Clinical trial NCT03376516
Conditions: Severe Hemophilia A
Sponsor: Octapharma
Start date: 2017-11-22; Completion date: 2018-11-03
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A prospective, non-controlled, international, multi-centre phase 3 study to investigate the pharmacokinetics, efficacy, safety, and immunogenicity of Wilate in previously treated children with severe haemophilia A

Detailed description:

Arms: arm 1: All patients will receive Wilate for prophylactic treatment. Patients will also receive Wilate for treatment of breakthrough bleeding events as required
Interventions: intervention 1: Wilate
Intervention descriptions: intervention 1: von Willebrand factor / Factor VIII (plasma derived)

Protocol documents:
Prot_002.pdf: 
 
 
 
CLINICAL STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, EFFICACY, SAFETY, AND 
IMMUNOGENICITY OF WILATE IN PREVIOUSLY TREATED 
PEDIATRIC PATIENTS WITH SEVERE HEMOPHILIA A 
 
 
Investigational Product: 
Wilate 
Indication: 
Severe hemophilia A (<1% FVIII:C) 
Study Design: 
Prospective, non-controlled, international, multi-center 
phase 3 study 
Sponsor: 
Octapharma AG 
Seidenstrasse 2, CH-8853 Lachen 
Switzerland 
Study Number: 
WIL-30 
EudraCT Number: 
2017-001531-40 
IND Number: 
IND 17181 
Development Phase: 
Phase 3 
Planned Clinical Start: 
Q4 2017 
Planned Clinical End: 
Q3 2018 
Date of Protocol: 
19-Jun-2017 
Version: 
02, for Ukraine only 
Co-ordinating Investigator: Professor Leonid Dubey 
Western Ukrainian Specialized Children’s Medical 
Centre, Pediatric Department, Danylo Halytsky Lviv 
National Medical University 
Office 224 
27 Av. Dnisterska 
Lviv, Ukraine, 79035 
 
 
This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
 
 
 
 
 
 
 
 
090-CSP-WIL-30-V01/DOC ID 2627 
CLINICAL STUDY PROTOCOL 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
19-Jun-2017 
Page 1 of 70 
 
 
 
STUDY OUTLINE 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Title of Study: Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Im- 
munogenicity of Wilate in Previously Treated Pediatric Patients with Severe Hemophilia A 
Indication: Severe hemophilia A (<1% FVIII:C) 
Number of Study Center(s): Approximately 5 sites in Europe 
Objectives: 
Primary Objective: 
The primary objective of this study is to determine the FVIII:C pharmacokinetics (PK) for 
Wilate in previously treated patients (PTP) with severe hemophilia A aged 1 to <12 years. 
Secondary Objectives: 
The secondary objectives of this study are to: 
• Determine the efficacy of Wilate in prophylactic treatment 
• Determine the efficacy of Wilate in the treatment of breakthrough 
bleeding episodes (BEs) 
• Calculate the FVIII:C incremental IVR of Wilate over time (at baseline, and at 3 and 
6 months of treatment) 
• Assess the association between AB0 blood type and the FVIII:C half-life of Wilate 
• Assess the association between the VWF:Ag concentration and the FVIII:C half-life 
of Wilate 
• Assess the safety and tolerability of Wilate 
• Assess the immunogenicity of Wilate 
Additional Objective: 
An additional objective of this study is the descriptive efficacy of Wilate in surgical prophy- 
laxis. 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
19-Jun-2017 
Page 2 of 70 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Study Design: 
Prospective, non-controlled, international, multi-center phase 3 study 
Number of Patients: 
Overall, 10 PTPs (5 patients aged 1 to <6 years of age and 5 patients aged 6 to <12 years) will 
be enrolled into this study. The aim is to obtain evaluable data on 8 patients who complete 
both the 2-day PK Phase and the 6-month Prophylactic Treatment Phase. Of the 8 evaluable 
patients, 4 patients must be 1 to <6 years of age, and another 4 patients must be 6 to <12 years 
of age. Enrolled patients will be replaced only if they do not complete the PK assessment. 
Patient Selection Criteria: 
Inclusion Criteria: 
1. Severe hemophilia A (<1% FVIII:C) according to medical history 
2. Male patients aged 1 to <12 years 
3. Previous treatment with a FVIII concentrate for at least 50 exposure days (EDs) 
4. Immunocompetence (CD4+ count >200/µL) 
5. Voluntarily given, fully informed written and signed consent obtained by the patient’s 
parent(s) or legal guardian and, depending on the children’s developmental stage and 
intellectual capacity, informed assent by the patients before any study-related proce- 
dures are performed 
The interval between the Screening Visit and the PK Visit should not exceed 30 days. If the 
30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be 
>200/µL for patients to be enrolled (i.e., inclusion criterion no. 4). 
Exclusion Criteria: 
1. Any coagulation disorders other than hemophilia A 
2. History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory antibodies 
(≥0.6 BU using the Nijmegen modification of the Bethesda assay) at screening, as de- 
termined by the central laboratory 
3. Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate 
transaminase [ASAT] levels >5 times of upper limit of normal, creatinine 
>120 µmol/L) 
4. Patients receiving or scheduled to receive immunomodulating drugs (other than anti- 
retroviral chemotherapy), such as alpha-interferon, prednisone (equivalent to 
>10 mg/day), or similar drugs 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
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Page 3 of 70 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
5. Treatment with any investigational medicinal product in another interventional clini- 
cal study currently or within 4 weeks before enrollment 
6. Hemoglobin level < 9 g/dL at the Screening Visit 
Test Product, Dose, and Mode of Administration: 
The factor VIII/VWF concentrate Wilate, produced from the plasma of human donors, is pre- 
sented as a powder and solvent for intravenous injection containing nominally 500 IU or 
1000 IU human von Willebrand factor (VWF) and human FVIII per vial. 
PK Assessment 
Single dose of 50 ± 5 IU kg BW. 
Prophylactic Treatment 
Wilate should be administered every 2 to 3 days at a dose of 20–40 IU/kg BW for 6 months. 
In case of unacceptably frequent spontaneous breakthrough BEs (i.e., more than 2 spontane- 
ous BEs or 1 major or life-threatening spontaneous BE within a 30-day period), the dose of 
Wilate should be increased by approximately 5 IU/kg (depending on the entire content of the 
additional vial(s) that need(s) to be reconstituted). 
Alternative prophylactic regimens at the discretion of the Investigator are also acceptable. 
Treatment of Breakthrough BEs 
• Early hemarthrosis, muscle bleeding or oral bleeding 
Target FVIII level: 20–40% 
Recommended dose: 10–20 IU/kg 
Repeat every 12–24 hours. At least 1 day, until the BE as indicated by pain has re- 
solved or healing has been achieved. 
• More extensive hemarthrosis, muscle bleeding or hematoma 
Target FVIII level: 30–60% 
Recommended dose: 15–30 IU/kg 
Repeat injection every 12–24 hours for 3 to 4 days or more until pain and disability 
have resolved. 
• Life-threatening hemorrhages 
Target FVIII level: 60–100% 
Recommended dose: 30–50 IU/kg 
Repeat injection every 8–24 hours until threat has resolved. 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
19-Jun-2017 
Page 4 of 70 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Surgical Prophylaxis 
• Minor surgeries, including tooth extractions 
Target FVIII level: 30–60% 
Recommended dose: 15–30 IU/kg 
Every 24 hours, at least 1 day, until healing is achieved. 
• Major surgeries 
Target FVIII level: 80–100% (pre- and postoperative) 
Recommended dose: 40–50 IU/kg 
Repeat injection every 8–24 hours until adequate wound healing, then therapy for at 
least another 7 days to maintain a FVIII activity of 30% to 60%. 
Duration of Treatment: 
The planned duration of treatment for an individual patient is about 6 months (+2 weeks) and 
at least 50 EDs, plus a Follow-up Contact 30 days after the Study Completion Visit. 
Reference Therapy, Dose, Mode of Administration: None 
Primary and Secondary Endpoints: 
Primary Endpoint 
The primary endpoint of this study is the PK profile of Wilate. 
Secondary Endpoints 
The secondary endpoints of this study are the: 
1. Total annualized bleeding rate (TABR) 
2. Spontaneous annualized bleeding rate (SABR) 
3. Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of 
BEs successfully treated with Wilate 
4. Wilate consumption data (FVIII IU/kg per week per patient) for prophylaxis 
5. Incremental IVR of Wilate over time (at baseline, and at 3 and 6 months of treatment) 
6. Association between AB0 blood type and the FVIII:C half-life of Wilate 
7. Association between VWF:Ag concentration and the FVIII:C half-life of Wilate 
8. Safety and tolerability of Wilate by monitoring adverse events (AEs) throughout the 
study 
9. Immunogenicity of Wilate by testing for FVIII inhibitors 
10. Virus safety in terms of parvovirus B19 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
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Page 5 of 70 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Exploratory Endpoint 
An exploratory endpoint of this study is the descriptive efficacy of Wilate in surgical 
prophylaxis. 
Study Outcome Parameters: 
PK Parameters 
The following PK parameters will be assessed (FVIII:C using both the chromogenic (CHR) 
and one-stage (OS) assays and actual IMP potencies): 
• Area under the curve (AUC) and AUC normalized for the administered dose 
(AUCnorm) 
• In vivo half-life (T1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vd) 
• Clearance (CL) 
• Incremental in vivo recovery (IVR) 
Efficacy Parameters 
Prophylactic Treatment  
Efficacy of prophylactic treatment will be assessed based on the TABR, i.e., the total number 
of BEs per patient per year. The number of spontaneous BEs per patient per year (SABR) will 
also be used to assess prophylactic treatment efficacy. 
Treatment of Breakthrough BEs 
At the end of a BE, treatment efficacy will be assessed by the patient (together with the In- 
vestigator in case of on-site treatment) using the predefined criteria ‘excellent,’ ‘good,’ ‘mod- 
erate,’ and ‘none’. 
The proportion of BEs successfully treated with IMP will be evaluated for all BEs taken 
together and by BE severity. All efficacy ratings assessed as either ‘excellent’ or ‘good’ will 
be considered ‘successfully treated.’ 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
19-Jun-2017 
Page 6 of 70 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Surgical Prophylaxis 
Efficacy will be assessed at the end of surgery by the surgeon and at end of the postoperative 
period by the hematologist. In both cases, predefined assessment criteria will be used. In ad- 
dition, the Investigator will assess the overall efficacy combining both the intra- and postop- 
erative assessments. 
Safety Parameters 
Any of the following drug safety information shall be collected: 
• Adverse events (AEs) and serious adverse events (SAEs) temporally associated with 
the administration of IMP 
• Drug overdose, interaction, medication error, and post-study SAEs 
Central Laboratory 
The following laboratory tests will be done at the central laboratory: 
• FVIII:C in the vials used for PK injections as well as in plasma using the CHR and 
OS assays 
• FVIII inhibitor activity will be determined at each study visit before the injection 
of Wilate using the modified Bethesda assay (Nijmegen modification). Blood sam- 
pling for inhibitor testing should preferably be performed at the time of trough 
FVIII:C levels. 
If inhibitor development is suspected between study visits (e.g., based on an unex- 
plained need to increase the dose, lack of efficacy of IMP injections, or prolonged 
bleeding), additional FVIII inhibitor tests will be performed and documented. 
In case of positive inhibitor results, inhibitor retesting using a second, separately 
drawn sample should be performed, preferably within 15 days of becoming aware of 
the positive result. If inhibitor development is confirmed by the second sample ana- 
lyzed in the central laboratory, patients with low-titer inhibitors (<5 BU) may con- 
tinue treatment with Wilate, while patients with high-titer inhibitors will be discon- 
tinued from the study. 
• VWF:Ag and VWF:Ac will be measured at prespecified time points. 
• Virus safety will be evaluated by taking a plasma sample for parvovirus B19 anti- 
body testing during the Screening Visit. All patients negative during screening will 
be tested again at the Study Completion Visit. 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
19-Jun-2017 
Page 7 of 70 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Retention serum sample for possible virus marker testing will be taken during the 
Screening Visit and stored at the central laboratory. 
Local Laboratory 
The following laboratory tests will be done by the local laboratories of each study site: 
• Hematology: red blood cell count, white blood cell count, hemoglobin, hematocrit, 
and platelet count 
• Chemistry: total bilirubin, alanine amino transferase, aspartate transaminase, blood 
urea nitrogen, serum creatinine 
• CD4+ count 
• AB0 blood type, unless known from medical history 
Study Procedures by Visit: 
Screening Visit 
The following assessments will be performed: 
• Obtaining voluntarily given, written (signed and dated) informed consent 
• Inclusion and exclusion criteria 
• Demographic characteristics 
• Weight 
• Height 
• Medical history (including FVIII treatment during the last 6 months before screening) 
• Vital signs 
• Physical examination 
• Hemophilia Joint Health Score (HJHS), unless obtained within 3 months before the 
Screening Visit 
• Blood sampling for the following purposes: 
– Routine safety laboratory 
– Determination of CD4+ levels 
– Determination of AB0 blood group (unless derived from medical history) 
– Determination of FVIII inhibitors 
– Testing for parvovirus B19 antibodies 
– Retention sample for possible additional virus marker testing 
• Concomitant medications 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
19-Jun-2017 
Page 8 of 70 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
The interval between the Screening Visit and the PK Visit should not exceed 30 days. If the 
30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be 
>200/µL for patients to be enrolled (i.e., inclusion criterion no. 4). 
Any BEs occurring between the Screening Visit and the PK Visit should be treated with the 
patient’s previously used FVIII concentrate. Similarly, prophylactic treatment between the 
Screening Visit and the PK Visit should be done with the patient’s previously used FVIII 
concentrate. 
PK Visit 
Patients will receive Wilate at a dose of 50 ± 5 IU/kg (labelled dose) after a washout period 
of at least 72 hours from their last FVIII injection. Patients must not be experiencing any 
bleeding. 
The following assessments will be performed: 
• Body weight before injection 
• Blood samples will be taken for the following purposes and at the following time 
points: 
– FVIII:C plasma concentration (OS and CHR) for PK assessment within 1 h 
before injection and 15±5 min, 1 h (±5 min), 6 h (±30 min), 24±2 h, and 48±2 h 
after the end of injection 
– Safety laboratory before and 48±2 h after injection 
– FVIII inhibitor before injection 
– Plasma VWF:Ag and VWF:Ac within 1 h before injection and 15±5 min after 
the end of injection 
• Vital signs before injection as well as 1 h (±5 min) and 48±2 h after injection 
• AE monitoring 
• Concomitant medications 
At the end of this visit, patients will receive a patient diary. The Investigator will explain to 
the patient how to fill in the diary and emphasize the importance of carefully documenting all 
treatment details, AEs, and concomitant medications. Also, patients will be provided with 
IMP for home treatment. They will be re-supplied whenever necessary during the study. 
The first prophylactic injection of Wilate after the PK Visit marks the beginning of the 
Prophylactic Treatment Phase. 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
19-Jun-2017 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Day-14 Visit 
The Day-14 Visit will take place 14–21 days after the start of the Prophylactic Treatment 
Phase, if possible after a washout period of at least 48 hours from the patient’s latest FVIII 
injection. The following assessments will be performed: 
• Review of patient diary 
• Blood samples will be taken for the following purposes and at the following time 
points: 
– FVIII inhibitor before injection 
– Plasma VWF:Ag and VWF:Ac before injection 
• AE monitoring 
• Concomitant medication 
Day-30 Visit 
The Day-30 Visit will take place 30±3 days after the start of the Prophylactic Treatment 
Phase, if possible after a washout period of at least 48 hours from the patient’s latest FVIII 
injection. The assessments performed will be the same as for the Day-14 Visit. 
3- Month Visit 
The 3-Month Visit will take place 3 months (±2 weeks) after the start of the Prophylactic 
Treatment Phase. 
A prophylactic injection of Wilate will be administered, if possible after a washout period of 
at least 48 hours from the patient’s latest FVIII injection. Patients must not be experiencing 
any bleeding. 
The following assessments will be performed: 
• Review of patient diary 
• Body weight before injection 
• Blood samples will be taken for the following purposes and at the following time 
points: 
– FVIII:C plasma concentration (OS and CHR) for IVR assessment within 1 h 
before and 15±5 min after the end of the injection 
– Safety laboratory before injection 
– FVIII inhibitor before injection 
– Plasma VWF:Ag and VWF:Ac within 1 h before injection and 15±5 min after 
the end of injection 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
19-Jun-2017 
Page 10 of 70 
 
 
 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
• Vital signs before and 15±5 min after the end of injection 
• AE monitoring 
• Concomitant medication 
Study Completion Visit 
The Study Completion Visit will take place 6 months (+2 weeks) after the start of the Prophy- 
lactic Treatment Phase. 
A prophylactic injection of Wilate will be administered, if possible after a washout period of 
at least 48 hours from the patient’s latest FVIII injection. Patients must not be experiencing 
any bleeding. 
The following assessments will be performed: 
• Review of patient diary 
• Body weight before injection 
• Blood samples will be taken for the following purposes and at the following time 
points: 
– FVIII:C plasma concentration (OS and CHR) for IVR assessment within 1 h 
before injection of the last prophylactic dose and 15±5 min after the end of the 
injection 
– Safety laboratory before and 15±5 minutes after injection 
– FVIII inhibitor before injection 
– Plasma VWF:Ag and VWF:Ac within 1 h before injection and 15±5 min after 
the end of injection 
– Parvovirus B19 antibodies before injection, if first sample was negative 
• Vital signs before and 15±5 min after the end of injection 
• AE monitoring 
• Concomitant medication 
• Physical examination 
All used and unused IMP vials will be returned by the patient. 
Patients prematurely withdrawing from the study for any reason will also be invited to attend 
the Study Completion Visit. 


Study Protocol 
No. WIL-30 
CONFIDENTIAL 
Version 02 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Follow-up Contact 30 days after Study Completion Visit 
The purpose of the Follow-up Contact 30 days after the 6-month Study Completion Visit is 
to document any thromboembolic events, whether or not they are suspected to be related to 
study treatment. 
The Follow-up Contact may either take the form of a personal visit by the patient to the study 
site or a telephone call by the Investigator. Any relevant AEs are to be recorded on the AE 
page of the eCRF. 
Unscheduled Visits and Additional Measures 
If inhibitor development is suspected (e.g., based on an unexplained need to increase the dose, 
lack of efficacy of IMP injections, or prolonged bleeding), FVIII inhibitor tests in addition to 
those scheduled during study visits will be performed and documented. 
In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sam- 
ple should be performed, preferably within 15 days of becoming aware of the positive result. 
If inhibitor development is confirmed by the second sample analyzed in the central laboratory, 
patients with low-titer inhibitors (<5 BU) may continue treatment with Wilate, while patients 
with high-titer inhibitors will be discontinued from the study. 
Other reasons for unscheduled visits may be the occurrence of serious AEs or hospitalizations 
because of severe BEs or because of a surgical intervention. 
Surgical Visits 
Patients may undergo surgical interventions in the course of the study. Whether or not patients 
undergoing surgeries will be hospitalized will depend on the type and severity of the surgery 
and be at the discretion of the Investigator. In patients undergoing major surgeries, standard 
methods of postsurgical thromboprophylaxis, such as gradated compression stockings and 
early mobilization, should be used to prevent venous thromboembolism. 


Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Statistical Analysis Plan: 
The primary approach to the statistical analysis will be descriptive, presenting sampling sta- 
tistics (n, mean, standard deviation, quartiles, and range) for continuous measurements and 
absolute and relative frequency counts for categorical/ordinal data. This will be comple- 
mented by exploratory confidence intervals (CIs) for means or proportions. 
Pharmacokinetic Analysis 
The PK profiles of Wilate and the associated PK parameters will be summarized by descrip- 
tive statistics as well as the presentation of concentration vs. time plots. Similarly, the results 
of the IVR assessments over time will also be analyzed in summary tables for each time point 
and their differences to baseline, along with 95% CIs for the mean differences. Analysis of 
variance (ANOVA) will be used in an exploratory sense to assess a possible association be- 
tween AB0 blood type, VWF:Ag, and the FVIII:C half-life of Wilate. 
Efficacy Analysis 
Primarily, all obtained data on treatment characteristics (IMP dosages, frequencies, total con- 
sumption) and BEs (duration, frequency, efficacy assessment) will be described using above 
summary statistics. 
Efficacy of Prophylactic Treatment with Wilate 
The efficacy of prophylactic treatment with Wilate will be statistically evaluated by presenting 
descriptive sampling statistics for the TABR and SABR. 
Efficacy in the Treatment of Breakthrough BEs 
To assess the hemostatic efficacy of Wilate in the treatment of breakthrough bleedings, a fre- 
quency distribution of all such BEs being successfully treated will be presented, along with 
an exploratory 95% CI. The statistical analysis of other secondary endpoints will be descrip- 
tive, including exploratory 95% CIs for the location parameters. 


Study Protocol 
No. WIL-30 
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Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
Wilate 
Protocol Identification Code: 
WIL-30 
Name of Active Ingredient: 
Factor VIII/VWF concentrate human 
Date of Final Protocol: 
19-Jun-2017 
 
 
Safety Analysis 
The analysis of safety will be based on the occurrence of AEs, the results of the safety labor- 
atory tests, immunogenicity measurements, and the occurrence of parvovirus B19 serocon- 
versions. Analysis of AEs will focus on treatment-emergent adverse events (TEAEs). Patient 
listings will be provided for patients with SAEs, AEs leading to withdrawal from study, and 
AEs leading to death. 
Time profiles of FVIII inhibitor testing results will be analyzed by presenting sampling sta- 
tistics for the values as well as frequency tables for positive findings, along with 95% Pearson- 
Clopper CIs. Incidences of parvovirus B19 seroconversions between screening and end of 
study will be estimated along with 95% Pearson-Clopper CIs. 
Other safety parameters (e.g., changes in physical examination findings) will be analyzed by 
summary tables or listings. The analysis of the safety parameters recorded during surgery 
(laboratory values) will be descriptive. 


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FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
For 
details, 
see 
Section 
Screening 
Visit 
PK 
Visit 
Prophylactic Treatment Phase 
(starts with first prophylactic injection of Wilate 
after the PK Visit) 
Follow-up 
Contact 
30 (±3) days 
after 
Study Completion 
Visit 
Day-14 
Visit 
(14–21 days) 
Day-30 
Visit 
(±3 days) 
3-Month 
Visit 
(±2 weeks) 
Study 
Completion 
(6-Month) Visit 
at 6 months 
(+2 weeks) 
Informed consent 
x 
Inclusion and exclusion criteria 
4.1 
x 
Demographics 
7.1.1 
x 
Weight 
x 
x [1] 
x [1] 
x [1] 
Height 
x 
Medical history (incl. FVIII treatment 6 months before screening) 
7.1.2 
x 
Vital signs 
7.3.6 
x 
x [2] 
x [4] 
x [4] 
Physical examination 
7.3.6 
x 
x 
Routine safety laboratory 
7.3.5 
x 
x [3] 
x [1] 
x [4] 
Determination of CD4+ levels [8] 
7.1.1 
x 
Determination of AB0 blood group [9] 
7.1.1 
x 
HJHS, unless obtained within 3 months before screening 
7.1.1 
x 
PK injection (50 ± 5 IU/kg) 
x 
Blood sampling for FVIII:C (OS and CHR) for PK assessment 
7.3.5 
x [5] 
IVR injection 
x 
x 
Blood sampling for FVIII:C IVR (OS and CHR) 
7.3.5 
x [6] 
x [6] 
Factor VIII inhibitor [10] 
7.3.5 
x 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
VWF:Ag and VWF:Ac 
7.3.5 
x [6] 
x [1] 
x [1] 
x [6] 
x [6] 
Parvovirus B19 antibodies 
7.3.5 
x 
x [7] 
Retention sample for possible virus marker testing 
7.3.5 
x 
Patient diary review 
x 
x 
x 
x 
Adverse event monitoring 
7.3 
x 
» 
» 
» 
x 
x [11] 
Concomitant medications 
7.1.2 
x 
» 
» 
» 
» 
x 
PK = pharmacokinetic, IVR = in vivo recovery, HJHS = Hemophilia Joint Health Score, OS = one-stage assay, CHR = chromogenic assay, 
VWF:Ag = von Willebrand factor antigen, VWF:Ac = VWF activity. 


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LEGEND TO THE FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
[1] 
Before injection 
[2] 
Before injection as well as 1 h (±5 min) and 48±2 h after injection 
[3] 
Before injection as well as 48±2 h after injection [local laboratory] 
[4] 
Before injection as well as 15±5 min after injection 
[5] 
Blood sampling within 1 h before injection and 15±5 min, 1 h (±5 min), 6 h (±30 min), 24±2 h, and 48±2 h after the end of injection [central laboratory] 
[6] 
Blood sampling within 1 h before injection as well as 15±5 min after the end of injection [central laboratory] 
[7] 
If first sample was negative for parvovirus B19 antibodies (sample to be taken before injection) [central laboratory] 
[8] 
CD4+ count to be repeated if interval between Screening Visit and first injection exceeds 30 days. To be included into the study, the patient’s CD4+ count must 
be >200/µL (i.e., inclusion criterion no. 4). 
[9] 
Unless obtainable from patient’s medical history 
[10] 
Blood sampling for inhibitor testing should preferably be done at the time of trough FVIII:C levels [central laboratory] 
In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample should be performed, preferably within 15 days of becoming 
aware of the positive result. 
[11] 
Documentation of any thromboembolic events only (to be documented on AE page) 


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FLOW CHART OF ASSESSMENTS FOR SURGICAL PROPHYLAXIS 
 
For details, 
see Section 
Within 
12 hours 
before start 
Within 
3 hours 
before start 
Surgery 
POP 
day 1 
Any 
POP day 
End of 
POP 
period 
3-8 weeks 
after 
surgery 
Intra- 
operatively 
End [1] 
Body weight 
x 
Type of surgery 
x 
Location of surgery 
x 
Severity of surgery 
7.2.5 
x 
Expected duration of surgery 
x 
Expected average/ maximum blood loss during surgery 
7.2.5 
x 
Actual duration of surgery 
x 
Actual blood loss during surgery 
x 
Administration of IMP 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
FVIII plasma levels 
7.2.5 
# 
(#) 
(#) 
(#) [2] 
(#) 
(#) 
VWF:Ag and VWF:Ac 
7.3.5 
# 
(#) [2] 
(#) 
(#) 
Presence of wound hematomas 
x 
x 
x 
Routine safety laboratory 
7.3.5 
x 
(x) 
(x) 
(x) 
Vital signs 
7.3.6 
x 
x 
x 
Efficacy assessment 
7.2.6 
S 
H 
Overall efficacy assessment 
7.2.6 
I 
Factor VIII inhibitor [3] 
7.3.5 
x 
Narrative of outcome 
x 
Concomitant medications 
throughout observation period 
Adverse event monitoring 
7.3 
throughout observation period 
POP = postoperative, VWF:Ag = von Willebrand factor antigen, VWF:Ac = VWF activity 
( ) Optional 
# Samples to be taken immediately before (≤ 30 min) and 30±15 min after IMP administration 
[1] Immediately after the last surgical suture 
[2] For major surgeries, mandatory for the first 3 postoperative doses 
[3] In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample should be performed, preferably within 15 days of becoming aware of 
the positive result. 
S, performed by surgeon; H, performed by hematologist; I performed by Investigator 


 
 
 
 
 
 
 
 
 
 
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PROTOCOL SIGNATURES 
 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
 
Signature of the Sponsor's Representative 
 
 
 
 
 
Dr. Wolfgang Frenzel 
International Medical Director 
Octapharma Pharmazeutika 
Produktionsgesellschaft m.b.H. 
Oberlaaerstrasse 235 
A-1100 Vienna 
Austria 
 
 
Dr. Cristina Solomon 
  
 
Senior Director 
Clinical R&D Haematology 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
Signature 
Date 
 
 
Signature of the Protocol Author/Clinical Project Manager 
 
 
 
 
Irena Dzhunova 
Clinical Trial Manager 
Clinical R&D Haematology 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
 
Date 
 
 
 
 
Page 17 of 70 


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PROTOCOL SIGNATURES 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
Professor Leonid Dubey 
Co-ordinating Investigator 
Western Ukrainian Specialized 
Children's Medical Centre, 
Pediatric Department, 
Danylo Halytsky Lviv National Medical University 
Office 224 
27 Av. Dnisterska 
Lviv, Ukraine, 79035 
cZDiv- O._b   2(  
Date 
 
 
 
 
 
 
 
 
Hans-Peter Hucke 
Biostatistician 
ERGOMED 
Im Mediapark 2 
50670K6ln 
Germany 
Signature .t:i 
ZJ-1-()t-2-1 
Date 
 
 
 
 
 
 
 
 
 
 
 
Page 18 of 71 


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TABLE OF CONTENTS 
STUDY OUTLINE ................................................................................................................................ 1 
FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT.................... 14 
FLOW CHART OF ASSESSMENTS FOR SURGICAL PROPHYLAXIS ................................... 16 
PROTOCOL SIGNATURES .............................................................................................................. 17 
PROTOCOL SIGNATURES .............................................................................................................. 18 
TABLE OF CONTENTS ..................................................................................................................... 19 
LIST OF ABBREVIATIONS .............................................................................................................. 22 
1 
INTRODUCTION ....................................................................................................................... 24 
1.1 
HEMOPHILIA A ....................................................................................................... 24 
1.2 
WILATE ............................................................................................................................................... 24 
1.3 
RATIONALE FOR CONDUCTING THE STUDY ............................................................................ 25 
1.4 
DOSE RATIONALE ............................................................................................................................ 25 
1.4.1 
Dose for PK Assessment .......................................................................................25 
1.4.2 
Doses for Prophylaxis ...........................................................................................25 
1.5 
BENEFIT-RISK STATEMENT .......................................................................................................... 26 
2 
STUDY OBJECTIVES ............................................................................................................... 27 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................... 27 
2.2 
SECONDARY OBJECTIVES .............................................................................................................. 27 
2.3 
ADDITIONAL OBJECTIVE ............................................................................................................... 27 
3 
INVESTIGATIONAL PLAN ..................................................................................................... 28 
3.1 
STUDY ENDPOINTS .......................................................................................................................... 28 
3.1.1 
Primary Endpoint .................................................................................................28 
3.1.2 
Secondary Endpoints ............................................................................................28 
3.1.3 
Exploratory Endpoint ...........................................................................................29 
3.2 
OVERALL STUDY DESIGN AND PLAN ........................................................................................ 29 
3.3 
DISCUSSION OF STUDY DESIGN .................................................................................................. 29 
4 
STUDY POPULATION .............................................................................................................. 30 
4.1 
POPULATION BASE .......................................................................................................................... 30 
4.1.1 
Number of Patients ...............................................................................................30 
4.1.2 
Inclusion Criteria ..................................................................................................30 
4.1.3 
Exclusion Criteria .................................................................................................30 
4.2 
PRIOR AND CONCOMITANT THERAPY ....................................................................................... 31 
4.3 
WITHDRAWAL AND REPLACEMENT OF PATIENTS ................................................................. 31 
4.3.1 
Premature Patient Withdrawal .............................................................................31 
4.3.2 
Patient Replacement Policy ..................................................................................31 
4.3.3 
Assignment of Patients to Treatment ....................................................................31 
4.4 
RELEVANT PROTOCOL DEVIATIONS .......................................................................................... 31 


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5 
INVESTIGATIONAL MEDICINAL PRODUCT ....................................................................32 
5.1 
CHARACTERIZATION OF WILATE ................................................................................................. 32 
5.2 
PACKAGING AND LABELLING ...................................................................................................... 32 
5.3 
CONDITIONS FOR STORAGE AND USE ....................................................................................... 32 
5.4 
DOSE AND DOSING SCHEDULE .................................................................................................... 32 
5.4.1 
PK Assessment Phase ...........................................................................................32 
5.4.2 
Prophylactic Treatment Phase ..............................................................................33 
5.4.3 
Treatment of Breakthrough BEs ...........................................................................33 
5.4.4 
Surgical Prophylaxis .............................................................................................34 
5.5 
PREPARATION AND METHOD OF ADMINISTRATION ............................................................. 34 
5.6 
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND .................. 34 
5.7 
TREATMENT COMPLIANCE ............................................................................................................ 35 
5.7.1 
Drug Dispensing and Accountability ....................................................................35 
5.7.2 
Assessment of Treatment Compliance ..................................................................35 
6 
STUDY CONDUCT ....................................................................................................................36 
6.1 
OBSERVATIONS BY VISIT FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 36 
6.1.1 
Screening Visit ......................................................................................................36 
6.1.2 
PK Visit .................................................................................................................37 
6.1.3 
Day-14 Visit ..........................................................................................................38 
6.1.4 
Day-30 Visit ..........................................................................................................38 
6.1.5 
3-Month Visit ........................................................................................................38 
6.1.6 
Study Completion (6-Month) Visit ........................................................................39 
6.1.7 
Follow-up Contact 30 days after Study Completion Visit .....................................39 
6.1.8 
Unscheduled Visits and Additional Measures ......................................................40 
6.1.9 
Surgical Visits .......................................................................................................40 
6.2 
DURATION OF STUDY ..................................................................................................................... 40 
6.2.1 
Planned Duration for an Individual Patient .........................................................40 
6.2.2 
Planned Duration for the Study as a Whole .........................................................40 
6.2.3 
Premature Termination of the Study .....................................................................41 
7 
ASSESSMENTS AND METHODS ...........................................................................................42 
7.1 
DEMOGRAPHIC AND BASELINE INFORMATION ...................................................................... 42 
7.1.1 
Demographic and Baseline Characteristics .........................................................42 
7.1.2 
Medical History and Concomitant Medications ...................................................42 
7.2 
EFFICACY ASSESSMENTS .............................................................................................................. 42 
7.2.1 
Pharmacokinetic Evaluation .................................................................................42 
7.2.2 
IMP Administration Data .....................................................................................43 
7.2.3 
Bleeding Episode (BE) Data .................................................................................43 
7.2.4 
Efficacy of the Treatment of Breakthrough BEs ...................................................44 
7.2.5 
Surgical Prophylaxis Data ....................................................................................45 
7.2.6 
Efficacy in Surgical Prophylaxis ..........................................................................46 
7.3 
SAFETY ASSESSMENTS ................................................................................................................... 48 
7.3.1 
Assessments for Safety Endpoints .........................................................................48 
7.3.2 
Adverse Events (AEs) ............................................................................................48 
7.3.3 
Serious Adverse Events (SAEs) .............................................................................52 


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7.3.4 
AE and SAE Reporting Timelines .........................................................................52 
7.3.5 
Laboratory Tests ...................................................................................................53 
7.3.6 
Vital Signs and Physical Examination ..................................................................55 
7.3.7 
Other Relevant Safety Information .......................................................................55 
7.4 
APPROPRIATENESS OF MEASUREMENTS .................................................................................. 56 
8 
DATA HANDLING AND RECORD KEEPING ...................................................................... 57 
8.1 
DOCUMENTATION OF DATA ......................................................................................................... 57 
8.1.1 
Source Data and Records .....................................................................................57 
8.1.2 
Case Report Forms ...............................................................................................57 
8.1.3 
Changes to Case Report Form (CRF) Data ..........................................................58 
8.2 
INFORMATION TO INVESTIGATORS ............................................................................................ 58 
8.3 
RESPONSIBILITIES ............................................................................................................................ 59 
8.4 
INVESTIGATOR’S SITE FILE .......................................................................................................... 59 
8.5 
PROVISION OF ADDITIONAL INFORMATION ............................................................................ 59 
9 
STATISTICAL METHODS AND SAMPLE SIZE ..................................................................60 
9.1 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 60 
9.2 
STATISTICAL ANALYSIS ................................................................................................................. 60 
9.2.1 
Populations for Analysis .......................................................................................60 
9.2.2 
PK and Efficacy Analysis Plan .............................................................................61 
9.2.3 
Safety Analysis Plan ..............................................................................................63 
9.2.4 
Handling of Missing Data .....................................................................................63 
9.3 
RANDOMIZATION, STRATIFICATION, AND CODE RELEASE ................................................ 63 
9.4 
INTERIM ANALYSIS ......................................................................................................................... 63 
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ...................... 64 
10.1 ETHICAL/REGULATORY FRAMEWORK ...................................................................................... 64 
10.2 APPROVAL OF STUDY DOCUMENTS ........................................................................................... 64 
10.3 PATIENT INFORMATION AND INFORMED CONSENT .............................................................. 64 
10.4 PROTOCOL AMENDMENTS ............................................................................................................ 65 
10.5 CONFIDENTIALITY OF PATIENT DATA ...................................................................................... 65 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................... 66 
11.1 PERIODIC MONITORING ................................................................................................................. 66 
11.2 AUDIT AND INSPECTION ................................................................................................................ 66 
12 
REPORTING AND PUBLICATION ........................................................................................ 67 
12.1 CLINICAL STUDY REPORT ............................................................................................................. 67 
12.2 PUBLICATION POLICY ..................................................................................................................... 67 
13 
LIABILITIES AND INSURANCE ............................................................................................68 
14 
REFERENCES ............................................................................................................................ 69 
15 
APPENDICES .............................................................................................................................. 70 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Description 
ABR 
Annualized Bleeding Rate 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALAT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
ASAT 
Aspartate Transaminase 
AUC 
Area Under the Concentration-Time Curve 
AUCnorm 
AUC Normalized for the Administered Dose 
BE 
Bleeding Episode 
BU 
Bethesda Units 
BW 
Body Weight 
CHR 
Chromogenic (Assay) 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Plasma Concentration 
eCRF 
Electronic Case Report Form 
ED 
Exposure Day 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IVR 
In Vivo Recovery 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
OS 
One-Stage (Assay) 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PTP 
Previously Treated Patient 
PUP 
Previously Untreated Patient 


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SABR 
Spontaneous Annualized Bleeding Rate 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SC 
Subcutaneous 
SURG 
Surgery (Population) 
T1/2 
In Vivo Half-Life 
TABR 
Total Annualized Bleeding Rate 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time to Reach Maximum Plasma Concentration 
Vd 
Volume of Distribution 
VWD 
Von Willebrand Disease 
VWF 
Von Willebrand Factor 
VWF:Ac 
Von Willebrand Factor Activity 
VWF:Ag 
Von Willebrand Factor Antigen 


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1 
INTRODUCTION 
 
1.1 Hemophilia A 
Hemophilia A is an inherited sex-linked disorder of blood coagulation in which affected males 
do not produce functional coagulation factor VIII (FVIII) in sufficient quantities to achieve 
satisfactory hemostasis. The incidence of congenital hemophilia A is approximately 1 in 10,000 
births. Disease severity is classified according to the level of FVIII activity (% of normal) as 
mild (>5% to <40%), moderate (1% to 5%), or severe (<1%). 
The deficiency in FVIII predisposes patients with hemophilia A to recurrent bleeding episodes 
(BEs) in joints, muscles, or internal organs, either spontaneously or as a result of accidental or 
surgical trauma. Without adequate treatment, these repeated hemarthroses and hematomas lead 
to long-term sequelae with severe disability. Less frequent but more severe bleeding sites are 
the central nervous system, the urinary or gastrointestinal tract, the eyes, and the retroperito- 
neum. 
Patients with hemophilia A are at high risk of developing major and life-threatening BEs after 
surgical procedures, even after minor interventions such as tooth extraction. Replacement ther- 
apy with exogenous FVIII, either plasma-derived or recombinant, successfully adjusts hemo- 
stasis in these patients in a temporary manner. 
 
1.2 Wilate 
Wilate is a plasma-derived, stable, highly purified, double virus inactivated concentrate of 
freeze-dried active von Willebrand factor (VWF) and factor VIII (FVIII) prepared from cryo- 
precipitate and intended for the treatment of patients with von Willebrand disease (VWD) 
and/or hemophilia A. By introducing new biotechnological methods and optimized chromato- 
graphic media into the Wilate manufacturing process, it has been possible to manufacture a 
preparation containing the FVIII/VWF complex in its native form and almost devoid of lower 
molecular weight proteins. 
Overall, 14 prospective clinical studies with Wilate have been completed, 8 in patients with 
VWD and 6 in patients with hemophilia A. The 6 clinical studies with Wilate in patients with 
hemophilia A were open, non-controlled studies investigating the efficacy and safety of the 
product in the prevention and treatment of BEs as well as in surgical prophylaxis in a total of 
109 individual patients with severe hemophilia A. Of these, 81 were previously treated patients 
(PTPs) and 28 were previously untreated patients (PUPs). 
Five of the 6 studies investigated the efficacy of Wilate both in the prevention and treatment of 
BEs and in surgical prophylaxis, and 1 study assessed the efficacy of Wilate in surgical prophy- 
laxis only. 


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Wilate received its first market authorization in Germany in February 2005 and is currently 
licensed in 65 countries worldwide. In Europe, Wilate is approved for the treatment of both 
VWD and hemophilia A. In the USA, it is approved for the treatment of VWD only. 
This study (WIL-30) in children aged 1 to <12 years is performed to obtain approval of Wilate 
for the treatment of hemophilia A in the USA and is carried out alongside a similar study (WIL- 
27) in patients with severe hemophilia A ≥12 years of age. 
A summary of findings from nonclinical and clinical studies with Wilate is provided in the 
product’s Investigator’s Brochure. 
 
1.3 Rationale for Conducting the Study 
The purpose of this study is to obtain additional data on the PK profile, safety, and efficacy of 
Wilate in previously treated children with hemophilia A, thus supplementing the existing data- 
base to obtain approval of Wilate for the indication hemophilia A in the USA. 
 
1.4 Dose Rationale 
 
1.4.1 Dose for PK Assessment 
The dose used for PK assessment, i.e., 50 ± 5 IU/kg, is in line with the current recommendations 
of the Guideline on the clinical investigation of recombinant and human plasma-derived factor 
VIII products (EMA/CHPM/BPWP/144533/2009), which recommends a dose of 
25–50 IU/kg. It is expected that this dose will result in measurable FVIII:C plasma concentra- 
tions after 48 hours in most, if not all, patients. 
The ± 5 IU/kg range (rather than a fixed dose) was included to allow the entire contents of 
reconstituted vials to be injected rather than taking out an exact volume, which is difficult tech- 
nically and might result in dosing errors. 
 
1.4.2 Doses for Prophylaxis 
The doses for prophylaxis (20–40 IU/kg Wilate/kg BW given at intervals of 2 to 3 days), the 
treatment of BEs and perioperative prophylaxis (see Section 5.4), are as indicated in the Euro- 
pean Summary of Product Characteristics. 
Alternative prophylactic regimens at the discretion of the Investigator are also acceptable. 


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1.5 Benefit-Risk Statement 
The following adverse reactions are known to occur with other VWF/FVIII preparations and 
may also occur with the use of Wilate: 
• Hypersensitivity or allergic reactions (which may include angioedema, burning, and 
stinging at the infusion site, chills, flushing, generalized urticaria, headache, hives, hy- 
potension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, 
vomiting, wheezing) have been observed upon use of Wilate and may, in some cases, 
progress to severe anaphylaxis (including shock) with or without fever. In rare occa- 
sions, fever has been observed. 
• The formation of neutralizing antibodies (inhibitors) to FVIII is a known compli- 
cation in the management of hemophilia A. These inhibitors are usually IgG immuno- 
globulins directed against the FVIII procoagulant activity, which are quantified in Be- 
thesda Units (BU) per mL of plasma. As preventive measure, hemophilia A patients 
should not be switched thoughtlessly from one FVIII concentrate to another. Patients 
should be carefully monitored for the development of inhibitors by appropriate clinical 
observations and laboratory tests. 
• As for all medicinal products prepared from human blood or plasma, infectious dis- 
eases due to transmission of infective agents cannot be totally excluded. This applies 
also to pathogens of hitherto unknown origin. The manufacturing process of Wilate, 
which includes 2 viral inactivation steps with different chemical/physical action prin- 
ciples represents a high standard for plasma-derived concentrates in terms of pathogen 
safety. The measures taken are considered effective for enveloped viruses such as hu- 
man immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus 
(HCV), and for the non-enveloped hepatitis A virus. The measures taken may be of 
limited value against non-enveloped viruses such as parvovirus B19. 
In view of its state-of-the-art manufacturing process and available clinical and postmarketing 
evidence, the benefit-risk evaluation of Wilate is positive. 


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2 
STUDY OBJECTIVES 
 
2.1 Primary Objective 
The primary objective of this study is to determine the FVIII:C pharmacokinetics (PK) for 
Wilate in previously treated patients (PTP) with severe hemophilia A aged 1 to <12 years. 
 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 
• Determine the efficacy of Wilate in prophylactic treatment 
• Determine the efficacy of Wilate in the treatment of breakthrough 
bleeding episodes (BEs) 
• Calculate the FVIII:C incremental IVR of Wilate over time (at baseline, and at 3 and 
6 months of treatment) 
• Assess the association between AB0 blood type and the FVIII:C half-life of Wilate 
• Assess the association between the VWF:Ag concentration and the FVIII:C half- 
life of Wilate 
• Assess the safety and tolerability of Wilate 
• Assess the immunogenicity of Wilate 
 
2.3 Additional Objective 
An additional objective of this study is the descriptive efficacy of Wilate in surgical prophy- 
laxis. 


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3 
INVESTIGATIONAL PLAN 
 
3.1 Study Endpoints 
 
3.1.1 Primary Endpoint 
The primary endpoint of this study is the PK profile of Wilate. 
The PK profile is based on the following baseline PK parameters for FVIII:C using both the 
chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies: 
• Area under the curve (AUC) and AUC normalized for the administered dose 
(AUCnorm) 
• In vivo half-life (T1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vd) 
• Clearance (CL) 
• Incremental in vivo recovery (IVR) 
 
3.1.2 Secondary Endpoints 
The secondary endpoints of this study are the: 
1. Total annualized bleeding rate (TABR) 
TABR will be calculated as the total number of BEs in the time period between first 
dose of IMP and the Study Completion Visit, divided by the duration (in years) be- 
tween first dose of IMP and the Study Completion Visit. Surgery periods, and BEs oc- 
curring within these periods, will be excluded from the calculation of TABR. 
2. Spontaneous annualized bleeding rate (SABR), calculated in analogy with TABR 
3. Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of 
BEs successfully treated with Wilate 
4. Wilate consumption data (FVIII IU/kg per week per patient) for prophylaxis 
5. Incremental IVR of Wilate over time (at baseline, and at 3 and 6 months of treatment) 
6. Association between AB0 blood type and the FVIII:C half-life of Wilate 
7. Association between VWF:Ag concentration and the FVIII:C half-life of Wilate 
8. Safety and tolerability of Wilate by monitoring adverse events (AEs) throughout the 
study 
9. Immunogenicity of Wilate by testing for FVIII inhibitors 
10. Virus safety in terms of parvovirus B19 


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3.1.3 Exploratory Endpoint 
An exploratory endpoint of this study is the descriptive efficacy of Wilate in surgical prophy- 
laxis. 
 
3.2 Overall Study Design and Plan 
This is a prospective, non-controlled, international, multi-center phase 3 study investigating the 
FVIII:C pharmacokinetics, efficacy, safety, and immunogenicity of Wilate in previously treated 
children with severe hemophilia A aged 1 to <12 years. 
Overall, 10 PTPs (5 patients aged 1 to <6 years of age and 5 patients aged 6 to <12 years) will 
be enrolled into this study by approximately 5 study sites in Europe. The aim is to obtain data 
on 8 patients (4 patients per age group) who are evaluable for the primary endpoint, i.e., the PK 
profile of Wilate. Enrolled patients will be replaced only if they do not complete the PK assess- 
ment. 
At baseline, all patients will undergo a 2-day PK Assessment Phase of 1 dose of 50 IU ± 5 IU 
Wilate/kg BW. The study is scheduled to start in the 4th quarter of 2017 and to be completed 
in the 3rd quarter of 2018. The planned duration for an individual patient is at least 6 months 
(+2 weeks) and at least 50 EDs, plus a Follow-up Contact 30 (±3) days after the Completion 
Visit. 
The primary objective of this study is to determine the FVIII:C pharmacokinetics for Wilate. 
Secondary objectives of this study include the total and spontaneous annualized bleeding rates, 
the efficacy of Wilate in the treatment of breakthrough BEs as well as the product’s safety and 
tolerability. An additional objective is the descriptive efficacy of Wilate in surgical prophylaxis. 
 
3.3 Discussion of Study Design 
This prospective, non-controlled, international, multi-center phase 3 study was designed keep- 
ing in mind the FDA Draft ‘Guidance for Industry on the General Clinical Pharmacology Con- 
siderations for Pediatric Studies for Drugs and Biological Products.’ For the choice of the sam- 
ple size we used the feedback provided by FDA with regard to the number of patients needed 
in a different paediatric age group in the WIL-27 study (IND 17181, FDA advice / information 
request dated 13-Dec-2016). 
Because clearance of FVIII differs between adolescents and children, this study in children aged 
1 to <12 years is performed to complement PK data on Wilate in adolescents and adults. 
During the study, safety and efficacy data will also be collected. 


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4 
STUDY POPULATION 
 
4.1 Population Base 
4.1.1 Number of Patients 
Overall, 10 PTPs (5 patients aged 1 to <6 years of age and 5 patients aged 6 to <12 years) will 
be enrolled into this study. 
The aim is to obtain evaluable data on 8 patients who complete both the 2-day PK Phase and 
the 6-month Prophylactic Treatment Phase. Of the 8 evaluable patients, 4 patients must be 1 to 
<6 years of age, and another 4 patients must be 6 to <12 years of age. Enrolled patients will be 
replaced only if they do not complete the PK assessment. 
4.1.2 Inclusion Criteria 
Patients who meet all of the following criteria are eligible for the study: 
1. Severe hemophilia A (<1% FVIII:C) according to medical history 
2. Male patients aged 1 to <12 years 
3. Previous treatment with a FVIII concentrate for at least 50 exposure days (EDs) 
4. Immunocompetence (CD4+ count >200/µL) 
5. Voluntarily given, fully informed written and signed consent obtained by the patient’s 
parent(s) or legal guardian and, depending on the children’s developmental stage and 
intellectual capacity, informed assent by the patients before any study-related proce- 
dures are performed 
The interval between the Screening Visit and the PK Visit should not exceed 30 days. If the 
30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be 
>200/µL for patients to be enrolled (i.e., inclusion criterion no. 4). 
 
4.1.3 Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for the study: 
1. Any coagulation disorders other than hemophilia A 
2. History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory antibodies 
(≥0.6 BU using the Nijmegen modification of the Bethesda assay) at screening, as de- 
termined by the central laboratory 
3. Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate trans- 
aminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 µmol/L) 
4. Patients receiving or scheduled to receive immunomodulating drugs (other than anti- 
retroviral chemotherapy), such as alpha-interferon, prednisone (equivalent to 
>10 mg/day), or similar drugs 


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5. Treatment with any investigational medicinal product in another interventional clinical 
study currently or within 4 weeks before enrollment 
6. Hemoglobin level < 9 g/dL at the Screening Visit 
 
4.2 Prior and Concomitant Therapy 
Patients receiving or scheduled to receive immunomodulating drugs (other than anti-retroviral 
chemotherapy), such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar 
drugs may not be enrolled. 
Concomitant therapies not interfering with the objectives of the study are permitted. Details of 
any concomitant medications must be recorded in the electronic Case Report Form (eCRF). 
 
4.3 Withdrawal and Replacement of Patients 
 
4.3.1 Premature Patient Withdrawal 
Patients have the right to withdraw from the study at any time for any reason, without the need 
to justify their decision. The Investigator also has the right to withdraw patients in case of AEs, 
poor compliance, or other reasons. 
For any withdrawals after study entry, the Investigator will obtain all the required details and 
document the reason(s) for discontinuation. If the reason for withdrawal of a patient is an AE, 
the main specific event or laboratory test will be recorded, and the Investigator will make thor- 
ough efforts to clearly document the outcome. 
 
4.3.2 Patient Replacement Policy 
Enrolled patients will be replaced only if they do not complete the PK assessment. 
 
4.3.3 
Assignment of Patients to Treatment 
The Investigator will enter a unique identifier for each patient in both the eCRF and the confi- 
dential patient identification list and inform the monitor of any new patient enrolled. 
Patients who enroll in the study will not be permitted to re-enroll. 
 
4.4 Relevant Protocol Deviations 
In case of any major protocol deviation, the Investigator and Octapharma will decide on the 
further participation of the patient in this study after having discussed all relevant aspects. 


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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
 
5.1 Characterization of Wilate 
Wilate, produced from the plasma of human donors, is presented as a powder and solvent for 
intravenous injection containing nominally 500 IU/1000 IU human von Willebrand factor 
(VWF) and human FVIII per vial. The ratio between von Willebrand factor ristocetin cofactor 
activity (VWF:RCo) and FVIII:C is 1:1. 
The product contains approximately 100 IU/mL human coagulation factor VIII when reconsti- 
tuted with 5 mL/10 mL water for injections with 0.1% Polysorbate 80. The FVIII potency (IU) 
is determined using the European Pharmacopoeia chromogenic assay. The injection or infusion 
rate should be 2–3 mL per minute. 
 
5.2 Packaging and Labelling 
Final labelling will comply with the national requirements of each country where the study is 
conducted. 
 
5.3 Conditions for Storage and Use 
The powder and solvent vials must be stored in a refrigerator (2–8°C). The vials must be kept 
in the outer carton to protect from light and must not be frozen. 
The product can be stored at room temperature (max. 25°C) for 2 months. In this case, the shelf- 
life expires 2 months after the product has been taken out of the refrigerator for the first time. 
The Investigator and any authorized personnel at the site will ensure that the IMP is stored in 
appropriate conditions with restricted access and in compliance with national regulations. 
 
5.4 Dose and Dosing Schedule 
 
5.4.1 PK Assessment Phase 
In the 2-day PK Assessment Phase performed before the start of the Prophylactic Treatment 
Phase, Wilate will be administered to all patients as a single dose of 50 ± 5 IU kg BW. 


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5.4.2 Prophylactic Treatment Phase 
In the Prophylactic Treatment Phase, Wilate should be administered every 2 to 3 days at a dose 
of 20–40 IU/kg BW for 6 months (+2 weeks) and at least 50 EDs. 
Alternative prophylactic regimens at the discretion of the Investigator are also acceptable. 
In case of unacceptably frequent spontaneous breakthrough BEs (i.e., more than 2 spontaneous 
BEs or 1 major or life-threatening spontaneous BE within a 30-day period), the dose of Wilate 
should be increased by approximately 5 IU/kg (depending on the entire content of the additional 
vial(s) that need(s) to be reconstituted). 
 
5.4.3 Treatment of Breakthrough BEs 
The dose (and duration) of treatment of BEs will depend on the location and extent of bleeding 
and on the clinical condition of the patient. The dose calculation is based on the empirical find- 
ing that 1 IU FVIII:C/kg BW raises the plasma level by 1.5–2.0% of normal activity. The rec- 
ommended dose is determined using the following formula: 
Recommended units = body weight (kg) x desired factor VIII rise (%) (IU/dL) x 0.5 
 
In the case of the following hemorrhagic events, the factor VIII activity should not fall below 
the given plasma FVIII activity level (%) in the corresponding period. The following can be 
used to guide dosing in BEs: 
• Early hemarthrosis, muscle bleeding, or oral bleeding 
Target FVIII level: 20–40% 
Recommended dose: 10–20 IU/kg 
Repeat injection every 12–24 hours. At least 1 day, until the BE as indicated by pain 
has resolved or healing has been achieved. 
• More extensive hemarthrosis, muscle bleeding, or hematoma 
Target FVIII level: 30–60% 
Recommended dose: 15–30 IU/kg 
Repeat injection every 12–24 hours for 3 to 4 days or more until pain and disability 
have resolved. 
• Life-threatening hemorrhages 
Target FVIII level: 60–100% 
Recommended dose: 30–50 IU/kg 
Repeat injection every 8–24 hours until threat has resolved. 


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5.4.4 Surgical Prophylaxis 
• Minor surgeries, including tooth extractions 
Target FVIII level: 30–60% 
Recommended dose: 15–30 IU/kg 
Every 24 hours, at least 1 day, until healing is achieved. 
• Major surgeries 
Target FVIII level: 80–100% (pre- and postoperative) 
Recommended dose: 40–50 IU/kg 
Repeat injection every 8–24 hours until adequate wound healing, then therapy for at 
least another 7 days to maintain a FVIII activity of 30% to 60%. 
During treatment, appropriate determination of FVIII:C levels is advised to guide the dose to 
be administered and the frequency of repeated infusions. In the case of major surgical interven- 
tions in particular, precise monitoring of the substitution therapy by means of coagulation anal- 
ysis (FVIII:C) is indispensable. Individual patients may vary in their response to FVIII treat- 
ment, achieving different half-lives and recoveries. 
 
5.5 Preparation and Method of Administration 
 
For more information on the method of administration of Wilate, please see the European Sum- 
mary of Product Characteristics. 
Throughout the study, several batches of Wilate will be used, and these will be recorded in the 
clinical study report. 
 
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
Not applicable. 


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5.7 Treatment Compliance 
 
5.7.1 Drug Dispensing and Accountability 
Any IMP provided to the site will be accounted for. This includes IMP received at the site, IMP 
dispensed to patients, and IMP returned unused by the patient. 
A Drug Inventory and Dispensing Log will be kept current by the Investigator, detailing the 
dates and quantities of IMP received and dispensed to each patient and the remaining quantity. 
The inventory and dispensing log will be available to the monitor to verify drug accountability 
during the study. 
Unused IMP can be destroyed at the study site or returned to the Sponsor for destruction. De- 
struction can be initiated only after accountability has been verified and fully reconciled by the 
monitor and after the Sponsor has granted written approval of destruction. 
 
5.7.2 Assessment of Treatment Compliance 
For PK and IVR assessments at baseline and at 3 and 6 months, the IMP will be administered 
at the study site, with compliance under the control of the Investigator. 
In the Prophylactic Treatment Phase, compliance will be assessed on the basis of the completed 
patient diaries and returned vials of Wilate. 


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6 
STUDY CONDUCT 
The flow chart of assessments for PK assessment and prophylactic treatment by study visit is 
given on page 14. The flow chart for surgical assessments is given on page 16. Details on the 
individual assessments and methods are provided in Section 7. 
 
6.1 Observations by Visit for PK Assessment and Prophylactic Treatment 
All enrolled patients will participate in the following study visits: 
• Screening Visit 
• PK Visit 
• Day-14 Visit 
• Day-30 Visit 
• 3-Month Visit 
• Completion Visit 
• Follow-up Contact 30 days after Completion Visit 
 
6.1.1 Screening Visit 
The following assessments will be performed during the Screening Visit: 
• Obtaining voluntarily given, written (signed and dated) informed consent 
• Inclusion and exclusion criteria 
• Demographic characteristics 
• Weight 
• Height 
• Medical history (including FVIII treatment during the last 6 months before screening) 
• Vital signs 
• Physical examination 
• Hemophilia Joint Health Score (HJHS), unless obtained within 3 months before the 
Screening Visit 
• Blood sampling for the following purposes: 
– Routine safety laboratory 
– Determination of CD4+ levels 
– Determination of AB0 blood group (unless derived from medical history) 
– Determination of FVIII inhibitors 
– Testing for parvovirus B19 antibodies 
– Retention sample for possible additional virus marker testing 
• Concomitant medications 


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The interval between the Screening Visit and the PK Visit should not exceed 30 days. If the 
30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be 
>200/µL for patients to be enrolled (i.e., inclusion criterion no. 4, see Section 4.1.2). 
Any BEs occurring between the Screening Visit and the PK Visit should be treated with the 
patient’s previously used FVIII concentrate. Similarly, prophylactic treatment between the 
Screening Visit and the PK Visit should be done with the patient’s previously used FVIII con- 
centrate. 
 
6.1.2 PK Visit 
Patients will receive Wilate at a dose of 50 ± 5 IU/kg (labelled dose) after a washout period of 
at least 72 hours from their last FVIII injection. Patients must not be experiencing any bleeding. 
The following assessments will be performed: 
• Body weight before injection 
• Blood samples will be taken for the following purposes and at the following time 
points: 
– FVIII:C plasma concentration (OS and CHR) for PK assessment within 1 h 
before injection and 15±5 min, 1 h (±5 min), 6 h (±30 min), 24±2 h, and 48±2 h 
after the end of injection 
– Safety laboratory before and 48±2 h after injection 
– FVIII inhibitor before injection 
– Plasma VWF:Ag and VWF:Ac within 1 h before injection and 15±5 min after the 
end of injection 
• Vital signs before injection as well as 1 h (±5 min) and 48±2 h after injection 
• AE monitoring 
• Concomitant medications 
At the end of this visit, patients will receive a patient diary. The Investigator will explain to 
the patient how to fill in the diary and emphasize the importance of carefully documenting all 
treatment details, AEs, and concomitant medications. Also, patients will be provided with IMP 
for home treatment. They will be re-supplied whenever necessary during the study. 
The first prophylactic injection of Wilate after the PK Visit marks the beginning of the 
Prophylactic Treatment Phase. 


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6.1.3 Day-14 Visit 
The Day-14 Visit will take place 14–21 days after the start of the Prophylactic Treatment Phase, 
if possible after a washout period of at least 48 hours from the patient’s latest FVIII injection. 
The following assessments will be performed: 
• Review of patient diary 
• Blood samples will be taken for the following purposes and at the following time 
points: 
– FVIII inhibitor before injection 
– Plasma VWF:Ag and VWF:Ac before injection 
• AE monitoring 
• Concomitant medication 
6.1.4 Day-30 Visit 
The Day-30 Visit will take place 30±3 days after the start of the Prophylactic Treatment Phase, 
if possible after a washout period of at least 48 hours from the patient’s latest FVIII injection. 
The following assessments will be performed: 
• Same assessments as for Day-14 Visit 
6.1.5 3-Month Visit 
The 3-Month Visit will take place 3 months (±2 weeks) after the start of the Prophylactic Treat- 
ment Phase. 
A prophylactic injection of Wilate will be administered, if possible after a washout period of at 
least 48 hours from the patient’s latest FVIII injection. Patients must not be experiencing any 
bleeding. 
The following assessments will be performed: 
• Review of patient diary 
• Body weight before injection 
• Blood samples will be taken for the following purposes and at the following time 
points: 
– FVIII:C plasma concentration (OS and CHR) for IVR assessment within 1 h 
before injection of the prophylactic dose and 15±5 min after the end of the injec- 
tion 
– Safety laboratory before injection 
– FVIII inhibitor before injection 
– Plasma VWF:Ag and VWF:Ac within 1 h before injection and 15±5 min after the 
end of injection 
• Vital signs before and 15±5 min after the end of injection 
• AE monitoring 
• Concomitant medication 


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6.1.6 Study Completion (6-Month) Visit 
The Study Completion Visit will take place 6 months (+2 weeks) after the start of the Prophy- 
lactic Treatment Phase. 
A prophylactic injection of Wilate will be administered, if possible after a washout period of at 
least 48 hours from the patient’s latest FVIII injection. Patients must not be experiencing any 
bleeding. 
The following assessments will be performed: 
• Review of patient diary 
• Body weight before injection 
• Blood samples will be taken for the following purposes and at the following time 
points: 
– FVIII:C plasma concentration (OS and CHR) for IVR assessment within 1 h 
before injection of the last prophylactic dose and 15±5 min after the end of the in- 
jection 
– Safety laboratory before and 15±5 minutes after injection 
– FVIII inhibitor before injection 
– Plasma VWF:Ag and VWF:Ac within 1 h before injection and 15±5 min after the 
end of injection 
– Parvovirus B19 antibodies before injection, if first sample was negative 
• Vital signs before and 15±5 min after the end of injection 
• AE monitoring 
• Concomitant medication 
• Physical examination 
All used and unused IMP vials will be returned by the patient. 
Patients prematurely withdrawing from the study for any reason will also be invited to attend 
the Study Completion Visit. 
6.1.7 Follow-up Contact 30 days after Study Completion Visit 
The purpose of the Follow-up Contact 30 (±3) days after the 6-month Study Completion Visit 
is to document any thromboembolic events, whether or not they are suspected to be related 
to study treatment. 
The Follow-up Contact may take either the form of a personal visit by the patient to the study 
site or a telephone call by the Investigator. Any relevant AEs are to be recorded on the AE page 
of the eCRF. 


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6.1.8 Unscheduled Visits and Additional Measures 
If inhibitor development is suspected (e.g., based on an unexplained need to increase the dose, 
lack of efficacy of IMP injections, or prolonged bleeding), FVIII inhibitor tests in addition to 
those scheduled during study visits will be performed and documented (see Section 7.3.5.1). 
In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample 
should be performed, preferably within 15 days of becoming aware of the positive result. If 
inhibitor development is confirmed by the second sample analyzed in the central laboratory, 
patients with low-titer inhibitors (<5 BU) may continue treatment with Wilate, while patients 
with high-titer inhibitors will be discontinued from the study. 
Other reasons for unscheduled visits may be the occurrence of serious AEs or hospitalizations 
because of severe BEs or because of a surgical intervention. 
6.1.9 Surgical Visits 
Patients may undergo surgical interventions in the course of the study. Whether or not patients 
will be hospitalized will depend on the type and severity of the surgery and be at the discretion 
of the Investigator.In patients undergoing major surgeries, standard methods of postsurgical 
thromboprophylaxis, such as gradated compression stockings and early mobilization, should be 
used to prevent venous thromboembolism. 
For the flow chart of assessments for surgeries, see page 16. For details on the surgery data to 
be documented and the surgical efficacy assessments to be performed, see Section 7.2.5 and 
Section 7.2.6. 
 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Patient 
The planned duration of treatment for an individual patient is about 6 months (+2 weeks) and 
at least 50 EDs, plus a Follow-up Contact 30 (±3) days after the Completion Visit. 
 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed at the time of database lock. 
The estimated start of the study (enrollment of first patient) is the 4th quarter of 2017, and the 
estimated end of the study (database lock) is the 3rd quarter of 2018. 


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6.2.3 Premature Termination of the Study 
Both the Investigator and the Sponsor reserve the right to terminate the study at any time. In 
this event, any necessary procedures will be arranged on an individual study basis after review 
and consultation by both parties. In terminating the study, the Sponsor and the Investigator will 
ensure that adequate consideration is given to the protection of the subjects’/patients’ interests. 
Regulatory authorities and IECs/IRBs should be informed in accordance with national regula- 
tions. Early termination of the study as a whole or by center may apply for the following rea- 
sons: 
 
6.2.3.1 Early Termination of the Entire Clinical Study 
At any time, the study as a whole will be terminated prematurely if new toxicological or phar- 
macological findings or safety reports invalidate the earlier positive benefit-risk-assessment. 
 
6.2.3.2 Early Termination at an Individual Study Center 
At any time, the study can be terminated at an individual center if: 
• The center cannot comply with the requirements of the protocol. 
• The center cannot comply with GCP standards. 
• The required recruitment rate is not met. 
Should the study be prematurely terminated, all study materials (completed and partially com- 
pleted CRFs, IMPs, etc.) must be returned to the Sponsor. 


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7 
ASSESSMENTS AND METHODS 
 
7.1 Demographic and Baseline Information 
The following information will be recorded during the Screening Visit (see Section 6.1.1): 
 
7.1.1 Demographic and Baseline Characteristics 
The demographic and baseline characteristics are age, ethnic origin, height, weight, CD4+ lev- 
els, and AB0 blood group (may also be derived from the patient’s medical history). In addition, 
the Hemophilia Joint Health Score (HJHS) will be obtained (unless done within 3 months be- 
fore the Screening Visit). 
 
7.1.2 Medical History and Concomitant Medications 
The medical history will be obtained by interviewing the patient’s parents or guardians. Records 
of past diseases and treatments (e.g., hospital discharge letters) will be obtained for the study 
files, if available. 
Concomitant medications will be also obtained by interview, and information about FVIII dos- 
ing in the previous 6 months will be collected. 
The history or presence of FVIII inhibitor activity is an exclusion criterion (see Section 4.1.3). 
 
7.2 Efficacy Assessments 
This section summarizes the assessments to be performed for the calculation of the primary (see 
Section 3.1.1) and secondary endpoints (see Section 3.1.2) of this study. 
 
7.2.1 Pharmacokinetic Evaluation 
The following PK parameters for FVIII:C will be determined using a non-compartment model: 
• AUCnorm and AUC 
• In vivo half-life (T1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vd) 
• Clearance (CL) 
• Incremental in vivo recovery (IVR) 
For details on the laboratory analyses, see Section 7.3.5. 


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7.2.2 IMP Administration Data 
The following parameters will be documented: 
• Dates and times of IMP injections 
• Doses of IMP in IU and IMP batch numbers 
• Purpose of IMP injection (PK, IVR, prophylaxis, treatment of BE, surgery) 
 
7.2.3 Bleeding Episode (BE) Data 
For any BE occurring during the study, the following data will be recorded: 
• BE type (spontaneous, traumatic, postoperative, other) 
• BE site 
• BE severity (minor, moderate, major, life-threatening) (see Table 1) 
• Date and time the BE first occurred or was first noticed 
• Date and time the BE ended 
• IMP administration data (see Section 7.2.2) 
• Assessment of the efficacy of treatment at the end of the BE (see Section 7.2.4) 
If the treatment of a BE in one bleeding site is interrupted for more than 48 hours, two separate 
BEs will have to be recorded; if, in addition to the original bleeding site, another bleeding site 
is affected, these events will be recorded as separate BEs at any time. 
All of these parameters will be documented by the patient (together with the Investigator in 
case of on-site treatments) in the patient diary. Patients who experience a major or life-threat- 
ening BE should be treated at the study site, if possible. 
Based on these data, the frequency of BEs and the ABR under prophylactic treatment will be 
calculated. 


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Table 1      Categorization for the Severity of Bleeding Episodes 
 
Severity 
Definition 
Example 
Minor 
Bleeding with few symptoms 
Early onset muscle and joint bleeds with no 
visible symptoms, such as little or no 
change in the range of motion of affected 
joint (if joint bleeding event); mild restriction 
of mobility and activity, scrapes, superficial 
cuts, bruises, superficial mouth bleeds, and 
most nose bleeds 
Moderate 
Bleeding that involves swelling or 
pain, including some decrease in 
range of motion of affected joint (if 
joint bleeding event) or moderate de- 
crease in mobility and activity 
Advanced soft tissue and muscle bleeds 
into the limbs, bleeding into the joint space, 
such as the elbow, knee, ankle, wrist, 
shoulder, hip, foot, or finger 
Major 
Bleeding that causes significant pain, 
substantial decrease in range of mo- 
tion of affected joint (if joint bleeding 
event), and incapacity 
Complicated joint bleeds, bleeds of the pel- 
vic muscles, eyes 
Life- 
threatening 
Bleedings in the abdomen, digestive sys- 
tem or chest, central nervous system 
bleeds, bleedings in the area of the neck or 
throat or pharynx, or other major trauma 
 
7.2.4 Efficacy of the Treatment of Breakthrough BEs 
At the end of a BE, treatment efficacy will be assessed by the patient (together with the Inves- 
tigator in case of on-site treatment) using the predefined criteria detailed in Table 2. 
Table 2 Efficacy Assessment of the Treatment of Breakthrough BEs 
 
Excellent 
Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within 
approximately 8 hours after a single injection 
Good 
Definite pain relief and/or improvement in signs of bleeding within approximately 8– 
12 hours after an injection, requiring up to 2 injections for complete resolution 
Moderate 
Probable or slight beneficial effect within approximately 12 hours after the first injection, 
requiring more than 2 injections for complete resolution 
None 
No improvement within 12 hours, or worsening of symptoms, requiring more than 2 in- 
jections for complete resolution 
 
The proportion of BEs successfully treated with IMP will be evaluated for all BEs taken 
together and by BE severity. All efficacy ratings assessed as either ‘excellent’ or ‘good’ will be 
considered ‘successfully treated.’ 


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7.2.5 Surgical Prophylaxis Data 
The following surgery-related parameters will be documented: 
• Body weight within 12 hours before the start of surgery 
• Safety laboratory tests (hematology, chemistry) within 12 hours before the start of sur- 
gery and 24 hours after the end of surgery (see Section 7.3.5.2) 
• Vital signs within 12 hours before the start of surgery (before blood sampling) 
• Type of surgery (planned or emergency) 
• Location of surgery 
• Severity of surgery (minor, major) (see definitions under (a) below) 
• Expected duration of surgery 
• Actual duration of surgery (start and end times, i.e., skin to skin) 
• Details on IMP dose(s) given pre-, intra-, or postoperatively (see Section 7.2.2) 
• Pre-, intra-, and postoperative FVIII plasma levels (see definitions under (b) below) 
• Expected and actual blood loss (see item (d) below) 
• Presence of wound hematomas and whether or not they require surgical evacuation 
• Efficacy assessments at the end of surgery by surgeon (see Section 7.2.6.1) 
• Efficacy assessment at the end of the postoperative period by hematologist (see 
Section 7.2.6.2) 
• Overall efficacy assessment by the Investigator (see Section 7.2.6.3) 
• Narrative describing the outcome and efficacy of the intervention 
• Monitoring of AEs 
• Details on concomitantly administered products, including any blood or blood product 
transfusions but excluding drugs given for routine anesthesia 
• Inhibitor testing (see Section 7.3.5.2), with a plasma sample obtained within 3–8 
weeks after the end of the surgery; this visit can coincide with another study visit with 
scheduled inhibitor testing. 
(a) Severity of surgery 
Surgeries are defined as major if any of the following criteria are met: 
• General or spinal anesthesia required 
• Opening into the great body cavities required 
• Hemostatic therapy for at least 6 days required 
• Orthopedic interventions involving joints (ankle, knee, hip, wrist, elbow, shoulder) 
• 3rd molar extraction or extraction of ≥ 3 teeth 
• Surgeries/conditions in which the patient’s life is at stake 
The classification is made prospectively. All other surgeries are classified as minor. 


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(b) Definitions of periods and time points before, during, and after surgery 
• Preoperative is defined as the time period of up to 3 hours before the start of surgery. 
• The end of surgery is defined as the time immediately after the last surgical suture. 
• Postoperative is the period from the end of surgery to the time the patient returns to 
his regular FVIII treatment regimen. 
• The end of the postoperative period is the time the patient returns to his regular 
FVIII treatment regimen. 
(c) FVIII plasma levels 
FVIII plasma levels will be documented for the following time points: 
• Immediately (≤ 30 min) before and 30±15 min after preoperative injection of IMP 
• Immediately (≤ 30 min) before and 30±15 min after each intraoperative bolus dose, if 
any 
• Immediately (≤ 30 min) before and 30±15 min after each postoperative dose, if any; in 
case of major surgery, the determination of FVIII plasma levels is mandatory for the 
first 3 postoperative doses 
(d) Estimated and actual blood loss 
Before surgery, the surgeon will provide written estimates of both the average and maximum 
volume (mL) of expected blood loss for the planned surgical procedure for a patient with 
normal hemostasis of the same sex, age, and stature as the patient enrolled in this study. After 
surgery, the surgeon will estimate the actual blood loss experienced by the patient. 
 
7.2.6 Efficacy in Surgical Prophylaxis 
Efficacy will be assessed at the end of surgery by the surgeon (see Section 7.2.6.1) and at end 
of the postoperative period by the hematologist (see Section 7.2.6.2). In both cases, predefined 
assessment criteria will be used. 
In addition, there will be an overall assessment of efficacy (see Section 7.2.6.3). 
 
7.2.6.1 At the End of Surgery (by Surgeon) 
At the end of surgery, the hemostatic efficacy of Wilate will be assessed by the surgeon using 
the criteria listed in Table 3. 


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Table 3 
Efficacy Assessment at the End of Surgery 
 
Excellent 
Intraoperative blood loss was lower than or equal to the average expected blood loss 
for the type of procedure performed in a patient with normal hemostasis and of the 
same sex, age, and stature. 
Good 
Intraoperative blood loss was higher than the average expected blood loss but lower 
or equal to the maximal expected blood loss for the type of procedure in a patient with 
normal hemostasis. 
Moderate 
Intraoperative blood loss was higher than the maximum expected blood loss for the 
type of procedure performed in a patient with normal hemostasis, but hemostasis was 
controlled. 
None 
Hemostasis was uncontrolled, necessitating a change in the clotting factor replace- 
ment regimen. 
 
 
7.2.6.2 At the End of the Postoperative Period (by Hematologist) 
At the end of the postoperative period, the hemostatic efficacy of Wilate will be assessed by the 
hematologist using the criteria listed in Table 4. 
Table 4 
Efficacy Assessment at the End of the Postoperative Period 
 
Excellent 
No postoperative bleeding or oozing that was not due to complications of surgery. All 
postoperative bleeding (due to complications of surgery) was controlled with Wilate as 
anticipated for the type of procedure. 
Good 
No postoperative bleeding or oozing that was not due to complications of surgery. 
Control of postoperative bleeding due to complications of surgery required increased 
dosing with Wilate or additional injections not originally anticipated for the type of pro- 
cedure. 
Moderate 
Some postoperative bleeding and oozing that was not due to complications of sur- 
gery. Control of postoperative bleeding required increased dosing with Wilate or addi- 
tional injections not originally anticipated for the type of procedure. 
None 
Extensive uncontrolled postoperative bleeding and oozing. Control of postoperative 
bleeding required use of an alternate FVIII concentrate. 


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7.2.6.3 Overall Efficacy Assessment at the End of the Postoperative Period (by 
Investigator) 
Overall efficacy using the ‘excellent,’ ‘good,’ moderate,’ and ‘none’ scale taking both the intra- 
and postoperative assessments into account will be assessed by the Investigator. 
Table 5 
Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis 
 
Intraoperative 
assessment 
Postoperative assessment 
Excellent 
Good 
Moderate 
None 
Excellent 
Excellent 
Good 
Good 
Moderate 
Good 
Good 
Good 
Moderate 
Moderate 
Moderate 
Good 
Moderate 
Moderate 
None 
None 
Moderate 
Moderate 
None 
None 
 
 
7.3 Safety Assessments 
 
7.3.1 Assessments for Safety Endpoints 
Any of the following drug safety information shall be collected: 
• Adverse events (AEs) and serious adverse events (SAEs) temporally associated with 
the administration of IMP (for definitions and reporting requirements, see 
Sections 7.3.2, 7.3.3, and 7.3.4) 
• Drug overdose, interaction, medication error, and post-study SAEs (see Section 7.3.7) 
 
7.3.2 Adverse Events (AEs) 
 
7.3.2.1 Definitions 
• Adverse event (AE): An AE is any untoward medical occurrence in a study sub- 
ject/patient receiving an IMP and which does not necessarily have a causal relation- 
ship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of an IMP, whether or not related to the IMP. 
• Treatment-emergent adverse event (TEAE): A TEAE is an AE that started or wors- 
ened after the start of IMP infusion. 


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• Adverse drug reaction (ADR): An ADR is any noxious and unintended response to 
an IMP related to any dose. The phrase ‘response to an IMP’ means that a causal rela- 
tionship between the IMP and an AE carries at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. 
• Other significant AEs: Any marked laboratory abnormalities or any AEs that lead to 
an intervention, including withdrawal of drug treatment, dose reduction, or significant 
additional concomitant therapy. 
• Withdrawal due to AE/ADR: AE/ADR leading to discontinuation of treatment with 
IMP. Any such events will be followed up by the Investigator until the event is re- 
solved or until the medical condition of the subject/patient is stable. All follow-up in- 
formation collected will be made available to the Sponsor. 
 
7.3.2.2 Collection of AEs 
The condition of the patient will be monitored throughout the study. At each visit, whether 
scheduled or unscheduled, AEs will be elicited using a standard nonleading question such as 
“How have you been since the last visit/during the previous study period?” In addition, the 
Investigator will check the patient diaries for any documented event. 
Any AE or ADR which occurs during the study will be noted in detail on the appropriate pages 
of the CRF. If the patient reports several signs or symptoms representing a single syndrome or 
diagnosis, the diagnosis should be recorded in the CRF. The Investigator will grade the severity 
of all AEs or ADRs (mild, moderate, or severe), the seriousness (non-serious or serious), and 
the causality as defined in Sections 7.3.2.3, 7.3.3, and 7.3.2.4. The Sponsor is responsible for 
assessing the expectedness of each ADR  (expected  or  unexpected)  as  defined  in  Sec-  
tion 7.3.2.5. 
In the event of clinically significant abnormal laboratory findings, the tests will be confirmed 
and the patient followed up until the laboratory values have returned to normal and/or an ade- 
quate explanation for the abnormality has become available. 
Diseases, signs and symptoms, and/or laboratory abnormalities already present before the first 
administration of IMP will not be considered AEs unless an exacerbation in intensity or fre- 
quency (worsening) occurs. 
The Investigator will provide detailed information about any abnormalities and about the nature 
of and reasons for any action taken as well as any other observations or comments that may be 
useful for the interpretation and understanding of an AE or ADR. 


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7.3.2.3 Severity of AEs 
The severity of AEs will be graded as follows: 
• Mild: an AE, usually transient, which causes discomfort but does not interfere with 
the patient’s routine activities 
• Moderate: an AE which is sufficiently discomforting to interfere with the patient’s 
routine activities 
• Severe: an AE which is incapacitating and prevents the pursuit of the patient’s routine 
activities 
The grading of an AE is up to the medical judgment of the Investigator and will be decided on 
a case-by-case basis. 
 
7.3.2.4 Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the Investigator: 
• Probable: reports including good reasons and sufficient documentation to assume a 
causal relationship, in the sense of plausible, conceivable, likely, but not necessarily 
highly probable. A reaction that follows a reasonable temporal sequence from admin- 
istration of the IMP; or that follows a known or expected response pattern to the sus- 
pected medicine; or that is confirmed by stopping or reducing the dosage of the medi- 
cine and that could not reasonably be explained by known characteristics of the sub- 
ject’s/patient’s clinical state. 
• Possible: reports containing sufficient information to accept the possibility of a causal 
relationship, in the sense of not impossible and not unlikely, although the connection 
is uncertain or doubtful, for example because of missing data or insufficient evidence. 
A reaction that follows a reasonable temporal sequence from administration of the 
IMP; that follows a known or expected response pattern to the suspected medicine; but 
that could readily have been produced by a number of other factors. 
• Unlikely: reports not following a reasonable temporal sequence from IMP administra- 
tion. An event which may have been produced by the subject’s/patient’s clinical state 
or by environmental factors or other therapies administered. 
• Not related (unrelated): events for which sufficient information exists to conclude 
that the etiology is unrelated to the IMP. 
• Unclassified: reports which for one reason or another are not yet assessable, e.g., be- 
cause of outstanding information (can only be a temporary assessment). 


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7.3.2.5 Classification of ADRs by Expectedness 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an ADR that is listed in the current edition of the Investigator’s Brochure. 
• Unexpected: an ADR that is not listed in the current edition of the Investigator’s Bro- 
chure or that differs because of greater severity or greater specificity. 
7.3.2.6 Outcome of AEs 
The outcome of all reported AEs has to be documented as follows: 
1. Recovered, resolved 
2. Recovering, resolving 
3. Not recovered, not resolved 
4. Recovered, resolved with sequelae 
5. Fatal 
6. Unknown 
NOTE: A patient’s death per se is not an event, but an outcome. The event which resulted in 
the patient’s death must be fully documented and reported, even in case the death occurs within 
4 weeks after IMP treatment end and regardless of whether or not it is considered treatment- 
related. 
 
7.3.2.7 Action(s) Taken 
AEs requiring action or therapy must be treated with recognized standards of medical care to 
protect the health and wellbeing of the patient. Appropriate resuscitation equipment and medi- 
cines must be available to ensure the best possible treatment in an emergency situation. 
The actions taken by the Investigator must be documented: 
 
(a) General actions taken in the event of an AE 
– None 
– Medication (other than IMP) or other (e.g., physical) therapy started 
– Test performed 
– Other (to be specified) 
 
(b) IMP-related actions taken in the event of an AE 
– None 
– Product withdrawn 
– Dose reduced 
– Dose increased 
The Investigator will follow up on each AE until it has resolved or until the medical condition 
of the patient has stabilized. Any relevant follow-up information will be reported to the Spon- 
sor. 


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7.3.3 Serious Adverse Events (SAEs) 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (see below), 
• requires hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is another important medical event (see below). 
 
NOTE: The term ‘life-threatening’ refers to an event in which the subject/patient was, in the 
view of the reporting Investigator, at immediate risk of death at the time of the event; it does 
not refer to an event which may hypothetically have caused death had it been more severe. 
In deciding whether an AE/ADR is serious, medical judgment should be exercised. Thus, im- 
portant AEs/ADRs that are not immediately life-threatening or do not result in death or hospi- 
talization but may jeopardize the subject/patient or may require intervention to prevent one of 
the other outcomes listed in the definitions above should also be considered serious. 
Examples of ‘important medical events’ are all suspected transmissions of an infectious agent, 
which therefore have to be reported as SAE. A suspected virus transmission means that virus 
antigen has been detected in the patient. A passive transmission of antibodies alone does not 
constitute a suspected virus transmission. Another such ‘important medical event’ that has to 
be reported as an SAE is the development of FVIII inhibitors. 
7.3.4 AE and SAE Reporting Timelines 
All thromboembolic events, whether or not they are suspected to be related to study treatment, 
are to be reported by telephone, fax, or email to the Clinical Trial Manager. They should be 
documented on AE page in eCRF. 
After the Study Completion Visit, all thromboembolic events will continue to be monitored 
proactively by performing a Follow-up Contact 30 days after the completion visit (see Section 
6.1.7). They should be documented on AE page in eCRF. 
All SAEs, whether or not they are suspected to be related to study treatment, are to be reported 
immediately by telephone, fax, or email to the Clinical Trial Manager. 
 
CLINICAL TRIAL MANAGER: 
Irena Dzhunova 
 
Phone: 
+41 55 451 21 84 
Mobile: 
+41 79 931 53 29 
Fax: 
+41 55 451 21 51 
Email: 
irena.dzhunova@octapharma.ch 
The contact details will also be communicated at the study initiation visit. 


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In addition, within 24 hours after recognition of an SAE, an Octapharma Serious Adverse Event 
Report must be completed and submitted to: 
Octapharma’s Corporate Drug Safety Unit 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Fax: +43 1 61032-9949 
Email: cdsu@octapharma.com 
24 hours emergency telephone number: +43 1 40 80 500 
 
Waivers the from SAE Reporting Requirement 
Waivers from the SAE reporting requirement include surgeries that are elective or were planned 
before study entry or prolongations of existing hospitalizations for economic or social, but not 
medical, reasons. Such surgeries or prolongations of hospitalizations should not be considered 
SAEs. 
 
7.3.5 Laboratory Tests 
The following laboratory parameters will be determined at the time points specified in the flow 
charts of assessments on pages 14 and 16 and in Section 6. 
 
7.3.5.1 Central Laboratory 
The following laboratory tests will be done at the central laboratory: 
• FVIII:C in the vials used for PK injections as well as in plasma using the CHR and 
OS assays 
• FVIII inhibitor activity will be determined at each study visit before the injection of 
Wilate using the modified Bethesda assay (Nijmegen modification). Blood sampling 
for inhibitor testing should preferably be performed at the time of trough FVIII:C lev- 
els. 
If inhibitor development is suspected between study visits (e.g., based on an unex- 
plained need to increase the dose, lack of efficacy of IMP injections, or prolonged 
bleeding) (see also Section 6.1.8), additional FVIII inhibitor tests will be performed 
and documented. 
In case of positive inhibitor results, inhibitor retesting using a second, separately 
drawn sample should be performed, preferably within 15 days of becoming aware of 
the positive result. If inhibitor development is confirmed by the second sample ana- 
lyzed in the central laboratory, patients with low-titer inhibitors (<5 BU) may continue 
treatment with Wilate, while patients with high-titer inhibitors will be discontinued 
from the study. 


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• VWF:Ag and VWF:Ac will be measured at prespecified time points. 
VWF:Ac will be measured by INNOVANCE® VWF Ac (Siemens Healthcare Diag- 
nostics), which is a particle enhanced assay for the automated determination of VWF 
activity in human citrated plasma. The assay principle makes use of the binding of 
VWF to its receptor Glycoprotein Ib (GPIb). GPIb is the main VWF receptor on plate- 
lets. Polystyrene particles are coated with an antibody against GPIb. Recombinant 
GPIb (two gain-of-function mutations included) is added and binds to the antibody as 
well as to the VWF of the sample. Due to the gain-of-function mutations, VWF bind- 
ing to GPIb does not require ristocetin. This VWF binding induces a particle aggluti- 
nation which can be measured as an increase in extinction by turbidimetric measure- 
ments. 
• Virus safety will be evaluated by taking a plasma sample for parvovirus B19 antibody 
testing during the Screening Visit. All patients negative during screening will be tested 
again at the Study Completion Visit. 
A retention serum sample for possible virus marker testing will be taken during the 
Screening Visit and stored at the central laboratory. 
 
Central laboratory: 
SYNLAB pharma institute 
Bayerstraße 53 
80335 Munich 
Germany 
SYNLAB pharma institute is a division of SYNLAB Umweltinstitut GmbH 
Hohner Straße 23 
70469 Stuttgart 
Germany 
 
7.3.5.2 Local Laboratory 
The following laboratory tests will be done by the local laboratories of each study site: 
• Hematology: red blood cell count, white blood cell count, hemoglobin, hematocrit, 
and platelet count 
• Chemistry: total bilirubin, alanine amino transferase, aspartate transaminase, blood 
urea nitrogen, serum creatinine 
CD4+ and AB0 blood-type testing as well as FVIII:C measurements in case of surgery will 
also be done by the local laboratories. Samples for surgery-related FVIII:C testing will also be 
shipped to the central laboratory for OS and CHR assay assessments. 
The methods of determination and normal ranges for each parameter will be provided in the 
clinical study report. 


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7.3.6 Vital Signs and Physical Examination 
The vital signs obtained at the time points specified in Section 6 are blood pressure, body tem- 
perature, heart rate, and respiratory rate. 
Physical examinations will be performed at the visits specified in Section 6. Both height and 
weight will be measured at baseline. In addition, weight will be measured at all visits prior to 
dosing. 
 
7.3.7 Other Relevant Safety Information 
 
(a) Post-study related safety reports 
After the Study Completion Visit, any thromboembolic events will continue to be monitored 
proactively by performing a Follow-up Contact 30 days after the Study Completion Visit (see 
Sections 6.1.7 and 7.3.4). They should be documented on AE page in eCRF. 
In addition, any SAE which occurs up to 4 weeks after the last IMP administration should be 
reported by the Investigator to the Sponsor in case the Investigator becomes aware of it. Proac- 
tive monitoring for post-study SAEs is not required. 
If any such post-study event is identified, the Investigator will complete an SAE form and trans- 
mit it to the Clinical Trial Manager (see Section 7.3.4). 
Deaths occurring within 4 weeks after the last IMP administration should also be reported, re- 
gardless of whether or not they are considered treatment-related. 
 
 
Overdose, interaction, medication error 
The following safety relevant information should be reported as AE or, if the reaction fulfils 
one of the criteria for seriousness, as SAE. 
(b) Drug overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol and higher than the known therapeutic dose that is of clinical relevance. 
The reaction must be clearly identified as an overdose. 
(c) Drug interaction 
A drug interaction is a situation in which a substance or medicinal product affects the activity 
of an IMP, i.e., increases or decreases its effects, or produces an effect that none of the products 
would exhibit on its own. The reaction must be clearly identified as a drug interaction. 


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(d) Medication error 
A medication error involves the inadvertent administration or unintended use of a medicinal 
product which may be caused by the naming, presentation of pharmaceutical form/packaging, 
or instructions for use/labelling. The reaction must be clearly identified as a medication error. 
 
7.4 Appropriateness of Measurements 
The criteria for assessing the safety and efficacy of Wilate in the prevention and treatment of 
BEs as well as in surgical prophylaxis are identical to those used in a similar study with Wilate 
in patients aged ≥12 years, i.e., WIL-27. The measurements of the essential tolerability and 
immunogenicity parameters assessed in this study are also identical to those used in WIL-27. 
Inhibitor measurements are performed by a central laboratory using validated assays. 


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8 
DATA HANDLING AND RECORD KEEPING 
 
8.1 Documentation of Data 
 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, observations, or other 
activities in the study, written down in original records or certified copies of original records, 
allowing reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (e.g., case histories or patient files for 
each patient enrolled). Source records should be preserved for the maximum period of time 
required by local regulations. 
For each patient enrolled, the Investigator will indicate in the source record(s) that the patient 
participates in this study. 
All data entered in the eCRF must be supported by source data in the patient records. 
The Investigator will permit study-related monitoring, audits, IEC/IRB reviews, and regulatory 
inspections, by providing direct access to the source data/records. 
The Investigator may authorize site staff (e.g., sub-investigators, nurses) to enter study data into 
the eCRF. This must be documented in the Delegation of Authority Log signed by the Investi- 
gator. 
 
8.1.2 Case Report Forms 
For each patient enrolled, an electronic CRF (eCRF) will be completed within the Electronic 
Data Capture (EDC) system and approved by the Investigator or an authorized sub-investigator. 
Study site staff (e.g., research nurse) will be responsible for entering patient data into the vali- 
dated EDC system. All site personnel will be trained on the EDC system and study-specific 
eCRFs prior to receiving access to the live database for data entry. 
The site is also provided with the approved eCRF Completion Guidelines which will assist in 
data entry and data issues/questions. The site will be notified once the database is active to 
begin data entry. Additional site training may be provided as refreshers throughout the study, if 
needed. All persons allowed to enter or change eCRF data must be listed in the Delegation of 
Authority Log. 


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8.1.3 Changes to Case Report Form (CRF) Data 
Monitors will perform source data verification (SDV) as defined for the study. 
If any errors or discrepancies in the eCRFs are found during data entry or review, discrepancies 
will be generated programmatically within the EDC system, and ‘manual’ queries will be gen- 
erated by either a monitor or Data Management. 
Discrepancies and queries can only be corrected by the Investigator(s) or other authorized site 
personnel. An audit trail documents all changes to the data over the entire study period. If the 
reason for a change is not obvious, a comment must be supplied in the query’s response, stating 
the reason for the change, prior to closing. The study monitor should provide guidance to In- 
vestigator(s) and the Investigator(s)’ designated representatives on making such corrections. 
Once queries have been resolved by the site staff, the resolutions are assessed by Data Manage- 
ment. If the query response provided confirms the data as correct, the discrepancy will be 
closed. If the response does not adequately address the question raised, a new query will be 
issued for further clarification. 
Manual checks are performed and programs are run throughout the study until the data is clean 
and the database is ready for lock. All discrepancies will be resolved prior to database lock. 
There will be a final run of the programmed checks to ensure all discrepancies are closed out, 
SDV will be confirmed as complete by the monitor, and all eCRFs will be approved by the 
Investigator prior to database lock. 
 
8.2 Information to Investigators 
An Investigator’s Brochure (IB) will be handed out to the Investigator before the start of the 
study. The IB contains all information in the Sponsor’s possession necessary for the Investiga- 
tor to be fully and accurately informed about the safety of the IMP under evaluation and the 
respective benefit-risk ratio. 
The IB will be updated by the Sponsor at regular intervals and whenever relevant new infor- 
mation concerning the IMP becomes available. 
The Investigator will be informed about the methods for rating relevant study outcomes and for 
completing eCRFs to reduce discrepancies between participating Investigator and study sites. 
The Investigator will be kept informed of important data that relate to the safe use of the IMP 
as the study proceeds. 


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8.3 Responsibilities 
The Principal Investigator is accountable for the conduct of the clinical study. Responsibilities 
may be delegated to appropriately qualified persons. 
A Delegation of Authority Log will be filled in and signed by the Principal Investigator. In 
accordance with this authority log, study site staff (e.g., sub-investigators, nurses) is authorized 
to perform tasks relating to the study. 
 
8.4 Investigator’s Site File 
At each study site, the Investigator is responsible for maintaining all records to enable the con- 
duct of the study to be fully documented. Essential documents as required by GCP guidelines 
and regulations (e.g., copies of the protocol, study approval letters, all original informed consent 
and assent forms, drug dispensing and accountability logs, correspondence pertaining to the 
study, etc.) should be filed accurately and kept by the Investigator for the maximum period of 
time required by local regulations. 
The Investigator is responsible for maintaining a confidential patient identification code list, 
which provides the unique link between named source records and CRF data for the Sponsor. 
The Investigator must arrange for the retention of this confidential list for the maximum period 
of time required by local regulations. 
No study document should be destroyed without prior written agreement between the Investi- 
gator and the Sponsor. Should the Investigator elect to assign the study documents to another 
party, or move them to another location, the Sponsor must be notified in writing. 
 
8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating to the study, 
or copies of relevant source records, ensuring that the patient’s confidentiality is maintained. 
This is particularly important when CRFs are illegible or when errors in data transcription are 
encountered. In case of particular issues or governmental queries, it is also necessary to have 
access to the complete study records, provided that the patient’s confidentiality is protected in 
accordance with applicable regulations. 


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9 
STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities to 
an external CRO that agrees to meet all Octapharma procedures and policies. 
 
9.1 Determination of Sample Size 
The sample size of 10 pediatric patients to be enrolled was based on medical and regulatory 
reasoning. No statistical sample size estimation was performed. 
 
9.2 Statistical Analysis 
The primary approach to the statistical analysis will be descriptive, presenting sampling statis- 
tics (n, mean, standard deviation, quartiles and range) for continuous measurements and abso- 
lute and relative frequency counts for categorical/ordinal data. This will be complemented by 
the presentation of exploratory confidence intervals (CIs) for means or proportions. 
A formal Statistical Analysis Plan (SAP) describing all details of the analyses to be performed 
will be prepared by the study statistician and approved by the Sponsor prior to the start of the 
statistical analysis. 
 
9.2.1 Populations for Analysis 
The safety (SAF) set will include all patients who received at least one infusion of IMP. 
The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle will in- 
clude all enrolled patients who received at least one infusion of IMP after the initial PK Visit. 
The pharmacokinetic (PK) set will include all patients for whom a valid Wilate PK profile 
has been obtained. 
The per-protocol (PP) set, i.e., a subset of the FAS, will exclude patients with major protocol 
deviations which may have an impact on the evaluation of the efficacy outcome parameters. 
Examples of major and minor protocol deviations will be described in the SAP. 
The surgery (SURG) set will be a subset of the FAS, containing all patients who underwent a 
surgical procedure treated with Wilate during their Prophylactic Treatment Phase. 


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A final decision about the classification of protocol deviations and their consequences regarding 
assignment of patients to analysis sets will be made during the data review meeting. Decisions 
and outcome will be approved by the Sponsor. 
• The analysis of safety will be based on the SAF set. 
• Analysis of the PK properties of Wilate will be based on the PK set. 
• The evaluation of the primary efficacy endpoint will be performed on the FAS (ITT 
analysis) and on the PP set (PP analysis). 
• For secondary endpoints, ITT and additionally PP analyses will be carried out unless 
these analysis sets are identical. 
• Analysis of the efficacy and safety of Wilate in surgeries will be based on the SURG 
set. 
 
9.2.2 PK and Efficacy Analysis Plan 
 
Pharmacokinetic Analysis 
The analysis of the pharmacokinetic profiles of Wilate will be based on the FAS and the PP set. 
The following PK parameters for FVIII:C will be analysed both for the chromogenic (CHR) 
and one-stage (OS) assays and actual IMP potencies: 
• Area under the curve (AUC) and AUC normalized for the administered dose 
(AUCnorm) 
• In vivo half-life (T1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vd) 
• Clearance (CL) 
• Incremental in vivo recovery (IVR) 
FVIII:C will be measured in the vials used for PK injections as well as in plasma using the CHR 
and OS assays. 
• AUC of Wilate will be calculated from FVIII:C plasma levels measured at predefined 
time points and normalized for the administered dose (AUCnorm) using actual IMP po- 
tencies. 
• All other PK parameters will be calculated from FVIII:C plasma levels measured at 
predefined time points using actual IMP potencies. 
• Incremental IVR will be calculated from FVIII:C plasma levels measured before injec- 
tion and peak levels obtained in the 15-min post-injection sample using actual IMP po- 
tencies. 
The PK profiles of Wilate and the PK parameters derived from them will be summarized by 
descriptive statistics as well as the presentation of concentration vs. time plots. 


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For all patients, the results of the IVR assessments over time will also be analyzed in summary 
tables for each time point and their differences to baseline along with 95% CIs for the mean 
differences. 
Analysis of variance (ANOVA) will be used in an exploratory sense to assess a possible asso- 
ciation between AB0 blood type, VWF:Ag, and the FVIII:C half-life of Wilate. 
 
Efficacy of Prophylactic Treatment with Wilate 
Primarily, all obtained data on treatment characteristics (IMP dosages, frequencies, total con- 
sumption) and BEs (duration, frequency, efficacy assessment) will be described by providing 
summary statistics. 
 
The efficacy of prophylactic treatment with Wilate will be statistically evaluated by presenting 
descriptive sampling statistics for the TABR and SABR, along with an exploratory 95% CI for 
the mean. 
 
Efficacy in the Treatment of Breakthrough BEs 
To assess the hemostatic efficacy of Wilate in the treatment of breakthrough bleedings, a fre- 
quency distribution of all such BEs being successfully treated will be presented, along with an 
exploratory 95% CI. 
 
Analysis of Other Secondary Endpoints 
The statistical analysis of other secondary endpoints will be descriptive, including exploratory 
95% CIs for the location parameters. 
 
Subgroup Analyses 
The analyses of the PK parameters and the efficacy endpoints ‘efficacy of prophylactic treat- 
ment’ and ‘efficacy in treatment of breakthrough BEs’ will be presented for the following sub- 
groups: 
• Age '1 to <6 years' 
• Age '6 to <12 years' 


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9.2.3 Safety Analysis Plan 
All safety analyses will be based on the SAF population. 
The analysis of safety will be based on the occurrence of AEs, the results of the safety laboratory 
tests, immunogenicity measurements, and the occurrence of parvovirus B19 seroconversions. 
AEs will be coded according to the latest Medical Dictionary for Regulatory Activities 
(MedDRA) version. The analysis will include only treatment-emergent adverse events 
(TEAEs), i.e., AEs that started or worsened after the start of IMP infusion. All TEAEs, related 
TEAEs (i.e., TEAEs probably or possibly related to the IMP), and serious TEAEs will be sum- 
marized and tabulated according to MedDRA primary system organ class and preferred term. 
Patient listings will be provided for patients with SAEs, AEs leading to withdrawal from study, 
and AEs leading to death. 
Time profiles of the safety laboratory parameters will be analyzed by presenting sampling sta- 
tistics for the values as well as their difference to baseline at each time point. Additionally, 
frequency tables for values outside the normal ranges will be presented. 
Similarly, time profiles of FVIII inhibitor testing results will be analyzed by presenting sam- 
pling statistics for the values as well as frequency tables for positive findings, along with 95% 
Pearson-Clopper CIs. 
To assess the viral safety of Wilate, incidences of parvovirus B19 seroconversions between 
screening and end of study will be estimated along with 95% Pearson-Clopper CIs. 
Other safety parameters (e.g., changes in physical examination findings) will be analyzed by 
summary tables or listings. 
The analysis of the safety parameters recorded during surgery (lab values) will be purely de- 
scriptive and presented as summary tables or listings. 
 
9.2.4 Handling of Missing Data 
In general, missing data will not be imputed. Calculations pertaining to the derivation of the 
ABR will be based on documented time periods only. 
Only in case of missing body weight will the last available weight measurement be used for 
calculating the dose per kg bodyweight (last observation carried forward, LOCF). 
 
9.3 Randomization, Stratification, and Code Release 
Not applicable. 
 
9.4 Interim Analysis 
Not applicable. 


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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
 
10.1 Ethical/Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down in the Decla- 
ration of Helsinki. The study protocol and any subsequent amendment(s) will be submitted to 
an Independent Ethics Committee (IEC)/Institutional Review Board (IRB) and to the Regula- 
tory Authority. The study will be conducted in compliance with the protocol, GCP guidelines, 
and applicable regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by the Sponsor 
or designated third party (e.g., CRO) as required by national law. 
 
10.2 Approval of Study Documents 
The study protocol, a sample of the patient information and informed consent form, any other 
materials provided to the patients, and further requested information will be submitted by the 
Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory Authority. The study 
must be approved by the IEC/IRB and the Regulatory Authority before any IMP may be shipped 
to the study sites and any patient is exposed to a study-related procedure. 
The Sponsor, the Investigator, and any third party (e.g., CRO) involved in obtaining approval 
must inform each other in writing that all ethical and legal requirements have been met before 
the first patient is enrolled in the study. 
 
10.3 Patient Information and Informed Consent 
The Investigator will obtain freely given written consent from each patient after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspect 
of the study which is relevant to the patient’s decision to participate. The informed consent form 
must be signed, with name and date and time noted by the patient, before the patient is exposed 
to any study-related procedure, including screening tests for eligibility. 
For patients not qualified to give legal consent, written consent must be obtained from the le- 
gal parent/guardian. If children are old enough to understand the risks and benefits of the 
study, they should also be informed and provide their oral or written assent. 
The Investigator will explain that the patients are completely free to refuse to enter the study or 
to withdraw from it at any time, without any consequences for their further care and without 
the need to justify. The Investigator will complete the informed consent section of the eCRF 
for each patient enrolled. 
Each patient will be informed that his medical (source) records may be reviewed by the study 
monitor, a quality assurance auditor, or a health authority inspector, in accordance with appli- 
cable regulations, and that these persons are bound by confidentiality obligations. 


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10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Investigator (Co-ordinating 
Investigator in multi-center studies) and the Sponsor prior to its implementation. Any such 
amendments will be submitted to the IEC/IRB and/or competent authority responsible as re- 
quired by applicable regulations. 
IEC/IRB approval will, at a minimum, be requested for any change to this protocol which could 
affect the safety of the patients, the objective/design of the study, any increase in dosage or 
duration of exposure to the IMP, an increase in the number of patients treated, the addition of a 
new test or procedure, or the dropping of a test intended to monitor safety. 
 
10.5 Confidentiality of Patient Data 
The Investigator will ensure that the patient’s confidentiality is preserved. On CRFs or any 
other documents submitted to the Sponsor, the patients will not be identified by their names, 
but by a unique patient identifier. Documents not intended for submission to the Sponsor, i.e., 
the confidential subject identification code list, original consent and assent forms, and source 
records, will be maintained by the Investigator in strict confidence. 


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11 QUALITY CONTROL AND QUALITY ASSURANCE 
 
11.1 Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to review all study-related 
source data/records, verify the adherence to the protocol and the completeness, correctness and 
accuracy of all eCRF entries compared to source data. The Investigator will co-operate with the 
monitor to ensure that any discrepancies identified are resolved. 
For this study, the first monitoring visit shall take place shortly after the inclusion of the first 
patient. Thereafter, monitoring frequency will depend on study progress. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyze, verify, and reproduce any rec- 
ords and reports that are important to the evaluation of the clinical study. Source data will be 
available for all data in the eCRFs, including all laboratory results. 
 
11.2 Audit and Inspection 
The Investigator will make all study-related source data and records available to a qualified 
quality assurance auditor mandated by the Sponsor, or to IEC/IRB/regulatory inspectors, after 
reasonable notice. The main purposes of an audit or inspection are to confirm that the rights 
and welfare of the patients have been adequately protected, and that all data relevant for the 
assessment of safety and efficacy of the IMP have been reported to the Sponsor. 


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12 REPORTING AND PUBLICATION 
 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s SOPs) will be 
prepared by the Sponsor after completion of the study. The Co-ordinating Investigator will ap- 
prove the final study report after review. 
 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. 
If this is envisaged by an Investigator, the Investigator agrees to inform the Sponsor and to 
submit all manuscripts or abstracts to the Sponsor prior to submission to an editorial board or 
scientific review committee. This will allow the Sponsor to protect proprietary information and 
to provide comments based on information that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will support publication 
of multi-center studies only in their entirety and not as individual center data. Authorship will 
be determined by mutual agreement. 


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13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in association with the 
IMP or participation in the study, the Sponsor will contract insurance in accordance with local 
regulations. 
The Investigator is responsible for dispensing the IMP according to this protocol and for its 
secure storage and safe handling throughout the study. 


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14 REFERENCES 
Not applicable. 


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15 APPENDICES 
Not applicable. 

SAP_003.pdf: 
CLINICAL STUDY REPORT 
WIL-30 
 
 
 
 
 
 
16.1.9 
Documentation of Statistical Methods 


FRM/BS/001.01 
 
Confidential 
This document contains confidential information which must not be disclosed to anyone other 
than the involved CRO. This information should not be used for any purpose other than the 
evaluation of the clinical investigation without prior written consent of Octapharma. 
No part of this document may be reproduced or stored in a retrieval system or transmitted in 
any other form or by any other means. 
Version 3.0, Effective April 2016 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No: WIL-30 
Version Number: 1.0 
Date of Issue: 
2017-04-26 
Page 1 of 27 
 
 
 
 
Sponsor: 
Octapharma AG 
Title of Protocol: 
Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, 
and Immunogenicity of Wilate in Previously Treated Pediatric Patients 
with Severe Hemophilia A 
Protocol Ver- 
sion/Date: 
Version 1.0 / 2017-04-26 
CRF Version: 
TBD 
Supersedes SAP Ver- 
sion: 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Version 3.0, Effective April 2016 
 
 
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Version Number: 1.0 
Date of Issue: 
2017-04-26 
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Document authorization 
 
 
 
 
 
Trial Statistician 
ERGOMED 
Signature 
Date (dd-mm.m-yyyy) 
 
 
 
 
Project Manager 
ERGOMED 
Signature 
Date (dd-tntnm-yyyy) 
 
 
 
 
 
Clinical Trial Manager 
Octapharma AG 
2G-  A·,p  r 20  (+-  
Signature 
Date (dd-mmm-yyyy) 
Hans-Peter --.. 
Dmytro Pomishchy 
Ire 


FRM/BS/001.01 
 
ERGOMED 
Version 3.0, Effective April 2016 
 
 
 
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ProtocolNo:WIL-30 
Version Number: 1.0 
Date of Issue: 
2017-04-26 
Page 3 of 27 
 
 
Consistency check with the Protocol (one option to be selected) 
 
This is to confirm that as part of the SAP finalization consistency check with the current 
protocol / protocol amendment was performed by the trial statistician, and no changes to 
the protocol (statistical section) are required 
 
 
 Changes to the analysis principles were required, and the responsible team has confirmed 
commitment to update the study protocol 
 
 
Changes to the analysis principles were required (as outlined in revision history section of 
this SAP), however it was not feasible to update the study protocol, for the reason 
 
 
 
 
 
 
 
 
 
Hans-Peter Hucke 
Trial Statistician 
ERGOMED 
Signature 
Date (dd-mmm-yyyy) 
x 


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Change control 
 
 
Date 
Author 
Reason 
Version 
2017-04-26 
Hans-Peter Hucke 
1.0 


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2017-04-26 
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TABLE OF CONTENTS 
Document authorization ................................................................................................................................. 2 
Consistency check with the Protocol (one option to be selected) ................................................................... 3 
Change control ................................................................................................................................................ 4 
Table of contents ............................................................................................................................................. 5 
List of abbreviations ........................................................................................................................................ 7 
1 Study material .............................................................................................................................................. 10 
2 Study information ........................................................................................................................................ 10 
2.1 Primary objective ........................................................................................................................................ 10 
2.2 Secondary objective .................................................................................................................................... 10 
2.3 Additional Objective: .................................................................................................................................. 10 
2.4 Study design ................................................................................................................................................ 11 
2.5 Planned sample size .................................................................................................................................... 13 
3 General Information .................................................................................................................................... 14 
3.1 Background details ..................................................................................................................................... 14 
3.2 Deviations from the trial protocol with regard to statistical analyses ......................................................... 14 
3.3 Individual protocol deviations .................................................................................................................... 14 
4 Analysis Populations ................................................................................................................................... 14 
4.1 Safety set ..................................................................................................................................................... 15 
4.2 Full analysis set ........................................................................................................................................... 15 
4.3 Pharmacokinetic set .................................................................................................................................... 15 
4.4 Per-protocol set ........................................................................................................................................... 15 
4.5 Surgery set .................................................................................................................................................. 15 
4.6 Subgroup analyses ...................................................................................................................................... 15 
5 Statistical Analyses ...................................................................................................................................... 15 
5.1 Conventions ................................................................................................................................................ 16 
5.1.1 
Baseline definition ............................................................................................................................ 16 
5.1.2 
Missing data ..................................................................................................................................... 16 
5.1.3 
Pooling of centers ............................................................................................................................. 17 
5.2 Demographic and other background data ................................................................................................... 17 
5.2.1 
Basic description .............................................................................................................................. 17 
5.3 IMP exposure, compliance ......................................................................................................................... 17 
5.4 Medical history ........................................................................................................................................... 18 
5.5 Concomitant medication ............................................................................................................................. 18 
5.6 Concomitant non-pharmacological measures, pre-medication ................................................................... 18 
5.7 PK and Efficacy .......................................................................................................................................... 18 
5.7.2 
Efficacy ............................................................................................................................................ 18 
5.7.3 
Exploratory Endpoint ....................................................................................................................... 19 
5.8 Pharmacokinetics / Pharmacodynamics ...................................................................................................... 20 
5.9 Surgeries ..................................................................................................................................................... 20 
5.10 Safety .......................................................................................................................................................... 21 
5.10.1 
Adverse events ............................................................................................................................. 21 
5.10.2 
Vital signs .................................................................................................................................... 22 
5.10.3 
Safety laboratory variables........................................................................................................... 22 
5.10.4 
Other safety variables .................................................................................................................. 23 
5.11 Other variables ............................................................................................................................................ 23 
5.12 Interim analyses .......................................................................................................................................... 23 
6 Quality Control ............................................................................................................................................ 23 
7 References ................................................................................................................................................... 23 
8 Appendices .................................................................................................................................................. 24 


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8.1 Formulas for derived variables ................................................................................................................... 24 
8.2 Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis ................................................. 26 
8.3 List of Tables, Listings, Figures ................................................................................................................. 27 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ABR 
Annual Bleeding Rate 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Curve 
AUCnorm 
AUC normalized for the administered dose 
AUMC 
Area Under the Moment Curve 
BE 
Bleeding Episode 
BMI 
Body Mass Index 
BW 
Body Weight 
CD4 
Cluster of Differentiation 4 
CHR 
Chromogenic assay 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DD 
Drug Dictionary (WHO Coding Thesaurus) 
DBR 
Database Review 
DMP 
Data Management Plan 
DVP 
Data Validation Plan 
ED 
Exposure Day 
EDC 
Electronic Data Capture 
EOT 
End of Trial 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FVIII 
Coagulation Factor VIII 
FVIII:C 
Factor VIII-coagulant 


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Abbreviation 
Description 
HJHS 
Hemophilia Joint Health Score 
ICF 
Informed Consent Form 
ID 
Identifier 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IU 
International Unit 
IV 
Intravenous 
IVR 
Incremental in Vivo Recovery 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
N 
Number of Subjects/Observations 
OS 
One-stage assay 
PK 
Pharmacokinetic 
POP 
Postoperative 
PP 
Per-Protocol 
PT 
Preferred Term 
PTP 
Previously Treated Subject 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software package 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SABR 
Spontaneous Annualized Bleeding Rate 
SURG 
Surgery analysis set 


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Abbreviation 
Description 
T1/2 
In Vivo Half-Life 
TABR 
Total Annualized Bleeding Rate 
TEAE 
Treatment Emergent Adverse Event 
TLFs 
Tables, Listings, Figures 
Tmax 
Time to Reach Maximum Plasma Concentration 
TS 
Trial Statistician 
Vd 
Volume of distribution 
VWD 
Von Willebrand Disease 
VWF 
Von Willebrand Factor 
VWF:Ac 
VWF activity 
VWF:Ag 
Von Willebrand Factor Antigen 
WHO 
World Health Organization 


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1 STUDY MATERIAL 
The following material was considered for this SAP: 
 
Document 
Version, Date 
Protocol 
Version 1.0, 2017-04-26 
CRF 
TBD 
DMP 
TBD 
DVP 
TBD 
 
 
2 STUDY INFORMATION 
2.1 Primary objective 
The primary objective of this study is to determine the FVIII:C pharmacokinetics (PK) for 
Wilate in previously treated patients (PTP) with severe hemophilia A aged 1 to <12 years. 
 
2.2 Secondary objective 
The secondary objectives of this study are to: 
• Determine the efficacy of Wilate in prophylactic treatment 
• Determine the efficacy of Wilate in the treatment of breakthrough bleeding episodes 
(BEs) 
• Calculate the FVIII:C incremental IVR of Wilate over time (at baseline, and at 3 and 6 
months of treatment) 
• Assess the association between AB0 blood type and the FVIII:C half-life of Wilate 
• Assess the association between the VWF:Ag concentration and the FVIII:C half-life of 
Wilate 
• Assess the safety and tolerability of Wilate 
• Assess the immunogenicity of Wilate 
 
2.3 Additional Objective: 
An additional objective of this study is the descriptive efficacy of Wilate in surgical prophylaxis. 


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2.4 Study design 
This study is designed as a prospective, non-controlled, international, multi-center phase 3 
study. Further details are given in the overview below: 
 
FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
 
Screen 
ing 
Visit 
PK 
Visit 
Prophylactic Treatment Phase 
(starts with first prophylactic injection of 
Wilate 
after the PK Visit) 
Follow-up 
Contact 
30 (±3) days 
after 
Study Com- 
pletion 
Visit 
Day-14 
Visit 
(14–21 
days) 
Day-30 
Visit 
(±3 
days) 
3-Month 
Visit 
(±2 
weeks) 
Study 
Completion 
(6-Month) 
Visit 
at 6 months 
(+2 weeks) 
Informed consent 
x 
Inclusion and exclusion criteria 
x 
Demographics 
x 
Weight 
x 
x [1] 
x [1] 
x [1] 
Height 
x 
Medical history (incl. FVIII treatment 6 months 
before screening) 
x 
Vital signs 
x 
x [2] 
x [4] 
x [4] 
Physical examination 
x 
x 
Routine safety laboratory 
x 
x [3] 
x [1] 
x [4] 
Determination of CD4+ levels [8] 
x 
Determination of AB0 blood group [9] 
x 
HJHS, unless obtained within 3 months be- 
fore screening 
x 
PK injection (50 ± 5 IU/kg) 
x 
Blood sampling for FVIII:C (OS and CHR) for 
PK assessment 
x [5] 
IVR injection 
x 
x 
Blood sampling for FVIII:C IVR (OS and 
CHR) 
x [6] 
x [6] 
Factor VIII inhibitor [10] 
x 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
VWF:Ag and VWF:Ac 
x [6] 
x [1] 
x [1] 
x [6] 
x [6] 
Parvovirus B19 antibodies 
x [1] 
x [7] 
Retention sample for possible virus marker 
testing 
x [1] 
Patient diary review 
x 
x 
x 
x 
Adverse event monitoring 
x 
» 
» 
» 
x 
x [11] 
Concomitant medications 
x 
» 
» 
» 
» 
x 
PK = pharmacokinetic, IVR = in vivo recovery, HJHS = Hemophilia Joint Health Score, OS = one-stage assay, CHR = chromo- 
genic assay, VWF:Ag = von Willebrand factor antigen, VWF:Ac = VWF activity 


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LEGEND TO THE FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
[1] 
Before injection 
[2] 
Before injection as well as 1 h (±5 min) and 48±2 h after injection 
[3] 
Before injection as well as 48±2 h after injection [local laboratory] 
[4] 
Before injection as well as 15±5 min after injection 
[5] 
Blood sampling within 1 h before injection and 15±5 min, 1 h (±5 min), 6 h (±30 min), 9±1 h, 24±2 h, 30±2 h, and 48±2 h 
after the end of injection [central laboratory] 
[6] 
Blood sampling within 1 h before injection as well as 15±5 min after the end of injection [central laboratory] 
[7] 
If first sample was negative for parvovirus B19 antibodies (sample to be taken before injection) [central laboratory] 
[8] 
CD4+ count to be repeated if interval between Screening Visit and first injection exceeds 30 days. To be included into 
the study, the patient’s CD4+ count must be >200/µL (i.e., inclusion criterion no. 4). 
[9] 
Unless obtainable from patient’s medical history 
[10] Blood sampling for inhibitor testing should preferably be done at the time of trough FVIII:C levels [central laboratory] 
In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample should be performed, 
preferably within 15 days of becoming aware of the positive result. 
[11] Documentation of any thromboembolic events only (to be documented on AE page) 


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FLOW CHART OF ASSESSMENTS FOR SURGICAL PROPHYLAXIS 
 
Within 
12 hours 
before 
start 
Within 
3 hours 
before 
start 
Surgery 
POP 
day 1 
Any 
POP 
day 
End of 
POP 
period 
3-8 
weeks 
after 
surgery 
Intra- 
opera- 
tively 
End 
[1] 
Body weight 
x 
Type of surgery 
x 
Location of surgery 
x 
Severity of surgery 
x 
Expected duration of surgery 
x 
Expected average/ maximum blood 
loss during surgery 
x 
Actual duration of surgery 
x 
Actual blood loss during surgery 
x 
Administration of IMP 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
FVIII plasma levels 
# 
(#) 
(#) 
# [2] 
# 
# 
VWF:Ag and VWF:Ac 
# 
# [2] 
# 
# 
Presence of wound hematomas 
x 
x 
x 
Routine safety laboratory 
x 
(x) 
(x) 
(x) 
Vital signs 
x 
x 
x 
Efficacy assessment 
S 
H 
Overall efficacy assessment 
I 
Factor VIII inhibitor [3] 
x 
Narrative of outcome 
x 
Concomitant medications 
throughout observation period 
Adverse event monitoring 
throughout observation period 
 
POP = postoperative, VWF:Ag = von Willebrand factor antigen, VWF:Ac = VWF activity 
( ) Optional 
# Samples to be taken immediately before (≤ 30 min) and 30±15 min after IMP administration 
[1] Time immediately after the last surgical suture 
[2] For major surgeries, mandatory for the first 3 postoperative doses 
[3] In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample should be performed, prefer- 
ably within 15 days of becoming aware of the positive result. 
S, performed by surgeon; H, performed by hematologist; I performed by Investigator 
 
 
2.5 Planned sample size 
Overall, 10 PTPs (5 patients aged 1 to <6 years of age and 5 patients aged 6 to <12 years) will 
be enrolled into this study. The aim is to obtain evaluable data on 8 patients who complete 
both the 2-day PK Phase and the 6-month Prophylactic Treatment Phase. Of the 8 evaluable 
patients, 4 patients must be 1 to <6 years of age, and another 4 patients must be 6 to <12 
years of age. Enrolled patients will be replaced only if they do not complete the PK assess- 
ment. 
The sample size of 10 pediatric patients to be enrolled was based on medical and regulatory 
reasoning. No statistical sample size estimation was performed. 


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3 GENERAL INFORMATION 
3.1 Background details 
The data will be transferred to SAS from the Clinical Data Management System OPVERDI 
via a validated procedure. If applicable, external data will also be transferred to SAS for 
presentation of these data in the statistical analyses. 
 
3.2 Deviations from the trial protocol with regard to statistical analyses 
No deviations from the protocol are planned. 
 
3.3 Individual protocol deviations 
Any deviation from protocol will be discussed case by case before database lock whether the 
deviation has to be regarded as minor or as major (and therefore will lead to exclusion from 
particular analysis populations). 
Examples for minor protocol violations may be deviations from scheduled investigation time. 
Criteria for major protocol violations will at least include: 
• Any substantial violation of in- or exclusion criteria. 
• Use of concomitant medication that may interfere with the assessment of efficacy. 
The final decision about the classification of individual protocol deviations and their conse- 
quences regarding assignment of subjects to analysis sets will be made during the data review 
meeting (DBR). A complete listing of protocol deviations and the judgment for assessment 
of subject disposition will be approved by the Sponsor and signed before database lock. All 
deviations along with the disposition of each subject will be recorded in a separate database 
member that will become part of the study database. A description of all major protocol 
violations will be included in the table part of the CSR. 
 
4 ANALYSIS POPULATIONS 
The disposition of subjects will be displayed according to the following analysis populations: 
• Safety (SAF) set 
• Full Analysis set (FAS) 
• Pharmacokinetic (PK) set 
• Per-Protocol (PP) set 
• Surgery (SURG) set 


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4.1 Safety set 
The safety (SAF) set will include all subjects who received at least one infusion of IMP. 
4.2 Full analysis set 
The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle will 
include all enrolled subjects who received at least one infusion of IMP (after the initial PK 
visit). 
4.3 Pharmacokinetic set 
The pharmacokinetic (PK) set will include all patients for which a valid Wilate PK profile 
has been obtained. 
4.4 Per-protocol set 
The per-protocol (PP) set, i.e. a subset of the FAS, will exclude subjects with major protocol 
deviations which may have an impact on the evaluation of the primary study outcome param- 
eter (major protocol deviations as defined during DBR). 
4.5 Surgery set 
The surgery (SURG) set will be a subset of the FAS, containing all subjects who underwent 
a surgical procedure treated with Wilate during their Prophylactic Treatment Phase. 
4.6 Subgroup analyses 
The analyses of the PK parameters and the efficacy endpoints ‘efficacy of prophylactic treat- 
ment’ and ‘efficacy in treatment of breakthrough BEs’ will be presented by age groups (‘1 to 
<6 years’ and ‘6 to <12 years’). 
 
 
 
5 STATISTICAL ANALYSES 
All statistical analyses will be performed using SAS® for Windows (Version 9.3 or later). 
Descriptive statistics will always be given for the entire population. 
The analysis of safety will be based on the SAF set. 
Analysis of the PK properties of Wilate will be based on the PK set. 
For secondary endpoints, FAS and PP analyses will be carried out, unless these analysis sets 
differ by no more than 1 patient from the FAS. 
Analysis of the efficacy and safety of Wilate in surgeries will be based on the SURG set. 
If not stated otherwise the following standard descriptive statistics will be presented: 


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Descriptive statistics for continuous data 
Number of subjects (N), arithmetic mean, standard deviation (SD), minimum, lower quartile, 
median, upper quartile and maximum will be presented. Usually mean and quartiles will have 
1 decimal more, SD 2 decimals more than the original values (as given with min, max); N has 
no decimals. These descriptive statistics will be determined for measured values and for dif- 
ferences to baseline. 
Descriptive statistics for categorical data 
Absolute frequencies (N) will be presented with 0, relative frequencies (%) with 1 decimal. 
For changes from baseline, shift tables may be generated. 
Inferential statistics 
If not stated otherwise all statistical tests will be performed as described in the corresponding 
sections below. 
All p-values will be rounded to 4 decimals (p<0.0001 will be displayed, if the p-values are less 
than 0.0001). Statistical significance will be declared if the rounded p-value will be less than 
0.05. 
All confidence intervals (CI) will be derived two-sided and at a confidence probability of 1-
α = 0.95. 
Listings 
All subject data will be listed by subject. Identification variable will be the subject ID (com- 
posed of study, center and subject number separated by a hyphen, e.g. ’30-01-01’. Any derived 
data listed will also be stored permanently and will be calculated as outlined in section 8.1 of 
this SAP. 
 
5.1 Conventions 
5.1.1 Baseline definition 
Assessments at PK visit or at screening visit (in case the corresponding assessment is not 
scheduled at PK visit) are considered as baseline. 
5.1.2 Missing data 
In case of missing weight documentation data will be imputed using the Last Observation 
Carried Forward (LOCF) approach to calculate the dose per kg body weight (IU/kg). For 
calculation of PK parameters, missing measurements on a subject's PK profile will be han- 
dled according to the algorithms included in the PK software WinNonlin (version 7.0). 
No further imputations for missing data will be performed. 
Calculations pertaining to the derivation of annual bleeding rates will be based on docu- 
mented time periods only. 


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5.1.3 Pooling of centers 
All tables will be presented in total over all participating countries and centers. The distribu- 
tion of number of subjects per country and center will be presented in the disposition section 
of the report. 
 
5.2 Demographic and other background data 
5.2.1 Basic description 
The disposition of subjects (cf. Section 4) will be tabulated for the entire population. Details 
on protocol deviations will be listed. 
Discontinued subjects will be described by frequency distributions including the reasons and 
in individual listings. 
Demographic data (age, weight, height, BMI, race, ethnic group) will be summarized in tables 
and presented for the SAF and FAS population. Other baseline or background data, e.g. dis- 
ease-specific information, will comprise descriptive tables for the SAF and FAS population 
for the following variables: 
• Blood group 
• Last CD4+ level before enrolment 
• VWF:Ag, VWF:Ac levels at PK visit 
• FVIII inhibitor level 
• Vital Signs (Systolic and diastolic blood pressure, pulse and body temperature) at 
screening 
• Physical examination (normal/abnormal) at screening 
• Hemophilia joint health score (HJHS) at screening 
• Results of Parvovirus B19 antibodies at PK visit 
The following background data will only be listed: 
• Medical history (including FVIII treatment during the last 6 months before screening) 
• Concomitant Medication 
 
5.3 IMP exposure, compliance 
Treatment will be administered prophylactically as defined in the protocol. Each home treat- 
ment will be recorded in the diary along with the reason for treatment (prophylaxis, bleeding, 
prevention of recurrent bleeding, prophylaxis after surgery or other reason). Treatments in 
context of IVR and PK measurements and surgeries will be documented in the patients notes. 
All treatments, from diary or patient’s notes, will be transferred into the eCRF. 
All IMP treatment details will be listed. 


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5.4 Medical history 
Data on medical history will be listed. Medical history will be coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Codes will be reviewed by a Medical Expert 
and approved by the sponsor before data base lock. 
 
5.5 Concomitant medication 
Any relevant medication taken at time of screening and all new medications taken by the sub- 
ject during the study period are defined as ‘Concomitant’. Any changes of medications during 
the study period will also be recorded. 
All details of concomitant medications will be listed including, the route, dose, frequency, start 
and stop date and indication. 
Medications will be coded using the WHO DD thesaurus in the version current at the time of 
database lock. Coding will be performed by the CRO and agreed upon with the sponsor before 
data base lock. (cf. DMP). For concomitant medications tables will show the frequencies of 
subjects by WHO DD preferred term. 
 
5.6 Concomitant non-pharmacological measures, pre-medication 
Not applicable. 
 
5.7 PK and Efficacy 
5.7.1 Pharmacokinetics 
The primary objective of this study is the analysis of the PK profile of Wilate (refer to section 5.8). 
 
5.7.2 Efficacy 
All efficacy variables will be analyzed based on the FAS and additionally on the PP set, unless 
these analysis sets are identical. 
Efficacy endpoints are: 
• Efficacy of prophylactic treatment with Wilate based on the total annualized bleeding 
rate (TABR) as well as the spontaneous annualized bleeding rate (SABR) 
• Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of 
BEs successfully treated with Wilate (successfully includes efficacy ratings assessed as 
either ‘excellent’ or ‘good’) 
• Wilate consumption data (FVIII IU/kg per week and per month per subject) for 
prophylaxis 


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• Incremental IVR of Wilate over time (at baseline, and at 3 and 6 months of treat- 
ment) (refer to section 5.8) 
 
Efficacy of Prophylactic Treatment with Wilate 
The analysis of the efficacy of prophylactic treatment with Wilate will be statistically evaluated 
by presenting descriptive sampling statistics for the TABR and SABR, along with an explor- 
atory 95% CI for the mean. TABR and SABR will be calculated as the total number of BEs 
or total number of spontaneous BEs, respectively, in the time period between first dose of 
IMP and the study completion visit, divided by the duration (in years) between first dose of 
IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, 
will be excluded from the calculation of annual bleeding rates 
 
Efficacy in the Treatment of Breakthrough BEs 
To assess the hemostatic efficacy of Wilate in the treatment of breakthrough bleedings, a fre- 
quency distribution of all such BEs being successfully treated will be presented, along with an 
exploratory 95% CI. 
 
Primarily, all obtained data on treatment characteristics (IMP dosages, frequencies, total con- 
sumption) and BEs (duration, frequency, efficacy assessment) will be described by providing 
summary statistics. 
In general, the efficacy of bleeding episodes will also be presented by type (spontaneous, trau- 
matic, postoperative, other), sites (nose, oral cavity, knee, ankle, elbow, arm, leg, intestinal and 
other. In addition, knee, ankle and elbow sites will be summarized as site ‘joint’) and severity 
(minor, moderate, major, life-threatening). 
 
Analysis of Other Secondary Endpoints 
The statistical analysis of other secondary endpoints will be descriptive, including exploratory 
95% CIs for the location parameters. 
 
5.7.3 Exploratory Endpoint 
An exploratory endpoint of this study is the descriptive efficacy of Wilate in surgical prophy- 
laxis (for details see section 5.9 ). 


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5.8 Pharmacokinetics / Pharmacodynamics 
For Pharmacokinetics and IVR assessments FVIII:C will be measured by both, the chromo- 
genic (CHR) and one-stage assay (OS) and analyzed based on actual IMP potency (refer to 
section 8.1). 
 
The PK profiles of Wilate and the PK parameters derived from them will be summarized by 
descriptive statistics as well as the presentation of concentration vs. time plots based on the 
PK set. In the analysis of the PK profiles geometric means and standard deviations will be 
presented in addition to the arithmetic means and standard deviations. 
The following PK parameter will be derived and presented using a non-compartment model: 
• Area under the curve (AUC) and AUC normalized for the administered dose (AUCnorm) 
• FVIII in vivo half-life (T1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vd) 
• Clearance (CL) 
• Incremental in vivo recovery (IVR) 
Analysis of variance (ANOVA) will be used in an exploratory sense to assess a possible asso- 
ciation between AB0 blood type, VWF:Ag, and the FVIII:C half-life of Wilate. 
Incremental IVR will be calculated from FVIII:C plasma levels measured before injection and 
peak levels obtained in the 15-min post-injection sample using actual IMP potencies. The 
results of the IVR assessments over time will be analyzed in summary tables for each time 
point and their differences to baseline along with 95% CIs for the mean differences. 
 
5.9 Surgeries 
Efficacy in surgical prophylaxis will be analyzed descriptively, presenting summary tables and 
listing on all aspects of surgical treatment and procedures as well as efficacy ratings. 
The following surgery-related parameters will be presented: 
• Number of minor and major surgeries 
• Location, severity (minor or major, for definitions see protocol), and type (planned or 
emergency) of surgery 
• Expected and actual duration of surgical procedure 
• Expected and actual blood loss 
• Pre-, intra-, and/or postoperative IMP administration data (only listed) 


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• Pre-, intra-, and postoperative FVIII plasma levels (only listed) 
• VWF:Ag and VWF:Ac (descriptive statistics including changes to pre-infusion) 
• Frequency and amount of blood transfusion requirements 
• Presence of wound hematomas and whether or not they require surgical evacuation 
(only listed) 
• Assessment of efficacy of surgical prophylaxis: 
1. at the end of surgery by the surgeon 
2. at end of the postoperative period by the hematologist 
3. Overall efficacy taking both the intra- and postoperative assessments into ac- 
count assessed by the Investigator. 
• Number of successively treated surgeries (‘excellent’ or ‘good’ overall efficacy rating) 
• Concomitantly administered products (only listed) 
• Narrative describing the outcome and efficacy of the intervention (only listed) 
• Inhibitor testing (within 3–8 weeks after the end of the surgery, this visit may coin- 
cide with another study visit with scheduled inhibitor testing) 
 
5.10 Safety 
All safety analyses will be based on the SAF population. 
The analysis of safety will include the occurrence of AEs, the results of the safety laboratory 
tests, immunogenicity measurements and the occurrence of parvovirus B19 seroconversions. 
 
5.10.1 Adverse events 
Adverse events (AEs) will be coded by the CRO according to the latest Medical Dictionary 
for Regulatory Activities (MedDRA). Coding will be agreed upon with the Sponsor before 
database lock (cf. DMP). 
All adverse events recorded since signing of the informed consent form (ICF) will be listed in 
appendix 16.2 of the report differentiating by treatment emergent and non-treatment emergent 
events. This includes also post-study serious adverse events (SAEs) which occurred up to 4 
weeks after the last IMP administration (not monitored proactively), thromboembolic events 
monitored proactively by performing a Follow-up Contact 30 days after the completion visit 
as well as safety relevant information on drug overdosing, drug interactions and medication 
errors. 
The analysis will include only treatment-emergent adverse events (TEAEs), i.e. all docu- 
mented AEs that started or worsened after the start of IMP infusion. It is assumed that for 
each increase in intensity of an AE a new entry of the AE will be done by the investigator; 
hence such cases will be analyzed like different phases of the same AE. 


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A descriptive analysis will be performed. Incidences will be presented by primary system or- 
gan classes (SOC) and incidences of PT within primary SOC sorted according to the Interna- 
tionally Agreed Order. 
Multiple counts within a PT or SOC (repeated or different included terms or changes in de- 
scriptors) will be counted only once for the calculation of incidences. 
Global incidences will be calculated for: 
• All TEAE irrespective of the causality assessment 
• Related TEAEs (‘Probably’ or ‘Possible’) 
• TEAEs by worst severity 
• Serious TEAEs 
A listing of "special cases" containing subject identification, age, sex, AE descriptors, start 
and end of treatment will be prepared for the following types of TEAEs: 
• Serious adverse events (SAE) 
• Adverse events which led to death 
• Adverse events which led to discontinuation 
Serious non-treatment emergent AEs will be listed separately. 
 
5.10.2 Vital signs 
Vital signs parameters (systolic/diastolic blood pressure, pulse, body weight, respiratory rates, 
body temperature) will be assessed at screening, PK visit, after 3 months at study completion 
visits and during surgery. 
Descriptive analyses of values will be performed and changes from baseline will be analyzed 
for vital signs parameters at visits. 
 
5.10.3 Safety laboratory variables 
The analysis of the safety parameters (lab values for Hematology and Clinical chemistry) rec- 
orded during visits (screening, PK visit, 3-month and study completion visits) and at surgery 
will be purely descriptive and presented as summary tables or listings. 
Time profiles of the safety laboratory parameters will be analyzed by presenting sampling sta- 
tistics for the values as well as their difference to baseline at each time point. Additionally, 
frequency tables for values outside the normal ranges will be presented. 
Similarly, time profiles of FVIII inhibitor testing results will be analyzed by presenting sam- 
pling statistics for the values as well as frequency tables for positive findings, along with 95% 
Pearson-Clopper CIs. 


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The thromboembolic risk will be monitored by determination of VWF:Ag and VWF:Ac dur- 
ing the study and especially postoperatively. Descriptive statistics including changes to pre- 
infusion will be presented by visit and timepoint (with 95% CI) for visits or by operative day 
and timepoint for surgeries, respectively. 
To assess the viral safety of Wilate incidences of parvovirus B19 seroconversions between 
baseline and end of study will be estimated along with 95% Pearson-Clopper CIs. 
 
5.10.4 Other safety variables 
Other safety parameters (e.g., changes in physical examination findings) will be analyzed by 
summary tables or listings. All abnormal findings from the physical examination will be listed. 
The analysis of the safety parameters recorded during surgery (lab values) will be purely de- 
scriptive and presented as summary tables or listings. 
 
5.11 Other variables 
Not applicable. 
 
5.12 Interim analyses 
Not applicable. 
 
6 QUALITY CONTROL 
The responsible project manager will review the SAP before it is provided to the Sponsor for 
review. The SAP will be signed off only when approval from the Sponsor's representative is 
received. 
Log files of all SAS® programs needed for analysis will be checked for errors, warnings and 
suspicious notes by the statistical programmer. All findings will be either eliminated or com- 
mented upon. The final version of each program will be stored along with its log file in the 
electronic archive. 
All programs will be validated by the author. 
The agreement of the program outputs with the SAP, their consistency and plausibility will 
be checked by the TS. Moreover, the TS will review the outputs regarding completeness, 
readability and comprehensibility. 
 
7 REFERENCES 
No specific references were used. 


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8 APPENDICES 
8.1 Formulas for derived variables 
 
Variable 
Description 
Actual potency 
Potency of IMP (IU) based on central laboratory measurements of 
FVIII content by two assay methods: CHR (chromogenic) and OS 
(one-stage). 
The analysis of PK and IVR assessment will be based on actual poten- 
cies 
Durations 
be- 
tween two dates 
Later date minus earlier date plus 1, expressed in days. (Remark: Du- 
ration will be 1, if both dates are the same.) 
Annual bleeding 
rate 
Number of bleeding / (last date of IMP – first date of IMP 
+ 1)/365.25 
AUC 
Area under the curve from baseline to infinity 
AUC = ∑ (Cn + Cn+1 ) ⋅ ∆t  + Clast 
 
 
 
 
 
2 
 
K 
(Clast is the last available measurement) 
AUCnorm 
AUC normalized for the administered dose 
AUMC 
Area under the moment curve (from baseline to infinity) 
AUMC = ∑ (tn ⋅ Cn + tn+1Cn+1 ) ⋅ ∆t  + Clast + tlast ⋅ Clast 
 
 
 
 
 
 
2 
 
K 2 
K 
CL 
Clearance 
CL =  D 
AUC 
where D is the actual dose administered (see remark above) 
C0 
FVIII concentration before IPM administration 
Cmax 
Maximal measured concentration after end of IMP infusion (peak con- 
centration) 
ED 
Exposure day = each calendar day the subject received IMP 
Incremental re- 
covery (IVR) 
IVR = (Cmax − C0 ) ⋅ BW 
D 
where BW stands for the body weight in kg and D is the dose accord- 
ing to the actual potency of the FVIII concentrate as described in 
above 
Labelled potency 
Potency of IMP (IU) based on label of vial (IU). 


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Dosing analyses will be based on labelled potency 
MRT 
Mean residence time 
MRT = AUMC 
AUC 
Success (for 
bleeding epi- 
sodes and sur- 
geries) 
Excellent or good efficacy rating 
T1/2 
In vivo half-life 
using linear regression on the terminal phase of the logarithm of the 
concentration; 
T 
= ln(2) 
1 
2 
K 
(where K, the elimination rate constant, is determined as the slope of 
the regression line) 
Tmax 
Time to reach maximum plasma concentration (Timing starts at end 
of infusion) 
Vd 
Volume of distribution 
Vd = CL ⋅ MRT 


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8.2 Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis 
The evaluation of overall efficacy of the treatment in surgeries based on the intraoperative 
and postoperative assessment is defined as described below: 
 
Intraoperative 
assessment 
Postoperative assessment 
Excellent 
Good 
Moderate 
None 
Excellent 
Excellent 
Good 
Good 
Moderate 
Good 
Good 
Good 
Moderate 
Moderate 
Moderate 
Good 
Moderate 
Moderate 
None 
None 
Good 
Moderate 
None 
None 


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8.3 List of Tables, Listings, Figures 
A complete lists of tables, listings figures (TLFs) will be given in a separate document which 
can be updated without updating the SAP. The list will serve as a reference for both the 
Sponsor, the trial statistician and the statistical programmer and includes the totality of statis- 
tical output to be produced. Therefore, this list will be approved by both parties before com- 
mencing the statistical programming. 
All output will be headed with an appropriate heading specifying the study ID and abbreviated 
study title. 
All output will be dated and have page numbers in the form 'Page [x / y]' where x denotes 
the current page within an output and y the total number of pages of that output. 
All statistical output will identify the underlying analysis populations and indicate the number 
of subjects / events in this population (N) and the number of subject/events actually con- 
tributing to the particular output (n). All statistical output will be presented per treatment 
group and in total (if applicable). 
All subject listings will contain additionally to the subject identification the analysis population 
and the treatment group. 


FRM/BS/001.01 
Version 3.0, Effective April 2016 
 
Confidential 
This document contains confidential information which must not be disclosed to anyone other 
than the involved CRO. This information should not be used for any purpose other than the 
evaluation of the clinical investigation without prior written consent of Octapharma. 
No part of this document may be reproduced or stored in a retrieval system or transmitted in 
any other form or by any other means. 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No: WIL-30 
Version Number: 1.1 
Date of Issue: 
2017-05-24 
Page 1 of 27 
 
 
 
 
Sponsor: 
Octapharma AG 
Title of Protocol: 
Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, 
and Immunogenicity of Wilate in Previously Treated Pediatric Patients 
with Severe Hemophilia A 
Protocol Ver- 
sion/Date: 
Version 1.0 / 2017-05-15 
CRF Version: 
TBD 
Supersedes SAP Ver- 
sion: 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
... 
... 
FRM/BS/001.01 
Version 3.0, Effective April 2016 
 
 
 
 
 
.'. 
 
 
Document authorization 
 
 
 
 
Hans-Peter ffucke 
······ 
· 
Trial Statistician 
ERGOMED 
 
 
Project Manager 
ERGOl\ffiD 
 
2,'(, I".,.., 7(/ ,,. 
Signature 
Date (dd-mmm-yyyy) 
 
 
 z M°3rz0 !':/- 
Signature 
Date (dd-mmm-yyyy) 
 
 
 
Octapharma AG 
Clinical··:•,;·., 
: Manager 
Dmytro Pomishch 
. ... 
STATISTICAL ANALYSIS PLAN 
Protocol No: WIL-30 
..... 
....   . ·    . 
. . 
..
 
Version Number: 1.1 
; 
Date of Issue: 
2017-05-24 
... 
. 
... ,. 
..
· 
.. 
• Page 2 of27 


FRM/BS/001.01 
 
ERGOMED 
Version 3.0, Effective April 2016 
 
 
 
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Protocol No: WIL-30 
Version Number: 1.1 
Date of Issue: 
2017-05-24 
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Consistency check with the Protocol (one option to be selected) 
 
This is to confttm that as part of the SAP finalization consistency check with the current 
protocol / protocol amendment was performed by the trial statistician, and no changes to the 
protocol (statistical section) are required 
 
D 
 Changes to the analysis principles were required, and the responsible team has confirmed 
commitment to update the study protocol 
 
 
D 
Changes to the analysis principles were required (as outlined in revision history section of 
this SAP), however it was not feasible to update the study protocol, for the reason 
 
 
 
 
 
 
 
 
Hans-Peter Hucke 
Trial Statistician 
ERGOMED 
Signature 
Date (dd-mmm-yyyy) 


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Change control 
 
 
Date 
Author 
Reason 
Version 
2017-04-26 
Hans-Peter Hucke 
1.0 
2017-05-24 
Hans-Peter Hucke 
SAP adapted to protocol version 
01, 15-May-2017 
1.1 


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TABLE OF CONTENTS 
Document authorization ................................................................................................................................. 2 
Consistency check with the Protocol (one option to be selected) ................................................................... 3 
Change control ................................................................................................................................................ 4 
Table of contents ............................................................................................................................................. 5 
List of abbreviations ........................................................................................................................................ 7 
1 Study material .............................................................................................................................................. 10 
2 Study information ........................................................................................................................................ 10 
2.1 Primary objective ........................................................................................................................................ 10 
2.2 Secondary objective .................................................................................................................................... 10 
2.3 Additional Objective: .................................................................................................................................. 10 
2.4 Study design ................................................................................................................................................ 11 
2.5 Planned sample size .................................................................................................................................... 13 
3 General Information .................................................................................................................................... 14 
3.1 Background details ..................................................................................................................................... 14 
3.2 Deviations from the trial protocol with regard to statistical analyses ......................................................... 14 
3.3 Individual protocol deviations .................................................................................................................... 14 
4 Analysis Populations ................................................................................................................................... 14 
4.1 Safety set ..................................................................................................................................................... 15 
4.2 Full analysis set ........................................................................................................................................... 15 
4.3 Pharmacokinetic set .................................................................................................................................... 15 
4.4 Per-protocol set ........................................................................................................................................... 15 
4.5 Surgery set .................................................................................................................................................. 15 
4.6 Subgroup analyses ...................................................................................................................................... 15 
5 Statistical Analyses ...................................................................................................................................... 15 
5.1 Conventions ................................................................................................................................................ 16 
5.1.1 
Baseline definition ............................................................................................................................ 16 
5.1.2 
Missing data ..................................................................................................................................... 16 
5.1.3 
Pooling of centers ............................................................................................................................. 17 
5.2 Demographic and other background data ................................................................................................... 17 
5.2.1 
Basic description .............................................................................................................................. 17 
5.3 IMP exposure, compliance ......................................................................................................................... 17 
5.4 Medical history ........................................................................................................................................... 18 
5.5 Concomitant medication ............................................................................................................................. 18 
5.6 Concomitant non-pharmacological measures, pre-medication ................................................................... 18 
5.7 PK and Efficacy .......................................................................................................................................... 18 
5.7.2 
Efficacy ............................................................................................................................................ 18 
5.7.3 
Exploratory Endpoint ....................................................................................................................... 19 
5.8 Pharmacokinetics / Pharmacodynamics ...................................................................................................... 20 
5.9 Surgeries ..................................................................................................................................................... 20 
5.10 Safety .......................................................................................................................................................... 21 
5.10.1 
Adverse events ............................................................................................................................. 21 
5.10.2 
Vital signs .................................................................................................................................... 22 
5.10.3 
Safety laboratory variables........................................................................................................... 22 
5.10.4 
Other safety variables .................................................................................................................. 23 
5.11 Other variables ............................................................................................................................................ 23 
5.12 Interim analyses .......................................................................................................................................... 23 
6 Quality Control ............................................................................................................................................ 23 
7 References ................................................................................................................................................... 23 
8 Appendices .................................................................................................................................................. 24 


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8.1 Formulas for derived variables ................................................................................................................... 24 
8.2 Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis ................................................. 26 
8.3 List of Tables, Listings, Figures ................................................................................................................. 27 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ABR 
Annual Bleeding Rate 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Curve 
AUCnorm 
AUC normalized for the administered dose 
AUMC 
Area Under the Moment Curve 
BE 
Bleeding Episode 
BMI 
Body Mass Index 
BW 
Body Weight 
CD4 
Cluster of Differentiation 4 
CHR 
Chromogenic assay 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DD 
Drug Dictionary (WHO Coding Thesaurus) 
DBR 
Database Review 
DMP 
Data Management Plan 
DVP 
Data Validation Plan 
ED 
Exposure Day 
EDC 
Electronic Data Capture 
EOT 
End of Trial 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FVIII 
Coagulation Factor VIII 
FVIII:C 
Factor VIII-coagulant 


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Abbreviation 
Description 
HJHS 
Hemophilia Joint Health Score 
ICF 
Informed Consent Form 
ID 
Identifier 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IU 
International Unit 
IV 
Intravenous 
IVR 
Incremental in Vivo Recovery 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
N 
Number of Subjects/Observations 
OS 
One-stage assay 
PK 
Pharmacokinetic 
POP 
Postoperative 
PP 
Per-Protocol 
PT 
Preferred Term 
PTP 
Previously Treated Subject 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software package 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SABR 
Spontaneous Annualized Bleeding Rate 
SURG 
Surgery analysis set 


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Abbreviation 
Description 
T1/2 
In Vivo Half-Life 
TABR 
Total Annualized Bleeding Rate 
TEAE 
Treatment Emergent Adverse Event 
TLFs 
Tables, Listings, Figures 
Tmax 
Time to Reach Maximum Plasma Concentration 
TS 
Trial Statistician 
Vd 
Volume of distribution 
VWD 
Von Willebrand Disease 
VWF 
Von Willebrand Factor 
VWF:Ac 
VWF activity 
VWF:Ag 
Von Willebrand Factor Antigen 
WHO 
World Health Organization 


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1 STUDY MATERIAL 
The following material was considered for this SAP: 
 
Document 
Version, Date 
Protocol 
Version 1.0, 2017-04-26 
CRF 
TBD 
DMP 
TBD 
DVP 
TBD 
 
 
2 STUDY INFORMATION 
2.1 Primary objective 
The primary objective of this study is to determine the FVIII:C pharmacokinetics (PK) for 
Wilate in previously treated patients (PTP) with severe hemophilia A aged 1 to <12 years. 
 
2.2 Secondary objective 
The secondary objectives of this study are to: 
• Determine the efficacy of Wilate in prophylactic treatment 
• Determine the efficacy of Wilate in the treatment of breakthrough bleeding episodes 
(BEs) 
• Calculate the FVIII:C incremental IVR of Wilate over time (at baseline, and at 3 and 6 
months of treatment) 
• Assess the association between AB0 blood type and the FVIII:C half-life of Wilate 
• Assess the association between the VWF:Ag concentration and the FVIII:C half-life of 
Wilate 
• Assess the safety and tolerability of Wilate 
• Assess the immunogenicity of Wilate 
 
2.3 Additional Objective: 
An additional objective of this study is the descriptive efficacy of Wilate in surgical prophylaxis. 


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2.4 Study design 
This study is designed as a prospective, non-controlled, international, multi-center phase 3 
study. Further details are given in the overview below: 
 
FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
 
Screen 
ing 
Visit 
PK 
Visit 
Prophylactic Treatment Phase 
(starts with first prophylactic injection of 
Wilate 
after the PK Visit) 
Follow-up 
Contact 
30 (±3) days 
after 
Study Com- 
pletion 
Visit 
Day-14 
Visit 
(14–21 
days) 
Day-30 
Visit 
(±3 
days) 
3-Month 
Visit 
(±2 
weeks) 
Study 
Completion 
(6-Month) 
Visit 
at 6 months 
(+2 weeks) 
Informed consent 
x 
Inclusion and exclusion criteria 
x 
Demographics 
x 
Weight 
x 
x [1] 
x [1] 
x [1] 
Height 
x 
Medical history (incl. FVIII treatment 6 months 
before screening) 
x 
Vital signs 
x 
x [2] 
x [4] 
x [4] 
Physical examination 
x 
x 
Routine safety laboratory 
x 
x [3] 
x [1] 
x [4] 
Determination of CD4+ levels [8] 
x 
Determination of AB0 blood group [9] 
x 
HJHS, unless obtained within 3 months be- 
fore screening 
x 
PK injection (50 ± 5 IU/kg) 
x 
Blood sampling for FVIII:C (OS and CHR) for 
PK assessment 
x [5] 
IVR injection 
x 
x 
Blood sampling for FVIII:C IVR (OS and 
CHR) 
x [6] 
x [6] 
Factor VIII inhibitor [10] 
x 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
VWF:Ag and VWF:Ac 
x [6] 
x [1] 
x [1] 
x [6] 
x [6] 
Parvovirus B19 antibodies 
x [1] 
x [7] 
Retention sample for possible virus marker 
testing 
x [1] 
Patient diary review 
x 
x 
x 
x 
Adverse event monitoring 
x 
» 
» 
» 
x 
x [11] 
Concomitant medications 
x 
» 
» 
» 
» 
x 
PK = pharmacokinetic, IVR = in vivo recovery, HJHS = Hemophilia Joint Health Score, OS = one-stage assay, CHR = chromo- 
genic assay, VWF:Ag = von Willebrand factor antigen, VWF:Ac = VWF activity 


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LEGEND TO THE FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
[1] 
Before injection 
[2] 
Before injection as well as 1 h (±5 min) and 48±2 h after injection 
[3] 
Before injection as well as 48±2 h after injection [local laboratory] 
[4] 
Before injection as well as 15±5 min after injection 
[5] 
Blood sampling within 1 h before injection and 15±5 min, 1 h (±5 min), 6 h (±30 min), 9±1 h, 24±2 h, and 48±2 h after 
the end of injection [central laboratory] 
[6] 
Blood sampling within 1 h before injection as well as 15±5 min after the end of injection [central laboratory] 
[7] 
If first sample was negative for parvovirus B19 antibodies (sample to be taken before injection) [central laboratory] 
[8] 
CD4+ count to be repeated if interval between Screening Visit and first injection exceeds 30 days. To be included into 
the study, the patient’s CD4+ count must be >200/µL (i.e., inclusion criterion no. 4). 
[9] 
Unless obtainable from patient’s medical history 
[10] Blood sampling for inhibitor testing should preferably be done at the time of trough FVIII:C levels [central laboratory] 
In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample should be performed, 
preferably within 15 days of becoming aware of the positive result. 
[11] Documentation of any thromboembolic events only (to be documented on AE page) 


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FLOW CHART OF ASSESSMENTS FOR SURGICAL PROPHYLAXIS 
 
Within 
12 hours 
before 
start 
Within 
3 hours 
before 
start 
Surgery 
POP 
day 1 
Any 
POP 
day 
End of 
POP 
period 
3-8 
weeks 
after 
surgery 
Intra- 
opera- 
tively 
End 
[1] 
Body weight 
x 
Type of surgery 
x 
Location of surgery 
x 
Severity of surgery 
x 
Expected duration of surgery 
x 
Expected average/ maximum blood 
loss during surgery 
x 
Actual duration of surgery 
x 
Actual blood loss during surgery 
x 
Administration of IMP 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
FVIII plasma levels 
# 
(#) 
(#) 
# [2] 
# 
# 
VWF:Ag and VWF:Ac 
# 
# [2] 
# 
# 
Presence of wound hematomas 
x 
x 
x 
Routine safety laboratory 
x 
(x) 
(x) 
(x) 
Vital signs 
x 
x 
x 
Efficacy assessment 
S 
H 
Overall efficacy assessment 
I 
Factor VIII inhibitor [3] 
x 
Narrative of outcome 
x 
Concomitant medications 
throughout observation period 
Adverse event monitoring 
throughout observation period 
 
POP = postoperative, VWF:Ag = von Willebrand factor antigen, VWF:Ac = VWF activity 
( ) Optional 
# Samples to be taken immediately before (≤ 30 min) and 30±15 min after IMP administration 
[1] Time immediately after the last surgical suture 
[2] For major surgeries, mandatory for the first 3 postoperative doses 
[3] In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample should be performed, prefer- 
ably within 15 days of becoming aware of the positive result. 
S, performed by surgeon; H, performed by hematologist; I performed by Investigator 
 
 
2.5 Planned sample size 
Overall, 10 PTPs (5 patients aged 1 to <6 years of age and 5 patients aged 6 to <12 years) will 
be enrolled into this study. The aim is to obtain evaluable data on 8 patients who complete 
both the 2-day PK Phase and the 6-month Prophylactic Treatment Phase. Of the 8 evaluable 
patients, 4 patients must be 1 to <6 years of age, and another 4 patients must be 6 to <12 
years of age. Enrolled patients will be replaced only if they do not complete the PK assess- 
ment. 
The sample size of 10 pediatric patients to be enrolled was based on medical and regulatory 
reasoning. No statistical sample size estimation was performed. 


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3 GENERAL INFORMATION 
3.1 Background details 
The data will be transferred to SAS from the Clinical Data Management System OPVERDI 
via a validated procedure. If applicable, external data will also be transferred to SAS for 
presentation of these data in the statistical analyses. 
 
3.2 Deviations from the trial protocol with regard to statistical analyses 
No deviations from the protocol are planned. 
 
3.3 Individual protocol deviations 
Any deviation from protocol will be discussed case by case before database lock whether the 
deviation has to be regarded as minor or as major (and therefore will lead to exclusion from 
particular analysis populations). 
Examples for minor protocol violations may be deviations from scheduled investigation time. 
Criteria for major protocol violations will at least include: 
• Any substantial violation of in- or exclusion criteria. 
• Use of concomitant medication that may interfere with the assessment of efficacy. 
The final decision about the classification of individual protocol deviations and their conse- 
quences regarding assignment of subjects to analysis sets will be made during the data review 
meeting (DBR). A complete listing of protocol deviations and the judgment for assessment 
of subject disposition will be approved by the Sponsor and signed before database lock. All 
deviations along with the disposition of each subject will be recorded in a separate database 
member that will become part of the study database. A description of all major protocol 
violations will be included in the table part of the CSR. 
 
4 ANALYSIS POPULATIONS 
The disposition of subjects will be displayed according to the following analysis populations: 
• Safety (SAF) set 
• Full Analysis set (FAS) 
• Pharmacokinetic (PK) set 
• Per-Protocol (PP) set 
• Surgery (SURG) set 


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4.1 Safety set 
The safety (SAF) set will include all subjects who received at least one infusion of IMP. 
4.2 Full analysis set 
The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle will 
include all enrolled subjects who received at least one infusion of IMP (after the initial PK 
visit). 
4.3 Pharmacokinetic set 
The pharmacokinetic (PK) set will include all patients for which a valid Wilate PK profile 
has been obtained. 
4.4 Per-protocol set 
The per-protocol (PP) set, i.e. a subset of the FAS, will exclude subjects with major protocol 
deviations which may have an impact on the evaluation of the primary study outcome param- 
eter (major protocol deviations as defined during DBR). 
4.5 Surgery set 
The surgery (SURG) set will be a subset of the FAS, containing all subjects who underwent 
a surgical procedure treated with Wilate during their Prophylactic Treatment Phase. 
4.6 Subgroup analyses 
The analyses of the PK parameters and the efficacy endpoints ‘efficacy of prophylactic treat- 
ment’ and ‘efficacy in treatment of breakthrough BEs’ will be presented by age groups (‘1 to 
<6 years’ and ‘6 to <12 years’). 
 
 
 
5 STATISTICAL ANALYSES 
All statistical analyses will be performed using SAS® for Windows (Version 9.3 or later). 
Descriptive statistics will always be given for the entire population. 
The analysis of safety will be based on the SAF set. 
Analysis of the PK properties of Wilate will be based on the PK set. 
For secondary endpoints, FAS and PP analyses will be carried out, unless these analysis sets 
differ by no more than 1 patient from the FAS. 
Analysis of the efficacy and safety of Wilate in surgeries will be based on the SURG set. 
If not stated otherwise the following standard descriptive statistics will be presented: 


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Descriptive statistics for continuous data 
Number of subjects (N), arithmetic mean, standard deviation (SD), minimum, lower quartile, 
median, upper quartile and maximum will be presented. Usually mean and quartiles will have 
1 decimal more, SD 2 decimals more than the original values (as given with min, max); N has 
no decimals. These descriptive statistics will be determined for measured values and for dif- 
ferences to baseline. 
Descriptive statistics for categorical data 
Absolute frequencies (N) will be presented with 0, relative frequencies (%) with 1 decimal. 
For changes from baseline, shift tables may be generated. 
Inferential statistics 
If not stated otherwise all statistical tests will be performed as described in the corresponding 
sections below. 
All p-values will be rounded to 4 decimals (p<0.0001 will be displayed, if the p-values are less 
than 0.0001). Statistical significance will be declared if the rounded p-value will be less than 
0.05. 
All confidence intervals (CI) will be derived two-sided and at a confidence probability of 1-
α = 0.95. 
Listings 
All subject data will be listed by subject. Identification variable will be the subject ID (com- 
posed of study, center and subject number separated by a hyphen, e.g. ’30-01-01’. Any derived 
data listed will also be stored permanently and will be calculated as outlined in section 8.1 of 
this SAP. 
 
5.1 Conventions 
5.1.1 Baseline definition 
Assessments at PK visit or at screening visit (in case the corresponding assessment is not 
scheduled at PK visit) are considered as baseline. 
5.1.2 Missing data 
In case of missing weight documentation data will be imputed using the Last Observation 
Carried Forward (LOCF) approach to calculate the dose per kg body weight (IU/kg). For 
calculation of PK parameters, missing measurements on a subject's PK profile will be han- 
dled according to the algorithms included in the PK software WinNonlin (version 7.0). 
No further imputations for missing data will be performed. 
Calculations pertaining to the derivation of annual bleeding rates will be based on docu- 
mented time periods only. 


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5.1.3 Pooling of centers 
All tables will be presented in total over all participating countries and centers. The distribu- 
tion of number of subjects per country and center will be presented in the disposition section 
of the report. 
 
5.2 Demographic and other background data 
5.2.1 Basic description 
The disposition of subjects (cf. Section 4) will be tabulated for the entire population. Details 
on protocol deviations will be listed. 
Discontinued subjects will be described by frequency distributions including the reasons and 
in individual listings. 
Demographic data (age, weight, height, BMI, race, ethnic group) will be summarized in tables 
and presented for the SAF and FAS population. Other baseline or background data, e.g. dis- 
ease-specific information, will comprise descriptive tables for the SAF and FAS population 
for the following variables: 
• Blood group 
• Last CD4+ level before enrolment 
• VWF:Ag, VWF:Ac levels at PK visit 
• FVIII inhibitor level 
• Vital Signs (Systolic and diastolic blood pressure, pulse and body temperature) at 
screening 
• Physical examination (normal/abnormal) at screening 
• Hemophilia joint health score (HJHS) at screening 
• Results of Parvovirus B19 antibodies at PK visit 
The following background data will only be listed: 
• Medical history (including FVIII treatment during the last 6 months before screening) 
• Concomitant Medication 
 
5.3 IMP exposure, compliance 
Treatment will be administered prophylactically as defined in the protocol. Each home treat- 
ment will be recorded in the diary along with the reason for treatment (prophylaxis, bleeding, 
prevention of recurrent bleeding, prophylaxis after surgery or other reason). Treatments in 
context of IVR and PK measurements and surgeries will be documented in the patients notes. 
All treatments, from diary or patient’s notes, will be transferred into the eCRF. 
All IMP treatment details will be listed. 


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5.4 Medical history 
Data on medical history will be listed. Medical history will be coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Codes will be reviewed by a Medical Expert 
and approved by the sponsor before data base lock. 
 
5.5 Concomitant medication 
Any relevant medication taken at time of screening and all new medications taken by the sub- 
ject during the study period are defined as ‘Concomitant’. Any changes of medications during 
the study period will also be recorded. 
All details of concomitant medications will be listed including, the route, dose, frequency, start 
and stop date and indication. 
Medications will be coded using the WHO DD thesaurus in the version current at the time of 
database lock. Coding will be performed by the CRO and agreed upon with the sponsor before 
data base lock. (cf. DMP). For concomitant medications tables will show the frequencies of 
subjects by WHO DD preferred term. 
 
5.6 Concomitant non-pharmacological measures, pre-medication 
Not applicable. 
 
5.7 PK and Efficacy 
5.7.1 Pharmacokinetics 
The primary objective of this study is the analysis of the PK profile of Wilate (refer to section 5.8). 
 
5.7.2 Efficacy 
All efficacy variables will be analyzed based on the FAS and additionally on the PP set, unless 
these analysis sets are identical. 
Efficacy endpoints are: 
• Efficacy of prophylactic treatment with Wilate based on the total annualized bleeding 
rate (TABR) as well as the spontaneous annualized bleeding rate (SABR) 
• Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of 
BEs successfully treated with Wilate (successfully includes efficacy ratings assessed as 
either ‘excellent’ or ‘good’) 
• Wilate consumption data (FVIII IU/kg per week and per month per subject) for 
prophylaxis 


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• Incremental IVR of Wilate over time (at baseline, and at 3 and 6 months of treat- 
ment) (refer to section 5.8) 
 
Efficacy of Prophylactic Treatment with Wilate 
The analysis of the efficacy of prophylactic treatment with Wilate will be statistically evaluated 
by presenting descriptive sampling statistics for the TABR and SABR, along with an explor- 
atory 95% CI for the mean. TABR and SABR will be calculated as the total number of BEs 
or total number of spontaneous BEs, respectively, in the time period between first dose of 
IMP and the study completion visit, divided by the duration (in years) between first dose of 
IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, 
will be excluded from the calculation of annual bleeding rates 
 
Efficacy in the Treatment of Breakthrough BEs 
To assess the hemostatic efficacy of Wilate in the treatment of breakthrough bleedings, a fre- 
quency distribution of all such BEs being successfully treated will be presented, along with an 
exploratory 95% CI. 
 
Primarily, all obtained data on treatment characteristics (IMP dosages, frequencies, total con- 
sumption) and BEs (duration, frequency, efficacy assessment) will be described by providing 
summary statistics. 
In general, the efficacy of bleeding episodes will also be presented by type (spontaneous, trau- 
matic, postoperative, other), sites (nose, oral cavity, knee, ankle, elbow, arm, leg, intestinal and 
other. In addition, knee, ankle and elbow sites will be summarized as site ‘joint’) and severity 
(minor, moderate, major, life-threatening). 
 
Analysis of Other Secondary Endpoints 
The statistical analysis of other secondary endpoints will be descriptive, including exploratory 
95% CIs for the location parameters. 
 
5.7.3 Exploratory Endpoint 
An exploratory endpoint of this study is the descriptive efficacy of Wilate in surgical prophy- 
laxis (for details see section 5.9 ). 


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5.8 Pharmacokinetics / Pharmacodynamics 
For Pharmacokinetics and IVR assessments FVIII:C will be measured by both, the chromo- 
genic (CHR) and one-stage assay (OS) and analyzed based on actual IMP potency (refer to 
section 8.1). 
 
The PK profiles of Wilate and the PK parameters derived from them will be summarized by 
descriptive statistics as well as the presentation of concentration vs. time plots based on the 
PK set. In the analysis of the PK profiles geometric means and standard deviations will be 
presented in addition to the arithmetic means and standard deviations. 
The following PK parameter will be derived and presented using a non-compartment model: 
• Area under the curve (AUC) and AUC normalized for the administered dose (AUCnorm) 
• FVIII in vivo half-life (T1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vd) 
• Clearance (CL) 
• Incremental in vivo recovery (IVR) 
Analysis of variance (ANOVA) will be used in an exploratory sense to assess a possible asso- 
ciation between AB0 blood type, VWF:Ag, and the FVIII:C half-life of Wilate. 
Incremental IVR will be calculated from FVIII:C plasma levels measured before injection and 
peak levels obtained in the 15-min post-injection sample using actual IMP potencies. The 
results of the IVR assessments over time will be analyzed in summary tables for each time 
point and their differences to baseline along with 95% CIs for the mean differences. 
 
5.9 Surgeries 
Efficacy in surgical prophylaxis will be analyzed descriptively, presenting summary tables and 
listing on all aspects of surgical treatment and procedures as well as efficacy ratings. 
The following surgery-related parameters will be presented: 
• Number of minor and major surgeries 
• Location, severity (minor or major, for definitions see protocol), and type (planned or 
emergency) of surgery 
• Expected and actual duration of surgical procedure 
• Expected and actual blood loss 
• Pre-, intra-, and/or postoperative IMP administration data (only listed) 


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• Pre-, intra-, and postoperative FVIII plasma levels (only listed) 
• VWF:Ag and VWF:Ac (descriptive statistics including changes to pre-infusion) 
• Frequency and amount of blood transfusion requirements 
• Presence of wound hematomas and whether or not they require surgical evacuation 
(only listed) 
• Assessment of efficacy of surgical prophylaxis: 
1. at the end of surgery by the surgeon 
2. at end of the postoperative period by the hematologist 
3. Overall efficacy taking both the intra- and postoperative assessments into ac- 
count assessed by the Investigator. 
• Number of successively treated surgeries (‘excellent’ or ‘good’ overall efficacy rating) 
• Concomitantly administered products (only listed) 
• Narrative describing the outcome and efficacy of the intervention (only listed) 
• Inhibitor testing (within 3–8 weeks after the end of the surgery, this visit may coin- 
cide with another study visit with scheduled inhibitor testing) 
 
5.10 Safety 
All safety analyses will be based on the SAF population. 
The analysis of safety will include the occurrence of AEs, the results of the safety laboratory 
tests, immunogenicity measurements and the occurrence of parvovirus B19 seroconversions. 
 
5.10.1 Adverse events 
Adverse events (AEs) will be coded by the CRO according to the latest Medical Dictionary 
for Regulatory Activities (MedDRA). Coding will be agreed upon with the Sponsor before 
database lock (cf. DMP). 
All adverse events recorded since signing of the informed consent form (ICF) will be listed in 
appendix 16.2 of the report differentiating by treatment emergent and non-treatment emergent 
events. This includes also post-study serious adverse events (SAEs) which occurred up to 4 
weeks after the last IMP administration (not monitored proactively), thromboembolic events 
monitored proactively by performing a Follow-up Contact 30 days after the completion visit 
as well as safety relevant information on drug overdosing, drug interactions and medication 
errors. 
The analysis will include only treatment-emergent adverse events (TEAEs), i.e. all docu- 
mented AEs that started or worsened after the start of IMP infusion. It is assumed that for 
each increase in intensity of an AE a new entry of the AE will be done by the investigator; 
hence such cases will be analyzed like different phases of the same AE. 


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A descriptive analysis will be performed. Incidences will be presented by primary system or- 
gan classes (SOC) and incidences of PT within primary SOC sorted according to the Interna- 
tionally Agreed Order. 
Multiple counts within a PT or SOC (repeated or different included terms or changes in de- 
scriptors) will be counted only once for the calculation of incidences. 
Global incidences will be calculated for: 
• All TEAE irrespective of the causality assessment 
• Related TEAEs (‘Probably’ or ‘Possible’) 
• TEAEs by worst severity 
• Serious TEAEs 
A listing of "special cases" containing subject identification, age, sex, AE descriptors, start 
and end of treatment will be prepared for the following types of TEAEs: 
• Serious adverse events (SAE) 
• Adverse events which led to death 
• Adverse events which led to discontinuation 
Serious non-treatment emergent AEs will be listed separately. 
 
5.10.2 Vital signs 
Vital signs parameters (systolic/diastolic blood pressure, pulse, body weight, respiratory rates, 
body temperature) will be assessed at screening, PK visit, after 3 months at study completion 
visits and during surgery. 
Descriptive analyses of values will be performed and changes from baseline will be analyzed 
for vital signs parameters at visits. 
 
5.10.3 Safety laboratory variables 
The analysis of the safety parameters (lab values for Hematology and Clinical chemistry) rec- 
orded during visits (screening, PK visit, 3-month and study completion visits) and at surgery 
will be purely descriptive and presented as summary tables or listings. 
Time profiles of the safety laboratory parameters will be analyzed by presenting sampling sta- 
tistics for the values as well as their difference to baseline at each time point. Additionally, 
frequency tables for values outside the normal ranges will be presented. 
Similarly, time profiles of FVIII inhibitor testing results will be analyzed by presenting sam- 
pling statistics for the values as well as frequency tables for positive findings, along with 95% 
Pearson-Clopper CIs. 


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The thromboembolic risk will be monitored by determination of VWF:Ag and VWF:Ac dur- 
ing the study and especially postoperatively. Descriptive statistics including changes to pre- 
infusion will be presented by visit and timepoint (with 95% CI) for visits or by operative day 
and timepoint for surgeries, respectively. 
To assess the viral safety of Wilate incidences of parvovirus B19 seroconversions between 
baseline and end of study will be estimated along with 95% Pearson-Clopper CIs. 
 
5.10.4 Other safety variables 
Other safety parameters (e.g., changes in physical examination findings) will be analyzed by 
summary tables or listings. All abnormal findings from the physical examination will be listed. 
The analysis of the safety parameters recorded during surgery (lab values) will be purely de- 
scriptive and presented as summary tables or listings. 
 
5.11 Other variables 
Not applicable. 
 
5.12 Interim analyses 
Not applicable. 
 
6 QUALITY CONTROL 
The responsible project manager will review the SAP before it is provided to the Sponsor for 
review. The SAP will be signed off only when approval from the Sponsor's representative is 
received. 
Log files of all SAS® programs needed for analysis will be checked for errors, warnings and 
suspicious notes by the statistical programmer. All findings will be either eliminated or com- 
mented upon. The final version of each program will be stored along with its log file in the 
electronic archive. 
All programs will be validated by the author. 
The agreement of the program outputs with the SAP, their consistency and plausibility will 
be checked by the TS. Moreover, the TS will review the outputs regarding completeness, 
readability and comprehensibility. 
 
7 REFERENCES 
No specific references were used. 


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8 APPENDICES 
8.1 Formulas for derived variables 
 
Variable 
Description 
Actual potency 
Potency of IMP (IU) based on central laboratory measurements of 
FVIII content by two assay methods: CHR (chromogenic) and OS 
(one-stage). 
The analysis of PK and IVR assessment will be based on actual poten- 
cies 
Durations 
be- 
tween two dates 
Later date minus earlier date plus 1, expressed in days. (Remark: Du- 
ration will be 1, if both dates are the same.) 
Annual bleeding 
rate 
Number of bleeding / (last date of IMP – first date of IMP 
+ 1)/365.25 
AUC 
Area under the curve from baseline to infinity 
AUC = ∑ (Cn + Cn+1 ) ⋅ ∆t  + Clast 
 
 
 
 
 
2 
 
K 
(Clast is the last available measurement) 
AUCnorm 
AUC normalized for the administered dose 
AUMC 
Area under the moment curve (from baseline to infinity) 
AUMC = ∑ (tn ⋅ Cn + tn+1Cn+1 ) ⋅ ∆t  + Clast + tlast ⋅ Clast 
 
 
 
 
 
 
2 
 
K 2 
K 
CL 
Clearance 
CL =  D 
AUC 
where D is the actual dose administered (see remark above) 
C0 
FVIII concentration before IPM administration 
Cmax 
Maximal measured concentration after end of IMP infusion (peak con- 
centration) 
ED 
Exposure day = each calendar day the subject received IMP 
Incremental re- 
covery (IVR) 
IVR = (Cmax − C0 ) ⋅ BW 
D 
where BW stands for the body weight in kg and D is the dose accord- 
ing to the actual potency of the FVIII concentrate as described in 
above 
Labelled potency 
Potency of IMP (IU) based on label of vial (IU). 


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Dosing analyses will be based on labelled potency 
MRT 
Mean residence time 
MRT = AUMC 
AUC 
Success (for 
bleeding epi- 
sodes and sur- 
geries) 
Excellent or good efficacy rating 
T1/2 
In vivo half-life 
using linear regression on the terminal phase of the logarithm of the 
concentration; 
T 
= ln(2) 
1 
2 
K 
(where K, the elimination rate constant, is determined as the slope of 
the regression line) 
Tmax 
Time to reach maximum plasma concentration (Timing starts at end 
of infusion) 
Vd 
Volume of distribution 
Vd = CL ⋅ MRT 


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8.2 Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis 
The evaluation of overall efficacy of the treatment in surgeries based on the intraoperative 
and postoperative assessment is defined as described below: 
 
Intraoperative 
assessment 
Postoperative assessment 
Excellent 
Good 
Moderate 
None 
Excellent 
Excellent 
Good 
Good 
Moderate 
Good 
Good 
Good 
Moderate 
Moderate 
Moderate 
Good 
Moderate 
Moderate 
None 
None 
Good 
Moderate 
None 
None 


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8.3 List of Tables, Listings, Figures 
A complete lists of tables, listings figures (TLFs) will be given in a separate document which 
can be updated without updating the SAP. The list will serve as a reference for both the 
Sponsor, the trial statistician and the statistical programmer and includes the totality of statis- 
tical output to be produced. Therefore, this list will be approved by both parties before com- 
mencing the statistical programming. 
All output will be headed with an appropriate heading specifying the study ID and abbreviated 
study title. 
All output will be dated and have page numbers in the form 'Page [x / y]' where x denotes 
the current page within an output and y the total number of pages of that output. 
All statistical output will identify the underlying analysis populations and indicate the number 
of subjects / events in this population (N) and the number of subject/events actually con- 
tributing to the particular output (n). All statistical output will be presented per treatment 
group and in total (if applicable). 
All subject listings will contain additionally to the subject identification the analysis population 
and the treatment group. 


FRM/BS/001.01 
Version 3.0, Effective April 2016 
 
Confidential 
This document contains confidential information which must not be disclosed to anyone other 
than the involved CRO. This information should not be used for any purpose other than the 
evaluation of the clinical investigation without prior written consent of Octapharma. 
No part of this document may be reproduced or stored in a retrieval system or transmitted in 
any other form or by any other means. 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No: WIL-30 
Version Number: 1.2 
Date of Issue: 
2019-07-08 
Page 1 of 27 
 
 
 
 
Sponsor: 
Octapharma AG 
Title of Protocol: 
Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, 
and Immunogenicity of Wilate in Previously Treated Pediatric Patients 
with Severe Hemophilia A 
Protocol Ver- 
sion/Date: 
Version 02, 2017-06-19 (Ukraine only) 
Version 03, 2018-07-06 
CRF Version: 
Version 2.0, 2017-08-14 
Supersedes SAP Ver- 
sion: 
Version 1.1, 2017-05-24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


FRM/BS/001.01 
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ERGOMED 
 
 
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Date of Issue: 
2019-07 -08 
Page 2 of27 
 
Document authorization 
 
 
 
 
Hans-Peter Huc ke 
Trial Statistician 
ERGOMED 
7 4 t - cJ? ..off 
Signature 
Date (dd-mmm-yyyy) 
 
 
 
 
Project Manager 
ERGOMED 
Signature 
Date (dd-mmm-yyyy) 
 
 
 
 
Ire 
Clinical Trial Manager 
Octapharma AG 
Signature 
Date (dd-mmm-yyyy) 


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Consistency check with the Protocol (one option to be selected) 
 
This is to confirm that as part of the SAP finalization consistency check with the current 
protocol/ protocol amendment was performed by the trial statistician, and no changes to 
the protocol (statistical section) are required 
 
0 
Changes to the analysis principles were required, and the responsible team has confirmed 
commitment to update the study protocol 
 
0 
Changes to the analysis principles were required (as outlined in revision history section of 
this SAP) 
 
 
 
 
 
 
 
 
Hans-Peter Hucke 
Tri.al Statistician 
ERGOMED 
Signature 
Date (dd-mmm-yyyy) 


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Change control 
 
 
Date 
Author 
Reason 
Version 
2017-04-26 
Hans-Peter Hucke 
1.0 
2017-05-24 
Hans-Peter Hucke 
SAP adapted to protocol version 
01, 15-May-2017 
1.1 
2019-07-08 
Natascha Blaudeck 
(update only) 
Subgroup for bleeding analysis 
added as agreed at Database Re- 
view Meeting, formulas for deriva- 
tions added 
1.2 


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TABLE OF CONTENTS 
Document authorization ................................................................................................................................. 2 
Consistency check with the Protocol (one option to be selected) ................................................................... 3 
Change control ................................................................................................................................................ 4 
Table of contents ............................................................................................................................................. 5 
List of abbreviations ........................................................................................................................................ 7 
1 Study material .............................................................................................................................................. 10 
2 Study information ........................................................................................................................................ 10 
2.1 Primary objective ........................................................................................................................................ 10 
2.2 Secondary objective .................................................................................................................................... 10 
2.3 Additional Objective: .................................................................................................................................. 10 
2.4 Study design ................................................................................................................................................ 11 
2.5 Planned sample size .................................................................................................................................... 13 
3 General Information .................................................................................................................................... 14 
3.1 Background details ..................................................................................................................................... 14 
3.2 Deviations from the trial protocol with regard to statistical analyses ......................................................... 14 
3.3 Individual protocol deviations .................................................................................................................... 14 
4 Analysis Populations ................................................................................................................................... 14 
4.1 Safety set ..................................................................................................................................................... 15 
4.2 Full analysis set ........................................................................................................................................... 15 
4.3 Pharmacokinetic set .................................................................................................................................... 15 
4.4 Per-protocol set ........................................................................................................................................... 15 
4.5 Surgery set .................................................................................................................................................. 15 
4.6 Subgroup analyses ...................................................................................................................................... 15 
5 Statistical Analyses ...................................................................................................................................... 15 
5.1 Conventions ................................................................................................................................................ 16 
5.1.1 
Baseline definition ............................................................................................................................ 16 
5.1.2 
Missing data ..................................................................................................................................... 17 
5.1.3 
Pooling of centers ............................................................................................................................. 17 
5.2 Demographic and other background data ................................................................................................... 17 
5.2.1 
Basic description .............................................................................................................................. 17 
5.3 IMP exposure, compliance ......................................................................................................................... 18 
5.4 Medical history ........................................................................................................................................... 18 
5.5 Concomitant medication ............................................................................................................................. 18 
5.6 Concomitant non-pharmacological measures, pre-medication ................................................................... 18 
5.7 PK and Efficacy .......................................................................................................................................... 18 
5.7.2 
Efficacy ............................................................................................................................................ 19 
5.7.3 
Exploratory Endpoint ....................................................................................................................... 20 
5.8 Pharmacokinetics / Pharmacodynamics ...................................................................................................... 20 
5.9 Surgeries ..................................................................................................................................................... 20 
5.10 Safety .......................................................................................................................................................... 21 
5.10.1 
Adverse events ............................................................................................................................. 21 
5.10.2 
Vital signs .................................................................................................................................... 22 
5.10.3 
Safety laboratory variables........................................................................................................... 23 
5.10.4 
Other safety variables .................................................................................................................. 23 
5.11 Other variables ............................................................................................................................................ 23 
5.12 Interim analyses .......................................................................................................................................... 23 
6 Quality Control ............................................................................................................................................ 23 
7 References ................................................................................................................................................... 24 
8 Appendices .................................................................................................................................................. 24 


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8.1 Formulas for derived variables ................................................................................................................... 24 
8.2 Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis ................................................. 26 
8.3 List of Tables, Listings, Figures ................................................................................................................. 27 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ABR 
Annual Bleeding Rate 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Curve 
AUCnorm 
AUC normalized for the administered dose 
AUMC 
Area Under the Moment Curve 
BE 
Bleeding Episode 
BMI 
Body Mass Index 
BW 
Body Weight 
CD4 
Cluster of Differentiation 4 
CHR 
Chromogenic assay 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DD 
Drug Dictionary (WHO Coding Thesaurus) 
DBR 
Database Review 
DMP 
Data Management Plan 
DVP 
Data Validation Plan 
ED 
Exposure Day 
EDC 
Electronic Data Capture 
EOT 
End of Trial 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FVIII 
Coagulation Factor VIII 
FVIII:C 
Factor VIII-coagulant 


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Abbreviation 
Description 
HJHS 
Hemophilia Joint Health Score 
ICF 
Informed Consent Form 
ID 
Identifier 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IU 
International Unit 
IV 
Intravenous 
IVR 
Incremental in Vivo Recovery 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
N 
Number of Subjects/Observations 
OS 
One-stage assay 
PK 
Pharmacokinetic 
POP 
Postoperative 
PP 
Per-Protocol 
PT 
Preferred Term 
PTP 
Previously Treated Subject 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software package 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SABR 
Spontaneous Annualized Bleeding Rate 
SURG 
Surgery analysis set 


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Abbreviation 
Description 
T1/2 
In Vivo Half-Life 
TABR 
Total Annualized Bleeding Rate 
TEAE 
Treatment Emergent Adverse Event 
TLFs 
Tables, Listings, Figures 
Tmax 
Time to Reach Maximum Plasma Concentration 
TS 
Trial Statistician 
Vd 
Volume of distribution 
VWD 
Von Willebrand Disease 
VWF 
Von Willebrand Factor 
VWF:Ac 
VWF activity 
VWF:Ag 
Von Willebrand Factor Antigen 
WHO 
World Health Organization 


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1 STUDY MATERIAL 
The following material was considered for this SAP: 
 
Document 
Version, Date 
Protocol 
Version 1.0, 2017-04-26 
CRF 
TBD 
DMP 
TBD 
DVP 
TBD 
 
 
2 STUDY INFORMATION 
2.1 Primary objective 
The primary objective of this study is to determine the FVIII:C pharmacokinetics (PK) for 
Wilate in previously treated patients (PTP) with severe hemophilia A aged 1 to <12 years. 
 
2.2 Secondary objective 
The secondary objectives of this study are to: 
• Determine the efficacy of Wilate in prophylactic treatment 
• Determine the efficacy of Wilate in the treatment of breakthrough bleeding episodes 
(BEs) 
• Calculate the FVIII:C incremental IVR of Wilate over time (at baseline, and at 3 and 6 
months of treatment) 
• Assess the association between AB0 blood type and the FVIII:C half-life of Wilate 
• Assess the association between the VWF:Ag concentration and the FVIII:C half-life of 
Wilate 
• Assess the safety and tolerability of Wilate 
• Assess the immunogenicity of Wilate 
 
2.3 Additional Objective: 
An additional objective of this study is the descriptive efficacy of Wilate in surgical prophylaxis. 


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2.4 Study design 
This study is designed as a prospective, non-controlled, international, multi-center phase 3 
study. Further details are given in the overview below: 
 
FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
 
Screen 
ing 
Visit 
PK 
Visit 
Prophylactic Treatment Phase 
(starts with first prophylactic injection of 
Wilate 
after the PK Visit) 
Follow-up 
Contact 
30 (±3) days 
after 
Study Com- 
pletion 
Visit 
Day-14 
Visit 
(14–21 
days) 
Day-30 
Visit 
(±3 
days) 
3-Month 
Visit 
(±2 
weeks) 
Study 
Completion 
(6-Month) 
Visit 
at 6 months 
(+2 weeks) 
Informed consent 
x 
Inclusion and exclusion criteria 
x 
Demographics 
x 
Weight 
x 
x [1] 
x [1] 
x [1] 
Height 
x 
Medical history (incl. FVIII treatment 6 months 
before screening) 
x 
Vital signs 
x 
x [2] 
x [4] 
x [4] 
Physical examination 
x 
x 
Routine safety laboratory 
x 
x [3] 
x [1] 
x [4] 
Determination of CD4+ levels [8] 
x 
Determination of AB0 blood group [9] 
x 
HJHS, unless obtained within 3 months be- 
fore screening 
x 
PK injection (50 ± 5 IU/kg) 
x 
Blood sampling for FVIII:C (OS and CHR) for 
PK assessment 
x [5] 
IVR injection 
x 
x 
Blood sampling for FVIII:C IVR (OS and 
CHR) 
x [6] 
x [6] 
Factor VIII inhibitor [10] 
x 
x [1] 
x [1] 
x [1] 
x [1] 
x [1] 
VWF:Ag and VWF:Ac 
x [6] 
x [1] 
x [1] 
x [6] 
x [6] 
Parvovirus B19 antibodies 
x [1] 
x [7] 
Retention sample for possible virus marker 
testing 
x [1] 
Patient diary review 
x 
x 
x 
x 
Adverse event monitoring 
x 
» 
» 
» 
x 
x [11] 
Concomitant medications 
x 
» 
» 
» 
» 
x 
PK = pharmacokinetic, IVR = in vivo recovery, HJHS = Hemophilia Joint Health Score, OS = one-stage assay, CHR = chromo- 
genic assay, VWF:Ag = von Willebrand factor antigen, VWF:Ac = VWF activity 


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LEGEND TO THE FLOW CHART FOR PK ASSESSMENT AND PROPHYLACTIC TREATMENT 
[1] 
Before injection 
[2] 
Before injection as well as 1 h (±5 min) and 48±2 h after injection 
[3] 
Before injection as well as 48±2 h after injection [local laboratory] 
[4] 
Before injection as well as 15±5 min after injection 
[5] 
Blood sampling within 1 h before injection and 15±5 min, 1 h (±5 min), 6 h (±30 min), 9±1 h, 24±2 h, and 48±2 h after 
the end of injection [central laboratory] 
[6] 
Blood sampling within 1 h before injection as well as 15±5 min after the end of injection [central laboratory] 
[7] 
If first sample was negative for parvovirus B19 antibodies (sample to be taken before injection) [central laboratory] 
[8] 
CD4+ count to be repeated if interval between Screening Visit and first injection exceeds 30 days. To be included into 
the study, the patient’s CD4+ count must be >200/µL (i.e., inclusion criterion no. 4). 
[9] 
Unless obtainable from patient’s medical history 
[10] Blood sampling for inhibitor testing should preferably be done at the time of trough FVIII:C levels [central laboratory] 
In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample should be performed, 
preferably within 15 days of becoming aware of the positive result. 
[11] Documentation of any thromboembolic events only (to be documented on AE page) 


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FLOW CHART OF ASSESSMENTS FOR SURGICAL PROPHYLAXIS 
 
Within 
12 hours 
before 
start 
Within 
3 hours 
before 
start 
Surgery 
POP 
day 1 
Any 
POP 
day 
End of 
POP 
period 
3-8 
weeks 
after 
surgery 
Intra- 
opera- 
tively 
End 
[1] 
Body weight 
x 
Type of surgery 
x 
Location of surgery 
x 
Severity of surgery 
x 
Expected duration of surgery 
x 
Expected average/ maximum blood 
loss during surgery 
x 
Actual duration of surgery 
x 
Actual blood loss during surgery 
x 
Administration of IMP 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
FVIII plasma levels 
# 
(#) 
(#) 
# [2] 
# 
# 
VWF:Ag and VWF:Ac 
# 
# [2] 
# 
# 
Presence of wound hematomas 
x 
x 
x 
Routine safety laboratory 
x 
(x) 
(x) 
(x) 
Vital signs 
x 
x 
x 
Efficacy assessment 
S 
H 
Overall efficacy assessment 
I 
Factor VIII inhibitor [3] 
x 
Narrative of outcome 
x 
Concomitant medications 
throughout observation period 
Adverse event monitoring 
throughout observation period 
 
POP = postoperative, VWF:Ag = von Willebrand factor antigen, VWF:Ac = VWF activity 
( ) Optional 
# Samples to be taken immediately before (≤ 30 min) and 30±15 min after IMP administration 
[1] Time immediately after the last surgical suture 
[2] For major surgeries, mandatory for the first 3 postoperative doses 
[3] In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample should be performed, prefer- 
ably within 15 days of becoming aware of the positive result. 
S, performed by surgeon; H, performed by hematologist; I performed by Investigator 
 
 
2.5 Planned sample size 
Overall, 10 PTPs (5 patients aged 1 to <6 years of age and 5 patients aged 6 to <12 years) will 
be enrolled into this study. The aim is to obtain evaluable data on 8 patients who complete 
both the 2-day PK Phase and the 6-month Prophylactic Treatment Phase. Of the 8 evaluable 
patients, 4 patients must be 1 to <6 years of age, and another 4 patients must be 6 to <12 
years of age. Enrolled patients will be replaced only if they do not complete the PK assess- 
ment. 
The sample size of 10 pediatric patients to be enrolled was based on medical and regulatory 
reasoning. No statistical sample size estimation was performed. 


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3 GENERAL INFORMATION 
3.1 Background details 
The data will be transferred to SAS from the Clinical Data Management System OPVERDI 
via a validated procedure. If applicable, external data will also be transferred to SAS for 
presentation of these data in the statistical analyses. 
 
3.2 Deviations from the trial protocol with regard to statistical analyses 
No deviations from the protocol are planned. 
 
3.3 Individual protocol deviations 
Any deviation from protocol will be discussed case by case before database lock whether the 
deviation has to be regarded as minor or as major (and therefore will lead to exclusion from 
particular analysis populations). 
Examples for minor protocol violations may be deviations from scheduled investigation time. 
Criteria for major protocol violations will at least include: 
• Any substantial violation of in- or exclusion criteria. 
• Use of concomitant medication that may interfere with the assessment of efficacy. 
The final decision about the classification of individual protocol deviations and their conse- 
quences regarding assignment of subjects to analysis sets will be made during the data review 
meeting (DBR). A complete listing of protocol deviations and the judgment for assessment 
of subject disposition will be approved by the Sponsor and signed before database lock. All 
deviations along with the disposition of each subject will be recorded in a separate database 
member that will become part of the study database. A description of all major protocol 
violations will be included in the table part of the CSR. 
 
4 ANALYSIS POPULATIONS 
The disposition of subjects will be displayed according to the following analysis populations: 
• Safety (SAF) set 
• Full Analysis set (FAS) 
• Pharmacokinetic (PK) set 
• Per-Protocol (PP) set 
• Surgery (SURG) set 


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4.1 Safety set 
The safety (SAF) set will include all subjects who received at least one infusion of IMP. 
4.2 Full analysis set 
The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle will 
include all enrolled subjects who received at least one infusion of IMP (after the initial PK 
visit). 
4.3 Pharmacokinetic set 
The pharmacokinetic (PK) set will include all patients for which a valid Wilate PK profile 
has been obtained. 
4.4 Per-protocol set 
The per-protocol (PP) set, i.e. a subset of the FAS, will exclude subjects with major protocol 
deviations which may have an impact on the evaluation of the primary study outcome param- 
eter (major protocol deviations as defined during DBR). 
4.5 Surgery set 
The surgery (SURG) set will be a subset of the FAS, containing all subjects who underwent 
a surgical procedure treated with Wilate during their Prophylactic Treatment Phase. 
4.6 Subgroup analyses 
The analyses of the PK parameters and the efficacy endpoints ‘efficacy of prophylactic treat- 
ment’ and ‘efficacy in treatment of breakthrough BEs’ will be presented by age groups (‘1 to 
<6 years’ and ‘6 to <12 years’). 
 
Efficacy analysis of secondary endpoint “efficacy of Wilate in the treatment of breakthrough 
(BEs) will be stratified by the following subgroups: 
• Treatment-emergent bleeding episodes treated according to protocol (‘BLEEDPP’) 
• Treatment-emergent bleeding episodes not treated according to protocol (‘BLEED’) 
 
All bleeding events, which have not been treated with IMP or treatment significantly deviates 
from recommended treatment will be excluded from ‘BLEED PP’. 
Treatment with less than 25% of the lowest or more than 40% of the highest recommended 
dose in more than 50% of infusions administered for the corresponding event is considered as 
significant deviation. 
 
 
5 STATISTICAL ANALYSES 
All statistical analyses will be performed using SAS® for Windows (Version 9.3 or later). 
Descriptive statistics will always be given for the entire population. 


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The analysis of safety will be based on the SAF set. 
Analysis of the PK properties of Wilate will be based on the PK set. 
For secondary endpoints, FAS and PP analyses will be carried out, unless these analysis sets 
differ by no more than 1 patient from the FAS. 
Analysis of the efficacy and safety of Wilate in surgeries will be based on the SURG set. 
If not stated otherwise the following standard descriptive statistics will be presented: 
 
Descriptive statistics for continuous data 
Number of subjects (N), arithmetic mean, standard deviation (SD), minimum, lower quartile, 
median, upper quartile and maximum will be presented. Usually mean and quartiles will have 
1 decimal more, SD 2 decimals more than the original values (as given with min, max); N has 
no decimals. These descriptive statistics will be determined for measured values and for dif- 
ferences to baseline. 
Descriptive statistics for categorical data 
Absolute frequencies (N) will be presented with 0, relative frequencies (%) with 1 decimal. 
For changes from baseline, shift tables may be generated. 
Inferential statistics 
If not stated otherwise all statistical tests will be performed as described in the corresponding 
sections below. 
All p-values will be rounded to 4 decimals (p<0.0001 will be displayed, if the p-values are less 
than 0.0001). Statistical significance will be declared if the rounded p-value will be less than 
0.05. 
All confidence intervals (CI) will be derived two-sided and at a confidence probability of 1-
α = 0.95. 
Listings 
All subject data will be listed by subject. Identification variable will be the subject ID (com- 
posed of study, center and subject number separated by a hyphen, e.g. ’30-01-01’. Any derived 
data listed will also be stored permanently and will be calculated as outlined in section 8.1 of 
this SAP. 
 
5.1 Conventions 
5.1.1 Baseline definition 
Assessments at PK visit or at screening visit (in case the corresponding assessment is not 
scheduled at PK visit) are considered as baseline. 


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5.1.2 Missing data 
In case of missing weight documentation data will be imputed using the Last Observation 
Carried Forward (LOCF) approach to calculate the dose per kg body weight (IU/kg). For 
calculation of PK parameters, missing measurements on a subject's PK profile will be han- 
dled according to the algorithms included in the PK software WinNonlin (version 7.0). 
No further imputations for missing data will be performed. 
Calculations pertaining to the derivation of annual bleeding rates will be based on docu- 
mented time periods only. 
 
5.1.3 Pooling of centers 
All tables will be presented in total over all participating countries and centers. The distribu- 
tion of number of subjects per country and center will be presented in the disposition section 
of the report. 
 
5.2 Demographic and other background data 
5.2.1 Basic description 
The disposition of subjects (cf. Section 4) will be tabulated for the entire population. Details 
on protocol deviations will be listed. 
Discontinued subjects will be described by frequency distributions including the reasons and 
in individual listings. 
Demographic data (age, weight, height, BMI, race, ethnic group) will be summarized in tables 
and presented for the SAF and FAS population. Other baseline or background data, e.g. dis- 
ease-specific information, will comprise descriptive tables for the SAF and FAS population 
for the following variables: 
• Blood group 
• Last CD4+ level before enrolment 
• VWF:Ag, VWF:Ac levels at PK visit 
• FVIII inhibitor level 
• Vital Signs (Systolic and diastolic blood pressure, pulse and body temperature) at 
screening 
• Physical examination (normal/abnormal) at screening 
• Hemophilia joint health score (HJHS) at screening 
• Results of Parvovirus B19 antibodies at PK visit 
The following background data will only be listed: 


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• Medical history (including FVIII treatment during the last 6 months before screening) 
• Concomitant Medication 
 
5.3 IMP exposure, compliance 
Treatment will be administered prophylactically as defined in the protocol. Each home treat- 
ment will be recorded in the diary along with the reason for treatment (prophylaxis, bleeding, 
prevention of recurrent bleeding, prophylaxis after surgery or other reason). Treatments in 
context of IVR and PK measurements and surgeries will be documented in the patients notes. 
All treatments, from diary or patient’s notes, will be transferred into the eCRF. 
All IMP treatment details will be listed. 
 
5.4 Medical history 
Data on medical history will be listed. Medical history will be coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Codes will be reviewed by a Medical Expert 
and approved by the sponsor before data base lock. 
 
5.5 Concomitant medication 
Any relevant medication taken at time of screening and all new medications taken by the sub- 
ject during the study period are defined as ‘Concomitant’. Any changes of medications during 
the study period will also be recorded. 
All details of concomitant medications will be listed including, the route, dose, frequency, start 
and stop date and indication. 
Medications will be coded using the WHO DD thesaurus in the version current at the time of 
database lock. Coding will be performed by the CRO and agreed upon with the sponsor before 
data base lock. (cf. DMP). For concomitant medications tables will show the frequencies of 
subjects by WHO DD preferred term. 
 
5.6 Concomitant non-pharmacological measures, pre-medication 
Not applicable. 
 
5.7 PK and Efficacy 
5.7.1 Pharmacokinetics 
The primary objective of this study is the analysis of the PK profile of Wilate (refer to section 5.8). 


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5.7.2 Efficacy 
All efficacy variables will be analyzed based on the FAS and additionally on the PP set, unless 
these analysis sets are identical. 
Efficacy endpoints are: 
• Efficacy of prophylactic treatment with Wilate based on the total annualized bleeding 
rate (TABR) as well as the spontaneous annualized bleeding rate (SABR) 
• Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of 
BEs successfully treated with Wilate (successfully includes efficacy ratings assessed as 
either ‘excellent’ or ‘good’) 
• Wilate consumption data (FVIII IU/kg per week and per month per subject) for 
prophylaxis 
• Incremental IVR of Wilate over time (at baseline, and at 3 and 6 months of treat- 
ment) (refer to section 5.8) 
 
Efficacy of Prophylactic Treatment with Wilate 
The analysis of the efficacy of prophylactic treatment with Wilate will be statistically evaluated 
by presenting descriptive sampling statistics for the TABR and SABR, along with an explor- 
atory 95% CI for the mean. TABR and SABR will be calculated as the total number of BEs 
or total number of spontaneous BEs, respectively, in the time period between first dose of 
IMP and the study completion visit, divided by the duration (in years) between first dose of 
IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, 
will be excluded from the calculation of annual bleeding rates 
 
Efficacy in the Treatment of Breakthrough BEs 
To assess the hemostatic efficacy of Wilate in the treatment of breakthrough bleedings, a fre- 
quency distribution of all such BEs being successfully treated will be presented, along with an 
exploratory 95% CI. 
 
Primarily, all obtained data on treatment characteristics (IMP dosages, frequencies, total con- 
sumption) and BEs (duration, frequency, efficacy assessment) will be described by providing 
summary statistics. 
In general, the efficacy of bleeding episodes will also be presented by type (spontaneous, trau- 
matic, postoperative, other), sites (nose, oral cavity, knee, ankle, elbow, arm, leg, intestinal and 
other. In addition, knee, ankle and elbow sites will be summarized as site ‘joint’) and severity 
(minor, moderate, major, life-threatening). 


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Analysis of Other Secondary Endpoints 
The statistical analysis of other secondary endpoints will be descriptive, including exploratory 
95% CIs for the location parameters. 
 
5.7.3 Exploratory Endpoint 
An exploratory endpoint of this study is the descriptive efficacy of Wilate in surgical prophy- 
laxis (for details see section 5.9 ). 
 
5.8 Pharmacokinetics / Pharmacodynamics 
For Pharmacokinetics and IVR assessments FVIII:C will be measured by both, the chromo- 
genic (CHR) and one-stage assay (OS) and analyzed based on actual IMP potency (refer to 
section 8.1). 
 
The PK profiles of Wilate and the PK parameters derived from them will be summarized by 
descriptive statistics as well as the presentation of concentration vs. time plots based on the 
PK set. In the analysis of the PK profiles geometric means and standard deviations will be 
presented in addition to the arithmetic means and standard deviations. 
The following PK parameter will be derived and presented using a non-compartment model: 
• Area under the curve (AUC) and AUC normalized for the administered dose (AUCnorm) 
• FVIII in vivo half-life (T1/2) 
• Maximum plasma concentration (Cmax) 
• Time to reach maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 
• Volume of distribution (Vd) 
• Clearance (CL) 
• Incremental in vivo recovery (IVR) 
Analysis of variance (ANOVA) will be used in an exploratory sense to assess a possible asso- 
ciation between AB0 blood type, VWF:Ag, and the FVIII:C half-life of Wilate. 
Incremental IVR will be calculated from FVIII:C plasma levels measured before injection and 
peak levels obtained in the 15-min post-injection sample using actual IMP potencies. The 
results of the IVR assessments over time will be analyzed in summary tables for each time 
point and their differences to baseline along with 95% CIs for the mean differences. 
 
5.9 Surgeries 
Efficacy in surgical prophylaxis will be analyzed descriptively, presenting summary tables and 
listing on all aspects of surgical treatment and procedures as well as efficacy ratings. 


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The following surgery-related parameters will be presented: 
• Number of minor and major surgeries 
• Location, severity (minor or major, for definitions see protocol), and type (planned or 
emergency) of surgery 
• Expected and actual duration of surgical procedure 
• Expected and actual blood loss 
• Pre-, intra-, and/or postoperative IMP administration data (only listed) 
• Pre-, intra-, and postoperative FVIII plasma levels (only listed) 
• VWF:Ag and VWF:Ac (descriptive statistics including changes to pre-infusion) 
• Frequency and amount of blood transfusion requirements 
• Presence of wound hematomas and whether or not they require surgical evacuation 
(only listed) 
• Assessment of efficacy of surgical prophylaxis: 
1. at the end of surgery by the surgeon 
2. at end of the postoperative period by the hematologist 
3. Overall efficacy taking both the intra- and postoperative assessments into ac- 
count assessed by the Investigator. 
• Number of successively treated surgeries (‘excellent’ or ‘good’ overall efficacy rating) 
• Concomitantly administered products (only listed) 
• Narrative describing the outcome and efficacy of the intervention (only listed) 
• Inhibitor testing (within 3–8 weeks after the end of the surgery, this visit may coin- 
cide with another study visit with scheduled inhibitor testing) 
 
5.10 Safety 
All safety analyses will be based on the SAF population. 
The analysis of safety will include the occurrence of AEs, the results of the safety laboratory 
tests, immunogenicity measurements and the occurrence of parvovirus B19 seroconversions. 
 
5.10.1 Adverse events 
Adverse events (AEs) will be coded by the CRO according to the latest Medical Dictionary 
for Regulatory Activities (MedDRA). Coding will be agreed upon with the Sponsor before 
database lock (cf. DMP). 
All adverse events recorded since signing of the informed consent form (ICF) will be listed in 
appendix 16.2 of the report differentiating by treatment emergent and non-treatment emergent 
events. This includes also post-study serious adverse events (SAEs) which occurred up to 4 


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weeks after the last IMP administration (not monitored proactively), thromboembolic events 
monitored proactively by performing a Follow-up Contact 30 days after the completion visit 
as well as safety relevant information on drug overdosing, drug interactions and medication 
errors. 
The analysis will include only treatment-emergent adverse events (TEAEs), i.e. all docu- 
mented AEs that started or worsened after the start of IMP infusion. It is assumed that for 
each increase in intensity of an AE a new entry of the AE will be done by the investigator; 
hence such cases will be analyzed like different phases of the same AE. 
A descriptive analysis will be performed. Incidences will be presented by primary system or- 
gan classes (SOC) and incidences of PT within primary SOC sorted according to the Interna- 
tionally Agreed Order. 
Multiple counts within a PT or SOC (repeated or different included terms or changes in de- 
scriptors) will be counted only once for the calculation of incidences. 
Global incidences will be calculated for: 
• All TEAE irrespective of the causality assessment 
• Related TEAEs (‘Probably’ or ‘Possible’) 
• TEAEs by worst severity 
• Serious TEAEs 
A listing of "special cases" containing subject identification, age, sex, AE descriptors, start 
and end of treatment will be prepared for the following types of TEAEs: 
• Serious adverse events (SAE) 
• Adverse events which led to death 
• Adverse events which led to discontinuation 
Serious non-treatment emergent AEs will be listed separately. 
 
5.10.2 Vital signs 
Vital signs parameters (systolic/diastolic blood pressure, pulse, body weight, respiratory rates, 
body temperature) will be assessed at screening, PK visit, after 3 months at study completion 
visits and during surgery. 
Descriptive analyses of values will be performed and changes from baseline will be analyzed 
for vital signs parameters at visits. 


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5.10.3 Safety laboratory variables 
The analysis of the safety parameters (lab values for Hematology and Clinical chemistry) rec- 
orded during visits (screening, PK visit, 3-month and study completion visits) and at surgery 
will be purely descriptive and presented as summary tables or listings. 
Time profiles of the safety laboratory parameters will be analyzed by presenting sampling sta- 
tistics for the values as well as their difference to baseline at each time point. Additionally, 
frequency tables for values outside the normal ranges will be presented. 
Similarly, time profiles of FVIII inhibitor testing results will be analyzed by presenting sam- 
pling statistics for the values as well as frequency tables for positive findings, along with 95% 
Pearson-Clopper CIs. 
The thromboembolic risk will be monitored by determination of VWF:Ag and VWF:Ac dur- 
ing the study and especially postoperatively. Descriptive statistics including changes to pre- 
infusion will be presented by visit and timepoint (with 95% CI) for visits or by operative day 
and timepoint for surgeries, respectively. 
To assess the viral safety of Wilate incidences of parvovirus B19 seroconversions between 
baseline and end of study will be estimated along with 95% Pearson-Clopper CIs. 
 
5.10.4 Other safety variables 
Other safety parameters (e.g., changes in physical examination findings) will be analyzed by 
summary tables or listings. All abnormal findings from the physical examination will be listed. 
The analysis of the safety parameters recorded during surgery (lab values) will be purely de- 
scriptive and presented as summary tables or listings. 
 
5.11 Other variables 
Not applicable. 
 
5.12 Interim analyses 
Not applicable. 
 
6 QUALITY CONTROL 
The responsible project manager will review the SAP before it is provided to the Sponsor for 
review. The SAP will be signed off only when approval from the Sponsor's representative is 
received. 


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Log files of all SAS® programs needed for analysis will be checked for errors, warnings and 
suspicious notes by the statistical programmer. All findings will be either eliminated or com- 
mented upon. The final version of each program will be stored along with its log file in the 
electronic archive. 
All programs will be validated by the author. 
The agreement of the program outputs with the SAP, their consistency and plausibility will 
be checked by the TS. Moreover, the TS will review the outputs regarding completeness, 
readability and comprehensibility. 
 
7 REFERENCES 
No specific references were used. 
 
8 APPENDICES 
8.1 Formulas for derived variables 
 
Variable 
Description 
Actual potency 
Potency of IMP (IU) based on central laboratory measurements of 
FVIII content by two assay methods: CHR (chromogenic) and OS 
(one-stage). 
The analysis of PK and IVR assessment will be based on actual poten- 
cies 
Durations 
be- 
tween two dates 
Later date minus earlier date plus 1, expressed in days. (Remark: Du- 
ration will be 1, if both dates are the same.) 
Spontaneous an- 
nualized bleeding 
rate (SABR) 
Number of spontaneous bleedings (excluding bleedings occurring in 
surgery periods) between first dose of IMP and Study Completion visit 
(or last dose of IMP in case completion visit not performed) 
/ time under prophylaxis (days)/365.25 (see prophylactic treatment 
phase) 
Total annualized 
bleeding 
rate 
(TABR) 
Number of bleedings (excluding bleedings occurring in surgery peri- 
ods) between first dose of IMP and Study Completion visit (or last 
dose of IMP in case completion visit not performed 
/ time under prophylaxis (days)/365.25 (see prophylactic treatment 
phase) 
Surgery Phase 
Last treatment for surgery – first treatment for surgery + 1 
Prophylactic 
treatment phase 
Date of completion visit or date of last treatment with IMP in case 
completion visit not performed) – (date of first prophylactic treatment 
after the PK visit) + 1 – Surgery phases 
Time in study 
Date of study completion – date of screening +1 


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Variable 
Description 
Time under treat- 
ment 
Date of last treatment – date of first treatment + 1 (average drug con- 
sumption data will be calculated relative to time under treatment) 
AUC 
Area under the curve from baseline to infinity 
AUC = ∑ (Cn + Cn+1 ) ⋅ ∆t  + Clast 
 
 
 
 
 
2 
 
K 
(Clast is the last available measurement) 
AUCnorm 
AUC normalized for the administered dose 
AUMC 
Area under the moment curve (from baseline to infinity) 
AUMC = ∑ (tn ⋅ Cn + tn+1Cn+1 ) ⋅ ∆t  + Clast + tlast ⋅ Clast 
 
 
 
 
 
 
2 
 
K 2 
K 
CL 
Clearance 
CL =  D 
AUC 
where D is the actual dose administered (see remark above) 
C0 
FVIII concentration before IPM administration 
Cmax 
Maximal measured concentration after end of IMP infusion (peak con- 
centration) 
ED 
Exposure day = each calendar day the subject received IMP 
Incremental re- 
covery (IVR) 
IVR = (Cmax  − C0 ) ⋅ BW 
D 
where BW stands for the body weight in kg and D is the dose accord- 
ing to the actual potency of the FVIII concentrate as described in 
above 
Labelled potency 
Potency of IMP (IU) based on label of vial (IU). 
Dosing analyses will be based on labelled potency 
MRT 
Mean residence time 
MRT = AUMC 
AUC 
Success (for 
bleeding epi- 
sodes and sur- 
geries) 
Excellent or good efficacy rating 


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Variable 
Description 
T1/2 
In vivo half-life 
using linear regression on the terminal phase of the logarithm of the 
concentration; 
T 
= ln(2) 
1 
2 
K 
(where K, the elimination rate constant, is determined as the slope of 
the regression line) 
Tmax 
Time to reach maximum plasma concentration (Timing starts at end 
of infusion) 
Vd 
Volume of distribution 
Vd = CL ⋅ MRT 
 
 
8.2 Algorithm for the Overall Efficacy Assessment for Surgical Prophylaxis 
The evaluation of overall efficacy of the treatment in surgeries based on the intraoperative 
and postoperative assessment is defined as described below: 
 
Intraoperative 
assessment 
Postoperative assessment 
Excellent 
Good 
Moderate 
None 
Excellent 
Excellent 
Good 
Good 
Moderate 
Good 
Good 
Good 
Moderate 
Moderate 
Moderate 
Good 
Moderate 
Moderate 
None 
None 
Good 
Moderate 
None 
None 


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8.3 List of Tables, Listings, Figures 
A complete lists of tables, listings figures (TLFs) will be given in a separate document which 
can be updated without updating the SAP. The list will serve as a reference for both the 
Sponsor, the trial statistician and the statistical programmer and includes the totality of statis- 
tical output to be produced. Therefore, this list will be approved by both parties before com- 
mencing the statistical programming. 
All output will be headed with an appropriate heading specifying the study ID and abbreviated 
study title. 
All output will be dated and have page numbers in the form 'Page [x / y]' where x denotes 
the current page within an output and y the total number of pages of that output. 
All statistical output will identify the underlying analysis populations and indicate the number 
of subjects / events in this population (N) and the number of subject/events actually con- 
tributing to the particular output (n). All statistical output will be presented per treatment 
group and in total (if applicable). 
All subject listings will contain additionally to the subject identification the analysis population 
and the treatment group.