Immune Tolerance Induction in Haemophilia A Patients Using Wilate or Nuwiq - A Canadian Study
Conditions: Hemophilia A
Sponsor: Octapharma

 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
Page 1 of 23 
 
ABBREVIATED STUDY REPORT FOR NON-INTERVENTIONAL 
STUDY 
 
 
Immune Tolerance Induction in Hemophilia A Patients using Wilate® 
or Nuwiq® – A Canadian Study (WIL-26) 
 
Version of the final study 
report 
V1.0 
Date of last version of 
report 
08-Oct-2021 
Study number 
WIL-26 
EU PAS register number 
Not applicable 
Active substance 
Human von Willebrand factor (VWF)/human coagulation 
factor VIII (FVIII) 
Recombinant factor VIII (rFVIII) 
Medicinal product 
Wilate® (VWF/FVIII) or Nuwiq® (rFVIII) 
Joint PASS 
Not applicable 
Research question and 
objectives 
This uncontrolled, multi-centre, non-interventional study with a 
prospective and a retrospective cohort aimed to investigate the 
efficacy and safety of Wilate and Nuwiq in immune tolerance 
induction (ITI). The primary objective of this study was to 
evaluate the efficacy of Wilate or Nuwiq in achieving complete 
or partial ITI success in severe, moderate and mild hemophilia 
A patients with inhibitors. The secondary objectives of this 
study were to evaluate the time to achieve immune tolerance 
to FVIII with ITI treatment using Wilate or Nuwiq, to evaluate 
the bleeding frequency while on Wilate or Nuwiq ITI treatment 
and to evaluate the relapse rate and time to relapse following 
successful ITI using Wilate or Nuwiq. The additional objectives 
of this study were to record the patients’ general and 
hemophilia-specific quality of life, inhibitor biology (i.e., epitope 
mapping, IgG subclasses, antibody binding affinity), thrombin 
generation assay (TGA), and genotyping. 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26) 
RESTRICTED 
Version 1.0 
08-Oct-2021
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407
      Page 2 of 23 
Country of study 
Canada 
Sponsor’s Medically 
Responsible Person 
Arturo Santisteban  
Associate Medical Manager 
Octapharma Canada 
308-214 King Street West
Toronto, ON
M5H 3S6, Canada
Coordinating 
Investigators 
Dr. Mark Belletrutti 
Dr. John Akabutu Centre for Bleeding Disorders 
Pediatric Hematology 
Department of Pediatrics 
3-511 Edmonton Clinic Health Academy
11405-87 Avenue
Edmonton, AB,
T6G 1C9, Canada
Dr. Paul Moorehead 
Section of Pediatric Hematology/Oncology 
Eastern Health, Janeway Site 
300 Prince Philip Drive 
St. John’s, Newfoundland  
A1B 3V6, Canada  
Marketing authorisation 
holder(s) 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland  
MAH contact person 
Not applicable 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26) 
RESTRICTED 
Version 1.0 
08-Oct-2021
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407
      Page 3 of 23 
REPORT SIGNATURE 
Signature of Octapharma’s Qualified Person Pharmacovigilance or Delegate 
Balasz Toth, MD 
Head of Corporate Drug Safety Unit & EU-QPPV 
Signature 
Date 
Octapharma Pharmazeutika Produktionsges.m.b.H 
Oberlaaer Strasse 235 
A-1100 Vienna
Austria 
Signature of the Sponsor’s responsible global Medical Person 
Sigurd Knaub, PhD 
SVP CR&D Haematology 
Signature 
Date 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
Signature of the Project Manager at Octapharma Responsible for the Study 
Sri Adapa 
General Manager 
Signature 
Date 
Octapharma Canada 
308-214 King Street West
Toronto, ON
M5H 3S6, Canada
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407  
 
               Page 4 of 23 
Table of Contents 
Table of Contents .................................................................................................................. 4 
1 
Synopsis ......................................................................................................................... 5 
2 
List of Abbreviations ...................................................................................................... 10 
3 
Investigational Plan ....................................................................................................... 11 
3.1 
Overall Study Design and Plan .......................................................................... 11 
4 
Changes in the Conduct of the Study or Planned Analyses .......................................... 15 
5 
Results .......................................................................................................................... 16 
5.1 
Disposition of Patients ....................................................................................... 16 
5.2 
Patient Demographics ....................................................................................... 16 
5.3 
Safety Evaluation ............................................................................................... 17 
5.3.1 
Extent of Exposure ............................................................................ 17 
5.3.2 
ADRs and Infections .......................................................................... 17 
5.3.3 
Deaths, Other Serious ADRs, and Other Significant ADRs ................ 18 
5.3.4 
Clinical Laboratory Evaluation............................................................ 19 
5.3.5 
Vital Signs, Physical Findings and Other Observations Related to 
Safety ................................................................................................ 19 
5.3.6 
Safety Conclusions ............................................................................ 19 
5.4 
Analysis of Efficacy ............................................................................................ 19 
5.5 
Discussion and Overall Conclusions .................................................................. 20 
6 
Tables, Figures and Graphs Referred to but Not Included in the Text ........................... 21 
7 
Appendices ................................................................................................................... 22 
7.1 
Protocol and Protocol Amendments ................................................................... 22 
7.2 
Sample Case Report Forms (Unique Pages Only) ............................................. 22 
7.3 
Case Report Forms for Deaths, Other Serious Adverse Events and 
Withdrawals for Adverse Events ........................................................................ 22 
7.4 
Patient Data Listings .......................................................................................... 22 
 
 
 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407  
 
               Page 5 of 23 
1 SYNOPSIS 
Name of Sponsor: 
Octapharma Canada 
Name of Investigational Products: 
Wilate and Nuwiq 
Study number: 
WIL-26 
Name of Active Ingredient: 
Human von Willebrand factor (VWF)/human 
coagulation factor VIII (FVIII) 
Recombinant factor VIII (rFVIII) 
Version / Date of Report: 
1.0 08-Oct-2021 
 
Title of Study: 
Immune Tolerance Induction in Hemophilia A Patients using Wilate® or Nuwiq® – A 
Canadian Study (WIL-26) 
Indication: Hemophilia A with inhibitor 
Number of Study Centre(s): 2 
Study Period 
First Patient In: 19-Jun-2018 
Last Patient Out: 12-May-2020 
Rationale and Background: 
Development of factor VIII (FVIII) inhibitors is the main complication in the treatment of 
patients with hemophilia A. Ideally, patients with hemophilia A should receive continuous, 
long-term prophylaxis to prevent joint and muscle bleeding and hemophilic arthropathy. 
However, prophylaxis with FVIII in patients with inhibitors is ineffective until there has been 
complete and sustained elimination of the inhibitor, defined as (1) no detectable inhibitor on 
at least 2 consecutive occasions, (2) normal in vivo recovery (IVR) and half-life, and (3) no 
reappearance of inhibitors during regular FVIII replacement. 
Immune tolerance induction (ITI) is a therapy intended to eradicate such inhibitors. High-
dose FVIII treatment has been shown to effectively induce immune tolerance and to exert a 
long-lasting effect in more than 80% of treated patients. Success rates may vary, depending 
both on patient variables and on factors related to the therapeutic regimen, as well as on the 
product chosen for ITI including concentrate purity and von Willebrand factor (VWF) content.  
ITI with Wilate or Nuwiq has been shown to be a safe and effective treatment approach in a 
high-risk, adult patients with severe hemophilia A. 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407  
 
               Page 6 of 23 
Name of Sponsor: 
Octapharma Canada 
Name of Investigational Products: 
Wilate and Nuwiq 
Study number: 
WIL-26 
Name of Active Ingredient: 
Human von Willebrand factor (VWF)/human 
coagulation factor VIII (FVIII) 
Recombinant factor VIII (rFVIII) 
Version / Date of Report: 
1.0 08-Oct-2021 
 
As the current study was underway, a larger, global multicentre Phase 4 investigator-
initiated study with a similar study objective, design and outcomes was launched. Given the 
similarities between the two studies, although the goal was to recruit 80 Canadian patients 
into the current study, it was decided that being a part of a larger study would both 
accelerate patient recruitment and address the clinical question with more robustness. 
Therefore, the investigators decided to stop the study and encourage all participating study 
sites to enrol eligible patients into the new international study. 
Objectives: 
Primary Objective: 
The primary objective of this study was to evaluate the efficacy of Wilate or Nuwiq in 
achieving complete or partial ITI success in severe, moderate and mild hemophilia A 
patients with inhibitors. 
Secondary Objectives: 
The secondary objectives of this study were to:  
• 
Evaluate the time to achieve immune tolerance to FVIII with ITI treatment using Wilate 
or Nuwiq, 
• 
Evaluate the bleeding frequency while on Wilate or Nuwiq ITI treatment, 
• 
Evaluate the relapse rate and time to relapse following successful ITI using Wilate or 
Nuwiq. 
Additional Objectives: 
The additional objectives of this study were to record the patients’ general and hemophilia-
specific quality of life, inhibitor biology (i.e., epitope mapping, IgG subclasses, antibody 
binding affinity), thrombin generation assay (TGA), and genotyping. 
Study Design: 
Uncontrolled, multi-centre, non-interventional study with a prospective and a retrospective 
cohort 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407  
 
               Page 7 of 23 
Name of Sponsor: 
Octapharma Canada 
Name of Investigational Products: 
Wilate and Nuwiq 
Study number: 
WIL-26 
Name of Active Ingredient: 
Human von Willebrand factor (VWF)/human 
coagulation factor VIII (FVIII) 
Recombinant factor VIII (rFVIII) 
Version / Date of Report: 
1.0 08-Oct-2021 
 
Subjects and Study Size, Including Dropouts: 
It was planned that a total of at least 80 patients will be enrolled into this study, i.e., at least 
40 evaluable hemophilia A patients with an inhibitor against FVIII into the prospective cohort 
and a maximum of 40 evaluable hemophilia A patients with an inhibitor against FVIII into the 
retrospective cohort. At the time of study termination, 14 patients had been enrolled. 
Patient Selection Criteria: 
Inclusion Criteria: 
1. Male patients of any age with mild, moderate or severe hemophilia A.  
2. Patients with a first occurrence of inhibitors, inhibitors refractory to previous ITI 
attempt(s), or relapsed inhibitors to FVIII, with an inhibitor titre of ≥0.6 Bethesda Units 
(BU) measured on 2 separate occasions at least 2 weeks apart. 
3. Informed written consent from the patient and/or the patient’s parent(s) or legal 
guardian(s). 
For patients included in the prospective cohort: 
4. Patients who were currently on Wilate or Nuwiq ITI, had just initiated ITI, or were 
planned to initiate ITI treatment with Wilate or Nuwiq. 
For patients included in the retrospective cohort: 
4. Patients having received Wilate or Nuwiq for ITI before entry into this study. 
Retrospective data was to be collected for a maximum of 3 years prior to enrolment 
into the study. To be eligible, the following information was needed for the time 
period while on ITI therapy: 
– Wilate or Nuwiq treatment details (start date, dose, treatment frequency, and dose 
change) 
– Reliably documented bleeding frequency 
– FVIII inhibitor titres 
– FVIII half-life 
– FVIII IVR 
 
 
 
 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407  
 
               Page 8 of 23 
Name of Sponsor: 
Octapharma Canada 
Name of Investigational Products: 
Wilate and Nuwiq 
Study number: 
WIL-26 
Name of Active Ingredient: 
Human von Willebrand factor (VWF)/human 
coagulation factor VIII (FVIII) 
Recombinant factor VIII (rFVIII) 
Version / Date of Report: 
1.0 08-Oct-2021 
 
Exclusion Criteria: 
1. Congenital or acquired bleeding disorders other than hemophilia A. 
2. A history of hypersensitivity to blood products and/or plasma-derived FVIII 
concentrates. 
3. Inability to speak/read English or French well enough to provide consent and adhere 
to the study. 
4. Receiving other non-factor therapies, e.g., concizumab. 
Test Product, Dose, Mode of Administration, and Batch Number(s): 
Although it was planned to enroll patients treated with either Wilate or Nuwiq, all of the 
enrolled patients ended up being treated with Wilate, and no patient received Nuwiq. 
Wilate was administered as an intravenous infusion. 
The batches used were: 
K634A1811, K634C1811, K617A1813, K617A1814, A550A1811, K637D1811, K642C1812, 
K646B1811, and K74801891. 
Reference Product, Dose, Mode of Administration, and Batch Number(s): 
Not applicable. 
Study Outcome Parameters (Primary and Secondary Endpoints): 
The primary endpoint was the proportion of patients achieving complete or partial ITI success. 
Secondary endpoints were: 
• 
Time to achievement of complete or partial ITI success,  
• 
Duration of immune tolerance (in case of complete or partial ITI success), 
• 
Bleeding frequency while on Wilate or Nuwiq ITI treatment, 
• 
Association of inhibitor titres at the start of and throughout ITI treatment, 
• 
Use of bypassing agents before and during ITI treatment with Wilate or Nuwiq, 
• 
Use of emicizumab (Hemlibra®), 
• 
Frequency and timing of relapses, 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407  
 
               Page 9 of 23 
Name of Sponsor: 
Octapharma Canada 
Name of Investigational Products: 
Wilate and Nuwiq 
Study number: 
WIL-26 
Name of Active Ingredient: 
Human von Willebrand factor (VWF)/human 
coagulation factor VIII (FVIII) 
Recombinant factor VIII (rFVIII) 
Version / Date of Report: 
1.0 08-Oct-2021 
 
• 
Treatment adherence, 
• 
Treatment safety. 
Additional endpoints planned to be assessed in substudies were: 
• 
The patients’ general and hemophilia-specific quality of life, 
• 
Inhibitor biology (i.e., epitope mapping, IgG subclasses, antibody binding affinity), 
• 
TGA, 
• 
Genotyping. 
Summary of Study Procedures and Statistical Methods: 
During the screening visit, the demographic and baseline data, including the patient’s 
medical, bleeding, and ITI history, comorbidities, Hemophilia Joint Health Score (HJHS), and 
history of present illness including inhibitor titres were documented. 
Patients received a study diary in which they documented all bleeding episodes, treatment 
details, adverse drug reactions (ADRs), central-line infections, and infections resulting in 
hospitalization. Follow-up visits were as per standard of care at each study site, with a 
recommended visit interval of at least 3 months. 
No statistical analysis was performed on the data collected. Safety and efficacy data are 
presented descriptively. 
Summary of Results & Discussion: 
No new safety signals emerged in this study and the ADRs were those expected in a 
population of patients with hemophilia A. Five ADRs were judged as unlikely related and 1 
not related to Wilate. There were no deaths during the study. Two patients experienced 3 
serious ADRs (gastroenteritis, an infected implantable venous access device [IVAD], 
respiratory distress). All ADRs resolved.  
Efficacy evaluation results were available for 8 of the 14 patients. For 7 patients, the 
treatment with Wilate was judged as ‘complete success’ and for 1 (12.5%) as ‘complete 
failure’, giving the success rate of 87.5%. 
Wilate ITI was well tolerated in this group of paediatric previously treated patients with 
hemophilia A and no new safety concerns were raised. 
 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407  
 
               Page 10 of 23 
2 LIST OF ABBREVIATIONS 
 
ADR 
Adverse drug reaction 
BE 
Bleeding episode 
BU 
Bethesda Units 
FVIII 
Coagulation factor VIII 
HJHS 
Hemophilia Joint Health Score 
 
ITI 
Immune tolerance induction 
IVAD 
Implantable venous access device 
IVR 
In vivo recovery 
PP 
Per-protocol (population) 
rFVIIa 
Recombinant activated factor VII 
SD 
Standard deviation 
TGA 
Thrombin generation assay 
VWF 
von Willebrand factor 
VWF:Ag 
von Willebrand factor antigen 
 
 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407  
 
               Page 11 of 23 
3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This was an uncontrolled, multi-centre non-interventional study with both a prospective and a 
retrospective cohort.  
A total of at least 80 patients were planned to be enrolled into this study, i.e., at least 40 
evaluable hemophilia A patients with an inhibitor against coagulation factor VIII (FVIII) into 
the prospective cohort and a maximum of 40 evaluable hemophilia A patients with inhibitors 
against FVIII into the retrospective cohort. Each patient was to be followed for a maximum 
time period of 5 years after the start of Wilate or Nuwiq immune tolerance induction (ITI) 
therapy. The study was planned to be conducted in a maximum of 15 hemophilia treatment 
centres throughout Canada. The overall study duration was planned to be 10 years (Q2 2017 
to Q4 2026).  
Based on the decision of the treating physician in the participating centre, male patients of 
any age with mild, moderate (1% to 5% factor activity) or severe hemophilia A (<1% factor 
activity) with inhibitors to FVIII scheduled to undergo ITI treatment with Wilate or Nuwiq 
(prospective cohort) or having received Wilate or Nuwiq ITI in the 3 years before enrolment 
into the study (retrospective cohort) were to be included into this study. This study was also 
open for subjects who failed earlier ITI attempt(s).  
The dose and frequency of ITI treatment were at the discretion of the treating physician. 
However, use of one of the treatment protocols described in the Protocol, Section 7.4.2 was 
recommended. 
The primary endpoint was the proportion of patients achieving complete or partial ITI success. 
The criteria for the definition of ITI success are summarized in Table 1. 
Table 1 
Criteria for the Definition of Success of ITI 
Complete success 
1. 
Inhibitor titre <0.6 BU (at least 2 separate blood samplings) 
2. 
Incremental IVR of FVIII in the normal range (≥66% of normal)  
3. 
FVIII half-life ≥6 hours  
Partial success 
Two of the three criteria above were met. 
Partial response 
One of the three criteria above was met. 
Partial failure 
None of the three criteria were met, but inhibitor titre has decreased to <5 BU. 
Complete failure 
None of the three criteria were met, and inhibitor titre was still ≥5 BU. 
BU, Bethesda Unit; FVIII, coagulation factor VIII; ITI, immune tolerance induction; IVR, in vivo recovery. 
Secondary endpoints included the time to achievement of complete or partial ITI success, the 
duration of immune tolerance (in case of complete or partial ITI success), bleeding frequency 
while on Wilate or Nuwiq ITI treatment, association of inhibitor titres at the start of and 
throughout ITI treatment with the probability of ITI success, use of bypassing agents before 
and during ITI treatment with Wilate or Nuwiq, the use of emicizumab (Hemlibra®), the 
frequency and timing of relapses, treatment adherence, and treatment safety. Additional 
endpoints planned to be assessed in substudies were the patients’ general and hemophilia-
specific quality of life, inhibitor biology (i.e., epitope mapping, IgG subclasses, antibody 
binding affinity), thrombin generation assay (TGA), and genotyping. 
An overview of the time points and assessments at screening/study visits is provided in 
Table 2 and Table 3 below.  
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407  
 
               Page 12 of 23 
Briefly, during the screening visit, the demographic and baseline data, including the patient’s 
medical, bleeding, and ITI history, comorbidities, Hemophilia Joint Health Score (HJHS), and 
history of present illness including inhibitor titres were documented. 
Patients received a study diary in which they documented all bleeding episodes (BEs), 
treatment details, adverse drug reactions (ADRs), central-line infections, and infections 
resulting in hospitalization. Follow-up visits were as per standard of care at each study site, 
with a recommended visit interval of at least 3 months. 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
 
 
 
 
            Page 13 of 23 
Table 2 
Recommended Flow Chart of Assessments for Patients in the Prospective Cohort 
 
Parameter 
 
Screening 
Pre- 
treatment 
Immune tolerance therapy (ITI) 
End of 
ITI 
ITI 
follow-up 
(every 
12 months 
until month 60) 
 
0–3 
months 
3–6 
months 
6–36 
months (c) 
 
Demographic and baseline information 
 
x 
 
 
 
 
 
 
 
Hemophilia Joint Health Score (HJHS) 
 
x 
 
 
every 6 months 
x 
x 
 
General condition 
 
x 
x 
x 
x 
x 
x 
x 
 
Inhibitor titre and FVIII trough levels 
 
x 
x 
twice monthly, 
at least monthly 
monthly 
3-monthly 
x 
approx.  
every 3 months 
 
VWF:Ag trough levels 
 
x 
 
1 month after ITI start 
 
 
 
 
 
VWF:Ag peak levels 
 
 
 
1 month after ITI start (j) 
 
 
 
 
 
FVIII IVR 
 
 
 
(a) 
(a) 
(a) 
x 
x 
 
FVIII half-life 
 
 
 
(a) and (b) 
(a) and (b) 
(a) and (b) 
x 
 
 
ITI efficacy assessment 
 
 
 
 
 
 
x 
 
Substudies 
Quality of life 
High-titre inhibitor patients 
 
 
x 
3 months after ITI start 
(d) 
(d) 
x 
(e) 
Low-titre inhibitor patients 
 
x 
3 months after ITI start 
 
 
x 
(e) 
Anti-FVIII antibody characterization studies (f) 
 
x (k) 
every 12 months (i) (k) 
 
 
Thrombin generation assay (TGA) 
Genotyping 
 
At any time during ITI 
 
Recording of ITI treatment regimen 
 
Continuously 
 
Documentation of bleeding episodes (g) 
 
Continuously 
 
Documentation of surgeries (g) 
 
Continuously 
 
ADRs and infections (h) 
 
Continuously 
 
Concomitant medications (l) 
 
Continuously 
 
(a) when Bethesda negative (<0.6 BU); (b) if recovery ≥66% of expected; (c) if applicable; (d) when patient had reached <5 BU; (e) after 12, 24, 36, 48, and 60 months; (f) included 
epitope mapping, determination of IgG subclasses, and assessment of antibody binding affinity (g) including treatment efficacy assessments; (h) Infections of special interest were 
defined as central-line infections and infections leading to hospitalization (i) as long as inhibitor levels were measurable using the Bethesda assay; (j) samples should have been 
taken 1 hour after infusion of Wilate; (k) blood sample for TGA assessment was to be taken 1 hour after infusion; (l) Concomitant medications included bypassing agents, 
vaccinations, and immunomodulating therapies. 
 
 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
  
 
 
                  
        Page 14 of 23 
Table 3  
Recommended Flow Chart of Assessments for Patients in the Retrospective Cohort 
 
Parameter 
 
Screening 
Pre- 
treatment 
Immune tolerance therapy (ITI) 
End of 
ITI 
ITI 
follow-up 
(every 12 
months until 
month 60) 
 
0–3 months 
3–6 months 
6–36 months (c) 
 
Demographic and baseline information 
 
x 
 
 
 
 
 
 
 
Hemophilia Joint Health Score (HJHS) 
 
Available data should be documented 
 
General condition 
 
x 
x 
x 
x 
x 
x 
x 
 
Inhibitor titre and FVIII trough levels 
 
Available data should be documented 
 
VWF:Ag trough levels 
 
 
VWF:Ag peak levels 
 
 
FVIII IVR 
 
 
FVIII half-life 
 
 
ITI efficacy assessment 
 
 
 
 
 
 
x 
 
Substudies 
Anti-FVIII antibody characterization studies (a) 
 
NA, but in case any retention samples are available, 
these can be provided for testing  
 
 
Thrombin generation assay (TGA) 
 
 
Genotyping 
 
At any time during the study 
 
Recording of ITI treatment regimen 
 
Continuously 
 
Documentation of bleeding episodes (b) 
 
Continuously 
 
Documentation of surgeries (b) 
 
Continuously 
 
ADRs and infections (c) 
 
Continuously 
 
Concomitant medications (d) 
 
Continuously 
 
(a) included epitope mapping, determination of IgG subclasses, and assessment of antibody binding affinity (b) including treatment efficacy assessments; (c) Infections of special 
interest were defined as central-line infections and infections leading to hospitalization; (d) Concomitant medications included bypassing agents, vaccinations, and immunomodulating 
therapies. 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
Page 15 of 23 
4 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES  
The current study was conceived as a Canadian study to evaluate the safety and efficacy of 
ITI in hemophilia A patients using either Wilate or Nuwiq. However, all of the enrolled patients 
ended up being treated with Wilate, and no patient received Nuwiq. Additionally, with the 
introduction of non-factor treatments as an option to treat hemophilia A patients with inhibitors 
to FVIIII, alone or in combination with emicizumab, the investigators amended the protocol to 
include emicizumab to the treatment protocol. At the same time, a larger, global multicentre 
Phase 4 investigator-initiated study with a similar study objective, design and outcomes was 
launched (MOTIVATE). Given the similarities between the two studies, although the goal was 
to recruit 80 Canadian patients into the current study, it was decided that being a part of a 
larger study would both accelerate patient recruitment and address the clinical question with 
more robustness. Therefore, the investigators decided to stop the study and encourage all 
participating study sites to enrol eligible patients into the new international study. 
 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
            Page 16 of 23 
5 RESULTS 
5.1 
Disposition of Patients  
A total of 14 patients were enrolled in this study, 8 in the retrospective and 6 in the 
prospective cohort. All patients were treated with Wilate. Two patients, both from the 
retrospective cohort, were excluded from the per-protocol (PP) population: one (26-01-02) 
switched to an alternative treatment and the other (26-01-07) experienced better response 
with recombinant activated factor VII (rFVIIa) (OCTA-WIL26_DM_Export, OCTA-
WIL26_DS_Export). No patient discontinued the study before it was terminated. 
5.2 
Patient Demographics 
Patient demographics and baseline characteristics are summarized in Table 4. Inhibitor levels 
prior to entering the study are shown in OCTA-WIL26_MHI_Export. 
Table 4. 
Baseline Characteristics 
 
Number of Patients 
N=14 
Age (years) 
n 
   Mean (SD) 
   Median 
   Range 
 
14 
12.4 (6.1)  
11.0 
(4‒23) 
Race, n (%) 
n 
   Asian 
   White 
   Other1 
   Missing 
 
14 
1 (7.1) 
9 (64.3) 
3 (21.4) 
1 (7.1) 
Blood type, n (%) 
n 
   0 
   A 
   B 
   AB 
   Missing 
 
14 
5 (35.7) 
4 (28.6) 
1 (7.1) 
3 (21.4) 
1 (7.1) 
Severity of hemophilia A, n (%) 
n 
   Mild 
   Moderate (1% to 5% factor activity) 
   Severe  (<1% factor activity) 
   Missing 
 
13 
7 (50) 
2 (14.3) 
4 (28.6) 
1 (7.1%) 
FVIII mutation, n (%) 
n 
   Intron 22 Inversion 
   Intron 1 Inversion 
   Missense mutations 
   Unknown 
   Missing 
 
13 
6 (42.9) 
1 (7.1) 
1 (7.1) 
5 (35.7) 
1 (7.1) 
Previous inhibitor treatment, n (%) 
n 
   Yes 
   No 
 
14 
10 (71.4) 
4 (28.6) 
1. 
Other includes: Asian/White n=1, Indian/White n=1, Middle-Eastern n=1. 
SD, standard deviation. 
Source: OCTA-WIL26_DM_Export, OCTA-WIL26_DH_Export, OCTA-WIL26_CMP_Export. 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
            Page 17 of 23 
5.3 
Safety Evaluation 
5.3.1 Extent of Exposure 
Available data on the exposure to Wilate is provided in OCTA-WIL26_EX_Export, OCTA-
WIL26_EXHL_Export and OCTA-WIL26_EXOP_Export. 
5.3.2 ADRs and Infections   
5.3.2.1 Brief Summary of ADRs 
Of the 14 patients, 2 experienced 6 ADRs in the study (patient 26-01-02 experienced 4 ADRs 
and patient 26-01-08 experienced 2 ADRs) (Table 5).  
Table 5: 
Summary Statistics on Patients with ADRs (Safety Population, N=14) 
 
All patients 
n (%) 
Number of ADRs 
ADR 
2 (14.3) 
6 
Serious ADR 
2 (14.3) 
3 
Related ADR1 
0 
0 
Serious related ADR 
0 
0 
Severe ADR2 
2 (14.3) 
4 
ADR leading to discontinuation of study medication 
0 
0 
Related ADR leading to discontinuation of study 
medication 
0 
0 
ADR leading to death 
0 
0 
1. 
Five ADRs were judged as “unlikely” related and one as “not related”. 
2. 
Severity of one ADR was not rated. 
ADR, adverse drug reaction. 
Source: OCTA-WIL26_AE_Export. 
 
Of the 6 ADRs, 4 (66.7%) were severe, 1 (16.7%) was of moderate severity and for 1 the 
severity was not recorded. Three (50%) of the ADRs were judged as serious. Three 
(2 serious) ADRs were of special interest. Serious ADRs and those of special interest are 
discussed in Section 5.3.2.3. All ADRs resolved and all patients recovered from the ADRs. 
Five of the ADRs were judged as unlikely related to the study drug and one was judged as 
not related. There were no deaths in the study (OCTA-WIL26_AE_Export). 
5.3.2.2 Display of Adverse Drug Reactions 
The list of ADRs recorded is shown in Table 6. 
Table 6: 
Display of ADRs by MedDRA Preferred Term (Safety Population, N=14) 
ADR 
Number of patients (%) 
Number of ADRs 
Any ADR 
2 (14.3) 
6 
Device-related infection 
1 (7.1) 
2 
Gastroenteritis 
1 (7.1) 
1 
Bronchial hyperreactivity  
1 (7.1) 
1 
Respiratory distress 
1 (7.1) 
1 
Pyrexia 
1 (7.1) 
1 
ADR, adverse drug reaction; IVAD, implantable venous access device. 
Source: OCTA-WIL26_AE_Export. 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
            Page 18 of 23 
5.3.2.3 Analysis of ADRs and Infections  
All ADRs were single occurrences, with 4 ADRs in one and 2 ADRs in another patient.  
A 5-year-old White patient (26-01-02) experienced 4 ADRs in the study. This patient was 
admitted for implantable venous access device (IVAD) line infection on 19-Mar-2014. This 
event was judged as severe. The patient underwent a removal of the IVAD on 20-Mar-2014 
(planned procedure, major surgery). On 26-Mar-2014, he experienced gastroenteritis of 
moderate severity and judged as a serious ADR, and the next day (27-Mar-2014), exacerbation 
of airway reactive disease, which was judged as severe. He underwent an insertion of a 6-
French petite port-a-cath at the right subclavian vein on 27-Mar-2014 and a port-a-cath revision 
on 11-May-2014 (both major surgeries). All 3 ADRs resolved by 03-Apr-2014. The ADRs were 
judged as unlikely related to the treatment. On 01-Jan-2015, this patient had an infected IVAD 
(ADR judged as severe and serious), which was removed the next day (02-Jan-2015; major 
surgery), and the ADR resolved by 04-Jan-2015. He additionally underwent an insertion of 
IVAD via left subclavian vein on 13-Jan-2015 (OCTA-WIL26_AE_Export, OCTA-
WIL26_OP_Export). 
A 17-month-old patient of Indian descent (26-01-08) experienced respiratory distress, judged 
as severe and serious and not related to the study treatment, on 12-May-2019. The ADR 
resolved on 17-May-2019. This patient also reported fever on 13-Sep-2019, which resolved 
the same day. The severity of this ADR was not reported. The event was judged as unlikely 
related to Wilate. The medical history of this patient shows that he was born prematurely at 35 
weeks, and exhibited a failure to thrive in the first week of life. He was diagnosed with 
tracheoesophageal fistula with esophageal atresia at birth. During the study, he underwent 
multiple procedures (7 esophageal dilations, 3 bronchoscopies and 3 laryngoscopies, 4 
esophagogastroduodenoscopies) as a result of this condition (OCTA-WIL26_AE_Export, 
OCTA-WIL26_MH_Export, OCTA-WIL26_OP_Export). 
The 2 IVAD line infections and the gastroenteritis in one patient were judged as ADR of special 
interest (infections).  
5.3.2.4 Listing of Adverse Events by Patient 
A complete list of ADRs by patient is given in OCTA-WIL26_AE_Export. 
5.3.3 Deaths, Other Serious ADRs, and Other Significant ADRs 
5.3.3.1 Listing of Deaths, other Serious ADRs and Other Significant ADRs 
There were no deaths in this study (OCTA-WIL26_AE_Export). Serious ADRs and ADRs of 
special interest are described in Section 5.3.2.3. 
5.3.3.2 Deaths 
Not applicable. 
5.3.3.3 Other Serious ADRs 
The 3 serious ADRs are described in Section 5.3.2.3. 
5.3.3.4 Other Significant ADRs 
The 3 ADRs of special interest are described in Section 5.3.2.3. 
5.3.3.5 Narratives of Deaths, Other Serious ADRs and Certain Other Significant ADRs 
The 3 serious ADRs are described in Section 5.3.2.3. 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
            Page 19 of 23 
5.3.3.6 Analysis and Discussion of Deaths, Other Serious ADRs and Other Significant 
ADRs 
The 3 serious ADRs are described in Section 5.3.2.3. 
5.3.4 Clinical Laboratory Evaluation 
5.3.4.1 Listing of Individual Laboratory Measurements by Patient and Each Abnormal 
Laboratory Value  
Individual patient data for hematology and biochemistry parameters during surgeries can be 
found in OCTA-WIL26_LBO_Export. Individual patient data for FVIII levels during surgeries 
can be found in OCTA-WIL26_OPLB_Export. 
5.3.4.2 Evaluation of Each Laboratory Parameter 
The following laboratory parameters examined included: hemoglobin, hematocrit, platelets, 
white blood cell count, alanine amino transferase, aspartate transaminase, serum creatinine 
and red blood cell count (OCTA-WIL26_LBO_Export). 
5.3.4.3 Individual Clinically Significant Abnormalities 
There were no laboratory values during surgeries judged as clinically significant 
(OCTA-WIL26_LBO_Export). 
5.3.4.4 FVIII Inhibitors 
Individual patient data for FVIII inhibitors can be found in OCTA-WIL26_LBIFV_Export. 
5.3.5 Vital Signs, Physical Findings and Other Observations Related to Safety 
Vital signs were not recorded. 
5.3.6 Safety Conclusions 
There were no deaths during the study. Two patients experienced 3 serious ADRs 
(gastroenteritis and infected IVAD in one and respiratory distress in the other). Gastroenteritis 
and infected IVAD were judged as unlikely related to Wilate and respiratory distress as not 
related to Wilate. All ADRs resolved.  
Wilate ITI was well tolerated in this group of paediatric previously treated patients with 
hemophilia A and no new safety concerns were identified. 
5.4 
Analysis of Efficacy 
The primary objective of this study was to evaluate the efficacy of Wilate or Nuwiq in ITI in 
moderate and severe hemophilia A patients with FVIII inhibitors by determining the 
proportion of patients achieving complete or partial ITI success based on predefined success 
criteria (Table 1). 
Efficacy evaluation was performed for 8 of the 14 patients. For 7 patients (87.5%), the 
treatment with Wilate was judged as ‘complete success’ and for 1 (12.5%) as ‘complete 
failure’ (OCTA-WIL26_EA_Export). The patient for whom the treatment was judged as a 
failure (26-01-07) had a low-level inhibitor (2.5 Bethesda Units [BU]) at the start of ITI (22-
May-2012). By 25-Jun-2012, his inhibitor levels were undetectable. Over the next 2 years, he 
had 2 more instances of low-level inhibitor, with other tests being negative for inhibitor 
activity. On 06-Oct-2014, he had a level of 0.8 BU, and at the next time point of 3.1 BU. On 
19-Nov-2015 his inhibitor level was 209.0 BU and his ITI treatment declared as failed. The in 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
            Page 20 of 23 
vivo recovery (IVR) values for this patient were not available. The patient was treated with 
1500 IU (92.6 IU/kg) Wilate daily from 07-Jun-2012 until 12-May-2014, at which point the 
dose was increased to 2000 IU (109.9 IU/kg) daily and he continued this treatment until 
04-Nov-2014. The dose was then increased to 3000 IU (152.3 IU/kg) daily, which he 
received until the end of ITI treatment. He experienced 8 bleeding episodes during the study 
(3 due to trauma, 1 spontaneous and 4 due to unknown causes). Five of the BEs were in an 
ankle, 1 one was a bilateral forearm muscle bleed, 1 was in his foot and 1 in his wrist. Five 
were moderate to major bleeds (3 ankle, 1 bilateral forearm and 1 wrist BE) and the severity 
for the other bleeds was not specified (OCTA-WIL26_LBIFV_Export, OCTA-
WIL26_LBFR_Export, OCTA-WIL26_EX_Export, OCTA-WIL26_BE_Export). 
5.5 
Discussion and Overall Conclusions 
The primary endpoint of this study was to evaluate the efficacy of Wilate or Nuwiq in 
achieving complete or partial ITI success in severe, moderate and mild hemophilia A patients 
with inhibitors. Due to the study termination, only 14 patients are included in this analysis. All 
patients were treated with Wilate. 
Efficacy evaluation results were available for 8 of the 14 patients. For 7 patients, the 
treatment with Wilate was judged as ‘complete success’ and for 1 (12.5%) as ‘complete 
failure’, giving the success rate of 87.5%. 
No new safety signals emerged in this study. There were no deaths during the study. Two 
patients experienced 3 serious ADRs (gastroenteritis and an infected IVAD in one and 
respiratory distress in the other). Gastroenteritis and infected IVAD were judged as unlikely 
related to Wilate and respiratory distress as not related. All ADRs resolved.  
Wilate ITI was well tolerated in this group of paediatric previously treated patients with 
hemophilia A and no new safety concerns were raised. Therefore, these results are in line with 
those reported for other studies with Wilate ITI treatment in Canadian patients  
 
 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
            Page 21 of 23 
6 TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE 
TEXT 
See Section 7.4. 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26) 
RESTRICTED 
Version 1.0 
08-Oct-2021
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407
   Page 22 of 23 
7 APPENDICES 
7.1 
Protocol and Protocol Amendments 
7.2 
Sample Case Report Forms (Unique Pages Only) 
7.3 
Case Report Forms for Deaths, Other Serious Adverse Events and Withdrawals 
for Adverse Events 
7.4 
Patient Data Listings 
OCTA-WIL26-AE-Export 
OCTA-WIL26-BE-Export 
OCTA-WIL26-BEP-Export 
OCTA-WIL26-CM-Export 
OCTA-WIL26-CMHT-Export 
OCTA-WIL26-CMP-Export 
OCTA-WIL26-CO-Export 
OCTA-WIL26-DH-Export 
OCTA-WIL26-DM-Export 
OCTA-WIL26-DS-Export 
OCTA-WIL26-EA-Export 
OCTA-WIL26-EX-Export 
OCTA-WIL26-EXHL-Export 
OCTA-WIL26-EXOP-Export 
OCTA-WIL26-FA-Export 
OCTA-WIL26-IE-Export 
OCTA-WIL26-ITIP-Export 
OCTA-WIL26-JS-Export 
OCTA-WIL26-LBFR-Export 
OCTA-WIL26-LBIFV-Export 
OCTA-WIL26-LBO-Export 
OCTA-WIL26-MH-Export 
OCTA-WIL26-MHI-Export 
OCTA-WIL26-MSW-Export 
OCTA-WIL26-OP-Export 
OCTA-WIL26-OPBL-Export 
OCTA-WIL26-OPLB-Export 
OCTA-WIL26-PE-Export 
OCTA-WIL26-QOLA-Export 
Property of Octapharma. Do not copy or distribute without written permission.

Abbreviated Study Report 
Wilate and Nuwiq (WIL-26)  
RESTRICTED 
Version 1.0 
08-Oct-2021 
 
090-CSR-WIL-26-Final_08-Oct-2021 / DOC ID 3407 
 
            Page 23 of 23 
OCTA-WIL26-QOLC-Export 
OCTA-WIL26-QOLHA-Export 
OCTA-WIL26-QOLHK-Export 
OCTA-WIL26-QOLI1-Export 
OCTA-WIL26-QOLI2-Export 
OCTA-WIL26-QOLT-Export 
OCTA-WIL26-QOLTO-Export 
OCTA-WIL26-QOLY-Export 
OCTA-WIL26-RA-Export 
OCTA-WIL26-REL-Export 
OCTA-WIL26-SA-Export 
OCTA-WIL26-SV-Export 
OCTA-WIL26-VS-Export 
OCTA-WIL26-WH-Export 
Property of Octapharma. Do not copy or distribute without written permission.