to 0.06.”
Adverse events were also conducted on the same subset of participants, with
no imputation for missing data.
For hospitalization and death, attrition was lower (< 10%) in each arm, though
no imputation was conducted.
Selective reporting (re- High risk The change in primary outcome was justified due to low recruitment levels
porting bias) and an inability to attain adequate numbers to reach primary outcome. This
was approved by the DSMB, and the final primary outcome was clinically rele-
vant, and a modification of initial secondary outcomes.
However, selective reporting of outcomes occurred separately from this, and

was not explained: the original ordinal primary outcome was not analysed
“because of the low event rate”. Despite the low event rate, such an analysis
should have been reported in the supplementary appendix.
Other bias High risk The trial was terminated early, and as the primary outcome was a longitudinal
time-updating variable, this could have led to misleading results.

Tang 2020
Methods RCT comparing outcomes for participants receiving HCQ ("HCQ arm") vs those not receiving HCQ
("standard care arm"). No blinding or placebo.
Follow-up: planned PCR on respiratory tract samples on days 4, 7, 10, 14, 21, and 28 from enrolment.
“In addition to SARS-CoV-2 testing, patients were assessed on each scheduled visit for vital signs, C re-
active protein, erythrocyte sedimentation rate, tumour necrosis factor α, interleukin 6, complete blood
cell count with differential, blood chemistry, coagulation panel, pulse oximetry, and respiratory symp-
toms. Records of administration of hydroxychloroquine and adverse events were reviewed daily to en-
sure fidelity to the protocol and, more importantly, patient safety. Computed tomography of the chest
was assessed on screening and at the last visit of the treatment period (day 14 for patients with mild to
moderate disease and day 21 for severe disease).”
Participants Setting: “16 government designated covid-19 treatment centres in three provinces in China (Hubei,
Henan, and Anhui)”, China.
Number of participants: 150 total: 75 HCQ arm; 75 standard care arm.
Inclusion criteria: “age 18 years or older, ongoing SARS-CoV-2 infection confirmed in upper or lower res-
piratory tract specimens with RT-PCR, willingness to participate, and consent not to be enrolled in oth-
er clinical trials during the study period”
Exclusion criteria: “age below 18 years; severe conditions including malignancies, heart, liver, or kid-
ney disease or poorly controlled metabolic diseases; unsuitability for oral administration; pregnancy
or lactation; allergy to hydroxychloroquine; inability to cooperate with investigators due to cognitive
impairments or poor mental status; severe hepatic impairment (for example, Child-Pugh grade C, ALT
more than fivefold the upper limit); and severe renal impairment (eGFR ≤30 mL/min/1.73 m2) or receipt
of continuous renal replacement therapy, haemodialysis, or peritoneal dialysis.” Initially excluded pa-
tients with severe disease; on 17 February this decision was overturned due to probable anti-inflamma-
tory effects of HCQ being seen as desirable for these patients.
Age: HCQ arm: mean 48.0 years (SD 14.1); standard care arm: mean 44.1 years (SD 15.0).
Sex: HCQ arm female:male 33:42; standard care arm female:male 35:40.

Collaboration.
Informed decisions.

Tang 2020 (Continued)
Method of diagnosis: positive RT-PCR for SARS-CoV-2 on upper or lower respiratory tract sample.
Clinical presentation: HCQ arm: 15/75 upper respiratory tract illness; 60/75 lower respiratory tract ill-
ness. Standard care arm: 7/75 upper respiratory tract illness; 68/75 lower respiratory tract illness.
COVID-19 disease severity at presentation: HCQ arm: 15/75 mild; 59/75 moderate; 1/75 severe. Stan-
dard care arm: 7/75 mild; 67/75 moderate; 1/75 severe.
Time from symptom onset to enrolment: HCQ arm: mean 16.0 days (SD 9.9; 73 participants); standard
care arm: mean 17.1 days (SD 11.1; 74 participants).
Comorbidities: 6/75 in the HCQ arm and 3/75 in the standard care arm had hypertension; 12/75 in the
HCQ arm and 9/75 in the standard care arm had diabetes mellitus.
Interventions HCQ arm: HCQ 400 mg orally 3 times a day for 3 days, then twice daily from day 4, for a total of 14 days
for those with mild/moderate disease, and 21 days for severe disease. 37/75 had umifenovir (Arbidol);
13/75 ribavirin; 13/75 lopinavir/ritonavir; 8/75 oseltamivir; 1/75 entecavir; 6/75 corticosteroids; 32/75
antibacterials.
Standard care arm: 33/75 had umifenovir (Arbidol); 15/75 ribavirin; 12/75 lopinavir/ritonavir; 9/75 os-
eltamivir; 1/75 entecavir; 2/75 ganciclovir; 4/75 corticosteroids; 27/75 antibacterials.
Outcomes Primary: “negative conversion of SARS-CoV-2 by 28 days and whether patients with severe COVID-19
had clinical improvement by 28 days” (Negative conversion: “two consecutive reports of a negative re-
sult for SARS-CoV-2 at least 24 hours apart without a subsequent report of a positive result by the end
of the study. We considered the date of the first negative report as the date of negative conversion.”)
Changed primary outcome on 17 February (6 days into trial) from “Negative conversion rate by Day 10”.
Secondary outcomes: “Probability of negative conversion at day 4, 7, 10, 14, or 21”; adverse events; al-
leviation of clinical symptoms within 28 days: “resolving from fever to an axillary temperature of 36.6°C
or below, normalization of SpO2 (>94% on room air), and disappearance of respiratory symptoms in-
cluding nasal congestion, cough, sore throat, sputum production, and shortness of breath.”
Also planned, but not reported: “probabilities of alleviation of clinical symptoms; improvement of C re-
active protein, erythrocyte sedimentation rate, tumour necrosis factor α, interleukin 6, and absolute
blood lymphocyte count; improvement of lung lesions on chest radiology; all cause death; and disease
progression in patients with mild to moderate disease. The time frame for these secondary outcomes
was from randomisation to 28 days.”
Notes Dates of recruitment: 11 February to 29 February 2020.
Sponsors/funders: “Emergent Projects of National Science and Technology (2020YFC0844500), Nation-

al Natural Science Foundation of China (81970020, 81770025), National Key Research and Develop-
ment Program of China (2016YFC0901104), Shanghai Municipal Key Clinical Specialty (shslczdzk02202,
shslczdzk01103), National Innovative Research Team of High-level Local Universities in Shanghai,
Shanghai Key Discipline for Respiratory Diseases (2017ZZ02014), National Major Scientific and Tech-
nological Special Project for Significant New Drugs Development (2017ZX09304007), Key Projects
in the National Science and Technology Pillar Program during the Thirteenth Five-year Plan Period
(2018ZX09206005-004, 2017ZX10202202-005-004, 2017ZX10203201-008)."
Risk of bias
Random sequence genera- Low risk Computer-generated sequence. Stratified by disease severity (mild/moderate
tion (selection bias) vs severe) with 1:1 randomization within strata.

Collaboration.
Informed decisions.

Tang 2020 (Continued)
Allocation concealment Low risk Cards kept in envelopes.
(selection bias)
Blinding of participants Low risk No blinding, but performance bias unlikely.

mance bias)
All outcomes
Blinding of outcome as- Low risk No blinding, but unlikely to have affected outcome assessment.
All outcomes
Incomplete outcome data Unclear risk Attrition appeared to be low, but is difficult to quantify, with varying denomi-
(attrition bias) nators, and follow-up beyond 21 days appears low.
All outcomes
Selective reporting (re- Unclear risk The primary outcome was changed during the trial, but a reasonable justifi-
porting bias) cation was provided. However, only the primary outcome and adverse events
were reported in the final report.
Other bias High risk The trial was stopped early, and follow-up was incomplete. This may lead to
changes in survival analysis, which is what was employed for the primary out-
come of time to negative PCR for SARS-CoV-2.
ALT - Alanine aminotransferase

AST - Aspartate aminotransferase
AZ - Azithromycin
CKD-EPI - Chronic Kidney Disease Epidemiology Collaboration
COPD - Chronic obstructive pulmonary disease
CQ - Chloroquine
CT - Computerized tomography
ECMO - Extracorporeal membrane oxygenation
eGFR - Estimated glomerular filtration rate
FiO2 - Fraction of inspired oxygen
HCQ - Hydroxychloroquine
HIV - Human Immunodeficiency Virus
IgG - Immunoglobulin G
IgM - Immunoglobulin M
ITT - Intention to treat
IQR - Interquartile range
L/min - Litres per minute
LPV/r - Lopinavir/ritonavir
MDRD - Modification of Diet in Renal Disease Study equation
msec - Milliseconds
PaO2 - Partial pressure of oxygen in arterial blood
PCR - Polymerase chain reaction
QTc - Corrected QT interval
QTcF - Corrected QT interval, calculated according to Fridericia's formula
RCT - Randomized controlled trial
RNA - Ribonucleic acid
RT-PCR - Reverse transcription polymerase chain reaction
SaO2 - Saturation of oxygen, ascertained by direct measurement of oxygen bound to haem protein of haemoglobin in the blood
SD - Standard deviation
SOC - Standard of care
SpO2 - Saturation of oxygen, ascertained by indirect measurement of oxygen bound to haem protein of haemoglobin in the blood using
pulse oximetry
WHO - World Health Organization


Collaboration.
Informed decisions.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Agrawal 2020 Not an RCT
Alia 2020 Not an RCT
Brown 2020 Not an RCT
ChiCTR2000029542 Not an RCT
ChiCTR2000029609 Not an RCT
ChiCTR2000029898 No control group without CQ/HCQ
ChiCTR2000029899 No control group without CQ/HCQ
Colson 2020a Not an RCT
Colson 2020b Not an RCT
EUCTR2020-000890-25-FR Not an RCT
EUCTR2020-001421-31-ES No control group without CQ/HCQ
Ferner 2020 Not an RCT
Gao 2020 Not an RCT
Gendrot 2020 Not an RCT
Heldwein 2020 Not an RCT
Lee 2020 Not an RCT
Lofgren 2020 Not an RCT
Nau 2020 Not an RCT
NCT04304053 Duplicate
NCT04321278 No control group without CQ/HCQ
NCT04321993 Not an RCT
NCT04329611 Duplicate

Collaboration.
Informed decisions.

Study Reason for exclusion
NCT04343677 Trial removed from trial registry.
NCT04362189 No CQ/HCQ
NCT04370262 CQ was part of standard care at the start of the trial, but then abandoned.
Pagliano 2020 Not an RCT
Patri 2020 Not an RCT
Principi 2020 Not an RCT
Rathi 2020 Not an RCT
Sahraei 2020 Not an RCT
Yu 2020 Not an RCT

Collaboration.
Informed decisions.

CQ, chloroquine; HCQ, hydroxychloroquine; RCT, randomized controlled trial

DATA AND ANALYSES

Comparison 1. HCQ versus standard care without HCQ, or placebo, for treatment
Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size
pants
1.1 Death due to any cause 9 8208 Risk Ratio (M-H, Random, 1.09 [0.99, 1.19]
95% CI)
1.2 Death due to any cause (sensitivity 9 8043 Risk Ratio (M-H, Random, 1.09 [0.99, 1.19]
analysis) 95% CI)
1.3 Negative PCR for SARS-CoV-2 on respi- 3 213 Risk Ratio (M-H, Random, 1.00 [0.91, 1.10]
ratory samples at day 14 from enrolment 95% CI)
1.5 Proportion admitted to hospital (if re- 1 465 Risk Ratio (M-H, Random, 0.41 [0.13, 1.27]
ceiving ambulatory treatment) 95% CI)
1.6 Progression to mechanical ventilation 3 4521 Risk Ratio (M-H, Random, 1.11 [0.91, 1.37]
95% CI)
1.7 Length of hospital admission (in days) 2 642 Mean Difference (IV, Ran- -0.15 [-0.75, 0.45]
dom, 95% CI)
1.8 Time to clinical improvement 1 Hazard Ratio (IV, Random, 1.01 [0.59, 1.74]
95% CI)
1.9 Time to negative PCR for SARS-CoV-2 1 Hazard Ratio (IV, Random, 0.85 [0.58, 1.23]
on respiratory samples 95% CI)
1.10 Participants with any adverse events 6 1394 Risk Ratio (M-H, Random, 2.90 [1.49, 5.64]
95% CI)
1.11 Participants with serious adverse 6 1004 Risk Ratio (M-H, Random, 0.82 [0.37, 1.79]
events 95% CI)
1.12 Participants with prolongation of QT- 1 147 Risk Ratio (M-H, Random, 8.47 [1.14, 63.03]
interval on electrocardiogram 95% CI)


Collaboration.
Informed decisions.

Analysis 1.1. Comparison 1: HCQ versus standard care without

HCQ, or placebo, for treatment, Outcome 1: Death due to any cause
HCQ Standard care or placebo Risk Ratio Risk Ratio Risk of Bias
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI A B C D E F G
Abd-Elsalam 2020 6 97 5 97 0.7% 1.20 [0.38 , 3.80] + - + + ? -

Cavalcanti 2020 7 221 6 227 0.8% 1.20 [0.41 , 3.51] + + ? + + -
Chen 2020a 0 15 0 15 Not estimable - ? + + + -
Chen 2020c 0 21 0 12 Not estimable + ? + + - -
Horby 2020 418 1561 788 3155 86.4% 1.07 [0.97 , 1.19] + + + + + +
Mitjà 2020a 0 136 0 157 Not estimable + ? + + - - -
Pan 2020 104 947 84 906 12.1% 1.18 [0.90 , 1.56] + ? + + + ?
Skipper 2020 1 244 1 247 0.1% 1.01 [0.06 , 16.09] + + + + ? - -
Tang 2020 0 75 0 75 Not estimable + + + + ? ? -
Total (95% CI) 3317 4891 100.0% 1.09 [0.99 , 1.19]

Total events: 536 884
Heterogeneity: Tau² = 0.00; Chi² = 0.52, df = 4 (P = 0.97); I² = 0% 0.1 0.2 0.5 1 2 5 10
Test for overall effect: Z = 1.72 (P = 0.09) Favours HCQ Favours standard care or placebo
Test for subgroup differences: Not applicable
Risk of bias legend

(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias

Analysis 1.2. Comparison 1: HCQ versus standard care without HCQ, or
placebo, for treatment, Outcome 2: Death due to any cause (sensitivity analysis)
HCQ Standard care or placebo Risk Ratio Risk Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Abd-Elsalam 2020 6 97 5 97 0.7% 1.20 [0.38 , 3.80]

Cavalcanti 2020 5 159 5 173 0.6% 1.09 [0.32 , 3.69]
Chen 2020a 0 15 0 15 Not estimable
Chen 2020c 0 21 0 12 Not estimable
Horby 2020 418 1561 788 3155 86.5% 1.07 [0.97 , 1.19]
Mitjà 2020a 0 122 0 148 Not estimable
Pan 2020 104 947 84 906 12.1% 1.18 [0.90 , 1.56]
Skipper 2020 1 231 1 234 0.1% 1.01 [0.06 , 16.10]
Tang 2020 0 75 0 75 Not estimable
Total (95% CI) 3228 4815 100.0% 1.09 [0.99 , 1.19]



Collaboration.
Informed decisions.

Analysis 1.3. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment,
Outcome 3: Negative PCR for SARS-CoV-2 on respiratory samples at day 14 from enrolment
HCQ Standard care without HCQ Risk Ratio Risk Ratio Risk of Bias
Chen 2020a 15 15 15 15 57.7% 1.00 [0.88 , 1.13] - ? + + + -

Chen 2020c 17 21 9 12 6.0% 1.08 [0.73 , 1.59] + ? + + - -
Tang 2020 60 75 61 75 36.4% 0.98 [0.84 , 1.15] + + + + ? ? -
Total (95% CI) 111 102 100.0% 1.00 [0.91 , 1.10]

Total events: 92 85
Heterogeneity: Tau² = 0.00; Chi² = 0.19, df = 2 (P = 0.91); I² = 0% 0.01 0.1 1 10 100
Test for overall effect: Z = 0.03 (P = 0.98) Favours Standard care without HCQ Favours HCQ
Risk of bias legend

(G) Other bias

Analysis 1.4. Comparison 1: HCQ versus standard care without HCQ, or placebo, for treatment,
Outcome 4: Negative PCR for SARS-CoV-2 on respiratory samples at day 7 from enrolment
Received HCQ Did not receive HCQ Risk Ratio Risk Ratio
Chen 2020a 13 15 14 15 60.1% 0.93 [0.73 , 1.18]

Tang 2020 33 75 43 75 39.9% 0.77 [0.56 , 1.06]
Total (95% CI) 90 90 100.0% 0.86 [0.68 , 1.09]

Total events: 46 57
Test for overall effect: Z = 1.26 (P = 0.21) Favours standard care without HCQ Favours HCQ

Analysis 1.5. Comparison 1: HCQ versus standard care without HCQ, or placebo, for
treatment, Outcome 5: Proportion admitted to hospital (if receiving ambulatory treatment)
HCQ Standard care Risk Ratio Risk Ratio

Skipper 2020 4 231 10 234 100.0% 0.41 [0.13 , 1.27]
Total (95% CI) 231 234 100.0% 0.41 [0.13 , 1.27]

Total events: 4 10
Heterogeneity: Not applicable 0.01 0.1 1 10 100


Collaboration.
Informed decisions.


placebo, for treatment, Outcome 6: Progression to mechanical ventilation
HCQ Standard care Risk Ratio Risk Ratio Risk of Bias
Cavalcanti 2020 16 221 13 227 8.4% 1.26 [0.62 , 2.57] + + ? + + -

Horby 2020 118 1300 215 2623 91.2% 1.11 [0.89 , 1.37] + + + + + +
Tang 2020 0 75 1 75 0.4% 0.33 [0.01 , 8.05] + + + + ? ? -
Total (95% CI) 1596 2925 100.0% 1.11 [0.91 , 1.37]

Test for overall effect: Z = 1.03 (P = 0.30) Favours HCQ Favours standard care
Risk of bias legend

(G) Other bias

placebo, for treatment, Outcome 7: Length of hospital admission (in days)
HCQ Standard care Mean Difference Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI
Abd-Elsalam 2020 11.04 2.71 97 11.27 2.19 97 75.7% -0.23 [-0.92 , 0.46]
Cavalcanti 2020 8.9 6.2 221 8.8 7 227 24.3% 0.10 [-1.12 , 1.32]
Total (95% CI) 318 324 100.0% -0.15 [-0.75 , 0.45]

Heterogeneity: Tau² = 0.00; Chi² = 0.21, df = 1 (P = 0.65); I² = 0%
Test for overall effect: Z = 0.49 (P = 0.63) -100 -50 0 50 100
Test for subgroup differences: Not applicable Favours HCQ Favours standard care

Analysis 1.8. Comparison 1: HCQ versus standard care without HCQ,
or placebo, for treatment, Outcome 8: Time to clinical improvement
Hazard Ratio Hazard Ratio

Study or Subgroup log[Hazard Ratio] SE Weight IV, Random, 95% CI IV, Random, 95% CI
Tang 2020 0.00995 0.278 100.0% 1.01 [0.59 , 1.74]
Total (95% CI) 100.0% 1.01 [0.59 , 1.74]

Heterogeneity: Not applicable
Test for overall effect: Z = 0.04 (P = 0.97) 0.01 0.1 1 10 100
Test for subgroup differences: Not applicable Favours usual care Favours HCQ


Collaboration.
Informed decisions.

treatment, Outcome 9: Time to negative PCR for SARS-CoV-2 on respiratory samples
Hazard Ratio Hazard Ratio

Study or Subgroup log[Hazard Ratio] SE Weight IV, Random, 95% CI IV, Random, 95% CI
Tang 2020 -0.167236 0.191774 100.0% 0.85 [0.58 , 1.23]
Total (95% CI) 100.0% 0.85 [0.58 , 1.23]

Test for overall effect: Z = 0.87 (P = 0.38) 0.01 0.1 1 10 100
Test for subgroup differences: Not applicable Favours standard care Favours HCQ

placebo, for treatment, Outcome 10: Participants with any adverse events
HCQ Standard care or placebo Risk Ratio Risk Ratio Risk of Bias
Cavalcanti 2020 (1) 67 199 40 177 22.8% 1.49 [1.07 , 2.08] + + ? + + -

Chen 2020a (2) 4 15 2 15 10.5% 2.00 [0.43 , 9.32] - ? + + + -
Chen 2020b 2 31 0 31 4.1% 5.00 [0.25 , 100.08] + ? - - + -
Mitjà 2020a (3) 121 169 16 184 21.5% 8.23 [5.11 , 13.28] + ? + + - - -
Skipper 2020 (4) 92 212 46 211 23.1% 1.99 [1.48 , 2.68] + + + + ? - -
Tang 2020 (5) 21 70 7 80 18.0% 3.43 [1.55 , 7.58] + + + + ? ? -
Total (95% CI) 696 698 100.0% 2.90 [1.49 , 5.64]

Heterogeneity: Tau² = 0.48; Chi² = 38.18, df = 5 (P < 0.00001); I² = 87% 0.01 0.1 1 10 100
Footnotes
(1) Cavalcanti 2020 - safety population included participants who received at least one dose of HCQ, and participants who received neither HCQ nor azithromycin.
(2) Chen 2020a and Chen 2020b - safety population assumed to be the same as ITT population. All participants assumed to have received treatment according to group they were randomised to.
(3) Mitjà 2020 - safety population was based on participants randomised to each group, rather than participants who received the study drug.
(4) Skipper 2020 - Safety population excludes participants with no follow up data, and those with only vital status data, including deaths.
(5) Tang 2020 - Safety population based on all those who received at least one dose of HCQ versus all those who received no HCQ.
Risk of bias legend

(G) Other bias


Collaboration.
Informed decisions.


placebo, for treatment, Outcome 11: Participants with serious adverse events
Cavalcanti 2020 (1) 2 199 2 177 15.4% 0.89 [0.13 , 6.25] + + ? + + -

Chen 2020a (2) 1 15 0 15 6.2% 3.00 [0.13 , 68.26] - ? + + + -
Chen 2020b 0 31 4 31 7.2% 0.11 [0.01 , 1.98] + ? - - + -
Chen 2020c 0 21 0 12 Not estimable + ? + + - -
Mitjà 2020a 8 169 12 184 64.6% 0.73 [0.30 , 1.73] + ? + + - - -
Tang 2020 (3) 2 70 0 80 6.6% 5.70 [0.28 , 116.84] + + + + ? ? -
Total (95% CI) 505 499 100.0% 0.82 [0.37 , 1.79]

Total events: 13 18
Test for overall effect: Z = 0.50 (P = 0.61) Favours standard care Favours HCQ
Footnotes
(1) Cavalcanti 2020 - safety population included participants who received at least one dose of HCQ, and participants who received neither HCQ nor azithromycin.
(2) Chen 2020a and Chen 2020b - safety population assumed to be the same as ITT population. All participants assumed to have received treatment according to group they were randomised to.
(3) Tang 2020 - Safety population based on all those who received at least one dose of HCQ versus all those who received no HCQ.
Risk of bias legend

(G) Other bias

treatment, Outcome 12: Participants with prolongation of QT-interval on electrocardiogram
Cavalcanti 2020 13 89 1 58 100.0% 8.47 [1.14 , 63.03] + + ? + + -
Total (95% CI) 89 58 100.0% 8.47 [1.14 , 63.03]

Total events: 13 1
Test for overall effect: Z = 2.09 (P = 0.04) Favours HCQ Favours standard care
Risk of bias legend

(G) Other bias

Comparison 2. CQ versus lopinavir/ritonavir for treatment
pants

Collaboration.
Informed decisions.

pants
2.3 Discharge from hospital at day 14 1 22 Risk Ratio (M-H, Random, 1.91 [1.09, 3.34]
from enrolment 95% CI)
2.4 Clinical improvement at day 10 from 1 22 Risk Ratio (M-H, Random, 1.37 [0.78, 2.42]
enrolment 95% CI)
2.5 Total adverse events 1 22 Risk Ratio (M-H, Random, 1.08 [0.78, 1.50]
95% CI)
2.6 Serious adverse events 1 22 Risk Ratio (M-H, Random, Not estimable
95% CI)

Analysis 2.1. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome
1: Negative PCR for SARS-CoV-2 on respiratory samples at day 7 from enrolment
CQ Lopinavir/ritonavir Risk Ratio Risk Ratio

Huang 2020 7 10 7 12 100.0% 1.20 [0.64 , 2.25]
Total (95% CI) 10 12 100.0% 1.20 [0.64 , 2.25]

Total events: 7 7
Test for overall effect: Z = 0.57 (P = 0.57) Favours lopinavir/ritonavir Favours CQ

Analysis 2.2. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome
2: Negative PCR for SARS-CoV-2 on respiratory samples at day 14 from enrolment

Huang 2020 10 10 11 12 100.0% 1.08 [0.85 , 1.36]
Total (95% CI) 10 12 100.0% 1.08 [0.85 , 1.36]

Total events: 10 11


Collaboration.
Informed decisions.

Analysis 2.3. Comparison 2: CQ versus lopinavir/ritonavir for treatment,

Outcome 3: Discharge from hospital at day 14 from enrolment

Huang 2020 10 10 6 12 100.0% 1.91 [1.09 , 3.34]
Total (95% CI) 10 12 100.0% 1.91 [1.09 , 3.34]

Total events: 10 6

Analysis 2.4. Comparison 2: CQ versus lopinavir/ritonavir for
treatment, Outcome 4: Clinical improvement at day 10 from enrolment

Huang 2020 8 10 7 12 100.0% 1.37 [0.78 , 2.42]
Total (95% CI) 10 12 100.0% 1.37 [0.78 , 2.42]

Total events: 8 7

Analysis 2.5. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome 5: Total adverse events

Huang 2020 9 10 10 12 100.0% 1.08 [0.78 , 1.50]
Total (95% CI) 10 12 100.0% 1.08 [0.78 , 1.50]

Total events: 9 10
Test for overall effect: Z = 0.46 (P = 0.64) Favours CQ Favours Lopinavir/ritonavir


Collaboration.
Informed decisions.

Analysis 2.6. Comparison 2: CQ versus lopinavir/ritonavir for treatment, Outcome 6: Serious adverse events
CQ Lopinavir/ritonavir Risk Ratio Risk Ratio Risk of Bias
Huang 2020 0 10 0 12 Not estimable - ? + + + -
Total (95% CI) 10 12 Not estimable

Total events: 0 0
Test for overall effect: Not applicable Favours CQ Favours Lopinavir/ritonavir
Risk of bias legend

(G) Other bias

Comparison 3. HCQ + azithromycin versus standard care for treatment
pants
3.1 Death due to any cause 1 444 Risk Ratio (M-H, Random, 0.52 [0.13, 2.07]
95% CI)
3.2 Progression to mechanical venti- 1 444 Risk Ratio (M-H, Random, 1.61 [0.82, 3.15]
lation 95% CI)
3.3 Length of hospital stay in days 1 444 Mean Difference (IV, Random, 0.50 [-0.81, 1.81]
95% CI)
3.4 Participants with any adverse 1 416 Risk Ratio (M-H, Random, 1.74 [1.27, 2.38]
events 95% CI)
3.5 Participants with serious adverse 1 416 Risk Ratio (M-H, Random, 1.85 [0.36, 9.43]
events 95% CI)
3.6 Participants with prolongation of 1 174 Risk Ratio (M-H, Random, 8.50 [1.16, 62.31]
QT-interval on electrocardiogram 95% CI)

Analysis 3.1. Comparison 3: HCQ + azithromycin versus
standard care for treatment, Outcome 1: Death due to any cause
HCQ+azithromycin Standard care Risk Ratio Risk Ratio

Cavalcanti 2020 3 217 6 227 100.0% 0.52 [0.13 , 2.07]
Total (95% CI) 217 227 100.0% 0.52 [0.13 , 2.07]

Total events: 3 6
Test for overall effect: Z = 0.92 (P = 0.36) Favours HCQ + azithromycin Favours standard care

Collaboration.
Informed decisions.


Analysis 3.2. Comparison 3: HCQ + azithromycin versus standard care
for treatment, Outcome 2: Progression to mechanical ventilation
HCQ + azithromycin Standard care Risk Ratio Risk Ratio

Cavalcanti 2020 20 217 13 227 100.0% 1.61 [0.82 , 3.15]
Total (95% CI) 217 227 100.0% 1.61 [0.82 , 3.15]

Total events: 20 13

for treatment, Outcome 3: Length of hospital stay in days
HCQ + azithromycin Standard Care Mean Difference Mean Difference
Study or Subgroup Mean [Days] SD [Days] Total Mean [Days] SD [Days] Total Weight IV, Random, 95% CI [Days] IV, Random, 95% CI [Days]
Cavalcanti 2020 9.4 7.8 217 8.9 6.2 227 100.0% 0.50 [-0.81 , 1.81]
Total (95% CI) 217 227 100.0% 0.50 [-0.81 , 1.81]

Test for overall effect: Z = 0.75 (P = 0.46) -100 -50 0 50 100
Test for subgroup differences: Not applicable Favours HCQ + azithromycin Favours standard care

for treatment, Outcome 4: Participants with any adverse events

Cavalcanti 2020 (1) 94 239 40 177 100.0% 1.74 [1.27 , 2.38]
Total (95% CI) 239 177 100.0% 1.74 [1.27 , 2.38]

Total events: 94 40
Footnotes
(1) The safety population in this trial included participants who received at least one dose of HCQ and azithromycin, versus participants who received neither HCQ nor azithromycin.


Collaboration.
Informed decisions.


for treatment, Outcome 5: Participants with serious adverse events

Cavalcanti 2020 (1) 5 239 2 177 100.0% 1.85 [0.36 , 9.43]
Total (95% CI) 239 177 100.0% 1.85 [0.36 , 9.43]

Total events: 5 2
Footnotes
(1) The safety population in this trial included participants who received at least one dose of HCQ and azithromycin, versus participants who received neither HCQ nor azithromycin.

Analysis 3.6. Comparison 3: HCQ + azithromycin versus standard care for treatment,
Outcome 6: Participants with prolongation of QT-interval on electrocardiogram

Cavalcanti 2020 (1) 17 116 1 58 100.0% 8.50 [1.16 , 62.31]
Total (95% CI) 116 58 100.0% 8.50 [1.16 , 62.31]

Total events: 17 1
Footnotes
(1) The safety population in this trial included participants who received at least one dose of HCQ and azithromycin, versus participants who received neither HCQ nor azithromycin. For

Comparison 4. HCQ versus febuxostat for treatment
pants
4.1 Death due to any cause 1 54 Risk Ratio (M-H, Random, 95% CI) Not estimable
4.2 Admission to hospital 1 54 Risk Ratio (M-H, Random, 95% CI) 1.16 [0.26, 5.24]


Collaboration.
Informed decisions.

Analysis 4.1. Comparison 4: HCQ versus febuxostat for treatment, Outcome 1: Death due to any cause
HCQ Febuxostat Risk Ratio Risk Ratio

Davoodi 2020 0 25 0 29 Not estimable

Total events: 0 0
Test for overall effect: Not applicable Favours HCQ Favours Febuxostat

Analysis 4.2. Comparison 4: HCQ versus febuxostat for treatment, Outcome 2: Admission to hospital
HCQ Febuxostat Risk Ratio Risk Ratio Risk of Bias
Davoodi 2020 3 25 3 29 100.0% 1.16 [0.26 , 5.24] ? + - + - -
Total (95% CI) 25 29 100.0% 1.16 [0.26 , 5.24]

Total events: 3 3
Test for overall effect: Z = 0.19 (P = 0.85) Favours HCQ Favours Febuxostat
Risk of bias legend

(G) Other bias

Comparison 5. HCQ versus placebo for postexposure prophylaxis
pants
5.1 Development of confirmed COVID-19 1 821 Risk Ratio (M-H, Random, 1.20 [0.50, 2.87]
at 14 days from enrolment 95% CI)
5.2 Patients hospitalized due to COV- 1 821 Risk Ratio (M-H, Random, 0.98 [0.06, 15.66]
ID-19 95% CI)
5.3 Participants with any adverse events 1 700 Risk Ratio (M-H, Random, 2.39 [1.83, 3.11]
95% CI)
5.4 Participants with serious adverse 1 700 Risk Ratio (M-H, Random, Not estimable
events 95% CI)


Collaboration.
Informed decisions.

Analysis 5.1. Comparison 5: HCQ versus placebo for postexposure prophylaxis,

Outcome 1: Development of confirmed COVID-19 at 14 days from enrolment
HCQ Placebo Risk Ratio Risk Ratio Risk of Bias
Boulware 2020 11 414 9 407 100.0% 1.20 [0.50 , 2.87] + + + + + ?
Total (95% CI) 414 407 100.0% 1.20 [0.50 , 2.87]

Total events: 11 9
Test for overall effect: Z = 0.41 (P = 0.68) Favours HCQ Favours placebo
Risk of bias legend

(G) Other bias

Analysis 5.2. Comparison 5: HCQ versus placebo for postexposure
prophylaxis, Outcome 2: Patients hospitalized due to COVID-19
HCQ Placebo Risk Ratio Risk Ratio

Boulware 2020 1 414 1 407 100.0% 0.98 [0.06 , 15.66]
Total (95% CI) 414 407 100.0% 0.98 [0.06 , 15.66]

Total events: 1 1
Test for overall effect: Z = 0.01 (P = 0.99) Favours HCQ Favours placebo

prophylaxis, Outcome 3: Participants with any adverse events
HCQ Placebo Risk Ratio Risk Ratio Risk of Bias
Boulware 2020 140 349 59 351 100.0% 2.39 [1.83 , 3.11] + + + + + ?
Total (95% CI) 349 351 100.0% 2.39 [1.83 , 3.11]

Test for overall effect: Z = 6.42 (P < 0.00001) Favours HCQ Favours placebo
Risk of bias legend

(G) Other bias


Collaboration.
Informed decisions.


prophylaxis, Outcome 4: Participants with serious adverse events
HCQ Placebo Risk Ratio Risk Ratio

Boulware 2020 0 349 0 351 Not estimable

Total events: 0 0
Test for overall effect: Not applicable Favours HCQ Favours placebo

ADDITIONAL TABLES

Table 1. Ongoing trials for treatment: actively recruiting or completed; not yet published
Trial registration num- Location(s) Interventions; abbreviated name Recruitment Estimated Target enrol-
ber; trial registry status completion ment
NCT02735707 13 countries; Adaptive platform trial including Recruiting December 7100

HCQ, or HCQ + lopinavir/ritonavir, 2021
ClinicalTrials.gov registered in vs no HCQ
the Nether-
lands REMAP-CAP
NCT04351724 Austria Platform trial including CQ/HCQ vs Recruiting Decem- 500

placebo ber 2020
ClinicalTrials.gov
ACOVACT
NCT04328012 USA Pragmatic adaptive HCQ vs Recruiting January 2021 4000

lopinavir/ritonavir vs losartan vs
ClinicalTrials.gov placebo
COVID MED
NCT04334382 USA HCQ vs azithromycin Recruiting December 1550

2020
ClinicalTrials.gov HyAzOUT
NCT04332991 USA HCQ vs placebo for hospitalized Completed April 2021 510
ClinicalTrials.gov patients with COVID-19

ORCHID
NCT04363827 Italy HCQ vs observation Recruiting September 2300

2020
ClinicalTrials.gov PROTECT
NCT04359953 France HCQ vs telmisartan vs Recruiting June 2021 1600

azithromycin
ClinicalTrials.gov
NCT04356495 France HCQ vs favipiravir vs imatinib vs Recruiting July 2020 1057

telmisartan vs placebo
ClinicalTrials.gov
COVERAGE

Collaboration.
Informed decisions.

Table 1. Ongoing trials for treatment: actively recruiting or completed; not yet published (Continued)
PACTR202004801273802 Nigeria CQ vs HCQ vs placebo Recruiting October 2020 600
Pan African Clinical Tri-

als Registry
ISRCTN86534580 UK HCQ vs standard care for treat- Recruiting March 2021 3000
ment
ISRCTN registry
NCT04324463 Canada Azithromycin plus hydroxychloro- Recruiting September 1500

quine or chloroquine (AZCT) vs 2020
ClinicalTrials.gov AZCT plus interferon beta vs inter-
feron beta vs usual care
NCT04345289 Denmark Convalescent plasma vs sarilum- Recruiting June 2021 1500

ab vs HCQ vs baricitinib vs intra-
ClinicalTrials.gov venous and subcutaneous placebo
vs oral placebo
NCT04358068 USA and Puer- HCQ vs azithromycin Completed October 2020 2000
to Rico
ClinicalTrials.gov
NCT04340544 Germany HCQ vs placebo Recruiting November 2700

2021
ClinicalTrials.gov
NCT04338698 Pakistan HCQ vs oseltamivir vs azithromycin Recruiting September 500

2020
ClinicalTrials.gov
NCT04353037 USA HCQ vs placebo Recruiting April 2021 850
ClinicalTrials.gov
NCT04321616 Norway HCQ vs remdesivir vs standard Recruiting August 2020 700

care
ClinicalTrials.gov
ACTRN12620000445976 Australia and HCQ vs lopinavir/ritonavir vs HCQ Recruiting Not reported 2500
New Zealand plus lopinavir/ritonavir vs stan-
ANZCTR dard care
NCT04315948 France and HCQ vs remdesivir vs lopinavir/ri- Recruiting March 2023 3100
Luxembourg tonavir vs interferon beta-1A vs
ClinicalTrials.gov standard care
UTN-A27736297878 Brazil HCQ vs placebo Recruiting July 2020 1300
Ensaiosclinicos.gov.br
NCT04410562 Spain HCQ vs placebo (pregnant women) Recruiting May 2021 714
ClinicalTrials.gov
NCT04392973 Saudi Arabia HCQ with favipiravir vs standard Recruiting November 520
care 2021
ClinicalTrials.gov
CQ, chloroquine; HCQ, hydroxychloroquine

Collaboration.
Informed decisions.


Table 2. Ongoing trials for prevention: actively recruiting or completed; not yet published
Trial registration num- Location(s) Interventions; population; ab- Recruitment Estimated Target enrol-
ber; trial registry breviated name status completion ment
NCT04333732 USA Low-/medium-/high-dose chloro- Recruiting February 2021 55,000

quine vs placebo
ClinicalTrials.gov
Healthcare workers
NCT04303507 Europe, Asia, HQC vs CQ vs placebo Recruiting April 2021 40,000

Africa
ClinicalTrials.gov Healthcare workers
COPCOV
NCT04334928 Spain Emtricitabine/tenofovir (Truva- Recruiting June 2020 4000

ClinicalTrials.gov da) vs HCQ vs Truvada + HCQ vs
placebo
Healthcare workers
EPICOS
NCT04334148 USA HCQ vs placebo Recruiting July 2020 15,000
NCT04363450 USA HCQ vs placebo Recruiting July 2020 1700
ClinicalTrials.gov Healthcare workers (pre-expo-

sure)
HCQPreP
NCT04318444 USA HCQ vs placebo Recruiting March 2021 1600
ClinicalTrials.gov Household contacts (postexpo-

sure)
NCT04341441 USA Daily HCQ vs weekly HCQ vs Recruiting June 2020 3000
placebo
ClinicalTrials.gov
Healthcare workers and first re-
sponders
IRCT20190122042450N4 Iran HCQ vs no HCQ Completed Not reported 1000

Iranian Clinical Trials
Registry All contacts (postexposure)
ISRCTN14326006 Canada HCQ vs placebo Recruiting January 2022 988
ISRCTN registry Healthcare workers
NCT04363827 Italy HCQ vs no HCQ Recruiting September 2300

2020
ClinicalTrials.gov All contacts
NCT04352933 UK HCQ weekly vs HCQ daily vs Recruiting October 2020 1000

placebo
ClinicalTrials.gov

Collaboration.
Informed decisions.

Table 2. Ongoing trials for prevention: actively recruiting or completed; not yet published (Continued)
Healthcare workers
NCT04353037 USA HCQ vs placebo Recruiting April 2021 850
ACTRN12620000501943 Australia HCQ vs placebo Recruiting December 2250

2020
ANZCTR Healthcare workers
NCT04374942 USA HCQ vs placebo Recruiting January 2022 988
EudraCT 2020-001987-28 Italy HCQ vs no HCQ Recruiting Not reported 1000
EudraCT Healthcare workers
CQ, chloroquine; HCQ, hydroxychloroquine

Table 3. Summary of characteristics of included studies
Study Objective; Study de- Countries; Age Number Types of participant at enrolment
compar- sign recruit- of partic- (type of contact; place of care; dis-
isons ment dates ipants in ease severity)
primary
compari-
son
Abd-El- 1: Treat- RCT, open- Egypt HCQ: mean 40.4 y 194 total: All hospitalized.
salam 2020 ment label (SD 18.7 y) 97 HCQ; 97
March to standard “The patients were randomized
1: HCQ vs June 2020 Standard care: care equally between the two groups re-
standard mean 41.1 y (SD garding the disease severity.” (Num-
care 20.1 y) bers not reported.)
Boulware 3: Postex- RCT, dou- USA and HCQ: median 41 y 821 total: HCQ: 275 healthcare contacts; 125
2020 posure pro- ble-blind Canada (IQR 33 to 51) 414 HCQ; household contacts; 14 NR
phylaxis 407 place-
17 March to Placebo: median bo Placebo: 270 healthcare contact-
5: HCQ vs 6 May 2020 40 y (IQR 32 to 50) s; 120 household contacts; 17 NR
placebo (in-
dividual-
ly random-
ized)
Cavalcanti 1: Treat- RCT, open- Brazil HCQ + 665 total: All hospitalized.
2020 ment label azithromycin: mean 217 HCQ +
29 March 49.6 y (SD 14.2 y) azithromycin; HCQ + azithromycin: 125/217
1: HCQ vs to 17 May 221 HCQ; mild; 92/217 moderate disease
standard 2020 HCQ: mean 51.3 y 227 stan-
care (SD 14.5 y) HCQ: 132/221 mild; 89/221 moder-
dard care
ate disease
3: HCQ Standard care:
+ azithromycin mean 49.9 y (SD Standard care: 130/227 mild; 97/227
vs standard 15.1 y) moderate disease
care
Chen 2020a 1: Treat- RCT, open- China HCQ: mean 50.5 y 30 total: All hospitalized.
ment label (SD 3.8 y) 15 HCQ; 15
Collaboration.
Informed decisions.

Table 3. Summary of characteristics of included studies (Continued)

1: HCQ vs 6 February Standard care: standard All 30 participants had moderate
standard to 25 Feb- mean 46.7 y (SD care disease.
care ruary 2020 3.6 y)
Chen 2020b 1: Treat- RCT, dou- China HCQ: mean 44.1 y 62 total: All hospitalized.
ment ble-blind (SD 16.1 y) 31 HCQ; 31
(no place- 4 February standard All 62 participants had mild disease.
1: HCQ vs bo) to 28 Feb- Standard care: care
standard ruary 2020 mean 45.2 y (SD
care 14.7 y)
Chen 2020c 1: Treat- RCT, open- Taiwan HCQ: mean 33 y 33 total: All hospitalized.
ment label (SD 12 y) 21 HCQ; 12
1 April to 31 standard HCQ: 19/21 mild; 2/21 moderate
1: HCQ vs May 2020 Standard care: care
standard mean 32.8 y (SD Standard care: 10/12 mild; 2/12
care 8.3 y) moderate
Davoodi 1: Treat- RCT, open- Iran HCQ: mean 57.3 y 54 total: All ambulatory patients, sympto-
2020 ment label (standard error 2.2 25 HCQ; 29 matic, with abnormalities on CT
16 March y) febuxostat scan of the chest, but no features of
4: HCQ vs to 10 April severe acute illness or severe under-
febuxostat 2020 Febuxostat: mean lying chronic disease.
58 y (standard er-
ror 1.47 y)
Horby 2020 1: Treat- RCT, open- UK HCQ: mean 65.2 y 4716 total: All hospitalized.
ment label (SD 15.2 y) 1561 HCQ;
25 March to 3155 stan- Inferred from level of oxygen/respi-
1: HCQ vs 5 June 2020 Standard care: dard care ratory support need:
standard mean 65.4 y (SD
care 15.4 y) HCQ: 362/1561 asympto-
matic/mild (no oxygen re-
ceived); 938/1561 moderate/severe
(received oxygen); 261/1561 criti-
cal disease (invasive ventilation)
Standard care: 750/3155 asymp-

tomatic/mild (no oxygen re-
ceived); 1873/3155 moderate/severe
(received oxygen); 532/3155 criti-
cal disease (invasive ventilation)
Huang 2020 1: Treat- RCT, open- China CQ: median 41.5 y 22 total: 10 All hospitalized.
ment label (IQR 33.8 to 50 y) CQ; 12 LPV/
27 January r CQ: 7/10 moderate; 3/10 severe dis-
2: CQ vs to 15 Feb- LPV/r: median 53 y ease
lopinavir/ ruary 2020 (IQR 41.8 to 63.5 y)
riton- LPV/r: 7/12 moderate; 5/12 severe
avir (LPV/r) disease
Mitjà 2020a 1: Treat- RCT, open- Spain HCQ: mean 41.6 y 293 total: All ambulatory patients with mild
ment label (SD 12.4 y) 136 HCQ; disease, except for 1 patient with
17 March 157 stan- severe disease included in the HCQ
1: HCQ vs to 26 May Standard care: dard care arm, despite this being an exclusion
standard 2020 mean 41.7 y (SD criterion (included in ITT analysis).
care 12.6 y)
Mitjà 2020b 3: Postex- Clus- Spain HCQ: mean 48.6 y 2525 total: HCQ: 131 (12%) healthcare workers;
posure pro- ter-RCT, (SD 18.7 y) 1225 HCQ; 302 (27%) household contacts; 550
phylaxis open-label
Collaboration.
Informed decisions.

Table 3. Summary of characteristics of included studies (Continued)

6: HCQ vs 17 March Standard 1300 stan- (49%) nursing home workers; 133
standard to 28 April care: mean 48.7 y dard care (12%) nursing home residents
care (clus- 2020 (SD 19.3 y)
ter ran- Standard care: 130 (11%) health-
domized) care workers; 338 (28%) household
contacts; 584 (49%) nursing home
workers; 160 (13%) nursing home
residents
Pan 2020 1: Treat- RCT, open- 30, across HCQ: 335 (< 50 1853 to- All hospitalized.
ment label all WHO re- years), 410 (50 to tal: 947 HC-
gions 69 years), 202 (≥ Q; 906 stan- HCQ: 862/947 moderate or severe
1: HCQ vs 70 years) dard care (of whom 517 receiving oxygen), 85
standard 22 March critical
care to 18 June Standard care: 317
2020 (< 50 years), 396 Standard care: 824/906 moderate or
(50 to 69 years), severe (of whom 483 receiving oxy-
193 (≥ 70 years) gen), 82 critical
Skipper 1: Treat- RCT, dou- USA and HCQ: median 41 y 491 total: All ambulatory patients, so pre-
2020 ment ble-blind Canada (IQR 33 to 49 y) 244 HCQ; sumed to have mild disease if symp-
247 place- tomatic.
1: HCQ vs 22 March Placebo: median bo
placebo to 6 May 39 y (IQR 31 to 50 HCQ: 48/244 asymptomatic
2020 y)
Placebo: 52/247 asymptomatic
Tang 2020 1: Treat- RCT, open- China HCQ: mean 48 y 150 total: All hospitalized.
ment label (no (SD 14.1 y) 75 HCQ; 75
placebo) 11 February standard HCQ: 15/75 mild; 59/75 moderate;
1: HCQ vs to 29 Feb- Standard care: care 1/75 severe disease
standard ruary 2020 mean 44.1 y (SD
care 15 y) Standard care: 7/75 mild; 67/75
moderate; 1/75 severe disease
CQ: chloroquine; CT: computed tomography; HCQ: hydroxychloroquine; IQR: interquartile range; ITT: intention-to-treat; NR: not reported;
RCT: randomized controlled trial; SD: standard deviation; WHO: World Health Organization; y: years.

Table 4. Dosing regimens in hydroxychloroquine treatment trials1
Study Hydroxychloroquine (HCQ) dose regimen Control group Total hydroxy-
chloroquine dose
Abd-Elsalam 2020 800 mg on day 1, followed by 400 mg daily for further 14 days Standard care 6400 mg
(total duration of treatment 15 days)
Cavalcanti 2020 2 400 mg orally twice daily for 7 days Standard care 5600 mg
Chen 2020a 3 400 mg once daily for 5 days Standard care 2000 mg
Chen 2020b 200 mg orally twice daily for 5 days Standard care 2000 mg
Chen 2020c 800 mg on day 1, followed by 400 mg daily for further 6 days Standard care 3200 mg
Davoodi 2020 200 mg orally twice daily for 5 days Standard care 2000 mg


Collaboration.
Informed decisions.

Table 4. Dosing regimens in hydroxychloroquine treatment trials1 (Continued)

Horby 2020 800 mg at 0 and 6 hours, then 400 mg at 12 hours from first dose Standard care 10,000 mg
and every 12 hourly for 10 days
Mitjà 2020a 800 mg on day 1, followed by 400 mg daily for further 6 days Standard care 3200 mg
Pan 2020 2000 mg on day 1, followed by 800 mg daily for further 9 days Standard care 9200 mg
Skipper 2020 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours lat- Placebo: folic acid 3800 mg
er, then 600 mg (3 tablets) once daily for 4 more days (5 days in in USA and lactose
total) in Canada
Tang 2020 400 mg orally 3 times a day for 3 days, then twice daily from day Standard care 12,400 mg mild/
4, for a total of 14 days for those with mild/moderate disease moderate disease;
and 21 days for those with severe disease
18,000 mg severe
disease
1See Table 5 for co-interventions given in each trial.

2 Cavalcanti 2020 - hydroxychloroquine plus azithromycin group received HCQ 400 mg orally twice daily and azithromycin 500 mg orally
once daily for seven days.
3 Chen 2020a - additionally, all participants in the HCQ arm had nebulized interferon alpha; 12/15 had umifenovir (Arbidol). Standard care
arm: no HCQ; all had nebulized interferon alpha; 10/15 had umifenovir (Arbidol).

Table 5. Pharmacological co-interventions given in treatment trials for comparison 1 (HCQ versus standard care or
placebo)
Study Co-interventions in HCQ arm Co-interventions in comparator arm
Abd-Elsalam 2020 Authors report: "The Egyptian Ministry of Health (MOH) adopted a standard of care treatment protocol for
COVID-19 patients. It included paracetamol, oxygen, fluids (according to assessment), empiric antibiotic
(cephalosporins), oseltamivir if needed (75 mg/12 hours for 5 days), and invasive mechanical ventilation
with hydrocortisone for severe cases if PaO2 < 60 mmHg, O2 saturation < 90% despite oxygen or nonin-
vasive ventilation, progressive hypercapnia, respiratory acidosis (pH < 7.3), and progressive or refractory
septic shock".
Cavalcanti 2020 1 Corticosteroids 5/221 Corticosteroids 8/227
Oseltamivir 38/221 Oseltamivir 51/227
Aciclovir 1/221 Aciclovir 0/227
Lopinavir/ritonavir 0/221 Lopinavir/ritonavir 0/227
Ceftriaxone 86/221 Ceftriaxone 99/227
Ceftaroline 11/221 Ceftaroline 17/227
Piperacillin/tazobactam 8/221 Piperacillin/tazobactam 15/227
Oxacillin 0/221 Oxacillin 1/227
Vancomycin 1/221 Vancomycin 4/227
Carbapenem 6/221 Carbapenem 3/227
Quinolone 22/221 Quinolone 28/227

Collaboration.
Informed decisions.

Table 5. Pharmacological co-interventions given in treatment trials for comparison 1 (HCQ versus standard care or
placebo) (Continued)
No other antiviral, antibiotic, or corticosteroids No other antiviral, antibiotic, or corticosteroids
21/221 18/227
Chen 2020a 2 Nebulized interferon alpha 15/15 Nebulized interferon alpha 15/15
Umifenovir 12/15 Umifenovir 10/15
Chen 2020b Authors report “all received the standard treatment (oxygen therapy, antiviral agents, antibacterial
agents, and immunoglobulin, with or without corticosteroids)”.
Chen 2020c 3 Azithromycin 1/21 Azithromycin 2/12
Horby 2020 4 Dexamethasone 8% Dexamethasone 9%
Azithromycin 17% Azithromycin 19%
Mitjà 2020a 5 Cobicistat-boosted darunavir 49/136 Cobicistat-boosted darunavir 0/157
Pan 2020 The authors report that co-medications will appear in supplementary tables, but these are not provided
with the currently available preprint publication.
Skipper 2020 6 Zinc 63/212 Zinc 53/211
Vitamin C 101/212 Vitamin C 101/211
Tang 2020 Umifenovir 37/75 Umifenovir 33/75
Ribavirin 13/75 Ribavirin 15/75
Lopinavir/ritonavir 13/75 Lopinavir/ritonavir 12/75
Oseltamivir 8/75 Oseltamivir 9/75
Entecavir 1/75 Entecavir 1/75
Antibiotics 32/75 Antibiotics 27/75
Corticosteroids 6/75 Corticosteroids 4/75
HCQ, hydroxychloroquine; PaO2, partial pressure of oxygen

1 Cavalcanti 2020 - this was a three-arm trial, of which the third arm received HCQ + azithromycin.
2 Chen 2020a - authors report that two participants received lopinavir/ritonavir, but it is unclear which study arms these participants were
in. Whether or not any participants received corticosteroids or antibiotics is not reported.
3 Chen 2020c - in addition to the above, authors report: "Both study group and comparison group received standard of care comprising
supportive treatment for subjects with mild clinical COVID-19 symptoms and antimicrobial therapy for subjects presenting with moderate
clinical COVID-19 symptoms. The treatment consisted of: (1) ceftriaxone 2 g daily for 7 days +/- azithromycin 500 mg on day 1 and 250 mg
on days 2–5; or (2) levofloxacin 750 mg daily for 5 d; or (3) levofloxacin 500 mg daily; or (4) moxifloxacin 400 mg daily for 7–14 days for
subjects allergic to ceftriaxone or azithromycin or according to physician discretion. Oseltamivir 75 mg b.i.d. will be administered for 5 days
to subjects presenting with concomitant influenza A or B infection".
4 Horby 2020 - authors presented the percentage of participants in each arm receiving dexamethasone or azithromycin. Data on antibiotics
and other antivirals not reported. This trial was a platform trial with other arms testing tocilizumab, azithromycin, and dexamethasone, as
well as convalescent plasma.
5 Mitjà 2020a - the trial was originally designed to test HCQ with cobicistat-boosted darunavir, but this was modified during the trial as
further information became available that cobicistat-boosted darunavir had no in vitro activity against SARS-CoV-2.
6 Skipper 2020 - whether or not participants received antimicrobials or corticosteroids is not reported.


Collaboration.
Informed decisions.

Table 6. Adverse events for HCQ versus standard care without HCQ, or placebo, for treatment
Study HCQ No HCQ
Cavalcanti 2020 QTc prolongation (13/89) QTc prolongation (1/58)
Arrhythmia (3/199) Arrhythmia (1/177)
Bradycardia (1/199) Bradycardia (1/177)
Supraventricular tachycardia (2/199) Bronchospasm (1/177)
Pneumothorax (1/199) Nausea (2/177)
Bloodstream infection (1/199) Vomiting (1/177)
Itching (1/199) Anaemia (11/177)
Nausea (9/199) Elevated ALT or AST (6/177)
Anaemia (14/199) Elevated bilirubin (2/177)
Elevated ALT or AST (17/199) Leucopenia (3/177)
Elevated bilirubin (5/199)
Hypoglycaemia (1/199)
Leucopenia (3/199)
Chen 2020a 1 Transient elevated AST with anaemia (1/15) Elevated AST (1/15)

Diarrhoea (2/15) Elevated creatinine (1/15)
Fatigue (1/15)
Chen 2020b Headache (1/31)

Rash (1/31)
Mitjà 2020a Gastrointestinal disorders (148/169) Gastrointestinal disorders (7/184)
General disorders (30/169) General disorders (1/184)
Infections and infestations (9/169) Infections and infestations

(12/184)
Injury, poisoning, and procedural complications (1/169)
Metabolic and nutrition disorders
Metabolic and nutrition disorders (2/169) (1/184)
Musculoskeletal and connective tissue disorders (1/169) Nervous system disorders (3/184)
Nervous system disorders (63/169)
Psychiatric disorders (2/169)
Renal and urinary disorders (1/169)
Reproductive system and breast disorders (1/169)
Respiratory, thoracic, and mediastinal disorders (2/169)
Skin and subcutaneous tissue disorders (11/169)
Vascular disorders (1/169)
Skipper 2020 2 Upset stomach/nausea (66/212) Upset stomach/nausea (26/211)

Collaboration.
Informed decisions.

Table 6. Adverse events for HCQ versus standard care without HCQ, or placebo, for treatment (Continued)
Diarrhoea, other GI symptoms, vomiting (50/212) Diarrhoea, other GI symptoms,
vomiting (20/211)
Neurologic (nervousness, irritability, dizziness, vertigo) (20/212)
Neurologic (nervousness, irritabili-
Skin reaction, rash (6/212) ty, dizziness, vertigo) (13/211)
Ringing in ears (8/212) Skin reaction, rash (2/211)
Allergic reaction, self-reported (5/212) Ringing in ears (5/211)
Changes in vision (4/212) Changes in vision (5/211)
Warmth, hot flashes, night sweats (2/212) Taste, dry mouth (1/211)
Headache (2/212) Heart racing, anxiety, panic attack
(1/211)
Tang 2020 Disease progression (1/70) Abdominal bloating (1/80)
Upper respiratory tract infection (1/70) Fever (1/80)
Diarrhoea (7/70) Liver abnormality (1/80)
Vomiting (2/70) Hepatic steatosis (1/80)
Nausea (1/70) Otitis externa (1/80)
Abdominal discomfort (1/70) Increased serum amyloid A (1/80)
Blurred vision (1/70)
Thirst (1/70)
Sinus bradycardia (1/70)
Hypertension (1/70)
Orthostatic hypotension (1/70)
Hypertriglyceridaemia (1/70)
Decreased appetite (1/70)
Fatigue (1/70)
Dyspnoea (1/70)
Flush (1/70)
Kidney injury (1/70)
Coagulation dysfunction (1/70)
Decreased white blood cell (1/70)
Increased ALT (1/70)
Increased serum amylase (1/70)
Decreased neutrophil count (1/70)
ALT: alanine aminotransferase; AST: aspartate transaminase; GI: gastrointestinal; HCQ: hydroxychloroquine

Collaboration.
Informed decisions.

1Authors of Chen 2020a comment that “among the test group the occurrence of adverse events in subjects with moderate to severe disease
is not related to medication. All adverse reactions after drug withdrawal or symptomatic treatment disappeared”.
2 Skipper 2020 - authors describe these adverse events as side effects reported at day 5.

APPENDICES
Appendix 1. Search strategies

Search strategy PubMed (MEDLINE)

#1 Search "Coronavirus"[Mesh]
#2 Search (coronavirus* or coronovirus* or coronavirinae* or Coronavirus* or Coronovirus* or Wuhan*

or Hubei* or Huanan or "2019-nCoV" or 2019nCoV or nCoV2019 or "nCoV-2019" or "COVID-19"
or COVID19 or "CORVID-19" or CORVID19 or "WN-CoV" or WNCoV or "HCoV-19" or HCoV19 or CoV
or "2019 novel*" or Ncov or "n-cov" or "SARS-CoV-2" or "SARSCoV-2" or "SARSCoV2" or "SARS-
CoV2" or SARSCov19 or "SARS-Cov19" or "SARSCov-19" or "SARS-Cov-19" or Ncovor or Ncorona* or
Ncorono* or NcovWuhan* or NcovHubei* or NcovChina* or NcovChinese*) Field: Title/Abstract
#3 Search (((respiratory* AND (symptom* or disease* or illness* or condition*)) or "seafood market*"

or "food market*") AND (Wuhan* or Hubei* or China* or Chinese* or Huanan*)). Field: Title/Abstract
#4 Search "severe acute respiratory syndrome*" Field: Title/Abstract
#5 Search ((outbreak* or wildlife* or pandemic* or epidemic*) AND (China* or Chinese* or Huanan*))

Field: Title/Abstract
#6 Search (corona* or corono*) AND (virus* or viral* or virinae*) Field: Title/Abstract
#7 Search (((((#1) OR #2) OR #3) OR #4) OR #6)
#8 Search chloroquin* Field: Title/Abstract
#9 Search Hydroxychloroquin* OR Oxychloroquin* Field: Title/Abstract
#10 Search ("Hydroxychloroquine"[Mesh]) OR "Chloroquine"[Mesh]
#11 Search Aralen or Plaquenil Field: Title/Abstract
#12 Search antimalaria* or anti-malaria* Field: Title/Abstract
#13 Search (((#8) OR #9) OR #10) OR #11OR #12
#14 Search (#13) AND #7
Database: Embase 1947-Present, updated daily
--------------------------------------------------------------------------------
1 coronavirus.mp. or Coronavirinae/
2 exp Coronavirinae/
3 (coronavirus* or coronovirus* or coronavirinae* or Coronavirus* or Coronovirus* or Wuhan* or Hubei* or Huanan or "2019-nCoV" or

2019nCoV or nCoV2019 or "nCoV-2019" or "COVID-19" or COVID19 or "CORVID-19" or CORVID19 or "WN-CoV" or WNCoV or "HCoV-19"
or HCoV19 or CoV or "2019 novel*" or Ncov or "n-cov" or "SARS-CoV-2" or "SARSCoV-2" or "SARSCoV2" or "SARS-CoV2" or SARSCov19

Collaboration.
Informed decisions.

(Continued)
or "SARS-Cov19" or "SARSCov-19" or "SARS-Cov-19" or Ncovor or Ncorona* or Ncorono* or NcovWuhan* or NcovHubei* or NcovChi-
na* or NcovChinese*).mp.
4 (respiratory* adj2 (symptom* or disease* or illness* or condition*)).mp.
5 ("seafood market*" or "food market*").mp.
6 4 or 5
7 (Wuhan* or Hubei* or China* or Chinese* or Huanan*).mp.
8 6 and 7
9 SARS coronavirus/ or severe acute respiratory syndrome/ or "severe acute respiratory syndrome*".mp.
10 ((outbreak* or wildlife* or pandemic* or epidemic*) adj2 (China* or Chinese* or Huanan*)).mp.
11 ((corona* or corono*) adj2 (virus* or viral* or virinae*)).mp.
12 1 or 2 or 3 or 8 or 9 or 10 or 11
13 hydroxychloroquine/ or chloroquine/ or chloroquin*.mp.
14 Oxychloroquin*.mp.
15 (Aralen or Plaquenil).mp.
16 (antimalaria* or anti-malaria*).mp.
17 antimalarial agent/ or antimalarial agent*.mp.
18 13 or 14 or 15 or 16 or 17
19 12 and 18
Search Name: Cochrane Central Register of Controlled Trials
Issue 9 of 12, September 2020
#1 MeSH descriptor: [Coronavirus] explode all trees
#2 (coronavirus* or coronovirus* or coronavirinae* or Coronavirus* or Coronovirus* or Wuhan* or Hubei* or Huanan or "2019-

nCoV" or 2019nCoV or nCoV2019 or "nCoV-2019" or "COVID-19" or COVID19 or "CORVID-19" or CORVID19 or "WN-CoV" or WNCoV or
"HCoV-19" or HCoV19 or CoV or "2019 novel*" or Ncov or "n-cov" or "SARS-CoV-2" or "SARSCoV-2" or "SARSCoV2" or "SARS-CoV2" or
SARSCov19 or "SARS-Cov19" or "SARSCov-19" or "SARS-Cov-19" or Ncovor or Ncorona* or Ncorono* or NcovWuhan* or NcovHubei*
or NcovChina* or NcovChinese*)
#3 respiratory* AND (symptom* or disease* or illness* or condition*) AND (Wuhan* or Hubei* or China* or Chinese* or Huanan*)
#4 ("seafood market*" or "food market*") AND (Wuhan* or Hubei* or China* or Chinese* or Huanan*)
#5 "severe acute respiratory syndrome*"
#6 ((outbreak* or wildlife* or pandemic* or epidemic*) AND (China* or Chinese* or Huanan*))
#7 (corona* or corono*) AND (virus* or viral* or virinae*)
#8 #1 or #2 or #3 or #4 or #5 or #6 or #7
#9 chloroquin*
#10 Hydroxychloroquin* OR Oxychloroquin*
#11 MeSH descriptor: [Chloroquine] explode all trees
#12 MeSH descriptor: [Hydroxychloroquine] explode all trees

Collaboration.
Informed decisions.

(Continued)
#13 Aralen or Plaquenil
#14 antimalaria* or anti-malaria*
#15 #9 or #10 or #11 or #12 or #13 or #14
#16 #8 and #15

HISTORY
Protocol first published: Issue 4, 2020
Review first published: Issue 2, 2021

Date Event Description
22 April 2020 Amended Amended protocol title and updated Hannah Ryan affiliation de-
tails

CONTRIBUTIONS OF AUTHORS
BS and HR prepared initial drafts of Background and Methods; selected studies; assessed risk of bias; extracted data; synthesized data; and
prepared initial drafts of results, 'Summary of findings' tables, discussion, and conclusions.
MC helped complete the Background and Methods; selected studies; assessed risk of bias; extracted data; synthesized data; and helped
prepare and complete results, 'Summary of findings' tables, discussion, and conclusions.
TK helped complete the Background and Methods; assessed risk of bias; extracted data; and helped prepare and complete
results, 'Summary of findings' tables, discussion, and conclusions.
TF helped complete the Background and Methods, results, 'Summary of findings' tables, discussion, and conclusions.
All authors read and approved the final version of the review.
DECLARATIONS OF INTEREST
BS is a Clinical Research Fellow for the National Institute for Health Research (NIHR) Global Health Research Group on Brain Infections at
the University of Liverpool (No. 17/63/110) and in the NIHR Health Protection Research Unit on Emerging and Zoonotic Infections, and also
works at the Royal Liverpool University Hospital, UK, and Christian Medical College, Vellore, India. He has no known conflicts of interest to
declare with respect to chloroquine or hydroxychloroquine for the management of COVID-19.
HR is a Specialist Registrar in Clinical Pharmacology in Liverpool, and is employed as a full-time NHS clinician, and has no conflicts of
interest to declare with respect to chloroquine or hydroxychloroquine for the management of COVID-19.
TK has no conflicts of interest to declare with respect to chloroquine or hydroxychloroquine for the management of COVID-19.
MC has no conflicts of interest to declare with respect to chloroquine or hydroxychloroquine for the management of COVID-19.
TF has no conflicts of interest to declare with respect to chloroquine or hydroxychloroquine for the management of COVID-19.
SOURCES OF SUPPORT
Internal sources
• Liverpool School of Tropical Medicine, UK
External sources
• Foreign, Commonwealth and Development Office (FCDO), UK
Project number 300342-104

Collaboration.
Informed decisions.

• National Institute for Health Research (NIHR), UK
BS receives support from the UK NIHR through its Global Health Research Group on Brain Infections (No. 17/63/110). The views
expressed in this review do not necessarily reflect UK government policy.
• Medical Research Council (MRC), UK
BS receives support from the MRC (project number MR/V033441/1). The views expressed in this review do not necessarily reflect UK
government policy.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
Regarding outcomes for Objective 1 - treatment of COVID-19, the review uses a different primary outcome measure for virological
clearance: negative polymerase chain reaction (PCR) test at 14 days is used in place of time to negative PCR for SARS-CoV-2; the latter
was not measured and reported consistently by trials. For serious adverse events, because most trials did not report attribution to
hydroxychloroquine, and as a comparative outcome it may also be more relevant, total participants with any serious adverse events was
used for analysis.
No subgroup analyses were conducted due to an inability to extract disaggregated data for the predefined subgroups.
Trials reported intention-to-treat as the primary analysis approach for the review's primary outcomes, so this was used for the primary
meta-analyses within the review, rather than the planned available-case analysis. We performed a sensitivity analysis using modified
intention-to-treat data, where trials reported this information.
INDEX TERMS
Medical Subject Headings (MeSH)

Antimalarials [adverse effects] [*therapeutic use]; Antiviral Agents [adverse effects] [therapeutic use]; Bias; Cause of Death;
Chloroquine [adverse effects] [*therapeutic use]; COVID-19 [*drug therapy] [epidemiology] [mortality] [*prevention & control];
COVID-19 Nucleic Acid Testing [statistics & numerical data]; Hydroxychloroquine [adverse effects] [*therapeutic use]; Pandemics;
Prognosis; Randomized Controlled Trials as Topic; Respiration, Artificial [statistics & numerical data]; *SARS-CoV-2; Standard of Care;
Treatment Outcome
MeSH check words

Adult; Aged; Humans; Middle Aged

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Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T

Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T.

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) ii

Chloroquine or hydroxychloroquine for prevention and treatment of

Contact address: Bhagteshwar Singh, bsingh@liverpool.ac.uk.

Editorial group: Cochrane Infectious Diseases Group.

1) treating people with COVID-19 on death and time to clearance of the virus;

2) preventing infection in people at risk of SARS-CoV-2 exposure;

3) preventing infection in people exposed to SARS-CoV-2.

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 1

Data collection and analysis

2. Preventing COVID-19 disease in people at risk of exposure to SARS-CoV-2

Ongoing trials are yet to report results for this objective.

3. Preventing COVID-19 disease in people who have been exposed to SARS-CoV-2

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 2

What is the aim of this review?

What was studied in the review?

What are the main results of our review?

Compared with usual care or placebo, hydroxychloroquine:

· how many people died;

· how many needed mechanical ventilation; or

· time spent in hospital.

Preventing COVID-19 in people exposed to it

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 3

How confident are we in our results?

How up-to-date is this review?

We included evidence published up to 15 September 2020.

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 4

Settings: hospital inpatients and ambulatory care in the community

Outcomes Anticipated absolute effects* Relative effect № of partici- Certainty of Comments

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

Outcomes Anticipated absolute effects* Relative effect № of partici- Certainty of Comments

Cochrane Database of Systematic Reviews

Cochrane Database of Systematic Reviews

BACKGROUND Transmission is common in, though not limited to, households

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 9

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 11

METHODS Secondary outcomes

• Development of COVID-19 in household contacts of the recipient

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 12

Figure 1. Study flow diagram.

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 14

Data synthesis RESULTS

Sensitivity analysis Trial size

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 15

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 17

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 18

Blinding of participants and personnel (performance bias): All outcomes

Selective reporting (reporting bias)

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 19

Allocation Incomplete outcome data

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 20

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 21

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 22

Comparison 5: HCQ versus placebo by individual randomization DISCUSSION

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 23

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 24

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) 25