The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Triple Inhaled Therapy at Two Glucocorticoid

Doses in Moderate-to-Very-Severe COPD
Klaus F. Rabe, M.D., Ph.D., Fernando J. Martinez, M.D., Gary T. Ferguson, M.D.,
Chen Wang, M.D., Ph.D., Dave Singh, M.D., Jadwiga A. Wedzicha, M.D.,
Roopa Trivedi, M.S., Earl St. Rose, M.S., Shaila Ballal, M.S., Julie McLaren, M.D.,
Patrick Darken, Ph.D., Magnus Aurivillius, M.D., Ph.D., Colin Reisner, M.D.,
and Paul Dorinsky, M.D., for the ETHOS Investigators*​​

A BS T R AC T

BACKGROUND
Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic From LungenClinic Grosshansdorf and
antagonist (LAMA), and a long-acting β2-agonist (LABA) for chronic obstructive Christian-Albrechts University Kiel, Airway
Research Center North, German Center
pulmonary disease (COPD) have been studied at single dose levels of inhaled glu- for Lung Research (DZL), Grosshansdorf,
cocorticoid, but studies at two dose levels are lacking. Germany (K.F.R.); the Joan and Sanford I.
Weill Department of Medicine, Weill Cor-
METHODS nell Medicine, New York (F.J.M.); the Pul-
In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple monary Research Institute of Southeast
Michigan, Farmington Hills (G.T.F.); the
therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to- National Clinical Research Center for Re-
very-severe COPD and at least one exacerbation in the past year, we assigned pa- spiratory Diseases, China–Japan Friend-
tients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled ship Hospital, Beijing (C.W.); the Medi-
cines Evaluation Unit, University of
glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], Manchester, Manchester University NHS
and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyr- Foundation Hospitals Trust, Manchester
rolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). (D.S.), and the National Heart and Lung
Institute, Imperial College London, Lon-
The primary end point was the annual rate (the estimated mean number per patient don (J.A.W.) — both in the United King-
per year) of moderate or severe COPD exacerbations, as analyzed in the modified dom; AstraZeneca, Durham, NC (R.T., P.
intention-to-treat population with the use of on-treatment data only. Dorinsky); AstraZeneca, Morristown, NJ
(E.S.R., S.B., P. Darken, C.R.); AstraZen-
RESULTS eca, Gaithersburg, MD (J.M.); and Astra-
The modified intention-to-treat population comprised 8509 patients. The annual Zeneca, Gothenburg, Sweden (M.A.).
Address reprint requests to Dr. Rabe at
rates of moderate or severe exacerbations were 1.08 in the 320-μg–budesonide LungenClinic Grosshansdorf, Wöhren-
triple-therapy group (2137 patients), 1.07 in the 160-μg–budesonide triple-therapy damm 80, 22927 Grosshansdorf, Ger-
group (2121 patients), 1.42 in the glycopyrrolate–formoterol group (2120 patients), many, or at ­k​.­f​.­rabe@​­lungenclinic​.­de.

and 1.24 in the budesonide–formoterol group (2131 patients). The rate was sig- *A complete list of the ETHOS trial inves-
nificantly lower with 320-μg–budesonide triple therapy than with glycopyrrolate– tigators is provided in the Supplemen-
tary Appendix, available at NEJM.org.
formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83;
P<0.001) or budesonide–formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to This article was published on June 24,
2020, at NEJM.org.
0.95; P = 0.003). Similarly, the rate was significantly lower with 160-μg–budesonide
triple therapy than with glycopyrrolate–formoterol (25% lower: rate ratio, 0.75; N Engl J Med 2020;383:35-48.
DOI: 10.1056/NEJMoa1916046
95% CI, 0.69 to 0.83; P<0.001) or budesonide–formoterol (14% lower: rate ratio, Copyright © 2020 Massachusetts Medical Society.
0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was
similar across the treatment groups (range, 61.7 to 64.5%); the incidence of con-
firmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled
glucocorticoid use and was 2.3% in the glycopyrrolate–formoterol group.
CONCLUSIONS
Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose),
glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD
exacerbations than glycopyrrolate–formoterol or budesonide–formoterol. (Funded by
AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.)
n engl j med 383;1  nejm.org  July 2, 2020 35
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 The n e w e ng l a n d j o u r na l of m e dic i n e

T
reatment recommendations for The trial was designed by the sponsor (Astra-
chronic obstructive pulmonary disease Zeneca) and the principal academic investigators.
(COPD) involve a stepwise approach, in Data were collected by the clinical investigators
which treatments are added as necessary to con- and were analyzed by the employees of Everest
A Quick Take is
trol symptoms and reduce or eliminate exacerba- Clinical Research Services and AstraZeneca. The
available at tions,1 with an additional goal of reducing mor- first draft of the manuscript was written by a
NEJM.org tality from the disease. Triple therapy with an medical writer (funded by the sponsor) under
inhaled glucocorticoid, a long-acting muscarinic the direction of the authors, in accordance with
antagonist (LAMA), and a long-acting β2-agonist Good Publication Practice guidelines.12 All the
(LABA) was shown to lead to a lower risk of authors critically reviewed and provided feed-
COPD exacerbations, a greater reduction in symp- back on all subsequent versions of the manu-
toms, and better lung function and health-related script and, along with the sponsor, made the deci-
quality of life than dual therapies2-6 and is rec- sion to submit the manuscript for publication. All
ommended for patients who continue to have the authors had access to the data, contributed
symptoms or exacerbations while receiving dual to the interpretation of the data, and vouch for
therapy with LAMA–LABA or inhaled glucocorti- the accuracy and completeness of the data and
coid–LABA.1 for the fidelity of the trial to the protocol.
Adverse events associated with inhaled gluco-
corticoids include pneumonia, bone fractures, Patients and Randomization
and cataracts, for which the magnitude of risk Eligible patients were 40 to 80 years of age and
may depend on the duration, dose, and type of had symptomatic COPD (defined as a score of
inhaled glucocorticoid treatment.7-10 Therefore, ≥10 on the COPD Assessment Test, on which
in a 52-week trial involving symptomatic patients scores range from 0 to 40, with higher scores
with moderate-to-very-severe COPD and at least indicating more symptoms; the minimum clini-
one exacerbation in the preceding year, we com- cally important difference is 2 points); were receiv-
pared the efficacy and safety of two single-inhaler, ing at least two inhaled maintenance therapies at
triple fixed-dose combinations (i.e., budesonide the time of screening; had a postbronchodilator
at two different doses plus a LAMA and a LABA) ratio of the forced expiratory volume in 1 second
with those of two dual therapies (LAMA–LABA (FEV1) to the forced vital capacity of less than
and inhaled glucocorticoid–LABA). 0.7, with a postbronchodilator FEV1 of 25 to 65%
of the predicted normal value; had a smoking
history of at least 10 pack-years; and had a docu-
Me thods
mented history of at least one moderate or severe
Trial Design and Oversight COPD exacerbation (if their FEV1 was <50% of
The Efficacy and Safety of Triple Therapy in Ob- the predicted normal value) or at least two mod-
structive Lung Disease (ETHOS) trial was a erate or at least one severe COPD exacerbation (if
phase 3, randomized, double-blind, parallel-group their FEV1 was ≥50% of the predicted normal
trial conducted in 26 countries. The trial design value) in the year before screening. Patients who
has been published previously,11 and the trial had a current diagnosis of asthma were exclud-
protocol and statistical analysis plan are avail- ed, but those who had had asthma in the past
able with the full text of this article at NEJM.org. (e.g., as a child or adolescent) were eligible. In-
The protocol and informed consent form were vestigators were advised not to enroll patients
approved by the appropriate institutional review who had received a diagnosis of active asthma
board, independent ethics committee, or health within the past 5 to 10 years.
authority; written informed consent was obtained Eligible patients were randomly assigned in a
from all patients before screening. An indepen- 1:1:1:1 ratio to receive triple therapy (an inhaled
dent data monitoring committee and an inde- glucocorticoid at one of two dose levels [bude­
pendent clinical end-point committee reviewed sonide, 160 μg or 80 μg per inhaler actuation],
safety data throughout the trial, including car- a LAMA [glycopyrrolate, 9 μg per actuation], and
diovascular and cerebrovascular events, pneu- a LABA [formoterol fumarate, 4.8 μg per actua-
monia, and cause-specific deaths. tion]) or one of two dual therapies (LAMA–LABA

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 Triple Inhaled Ther apy in Moder ate-to-Very-Severe COPD

[glycopyrrolate, 9 μg per actuation, and formoterol secondary end points included in the statistical
fumarate, 4.8 μg per actuation] or inhaled glu- approach used outside the United States and of
cocorticoid–LABA [budesonide, 160 μg per ac- additional predefined end points are provided in
tuation, and formoterol fumarate, 4.8 μg per Table S1 in the Supplementary Appendix, avail-
actuation]). All treatments were administered able at NEJM.org.
through identical metered-dose inhalers (Aero- Subgroup analyses of the primary end point
sphere, AstraZeneca) that were supplied by the were also performed. Three subgroup analyses
sponsor. The patients received two doses per day were prespecified for subgroups defined accord-
over a 52-week period, and each dose consisted ing to exacerbation history (≥2 moderate or se-
of two actuations (i.e., each dose of triple thera- vere exacerbations in the preceding year), in-
py delivered 320 μg or 160 μg of budesonide). haled glucocorticoid use at the time of screening
Randomization was stratified according to exac- (using or not using inhaled glucocorticoids), and
erbation history (1 or ≥2 moderate or severe ex- blood eosinophil count (<150 or ≥150 cells per
acerbations), postbronchodilator FEV1 (25 to cubic millimeter); the subgroup analysis accord-
<50% or 50 to <65% of the predicted normal ing to blood eosinophil count was supplemented
value), blood eosinophil count (<150 or ≥150 by a generalized additive model predicting exac-
cells per cubic millimeter), and country. Patients erbation rates on the basis of eosinophil count
discontinued maintenance medications for as a continuous variable. One subgroup analysis
COPD after the first screening visit (except for was performed post hoc for a subgroup defined
inhaled glucocorticoids if used before screening) according to bronchodilator reversibility at the
and received scheduled treatment with ipratro- time of screening (with or without bronchodila-
pium and as-needed treatment with albuterol tor reversibility, defined as an increase in FEV1
during the screening period (1 to 4 weeks). Ip- of ≥12% and ≥200 ml after administration of
ratropium and inhaled glucocorticoids were dis- albuterol).
continued at the time of randomization. A comprehensive framework, as described in
recent regulatory guidelines,13 was used to pro-
End Points vide clarity in the description of estimates of
The primary efficacy end point was the annual treatment effect, including the handling of po-
rate (the estimated mean number per patient per tentially confounding events, such as treatment
year) of moderate or severe COPD exacerbations. discontinuations. Each approach is denoted by a
Moderate exacerbations were defined as those different “estimand” — a target of estimation
leading to treatment with systemic glucocorti- that includes the analysis population and the
coids, antibiotics, or both for at least 3 days; end-point variable or variables and prespecifies
severe exacerbations were defined as those re- the way in which these confounding events will
sulting in hospitalization or death. Secondary be handled in the analysis. Although this termi-
end points were defined according to the re- nology is relatively new, analyses that use an
gional statistical approach used.11 The secondary efficacy estimand are similar to those tradition-
end points included in the statistical approach ally used in previous trials evaluating COPD ex-
used in the United States were the time to the acerbations, as is the approach of using a treat-
first moderate or severe COPD exacerbation, the ment policy estimand to evaluate time to death.
change from baseline in average daily use of Most efficacy analyses were conducted in the
rescue medication over 24 weeks, the percentage modified intention-to-treat population (all pa-
of patients who had a St. George’s Respiratory tients who underwent randomization, received a
Questionnaire (SGRQ) response (defined as a trial treatment, and had postrandomization data
decrease from baseline in the total score on the obtained before discontinuation of treatment)
SGRQ of ≥4 points at week 24 [total scores range with the use of an efficacy estimand, which in-
from 0 to 100, with lower scores indicating bet- cluded only data obtained from patients while
ter health-related quality of life; the minimum they were receiving a trial treatment. There were
clinically important difference is 4 points]), the two exceptions: the secondary analysis of the
annual rate of severe COPD exacerbations, and primary end point and the analysis of time to
time to death from any cause. Details of the death. The secondary analysis of the primary

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 The n e w e ng l a n d j o u r na l of m e dic i n e

end point was conducted in the modified inten- Figure 1 (facing page). Screening, Randomization,
tion-to-treat population with the use of an attrib- and Treatment.
utable estimand, in which data obtained after Shown is the distribution of patients during screening,
treatment discontinuation due to lack of efficacy randomization, and treatment. The patients in the 320-μg–
or adverse events were imputed as “poor respons- budesonide triple-therapy group received twice-daily
es.”14 Time to death was assessed in the inten- doses of 320 μg of budesonide, 18 μg of glycopyrrolate,
and 9.6 μg of formoterol fumarate; those in the 160-μg–
tion-to-treat population (all patients who under- budesonide triple-therapy group received twice-daily
went randomization and received any amount of doses of 160 μg of budesonide, 18 μg of glycopyrrolate,
trial treatment) with the use of a treatment pol- and 9.6 μg of formoterol fumarate; those in the glyco-
icy estimand, which included all observed data pyrrolate–formoterol group received twice-daily doses
obtained from patients regardless of whether they of 18 μg of glycopyrrolate and 9.6 μg of formoterol fu-
marate; and those in the budesonide–formoterol group
continued to receive their assigned treatment. received twice-daily doses of 320 μg of budesonide and
With respect to the primary end point, the 9.6 μg of formoterol fumarate. The intention-to-treat
treatment groups were compared in the follow- population included all patients who underwent ran-
ing order: the 320-μg–budesonide triple-therapy domization and received any amount of trial treatment.
group versus the glycopyrrolate–formoterol group, The modified intention-to-treat population included all
patients in the intention-to-treat population with post-
the 320-μg–budesonide triple-therapy group versus randomization data obtained before discontinuation
the budesonide–formoterol group, the 160-μg– of treatment. Any data collected after completion of,
budesonide triple-therapy group versus the glyco- or discontinuation of, the assigned trial regimen was
pyrrolate–formoterol group (all to assess superi- excluded from the modified intention-to-treat analysis
ority), and the 160-μg–budesonide triple-therapy but included in the intention-to-treat analysis. The safety
population included all patients who underwent random-
group versus the budesonide–formoterol group ization, received any amount of treatment, and had a
(to assess noninferiority and then superiority). postrandomization safety assessment. Forty-four pa-
The safety population was similar to the tients were excluded from all analysis populations be-
modified intention-to-treat population, except cause of overlapping treatment exposure from partici-
that the patients were evaluated according to the pating multiple times in the same study or participating
concurrently in another study. An additional 20 patients
treatment they received rather than to their as- were not included in the modified intention-to-treat pop-
signed treatment; those with no postrandomiza- ulation (8509 patients) because they had multiple enroll-
tion safety assessment were excluded. Safety as- ments, although with nonoverlapping treatment expo-
sessments included physical examinations, vital sure (19 patients) or because of administrative reasons
signs, electrocardiograms, clinical laboratory tests, (1 patient); these patients were included in the safety
population (8529 patients).
and monitoring of adverse events. Subgroups of
patients also participated in substudies that in-
cluded 4-hour pulmonary-function testing and
24-hour Holter monitoring, but the results are was analyzed by means of a linear mixed model
not reported in this article. with repeated measures, and analysis of SGRQ
response was performed with the use of logis-
Statistical Analysis tic regression. For the comparison between the
A sample size of 8400 patients was estimated to 160-μg–budesonide triple-therapy group and
provide the trial with 93% power to detect a 15% the budesonide–formoterol group, the noninferi-
lower annual rate of moderate or severe exacer- ority margin for exacerbation end points was a
bations in the 320-μg–budesonide triple-therapy rate ratio of 1.1 for the upper bound of the two-
group than in both the glycopyrrolate–formoterol sided 95% confidence interval.
group and the budesonide–formoterol group
(96% power for each comparison), with type I R e sult s
error controlled at an equivalent of a two-sided
alpha level of 0.05 (further details are provided Patient Population
in the Supplementary Appendix). A total of 8588 patients underwent randomiza-
Rates of exacerbations were analyzed by means tion, and 8573 received a trial treatment (Fig. 1).
of negative binomial regression. Time-to-first- The safety population comprised 8529 patients,
event analyses were performed with the use of and the intention-to-treat and modified intention-
Cox regression. The use of rescue medication to-treat populations comprised 8509 patients each.

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 16,033 Patients assessed for eligibility

7445 Were excluded

8588 Underwent randomization

2157 Were assigned to 2137 Were assigned to 2143 Were assigned to 2151 Were assigned to
the 320-µg–budesonide the 160-µg–budesonide the glycopyrrolate– the budesonide–
triple-therapy group triple-therapy group formoterol group formoterol group

2156 Received any amount 2132 Received any amount 2139 Received any amount 2146 Received any amount
of treatment of treatment of treatment of treatment

2137 Were included 2144 Were included 2121 Were included 2124 Were included 2125 Were included 2120 Were included 2136 Were included 2131 Were included
in the modified in the safety in the modified in the safety in the safety in the modified in the safety in the modified

n engl j med 383;1  nejm.org  July 2, 2020

intention-to-treat population intention-to-treat population population intention-to-treat population intention-to-treat

The New England Journal of Medicine

and intention-to- and intention-to- and intention-to- and intention-to-
treat populations treat populations treat populations treat populations

1707 Completed 52 wk of treatment 1712 Completed 52 wk of treatment 1581 Completed 52 wk of treatment 1644 Completed 52 wk of treatment
Triple Inhaled Ther apy in Moder ate-to-Very-Severe COPD

Copyright © 2020 Massachusetts Medical Society. All rights reserved.

437 Discontinued treatment 412 Discontinued treatment 544 Discontinued treatment 492 Discontinued treatment
118 Had adverse event 114 Had adverse event 171 Had lack of efficacy 138 Had adverse event
104 Withdrew from trial 102 Had lack of efficacy 147 Had adverse event 136 Had lack of efficacy
103 Had lack of efficacy 94 Withdrew from trial 123 Withdrew from trial 130 Withdrew from trial
30 Had protocol deviation 33 Were withdrawn by investigator 38 Were withdrawn by investigator 28 Had protocol deviation
25 Were lost to follow-up 27 Had protocol deviation 26 Had protocol deviation 28 Were withdrawn by investigator
23 Were withdrawn by investigator 21 Were lost to follow-up 19 Were lost to follow-up 15 Were lost to follow-up
20 Met protocol-specified withdrawal 10 Met protocol-specified withdrawal 11 Had administrative reasons 12 Met protocol-specified withdrawal
criteria criteria 9 Met protocol-specified withdrawal criteria
13 Had administrative reasons 10 Had administrative reasons criteria 5 Had administrative reasons
1 Had no reason recorded 1 Had no reason recorded

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39
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Demographic Characteristics of the Patients at Baseline (Modified Intention-to-Treat Population).*

320-μg–Budesonide 160-μg–Budesonide Glycopyrrolate– Budesonide–

Triple Therapy Triple Therapy Formoterol Formoterol
Characteristic (N = 2137) (N = 2121) (N = 2120) (N = 2131)
Age — yr 64.6±7.6 64.6±7.6 64.8±7.6 64.6±7.6
Male sex — no. (%) 1260 (59.0) 1298 (61.2) 1244 (58.7) 1279 (60.0)
Current smoker — no. (%) 910 (42.6) 865 (40.8) 856 (40.4) 864 (40.5)
Pack-years of smoking 47.0±25.1 47.9±25.8 48.4±26.5 47.1±26.3
COPD exacerbations in the past 12 mo 1.7±0.8 1.7±0.9 1.7±0.8 1.7±0.9
— no.
0 Moderate or severe — no. (%) 2 (0.1) 2 (0.1) 2 (0.1) 2 (0.1)
1 Moderate or severe — no. (%) 940 (44.0) 932 (43.9) 907 (42.8) 912 (42.8)
≥2 Moderate or severe — no. (%) 1195 (55.9) 1187 (56.0) 1211 (57.1) 1217 (57.1)
≥1 Severe — no. (%) 451 (21.1) 463 (21.8) 429 (20.2) 458 (21.5)
Blood eosinophil count
Median (range) — cells/mm3 165 (0–2510) 167 (5–1590) 170 (5–2305) 167 (0–2430)
≥150 cells/mm3 — no. (%) 1277 (59.8) 1258 (59.3) 1272 (60.0) 1294 (60.7)
3
≥300 cells/mm — no. (%) 310 (14.5) 318 (15.0) 293 (13.8) 333 (15.6)
FEV1 after administration of albuterol 43.6±10.3 43.1±10.4 43.5±10.2 43.4±10.4
— % of the predicted normal value
50 to <80% of the predicted normal 613 (28.7) 604 (28.5) 596 (28.1) 614 (28.8)
value: moderate COPD — no. (%)
30 to <50% of the predicted normal 1305 (61.1) 1270 (59.9) 1293 (61.0) 1283 (60.2)
value: severe COPD — no. (%)
<30% of the predicted normal value: very 217 (10.2) 245 (11.6) 229 (10.8) 233 (10.9)
severe COPD — no. (%)
Change in FEV1 from before to after adminis- 146.3±158.0 144.4±151.7 148.7±151.1 142.3±144.8
tration of albuterol — ml
Bronchodilator reversibility — no. (%)† 657 (30.7) 631 (29.8) 669 (31.6) 654 (30.7)
Use of inhaled glucocorticoid at screening 1706 (79.8) 1729 (81.5) 1707 (80.5) 1704 (80.0)
— no. (%)
COPD Assessment Test score‡ 19.7±6.5 19.6±6.6 19.5±6.6 19.5±6.5

* Plus–minus values are means ±SD. The modified intention-to-treat population included all patients who underwent randomization, received
any amount of trial treatment, and had postrandomization data obtained before discontinuation of treatment. The 320-μg–budesonide triple-
therapy group received twice daily doses of 320 μg of budesonide, 18 μg of glycopyrrolate, and 9.6 μg of formoterol fumarate; the 160-μg–
budesonide triple-therapy group received twice-daily doses of 160 μg of budesonide, 18 μg of glycopyrrolate, and 9.6 μg of formoterol fuma-
rate; the glycopyrrolate–formoterol group received twice-daily doses of 18 μg of glycopyrrolate and 9.6 μg of formoterol fumarate; and the
budesonide–formoterol group received twice-daily doses of 320 μg of budesonide and 9.6 μg of formoterol fumarate. The doses of glycopyr-
rolate and formoterol fumarate are equivalent to 14.4 μg of glycopyrronium and 10 μg of formoterol fumarate dihydrate, respectively. COPD
denotes chronic obstructive pulmonary disease, and FEV1 forced expiratory volume in 1 second.
† Bronchodilator reversibility was defined as an increase in FEV1 of at least 12% and at least 200 ml after administration of albuterol.
‡ Scores on the COPD Assessment Test range from 0 to 40, with higher scores indicating more symptoms; the minimum clinically important
difference in score is 2 points.

A total of 7187 patients (83.8%) completed the rolate–formoterol group, and 76.6% in the
trial, of whom 6654 (77.6%) completed 52 weeks budesonide–formoterol group).
of treatment (79.4% and 80.4% in the 320-μg– The demographic characteristics of the patients
budesonide and 160-μg–budesonide triple-ther- in the modified intention-to-treat population
apy groups, respectively, 74.1% in the glycopyr- were similar across treatment groups (Table 1).

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 Triple Inhaled Ther apy in Moder ate-to-Very-Severe COPD

Overall, 80.5% of the patients were using in- inferiority analysis of the annual rate of severe
haled glucocorticoids at the time of screening; exacerbations that was performed in the per-
other previously used COPD medications are protocol population (all patients with postran-
listed in Table S3. domization data obtained before any major pro-
tocol deviations), 160-μg–budesonide triple therapy
Primary Efficacy Analyses was shown to be noninferior to budesonide–
The model-estimated annual rates of moderate or formoterol (rate ratio, 0.82; 95% CI, 0.68 to
severe exacerbations were 1.08 in the 320-μg– 1.00); however, differences between the 160-μg–
budesonide triple-therapy group, 1.07 in the budesonide triple-therapy group and either dual-
160-μg–budesonide triple-therapy group, 1.42 in therapy group were not significant (Table 2). The
the glycopyrrolate–formoterol group, and 1.24 change from baseline in the use of rescue medi-
in the budesonide–formoterol group. The annual cation over 24 weeks and the proportion of pa-
rate of moderate or severe exacerbations was tients with an SGRQ response at week 24 are
significantly lower with 320-μg–budesonide tri- shown in Table S4.
ple therapy than with glycopyrrolate–formoterol In time-to-first-event analyses performed with
(24% lower: rate ratio, 0.76; 95% confidence in- the use of the treatment policy estimand in the
terval [CI], 0.69 to 0.83; P<0.001) or budesonide– intention-to-treat population, the risk of death
formoterol (13% lower: rate ratio, 0.87; 95% CI, from any cause in the 320-μg–budesonide triple-
0.79 to 0.95; P = 0.003). Similarly, the annual rate therapy group was 46% lower than that in the
of moderate or severe exacerbation was signifi- glycopyrrolate–formoterol group (28 vs. 49 deaths;
cantly lower with 160-μg–budesonide triple ther- hazard ratio, 0.54; 95% CI, 0.34 to 0.87) and
apy than with glycopyrrolate–formoterol (25% 22% lower than that in the budesonide–formoterol
lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; group (28 vs. 34 deaths; hazard ratio, 0.78; 95%
P<0.001) or budesonide–formoterol (14% lower: CI, 0.47 to 1.30). The risk of death from any
rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002) cause in the 160-μg–budesonide triple-therapy
(Table 2). No difference was observed between group was lower than that in the glycopyrrolate–
the two triple-therapy groups (rate ratio, 1.00; formoterol group (39 vs. 49 deaths; hazard ratio,
95% CI, 0.91 to 1.10). 0.79; 95% CI, 0.52 to 1.20) but higher than that
in the budesonide–formoterol group (39 vs. 34
Secondary and Other Efficacy Analyses deaths; hazard ratio, 1.13; 95% CI, 0.72 to 1.80)
In the secondary analysis of the primary end (Fig. 2B and Table 2). Adjudicated causes of death
point, the rate ratios of moderate or severe exac- are provided in Table S5.
erbations that were determined with the use of the Data on prespecified subgroup analyses of
attributable estimand were similar to the rate the rates of moderate or severe exacerbations
ratios in the primary analysis (Table 2). Both according to baseline eosinophil counts, the use
triple-therapy regimens significantly prolonged of inhaled glucocorticoids at the time of screen-
the time to the first moderate or severe exacer- ing, and bronchodilator reversibility at the time
bation as compared with both dual therapies of screening are provided in Figures S4 and S5
(Fig. 2A and Table 2). and Table S6. The triple-therapy regimens showed
The model-estimated annual rates of severe a benefit over the dual-therapy regimens with
exacerbations were 0.13 in the 320-μg–bude­ respect to the annual rate of moderate or severe
sonide triple-therapy group, 0.14 in the 160-μg– exacerbations in both eosinophil subgroups
budesonide triple-therapy group, 0.15 in the (<150 and ≥150 cells per cubic millimeter) and
glycopyrrolate–formoterol group, and 0.16 in the regardless of whether the patients were using
budesonide–formoterol group. The rate ratio of inhaled glucocorticoids or had bronchodilator
severe exacerbations over 52 weeks in the 320-μg– reversibility at the time of screening.
budesonide triple-therapy group was 16% lower
than in the glycopyrrolate–formoterol group Safety and Adverse-Event Profile
(0.84; 95% CI, 0.69 to 1.03; P = 0.09) and 20% The percentage of patients who had at least one
lower than in the budesonide–formoterol group adverse event ranged from 61.7 to 64.5% across
(0.80; 95% CI, 0.66 to 0.97; P = 0.02). In the non- treatment groups. The percentage of patients

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Efficacy End Points.*

320-μg–Budesonide 160-μg–Budesonide Glycopyrrolate– Budesonide–

Triple Therapy Triple Therapy Formoterol Formoterol
End Point (N = 2137) (N = 2121) (N = 2120) (N = 2131)
Primary end point
Primary analysis: model-estimated annual rate of mod- 1.08 1.07 1.42 1.24
erate or severe COPD exacerbations
320-μg–Budesonide triple therapy vs. comparators
Rate ratio for moderate or severe exacerbations — 1.00 (0.91–1.10) 0.76 (0.69–0.83) 0.87 (0.79–0.95)
(95% CI)
P value† — <0.001 0.003
160-μg–Budesonide triple therapy vs. comparators
Rate ratio for moderate or severe exacerbations — — 0.75 (0.69–0.83) 0.86 (0.79–0.95)
(95% CI)
P value <0.001 0.002
Secondary analysis: model-estimated annual rate of 1.25 1.23 1.63 1.47
moderate or severe COPD exacerbations
(attributable estimand)‡
320-μg–Budesonide triple therapy vs. comparators
Rate ratio for moderate or severe exacerbations — 1.01 (0.94–1.10) 0.76 (0.71–0.83) 0.85 (0.78–0.92)
(95% CI)
P value† — <0.001 <0.001
160-μg–Budesonide triple therapy vs. comparators
Rate ratio for moderate or severe exacerbations — — 0.75 (0.70–0.82) 0.84 (0.77–0.90)
(95% CI)
P value <0.001 <0.001
Secondary exacerbation and mortality end points
Time to first moderate or severe COPD exacerbation
over 52 wk
Patients with exacerbations — no. (%) 1026 (48.0) 1013 (47.8) 1056 (49.8) 1085 (50.9)
320-μg–Budesonide triple therapy vs. comparators
Hazard ratio for moderate or severe exacerba- — 1.02 (0.93–1.11) 0.88 (0.81–0.96) 0.89 (0.81–0.97)
tion (95% CI)
P value† — 0.004 0.006
160-μg–Budesonide triple therapy vs. comparators
Hazard ratio for moderate or severe exacerba- — — 0.87 (0.79–0.94) 0.87 (0.80–0.95)
tion (95% CI)
P value 0.001 0.002
Model-estimated annual rate of severe COPD exacer- 0.13 0.14 0.15 0.16
bations
320-μg–Budesonide triple therapy vs. comparators
Rate ratio for severe exacerbations (95% CI) — 0.96 (0.78–1.17) 0.84 (0.69–1.03) 0.80 (0.66–0.97)
P value† — 0.09 0.02
160-μg–Budesonide triple therapy vs. comparators
Rate ratio for severe exacerbations (95% CI) — — 0.88 (0.72–1.08) 0.83 (0.69–1.01)
Time to death from any cause over 52 wk (treatment
policy estimand)§
Patient deaths — no. (%) 28 (1.3) 39 (1.8) 49 (2.3) 34 (1.6)

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 Triple Inhaled Ther apy in Moder ate-to-Very-Severe COPD

Table 2. (Continued.)

320-μg–Budesonide 160-μg–Budesonide Glycopyrrolate– Budesonide–

Triple Therapy Triple Therapy Formoterol Formoterol
End Point (N = 2137) (N = 2121) (N = 2120) (N = 2131)
320-μg–Budesonide triple therapy vs. comparators
Hazard ratio for death (95% CI) — 0.69 (0.42–1.13) 0.54 (0.34–0.87) 0.78 (0.47–1.30)
160-μg–Budesonide triple therapy vs. comparators
Hazard ratio for death (95% CI) — — 0.79 (0.52–1.20) 1.13 (0.72–1.80)

* Efficacy analyses were performed in the modified intention-to-treat population with the use of an efficacy estimand, unless otherwise speci-
fied; the efficacy estimand included only data obtained from patients while they were receiving a trial treatment. The annual rate is the esti-
mated mean number of exacerbations per patient per year. Additional secondary end points are reported in Table S4.
† Comparisons between the 320-μg–budesonide triple-therapy group and the 160-μg–budesonide triple-therapy group were not included in
the testing hierarchy and thus no P values are provided.
‡ The secondary analysis of the primary end point was performed with an attributable estimand, where data obtained after treatment discon-
tinuation due to lack of efficacy or adverse events were imputed as “poor responses.”
§ The analysis of time to death from any cause over 52 weeks was performed in the intention-to-treat population (all patients who underwent
randomization and received any amount of trial treatment) with the use of a treatment policy estimand, which included all observed data
from the patients regardless of whether they continued to receive their assigned treatment.

who had serious adverse events ranged from findings, or clinical laboratory test results were
19.9 to 21.0% across treatment groups. The most observed among the treatment groups.
frequently reported adverse events overall were
nasopharyngitis (10.5%), COPD (10.4%), and up- Discussion
per respiratory tract infection (5.6%) (Table 3).
The incidence of confirmed pneumonia In this randomized trial involving more than
ranged from 3.5 to 4.5% in the treatment groups 8500 patients with moderate-to-very-severe COPD,
that received an inhaled glucocorticoid (41.3 to single-inhaler triple therapy with an inhaled
57.8 events per 1000 patient-years) and was 2.3% glucocorticoid (budesonide, 320 μg or 160 μg
in the glycopyrrolate–formoterol group (28.8 twice daily) plus LAMA–LABA (glycopyrrolate–
events per 1000 patient-years). The time to the formoterol) resulted in significantly lower rates
first confirmed pneumonia event was longer in of moderate or severe exacerbations than dual
the glycopyrrolate–formoterol group than in the therapy with LAMA–LABA or inhaled glucocor-
treatment groups that received an inhaled gluco- ticoid–LABA. In addition, both triple-therapy
corticoid (P<0.05 for all comparisons) (Table S7). regimens significantly improved patient-reported
The incidence of serious confirmed pneumonia outcomes as compared with either dual-therapy
events was higher in the treatment groups that regimen.
received an inhaled glucocorticoid (range, 2.4 to The ETHOS trial assessed two different doses
3.0%) than in the glycopyrrolate–formoterol group of an inhaled glucocorticoid in fixed-dose triple
(1.3%) (P<0.05 for all comparisons) (Table 3 and therapy for COPD. Although a statistical evalua-
Table S8). A similar pattern was observed for tion of a dose–response relationship was not
pharmacologically expected local effects of glu- part of our testing hierarchy and the trial was
cocorticoids (dysphonia and candidiasis), with a not powered to detect a significant difference
lower incidence in the glycopyrrolate–formoterol between the triple-therapy regimens, unadjusted
group than in the treatment groups that received comparisons between these regimens showed
an inhaled glucocorticoid (P<0.05 for all com- similar efficacy with respect to most exacerba-
parisons), whereas the incidence of other sys- tion-related end points. These comparisons also
temic effects of glucocorticoids (diabetes melli- showed trends in favor of 320-μg–budesonide
tus, bone fracture, and ocular effects) were triple therapy with respect to severe exacerba-
similar across treatment groups (P>0.05 for all tions, SGRQ response, and use of rescue medica-
comparisons; Table S10). No clinically meaning- tion. Furthermore, despite a mortality of 1.8%
ful differences in vital signs, electrocardiogram overall, when the triple-therapy regimens were

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 The n e w e ng l a n d j o u r na l of m e dic i n e

320-µg–Budesonide 160-µg–Budesonide Glycopyrrolate– Budesonide–

triple therapy triple therapy formoterol formoterol

A Moderate or Severe COPD Exacerbation in the Modified Intention-to-Treat Population

100

90

80

Cumulative Incidence (%)

70

60

50

40

30

20

10

0
0 4 8 12 16 20 24 28 36 44 52
Weeks since Randomization
No. at Risk
320-µg–Budesonide 2137 1989 1776 1651 1523 1402 1318 1241 1106 996 760
triple therapy
160-µg–Budesonide 2121 1936 1767 1623 1510 1426 1347 1259 1108 985 767
triple therapy
Glycopyrrolate– 2120 1849 1633 1466 1338 1251 1166 1096 988 907 692
formoterol
Budesonide– 2131 1935 1721 1564 1410 1300 1196 1119 989 899 678
formoterol

B Death from Any Cause in the Intention-to-Treat Population

100

90
3
80
Cumulative Incidence (%)

70 2
60

50 1

40
0
30 0 4 8 12 16 20 24 28 32 36 40 44 48 52
20

10

0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Weeks since Randomization
No. at Risk
320-µg–Budesonide 2137 2134 2123 2113 2104 2094 2083 2071 2063 2053 2037 2024 2015 1984
triple therapy
160-µg–Budesonide 2121 2119 2108 2102 2088 2077 2067 2059 2047 2036 2023 2010 2002 1989
triple therapy
Glycopyrrolate– 2120 2113 2100 2090 2071 2063 2053 2036 2023 2015 2002 1985 1979 1950
formoterol
Budesonide– 2131 2123 2106 2097 2088 2078 2066 2055 2044 2038 2029 2021 2009 1989
formoterol

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 Triple Inhaled Ther apy in Moder ate-to-Very-Severe COPD

Figure 2 (facing page). Kaplan–Meier Estimates The lower rates of moderate or severe exacer-
of the Cumulative Incidence of Moderate or Severe bations in the triple-therapy groups than in the
COPD Exacerbations and Death from Any Cause dual-therapy groups in the ETHOS trial were
in Time-to-First-Event Analyses. similar to the findings from previous 52-week
Panel A shows the time to the first moderate or severe trials, including the IMPACT, TRILOGY, and
exacerbation of chronic obstructive pulmonary disease
TRIBUTE trials.4-6 In addition, the results of the
(COPD). The analysis was performed in the modified
intention-to-treat population with the use of an efficacy ETHOS trial further build on the findings from
estimand, which included only data obtained from pa- the KRONOS trial, a 24-week trial that showed
tients while they were receiving a trial treatment. Panel B benefits of triple therapy with a 320-μg dose of
shows the time to death from any cause. The analysis budesonide plus glycopyrrolate and formoterol
was performed in the intention-to-treat population with
over dual therapies with respect to lung func-
the use of a treatment policy estimand, which included
all observed data obtained from the patients regardless tion, symptoms, and exacerbations for COPD in
of whether they continued to receive their assigned treat- a population in which most patients (74%) had
ment. The inset shows the same data on an enlarged not had an exacerbation in the preceding year.2
y axis. Tick marks indicate the time of data censoring. It has been proposed that the benefits of triple
therapy over LAMA–LABA therapy in previous
studies may have resulted from a short-term
compared with glycopyrrolate–formoterol, a lower increase in the rates of exacerbations in the
risk of death from any cause was observed only in LAMA–LABA groups due to the discontinuation
the 320-μg–budesonide triple-therapy group, as of inhaled glucocorticoids in patients who had
shown by the 95% confidence interval. The haz- been using inhaled glucocorticoids before trial
ard ratio for death from any cause in the 320-μg– entry.18 However, in the ETHOS trial, the bene-
budesonide triple-therapy group, as compared fits of both triple-therapy regimens over the
with the 160-μg–budesonide triple-therapy group, LAMA–LABA regimen were similar among the
was 0.69, but the 95% confidence interval was patients who were using inhaled glucocorticoids
0.42 to 1.13, which precluded any definitive con- at the time of screening and those who were not;
clusions regarding a dose–response relationship. this finding indicates that the results were not
This is the second trial to show a benefit of tri- driven by the immediate discontinuation of in-
ple therapy over dual therapy with LAMA–LABA haled glucocorticoids.
with respect to mortality among patients with Current recommendations from the Global
COPD. In analyses including both on-treatment Initiative for Chronic Obstructive Lung Disease
and off-treatment data, the risk of death from (GOLD) suggest that patients with elevated eosino-
any cause was 46% lower in the ETHOS trial (for phil levels who continue to have exacerbations
320-μg–budesonide triple therapy vs. glycopyrro- while receiving a single bronchodilator regimen
late-formoterol) and 29% lower in the Informing with either a LAMA or a LABA should initially
the Pathway of COPD Treatment (IMPACT) trial step up to inhaled glucocorticoid–LABA therapy.1
(for triple therapy with fluticasone furoate–umecli- In the current trial, triple therapy with a 160-μg
dinium–vilanterol vs. umeclidinium–vilanterol).4 dose of budesonide showed significant benefits
The difference observed between the 320-μg– over inhaled glucocorticoid–LABA therapy with
budesonide and the 160-μg–budesonide triple- a 320-μg dose of budesonide with respect to ex-
therapy groups with respect to mortality but not acerbations and symptoms, a finding that calls
the other end points is unexplained but may re- into question the role for inhaled glucocorticoid–
flect a beneficial effect on cardiovascular out- LABA therapy in patients with moderate-to-very-
comes in this high-risk population. This pos- severe COPD who are symptomatic and have a
sibility has been previously suggested by the history of exacerbations. In the subgroups de-
findings from the Towards a Revolution in COPD fined according to blood eosinophil counts, the
Health (TORCH) trial,15,16 but was not proven in benefits of triple therapy (with either dose of
a subsequent interventional study involving pa- budesonide) over LAMA–LABA therapy with re-
tients with cardiovascular risk factors but less spect to exacerbations were greater among the
severe respiratory disease (Study to Understand patients with higher counts, a finding consistent
Mortality and Morbidity in COPD [SUMMIT]).17 with observations in previous studies of the re-

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 46
Table 3. Adverse Events during the 52-Week Treatment Period (Safety Population).*

320-μg–Budesonide Triple Therapy 160-μg–Budesonide Triple Therapy Glycopyrrolate–Formoterol Budesonide–Formoterol

Event (N = 2144) (N = 2124) (N = 2125) (N = 2136)

no. of events no. of events no. of events no. of events

no. of patients (no. per 1000 no. of patients (no. per 1000 no. of patients (no. per 1000 no. of patients (no. per 1000
(%) patient-yr) (%) patient-yr) (%) patient-yr) (%) patient-yr)
The

Any adverse event 1368 (63.8) 4527 (2388.4) 1356 (63.8) 4382 (2318.7) 1312 (61.7) 4074 (2301.7) 1377 (64.5) 4746 (2587.0)
Serious adverse events 426 (19.9) 664 (350.3) 445 (21.0) 681 (360.3) 433 (20.4) 639 (361.0) 440 (20.6) 653 (355.9)
Adverse events that led to early 119 (5.6) 150 (79.1) 112 (5.3) 146 (77.3) 146 (6.9) 187 (105.7) 140 (6.6) 160 (87.2)
discontinuation
Confirmed major adverse 31 (1.4) 32 (16.9) 30 (1.4) 31 (16.4) 44 (2.1) 47 (26.6) 23 (1.1) 24 (13.1)
cardiovascular event†
Confirmed pneumonia† 90 (4.2) 93 (49.1) 75 (3.5) 78 (41.3) 48 (2.3) 51 (28.8) 96 (4.5) 106 (57.8)
Deaths from any cause during 20 (0.9) 19 (10.0)‡ 28 (1.3) 28 (14.8) 35 (1.6) 35 (19.8) 29 (1.4) 29 (15.8)
treatment period
Adverse events that occurred in
n e w e ng l a n d j o u r na l

≥3% of patients overall

The New England Journal of Medicine

of

Nasopharyngitis 227 (10.6) 290 (153.0) 239 (11.3) 315 (166.7) 199 (9.4) 255 (144.1) 234 (11.0) 331 (180.4)
COPD 203 (9.5) 256 (135.1) 221 (10.4) 263 (139.2) 219 (10.3) 268 (151.4) 242 (11.3) 300 (163.5)

n engl j med 383;1  nejm.org  July 2, 2020

Upper respiratory tract infec- 123 (5.7) 149 (78.6) 137 (6.5) 176 (93.1) 102 (4.8) 129 (72.9) 115 (5.4) 154 (83.9)
tion

Copyright © 2020 Massachusetts Medical Society. All rights reserved.

m e dic i n e

Pneumonia 98 (4.6) 101 (53.3) 85 (4.0) 93 (49.2) 61 (2.9) 66 (37.3) 107 (5.0) 117 (63.8)
Bronchitis 66 (3.1) 74 (39.0) 68 (3.2) 76 (40.2) 76 (3.6) 81 (45.8) 69 (3.2) 83 (45.2)

* The safety population included all patients who underwent randomization, received treatment, and had any postrandomization safety assessment.
† Confirmation was obtained from an independent clinical end-point committee.
‡ A total of 20 patients in the 320-μg–budesonide triple-therapy group had adverse events while they were receiving treatment that were linked to an outcome of death; however, death in
1 patient was adjudicated on the basis of a post-treatment adverse event and therefore was not included in the calculation of the event rate in the on-treatment analysis.

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 Triple Inhaled Ther apy in Moder ate-to-Very-Severe COPD

sponse to inhaled glucocorticoids,19,20 as well as with a LAMA–LABA or an inhaled glucocorti-

with the current GOLD recommendations.1 coid–LABA combination with respect to the an-
No unexpected safety signals were identified nual rate of moderate or severe COPD exacerba-
in the ETHOS trial. As previously shown in other tions, symptoms, and health-related quality of life
52-week trials involving patients with COPD,4,21 in patients with moderate-to-very-severe COPD
the incidence of pneumonia was higher in the who are at risk of exacerbations. Triple therapy
treatment groups that received an inhaled gluco- with a 320-μg dose of budesonide also resulted
corticoid than in those that received the LAMA– in a lower all-cause mortality than LAMA–LABA
LABA combination. The incidence of confirmed therapy. We also showed that triple therapy with
pneumonia was higher in the 160-μg–budesonide a 160-μg dose of budesonide was an effective treat-
triple-therapy group (3.5%), the 320-μg–bude­ ment option for COPD; this lower-dose inhaled
sonide triple-therapy group (4.2%), and the glucocorticoid triple-therapy regimen showed
budesonide–formoterol group (4.5%) than in the greater efficacy than the higher-dose inhaled
glycopyrrolate–formoterol group (2.3%). Across glucocorticoid–LABA regimen, with lower rates
treatment groups, the incidence of pneumonia of exacerbations, greater reductions in symp-
was higher in the ETHOS trial than in the Key toms, and greater improvement in health-related
Assessment of Triple Therapy on Lung Function quality of life.
in Obstructive Lung Disease (KRONOS) trial
(1.3 to 1.9%),2 which may reflect the longer dura- A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
tion of the current trial as well as the differences Supported by AstraZeneca. Dr. Singh is supported by the
in patient populations; the current trial involved National Institute for Health Research, Manchester Biomedical
patients with more severe airflow limitation and Research Centre.
Disclosure forms provided by the authors are available with
frequent exacerbations, which have been associ- the full text of this article at NEJM.org.
ated with a greater risk of pneumonia.22 We thank all the patients, their families, and the team of
In conclusion, our findings show the benefits investigators, research nurses, and operations staff involved
in the ETHOS trial, and Julia King, Ph.D., of CMC Connect,
of triple therapy with a budesonide–glycopyrro- McCann Health Medical Communications, for medical writing
late–formoterol combination over dual therapy support.

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 Triple Inhaled Ther apy in Moder ate-to-Very-Severe COPD

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