Original Article

A phase III study comparing secondary long-term prophylaxis versus

on-demand treatment with vWF/FVIII concentrates in severe inherited
von Willebrand disease

Flora Peyvandi1,2, Giancarlo Castaman3,4, Paolo Gresele5, Raimondo De Cristofaro6, Piercarla Schinco7,
Antonella Bertomoro8, Massino Morfini9, Gabriella Gamba10, Giovanni Barillari11, Víctor Jiménez-Yuste12,
Cristoph Königs13, Alfonso Iorio5,14, Augusto B. Federici15,16

1
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Haemophilia and
Thrombosis Centre, Milan, Italy; 2Department of Pathophysiology and Transplantation, University of Milan, Milan,
Italy; 3Haemophilia and Thrombosis Center, "San Bortolo" Hospital, Vicenza; 4Centre for Bleeding Disorders and
Coagulation, "Careggi" University Hospital, Florence, Italy; 5Department of Medicine, University of Perugia,
Haemophilia Center, Azienda Ospedaliera di Perugia, Perugia, Italy; 6Haemorrhagic and Thrombotic Diseases

l
Unit, "A. Gemelli" University Hospital Foundation IRCCS, Institute of Internal Medicine and Geriatrics, Catholic

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University "S. Cuore", Rome, Italy; 7Regional Reference Center for Hereditary Haemorrhagic and Thrombotic
Diseases of Adult Patients, "Le Molinette" Hospital, Turin Italy; 8Haemophilia Centre, II Clinica Medica, University of
Padua, Padua, Italy; 9Italian Association of Haemophilia Centres, Milan, Italy; 10Haemophilia Centre and Congenital
Coagulopathies Unit,"S. Matteo" University Hospital, Pavia, Italy; 11Sos Malattie Emorragiche e Trombotiche,
Dipartimento di Area Vasta di Medicina Trasfusionale, Presidio Ospedaliero "S. Maria della Misericordia", ASUI

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di Udine, Udine, Italy; 12Haematology Department, "La Paz" University Hospital, "Autonoma" University, Madrid,
Spain; 13University Hospital Frankfurt, "Goethe" University, Department of Pediatrics, Frankfurt am Main, Germany;
14
Department of Health Research Methods, Evidence, and Impact and Department of Medicine, McMaster University,
PR
Hamilton, Canada; 15Division of Haematology and Transfusion Medicine, "Luigi Sacco" University Hospital, Milan,
Italy; 16Department of Oncology and Onco-Haematology, University of Milan, Milan, Italy

Background. There is a lack of prospective clinical trials specifically designed to evaluate the benefits
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of prophylaxis with vWF/FVIII concentrates in patients with inherited von Willebrand disease (vWD). The
aim of the study was to compare efficacy of secondary long-term prophylaxis (PRO) with vWF/FVIII in the
prevention of bleeding episodes in severe vWD patients to standard of care (on-demand treatment; ODT).
Materials and methods. In this 12-month, phase III, open-label study (PRO.WILL), vWD patients (aged
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≥6 years) were randomised to PRO (n=9; 5 completed) or ODT (n=10; 7 completed) treatment with Fanhdi®/
Alphanate® (Grifols) according to current licensing status for use in vWD. We assessed the proportion of
patients who did not present any spontaneous bleeding episode, adverse events (AEs) or thrombotic events.
Results. All patients on ODT had vWD type 2 or 3 vs 70% of patients on PRO. All ODT patients
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experienced bleeds vs 60% on PRO. PRO patients showed fewer bleeds (n=32 vs n=172 [112 in the
same patient, mostly mucosal]; p<0.0001) and lower risk of bleeding (relative attributable risk estimate:
−0.667; 95% CI: −2.374, −0.107; p<0.001). Most frequent bleeds in ODT and PRO groups were,
respectively, epistaxis (n=52 vs n=15) and gastrointestinal (n=13 [9 in the same patient] vs n=1). While
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most bleeds lasted one day under ODT (31/32), only epistaxis did so in PRO group (14/15). No AEs
due to study medication were observed.
Discussion. Despite the small sample size and the heterogeneity of the study population, patients on
vWF/FVIII prophylaxis showed a reduction in bleeding risk and rate compared to on-demand treatment.

Keywords: secondary long-term prophylaxis, on-demand treatment, von Willebrand disease, von
Willebrand factor, factor VIII.

Introduction show excessive and frequent mucocutaneous

von Willebrand disease (vWD) is caused by bleeding episodes (e.g. epistaxis, menorrhagia
reduced or dysfunctional von Willebrand factor and gastrointestinal bleeds) 2, and in severe cases,
(vWF), a complex multimeric glycoprotein that especially in vWD type 3, spontaneous bleeds into
plays a key role in haemostasis 1 . vWD patients joints, soft tissues and other sites may occur3-5.

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 Peyvandi F et al

vWD is categorised into three major types. Type 1 obtained from the patients or, in the case of children, from
vWD is the most common (65-70% of all cases), and their legal guardian.
is characterised by a quantitative deficiency of vWF. The primary objective was to evaluate if PRO with
A qualitative defect in the vWF molecule is the cause a vWF/FVIII concentrate was effective in preventing
of type 2 vWD (25-30% of all cases), which is in turn spontaneous bleedings in patients with severe vWD
classified into types: 2A and 2B, 2M, and 2N, depending unresponsive to DDAVP when compared with ODT.
on their functional defects. Total or near total absence
of vWF characterises type 3 vWD, the most severe and Patients and randomisation
rare type affecting about 1 in 500,000 people1. Patients who met the following criteria were included
The main treatment options for vWD patients in the study: ≥6 years of age with severe inherited
are desmopressin (DDAVP)6, plasma-derived vWF- vWD as previously defined12, with frequent bleeding
containing FVIII concentrate (vWF/FVIII) or pure vWF episodes (defined as ≥5 bleeding episodes in the last 12
(plasma-derived or recombinant)7. DDAVP induces the months, or ≥3 episodes of haemarthrosis at the same
transient increase of vWF, FVIII and tissue plasminogen joint or ≥2 episodes of gastrointestinal haemorrhage

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activator (t-PA), although its cellular mechanism of either unexplained or in association with underlying

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action has not been fully elucidated8. Importantly, gastrointestinal angiodysplasia with requirement
severe/moderate vWD forms, particularly vWD type of vWF/FVIII therapy), and with lack of DDAVP
2A and 2M, are unresponsive to DDAVP due to a lack responsiveness (defined as a relative increase in
of vWF in storage compartments or to the release of an plasma Factor VIII procoagulant activity [FVIII:C]
abnormal vWF8. a nd r i s t o c e t i n c o -fa c t or a c t iv it y [vW F:RC o]

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Substitutive therapy with vWF/FVIII or pure levels of at least 3-fold over baseline and absolute
vWF is the treatment of choice for type 3 and type increase to 30 IU/dL or more for both measures) or
2B vWD, and also for patients responsive to DDAVP contraindication or intolerance to DDAVP.
who are undergoing surgery or a procedure with
PR Key exclusion criteria included the presence
high bleeding risk7. The relative content of FVIII and of alloantibodies against vWF or FVIII, acquired
vWF in commercially available vWF/FVIII products von Willebrand syndrome (AvWS), advanced liver
varies, with products with a vWF:FVIII ratio >1 cir rhosis, pregnancy or breastfeeding, planned
being preferred for vWD treatment 7. On-demand invasive procedures within three months, conditions
treatment (ODT) is the standard of care for bleeding, predisposing to gastrointestinal bleeding (unrelated
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primarily through the administration of DDAVP and/or to vWD), concomitant autoimmune anaemia and
vWF/FVIII concentrates. Conversely, prophylaxis with thrombocytopenia.
vWF/FVIII concentrates is a preventive treatment The randomisation list was generated by SAS
option in patients with vWD, and its efficacy and software (SAS Institute Inc., Cary, NC, USA). The
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safety have been suggested 3. Although secondary random codes for treatment assignment and to track
long-term prophylaxis (PRO) is currently an option recruitment were provided by a centralised computerised
for an increasing number of vWD patients9, there is a system. Randomisation was stratified according to the
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lack of prospective clinical trials specifically designed type of bleeding (gastrointestinal, haemarthrosis and
to evaluate the benefits of such a PRO vs ODT using epistaxis/other bleeding).
vWF/FVIII concentrates in severe vWD10,11.
Here we report the results of the PRO.WILL study, Investigational vWF/FVIII product
which aimed to assess the efficacy of PRO with Fanhdi® (Instituto Grifols S.A., Barcelona, Spain)
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vWF/FVIII concentrates in the prevention of bleeding and Alphanate® (Grifols Biologicals Inc., Los Angeles,
episodes in severe vWD patients unresponsive to CA, USA) used in this study are highly purified
DDAVP, compared to ODT. doubly virus-inactivated vWF/FVIII concentrates
with standardised vWF:RCo content13 that share the
Materials and methods manufacturing process. Retrospective studies have
Study design and objectives demonstrated the clinical efficacy and safety of
This was a 12-month, international, multicentre, phase the study product in vWD patients, not only in the
III, randomised, open-label, parallel-group study conducted management of bleeding episodes and surgery14,15,
at 13 centres in Italy, Germany and Spain (EUDRACT n: but also in secondary prophylaxis of severe vWD3. In
2006-001383-23). The study was conducted in accordance addition, a prospective, multicentre study showed the
with the ethical principles set out in the Declaration of product to effectively stop active bleeding episodes and
Helsinki and was approved by the ethics committees of provide adequate haemostasis for surgical or invasive
the participating centres. Written informed consent was procedures16.

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Prophylaxis treatment in von Willebrand disease

vWF/FVIII treatment procedures group) would have provided a power of 90% to prove an
Before entering the study, a wash out of ten days absolute difference between the two groups in preventing
from the last vWF/FVIII infusion was mandatory17. For spontaneous bleeding of around 60% and a power
both PRO and ODT, vWF/FVIII was used according of 80% to prove an absolute difference of around 50%
to current licensing status for use in vWD in each (NQuery Advisor, 6.0 [Statsols, Cork, Ireland]).
participating country. Data are presented as mean±standard deviation
Prophylaxis patients with previous recurrent (SD), median and range, or median and first and third
haematomas or haemarthrosis received 60 IU vWF:RCo quartiles (Q1, Q3), whenever appropriate. For primary
per kg of body weight every third day (rounded up to efficacy analysis, a χ2 test was performed. For secondary
available pack sizes). Patients with previous mucosal efficacy analysis, Student's t-test or non-parametric
bleedings received the same dose every second day. Wilcoxon test, in case of non-normality, were performed.
On-demand treatment patients received 40-60 IU Attributable risk (AR) and its 95% confidence interval
vWF:RCo per kg of body weight (rounded up to (CI) were estimated to evaluate the absolute difference
available pack sizes) at the onset of each bleeding of incidence between treatment groups. p<0.05 was

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episode. Infusions could be repeated every 12 hours at considered statistically significant. Log rank test was

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the discretion of the investigator responsible. performed to compare the difference between treatments
in time (days) elapsed between randomisation visit and
Efficacy and safety assessments the first bleeding episode (time free from event). All
Patients were evaluated at the baseline randomisation statistical analyses were produced using SAS® release
visit and at monthly follow-up visits. The primary 9.4 or later (SAS Institute Inc).

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efficacy end point was the proportion of patients who did
not present any spontaneous bleeding episode (defined Results
as occurring in the absence of concomitant trauma, local A total of 22 patients were screened between October
PR
injury, invasive diagnostic or surgical procedures) during 2006 and August 2016, and 19 were randomised: 9 to the
the study period. ODT group and 10 to the PRO group. Twelve patients
Secondary efficacy end points included: the incidence (7 ODT and 5 PRO) completed the full set of study
rate of spontaneous bleeds (episodes per patient-time), visits, 3 of whom presented major protocol deviations
the interval between randomisation and the first bleeding (all in the ODT group). A flowchart showing patients'
details during the study and reasons for discontinuation
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episode after randomisation, the mean duration of
spontaneous bleeding episodes, the mean number of is available in Figure 1.
infusions per spontaneous bleeding episode, and the
mean dose of vWF/FVIII concentrate administered per Patients' characteristics
Most patients were male (7 ODT, 7 PRO). The
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spontaneous bleeding episode (only for bleeding episodes

requiring treatment with FVIII/vWF concentrates). median age at study inclusion was 54 years (Q1, Q3:
Safety end points included monitoring adverse 45-64) in the ODT group and 28 years (Q1, Q3: 15-48) in
events (AEs) and thrombotic events, together with blood the PRO group. Following randomisation at enrolment,
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analysis parameters. AEs were classified according vWD type 3 was the most common disease type in the
to severity (serious [SAE], non-serious), maximum ODT group while vWD types 1, 2A and 3 were equally
intensity (mild, moderate, severe), and causality to common in PRO group (Table I). The detailed clinical
the study treatments (unrelated, unlikely, possibly, characteristics of patients at baseline are shown in Table
probably). II. Due to the different distribution of vWD types in
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ODT vs PRO, the levels of vWF/FVIII activities were

Statistical analysis higher in PRO but the clinical severity of the two groups
The sample size estimation was based on the assessed by bleeding score was similar (Table II).
preliminary data presented by Federici et al.18 where,
in a cohort of 11 patients enrolled in a programme of Efficacy outcomes
secondary long-term prophylaxis and observed for a All 9 patients (100%) in the ODT group and 6 out of
period of 3-15 months, a proportion of 64% reached 10 patients (60%) in the PRO group experienced bleeding
the end point "complete prevention of spontaneous during the study. Four PRO patients discontinued the
bleeding". It was also expected that approximately study despite not having any bleeding episodes (2
10% of ODT patients would not show any recurrence patients withdrew their consent and 2 patients were lost
of bleeding, given the brief observation period and the to follow up). Considering those patients who dropped
unpredictability of these events. Assuming a one-sided out, the actual statistical power was 69.2%.
significance level of 0.05, 24 patients (12 per treatment The mean number of bleeding episodes per patient

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 Peyvandi F et al

Table II - Clinical characteristics of patients at baseline

according to treatment groups. Data are presented
as mean±standard deviation or number (%).

Parameter On-demand Prophylaxis

(N= 9) (N= 10)
FVIII:C (IU/dL) 31.0±27.5 43.4±36.5*
vWF:RCo (IU/dL) 6.0±0.0 10.3±11.3*
vWF:Ag (IU/dL) 32.9±45.4 67.9±93.6*
Bleeding time (minutes) 35.7±1.15 18.2±6.6*
Prothrombin time ratio 1.1±0.1 1.1±0.1
Partial thromboplastin time ratio 1.5±0.4 1.8±0.5
Bleeding score 15.0±8.5 14.7±6.7

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Number of bleeding episodes
11.8±8.9 12.8±14.2
needing vWF/FVIII treatment†

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Epistaxis 8.2±9.5 9.0±14.9
Gastrointestinal 0.2±0.7 1.1±1.5
Haemarthrosis 1.3±2.7 2.0±6.3
Muscular haematoma 1.8±5.0 0

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Other 0.2±0.4 0.7±2.2
Number of patients who:
had a family history of
PR bleeding episodes
6 (67) 3 (30)

received on-demand treatment

8 (89) 9 (90)
with vWF/FVIII†
received other drugs or
1 (11) 1 (10)
transfusions related to vWD†
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Figure 1 - Patient flowchart during the study. N: number. were hospitalised† due to
bleeding:
melena 0 1 (10)
Table I - Distribution of von Willebrand disease types
between patients according to treatment groups. gastrointestinal 1 (11) 1 (10)
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anal fissure 1 (11) 0

vWD type On-demand Prophylaxis
N (%) N (%) had a relevant medical history‡ 3 (33) 4 (40)
1 0 3 (30.0) *p <0.05. †In the 12 months before baseline. ‡Including anaemia,
splenomegaly, hypertension, coronary bypass, ventricular arrhythmia,
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2A 2 (22.2) 3 (30.0) hepatomegaly, chronic viral infection, diabetes mellitus, hyperlipidaemia,

2B 3 (33.3) 0 vertigo. N: number; FVIII: factor VIII; vWD: von Willebrand disease;
vWF:RCo: ristocetin co-factor activity; vWF:Ag: vWF antigen.
2M 0 1 (10.0)
3 4 (44.4) 3 (30.0)
Overall, the risk of bleeds was lower in the PRO vs the
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vWD: von Willebrand disease; N: number.

ODT group with a relative AR estimate of −0.667 (95%
CI: −2.374, −0.107; p<0.001).
was higher in the ODT group (medians: 8.0 [Q1, Q3: The mean time from baseline to the first bleeding
2.0, 13.0] vs 5.5 [Q1, Q3: 2.0, 9.0] in the PRO group; episode was 66.0±33.7 days vs 34.6±10.5 days in the
p<0.0001), resulting in an incidence rate of 1.41 per ODT group. The median event-free interval was 23 days
patient-month in the ODT group (172 episodes, although in both groups. According to a Kaplan-Meier analysis,
it should be noted that 112 of them occurred in a single the difference was not significantly different (p =0.2795)
patient) and 0.34 in the PRO group (32 episodes). (Figure 2).
The frequency and incidence rate of bleeding The duration (days) of bleeding episodes per
episodes during the study is shown in Table III. The patient was shorter in the ODT group for each type
most frequent site of "other" bleeding events in ODT of haemorrhage (Table IV). Most episodes lasted one
was gums. In the PRO group, 9 of the 13 gastrointestinal day (151/172; 88%) or two days (19/172; 11%) in the
bleeding episodes occurred in one single patient. ODT group, with a single muscle haematoma lasting

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Prophylaxis treatment in von Willebrand disease

Table III - Number and incidence rate of bleeding episodes during the study according to treatment groups.
Type of bleeding episode On-demand Prophylaxis
(N= 9) (N= 10)
N Rate N Rate
Any type 172 1.41 32 0.34
Mucosal bleeding 164 1.34 17 0.18
epistaxis 52 0.42 15 0.16
other bleedings 112† 0.92 2 0.02
Joint and muscle bleeding 7 0.05 2 0.02
haemarthrosis 3 0.02 1 0.01
muscle haematoma 4 0.03 1 0.01
Gastrointestinal haemorrhage 1 0.01 13‡ 0.14
†All in one single patient (106/112 bleeding gums). ‡Nine in one single patient. N: number.

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PR
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Figure 2 - Probability of remaining free of a first spontaneous bleeding episode during the study.
ODT: on-demand treatment; PRO: prophylaxis treatment; n: number.

Table IV - Duration of bleeding episodes during the study and number of patients who experienced them, according to
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treatment groups.
Type of bleeding episode On-demand Prophylaxis
Patients Duration (days) Patients Duration (days)
(N) (N)
1 2 3 ≥4 1 2 3 ≥4
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Epistaxis 6 36 16 3 9 5 1
Gastrointestinal bleeding 1 1 3 2 11
Haemarthrosis 2 2 1 1 1
Muscle haematoma 2 3 1 1 1
Other 4 110 1 1 2 1 1
N: number.

three days and a single episode of other bleedings lasting bleeds; ≥4 days for one (3%) episode of other bleedings;
≥4 days. In the PRO group, a 1-2-day duration was and 6 days for one (3%) muscle haematoma.
observed for 14/32 episodes of epistaxis (44%) and one
episode of other bleedings (3%), while other episodes vWF/FVIII treatment during the study
lasted longer: 3 days for one (3%) epistaxis and one (3%) The median study duration was 12.1 months (Q1, Q3:
haemarthrosis; ≥3 days for 13/32 (41%) gastrointestinal 11.7-12.9) in the ODT group and 10.5 (Q1, Q3: 2.3-11.9) in

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 Peyvandi F et al

the PRO group. In the PRO group, vWF/FVIII concentrate Table V - Summary and numbers of patients with adverse
doses were infused either every third day (n=2) or every events according to treatment groups.
second day (n=3). On-demand Prophylaxis Total
Variable
The mean dose of FVIII recorded at the (N=9) (N=10) (N=19)
randomisation visit for 8 PRO patients was 38.6±16.0 Number of AEs 12 25 37
IU/kg. On subsequent visits, the mean doses of reported
FVIII remained consistent with that at randomisation Number of distinct AEs 9 21 30
(range: 36.3±9.25 IU/kg to 42.0±3.5 IU/kg). by preferred term
In the ODT group, most bleeding episodes required Number of patients with
the use of vWF/FVIII concentrates (162/172; 94.2%) AEs, N (%)

compared to 14/32 (43.7%) in the PRO group. The Any AE 3 (33.3) 6 (60.0) 9 (47.4)
mean dose of FVIII was higher in the ODT group for Serious AEs 0 1 (10.0) 1 (5.3)
epistaxis (ODT 47.9 IU/kg vs PRO 17.9 IU/kg) and Severe AEs 1 (11.1) 1 (10.0) 2 (10.5)
muscular haematoma episodes (ODT 81.5 IU/kg/PRO
Concomitant 3 (33.3) 4 (40.0) 7 (36.8)

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47.2 IU/kg); the reverse was observed for gastrointestinal medication for AEs

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bleeding (ODT 160.0 IU/kg / PRO 272.5 IU/kg) and
Treatment dose 0 1 (10.0) 1 (5.3)
haemarthrosis (ODT 49.1 IU/kg / PRO 92.2 IU/kg). adjusted/temporarily
interrupted due to AEs
Safety outcomes N: number; AEs: adverse events.
All 19 patients were evaluable for AEs. None

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of the clinical AEs observed were considered to be enrolment problems occurred in this PRO.WILL study,
due to study medication. Seven patients prematurely resulting in the study to unfold in a rather atypical
discontinued the study (2 ODT; 5 PRO) (Figure 1). manner. First, the number of patients enrolled was
PR
No patient discontinued the study due to an AE. One smaller than planned (19 randomised vs 24 planned),
patient in the PRO group had an intestinal perforation and many patients discontinued the study (12 patients
(reported as severe) that resolved with a combination of completed the study). Secondly, likely due to the small
concomitant medication and hospitalisation. This event sample size, the randomisation process did not efficiently
was not considered to be related to the study medication. balance the vWD types and patients' age between the
No patient died during the study. treatment groups. This introduced a baseline imbalance
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Three patients (33.3%) in the ODT group and 6 in the coagulation parameters, with the ODT group
patients in the PRO group (60.0%) experienced AEs. showing longer bleeding times, and lower FVIII:C,
AEs consisted mostly of blood and lymphatic system vWF:RCo and vWF antigen (vWF:Ag) levels, which
disorders (anaemia and lymphadenopathy). Only one was consistent with the differential influence of age in
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SAE, an intestinal perforation (reported as severe and vWF and FVIII levels and bleeding phenotype in type
resolved during the study) was observed in the PRO 1 and type 2 vWD30. However, other key parameters,
group. Severe hypertension was reported in one ODT such as the clinical severity of the vWD as assessed by
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patient. No thromboembolic events were observed. A the bleeding score and the number of bleeding episodes
summary of patients with AEs is shown in Table V. that had needed vWF/FVIII treatment in the previous 12
Haematologic abnormalities at the end of study were months4, were similar between groups, hence supporting
observed in 8 ODT patients and 4 PRO patients. Low the consistency of the study comparisons. Lastly, the
haemoglobin levels (5/8 ODT patients and 2/4 PRO presence of outliers should also be considered when
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patients) and low erythrocyte counts (5/8 ODT patients interpreting the results.
and 3/4 PRO patients) were the most frequent. More patients in the ODT group (100%) than
in the PRO group (60%) experienced spontaneous
Discussion bleedings during the study (primary efficacy end point).
While there have been a number of retrospective However, the discontinuation of 4 PRO patients with
and prospective clinical studies using vWF/FVIII to no bleeds should be taken into account when analysing
assess secondary long-term prophylaxis in clinically this result. Even excluding 112 of the 172 bleeds in
severe vWD3,19-27, the PRO.WILL is the first randomised the ODT group as occurring all in one single patient,
clinical trial to compare the efficacy in the prevention the number of bleeding episodes of the ODT group
of bleeds of PRO treatment with vWF/FVIII in severe was still 2-fold higher than the number of the PRO
DDAVP-unresponsive vWD patients. group (60 vs 32, respectively), although in that case
In most of the previous studies, the targeted vWD the statistical relevance of the difference is probably
patient profile was a challenging one27-29. The same lower. The mean number of bleeds per patient, the

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396 All rights reserved - For personal use only
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Prophylaxis treatment in von Willebrand disease

incidence rate and the overall risk of bleeds were in the (Grifols) is acknowledged for medical writing and
expected ranges31 and lower in the PRO group, with the editorial support in the preparation of this manuscript,
exception of gastrointestinal haemorrhage. The reasons under the direction of the Authors.
why gastrointestinal bleeds seemed to respond poorly
to PRO treatment remains unclear, although that could Funding and resources
be partially ascribed to the propensity for this bleeding This study was supported by Grifols, a manufacturer
type, including a possible underlying gastrointestinal of vWF/FVIII concentrates.
angiodysplasia, of the single outlier patient who
experienced most (80%) of the episodes. Authorship contributions
While there was no significant difference in the time FP and ABF were the lead investigators. ABF
to the first bleeding episode between groups, the duration contributed to the study design. FP and ABF analysed
of bleeds was longer in the PRO group for all bleeding the data and interpreted the results. FP, GC, PG, RDC,
types except epistaxis. This could be explained by the PS, AB, MM, GG, GB, VJY, CK and AI recruited the
fact that almost all bleeds in the ODT group required patients and collected the data. GC, PG, RDC, PS, ABF,

l
treatment with vWF/FVIII concentrate, whereas less MM, GG, GB, VJ-Y, CK, and AI interpreted the results

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than half of the bleeding episodes in the PRO group and contributed intellectual content. FP and ABF helped
required additional treatment. write the manuscript. All Authors read and approved the
Regarding safety, the infusion of vWF/FVIII final version for publication.
was well tolerated in this patient population and no
clinical AEs related to the study medication were Disclosure of conflicts of interest

O
reported. Importantly, there were no thromboembolic FP received honoraria or consultation fees from Kedrion
events, which constitute a theoretical risk associated Biopharma and LFBa, and speaker's fees for participating
with repeated infusions of vWF/FVIII usually due to at educational meetings organised by Ablynx Alnylam,
high circulating levels of FVIII32. The most common
PR Grifols, Sobi, F. Hoffmann-La Roche, and Shire. Member of
hematologic laboratory abnormalities were consistent Ablynx, F. Hoffmann-La Roche Advisory Board, and Shire.
with the underlying vWD33. GC received research funding (directly to the Institution
from Pfizer, CSL Behring). Member of an Entity's Board
Conclusions of Directors, Speakers Bureau, or its Advisory Committee
Overall, the prophylactic use of vWF/FVIII (CSL Behring, Shire, Bayer, Sobi, Novo Nordisk, Kedrion,
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concentrates appeared to be associated with a lower Genzyme, Pfizer, Roche, and Uniqure). RDC received
risk and frequency of bleeding episodes in severe vWD consultation fees from Grifols and Pfizer, and a speaker's
patients unresponsive to DDAVP, although more data fee for participating at educational meetings organised by
are needed for gastrointestinal bleeding. Despite the Shire. Member of Bayer Advisory Board. VJ-Y received a
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small sample size of clinically severe vWD and its reimbursement for attending symposia/congresses and/or
associated heterogeneity in the baseline characteristics honoraria for speaking and/or honoraria for consulting,
of the participating patients, the PRO.WILL study and/or funds for research from Shire, Bayer, CSL-Behring,
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supports for the first time in a randomised manner the Grifols, Novo Nordisk, Sobi, Octapharma, and Pfizer. CK
efficacy of secondary long-term prophylaxis in reducing received an honoraria for speaking or consulting from
the bleeding risk and rate in severe vWD. Further Bayer, Biotest, CSL Behring, Grifols, Pfizer, Roche, Shire
prospective clinical trials should address the obstacles and Sobi and institutional research funding from Bayer,
to the use of prophylaxis in vWD and enrolment issues Biotest, Intersero, Pfizer, Shire, and Sobi. AI received
©

identified in this trial. Finally, larger cohorts of patients institutional research funding from Bayer, Bioverativ, CSL,
are required to allow a concrete assessment of the value Grifols, Novo Nordisk, Octapharma, and Pfizer. ABF is
of the prophylactic use of vWF/FVIII in high-risk vWD involved in the advisory boards of Baxalta-Shire, CSL-
patients to be made. Behring, Grifols, Kedrion, LFB, and Octapharma with
honoraria related to vWD.
Acknowledgements The other Authors declare no conflicts of interest.
Dr. E. Marchesini and Dr. T. Fierro at the Haemophilia
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