Prospective, Open-label, Multi-centre Phase 3b Study to Assess the Efficacy and Safety of Personalized Prophylaxis With Human-cl rhFVIII in Previously Treated Adult Patients With Severe Haemophilia A
Phase: PHASE3
Conditions: Severe Haemophilia A
Sponsor: Octapharma

Human-cl rhFVIII 
Study Protocol No. GENA-21b 
 
This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
 
 
 
 
Prospective, open-label, multicentre phase 3b study 
to assess the efficacy and safety of personalized prophylaxis with 
Human-cl rhFVIII in previously treated adult patients 
with severe haemophilia A 
 
Investigational Product: 
Human-cl rhFVIII 
Indication: 
Severe haemophilia A 
Study Design: 
Prospective, open-label, multicentre study 
Sponsor: 
Octapharma AG 
Seidenstrasse 2, 8853 Lachen, Switzerland 
Study Number: 
GENA-21b 
IND Number: 
BB-IND 13722 
EudraCT Number: 
2014-002986-30 
Development Phase: 
3b 
Clinical Start: 
2nd Quarter 2015 
Planned Clinical End: 
3rd Quarter 2018 
4th Quarter 2020 (for “Sub-Study Extension 
Phase” in Japan) 
Date of Protocol: 
Original Protocol Version 01 
Amended Protocol Version 02 
Amended Protocol Version 03 
Amended Protocol Version 04 
Amended Protocol Version 05 
Amended Protocol Version 06 
Amended Protocol Version 07 
Amended Protocol Version 08 
Amended Protocol Version 09 
Amended Protocol Version 10 
July 30, 2014 
March 30, 2015 (France only) 
June 23, 2015 (all countries except France) 
June 23, 2015 (France only) 
October 26, 2015 
April 4, 2016 (Japan only) 
May 19, 2016 (Japan only) 
February 15, 2017 (Japan only) 
June 7, 2017 (Japan only) 
July 24, 2019 (Japan only) 
Version: 
10 
Co-ordinating Investigators: 
Craig M. Kessler, MD 
Georgetown University 
Medical Center 
Washington, DC, USA 
Midori Shima, MD 
Nara Medical 
University 
Nara, Japan 
 
 
090-CSP-GENA-21b-Version 10/DOC ID 3008 
CLINICAL STUDY PROTOCOL 

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STUDY OUTLINE 
 
Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
Title of Study: Prospective, open-label, multicentre phase 3b study to assess the efficacy 
and safety of personalized prophylaxis with Human-cl rhFVIII in previously treated adult 
patients with severe haemophilia A 
Indication: Haemophilia A 
Number of Study Centre(s): Approximately 30 centres worldwide 
Study Duration: 2nd Quarter 2015 to 3rd Quarter 2018 
2nd Quarter 2017 to 4th Quarter 2020 for “Sub-Study 
Extension Phase” in Japan 
Development Phase: 3b 
Objectives 
Primary Objective 
• To compare the annualised total bleeding rate of individually tailored prophylaxis 
with the historical bleeding rate observed in patients having received on-demand 
treatment with Human-cl rhFVIII from study GENA-01 
Secondary Objectives 
1. To compare the annualised spontaneous bleeding rate of individually tailored 
prophylaxis with the historical bleeding rate observed in patients having received 
on-demand treatment with Human-cl rhFVIII 
2. To compare the annualised total bleeding rate in patients with 2x/week (or less) 
prophylaxis with the historical bleeding rate observed in patients having received 
on-demand treatment with Human-cl rhFVIII 
3. To assess the median prophylactic dosing interval 
4. To assess the PK of Human-cl rhFVIII in terms of FVIII:C 
5. To assess the safety of Human-cl rhFVIII 

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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
Additional Objectives 
1. To assess the efficacy of Human-cl rhFVIII in the treatment of breakthrough 
bleeding episodes (BEs) 
2. To assess the efficacy of Human-cl rhFVIII in surgical prophylaxis 
3. To assess the correlation of VWF antigen concentration and half-life of Human-cl 
rhFVIII 
4. To assess the association between ABO blood type and half-life of Human-cl 
rhFVIII 
5. To assess Human-cl rhFVIII consumption data (exploratory) 
Objectives of the “Sub-Study Extension Phase” to GENA-21b (Japan) 
1. To investigate the long-term safety of Human-cl rhFVIII in patients with severe 
haemophilia A who participated in the GENA-21b study 
2. To assess the long-term efficacy of Human-cl rhFVIII during prophylactic 
treatment (based on the frequency of total and spontaneous break-through bleeds) 
3. To assess the efficacy of Human-cl rhFVIII during treatment of bleeding episodes 
(BEs) 
4. To assess the efficacy of Human-cl rhFVIII in surgical prophylaxis 
Study Design: Prospective, open-label, multicentre phase 3b study 
Number of Patients: Approximately 55 subjects (50 evaluable) of which the patients 
recruited in Japan (approx. 10 ) will continue in the “Sub-Study Extension Phase” 
Patient Selection Criteria 
Inclusion Criteria 
(a) Severe haemophilia A (FVIII:C < 1%) according to medical history 
(b) Male patients ≥ 18 years of age 
(c) Previous treatment with any FVIII product(s) (regular prophylaxis with good 
compliance or on-demand treatment) for at least 150 EDs 

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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
(d) Good documentation regarding dosing and bleeding frequency in the 6 months 
preceding study start 
(e) Immunocompetence (CD4+ count > 200/µL) 
(f) Freely given written informed consent 
Exclusion Criteria 
(a) Any coagulation disorder other than haemophilia A 
(b) Present or past FVIII inhibitor activity (≥ 0.6 BU) according to medical history 
(c) Severe liver or kidney disease (ALT and AST levels > 5 times of upper limit of 
normal, creatinine > 120 µmol/L) 
(d) Treatment with any investigational medicinal product (IMP) except FVIII IMP 
within 14 days prior to the screening visit 
Patient Selection Criteria for “Sub-Study Extension Phase” (Japan) 
Inclusion criteria: 
a) Patients who completed the GENA-21b study with 6 months of prophylactic 
treatment in Treatment Phase II 
b) Voluntarily given, fully informed written and signed consent obtained before any 
“Sub-Study Extension Phase”-related procedures are conducted 
Exclusion criteria: 
a) Other FVIII product than Human-cl rhFVIII was received between completion 
visit of GENA-21b study and start of “Sub-Study Extension Phase” (except 
emergency cases). 

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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
IMP and Mode of Administration 
Human-cl rhFVIII is a human cell line derived recombinant FVIII concentrate for 
intravenous use. Vials contain either 250, 500, 1000, 2000, 2500, 3000, or 
4000 international units (IU) of freeze-dried FVIII concentrate, each to be reconstituted 
in 2.5 mL water for injections. Human-cl rhFVIII should be injected intravenously by 
bolus injection at a maximum rate of 4 mL/min. Continuous infusion is prohibited. 
Dosing of the IMP 
Initial PK Evaluation (72 hours): 
60 ± 5 IU FVIII/kg, according to labelled potency 
Prophylactic Treatment—Phase I (1–3 months): 
Patients will be treated prophylactically every other day or 3x/week with a dose of 30–
40 IU/kg BW for about 1–3 months until PK data have been analysed and discussed 
with the investigator. Dose escalations are allowed in case of an inadequate frequency and 
severity of breakthrough bleeding episodes in accordance with the institution’s standard 
clinical care. 
The maximum dose for a single infusion in Prophylaxis Treatment Phase I is 45 IU/kg 
BW. 
Prophylactic Treatment—Phase II (6 months): 
Patients will be treated prophylactically for 6 months. Prophylactic doses and dosing 
intervals will be recommended by the Sponsor for each patient based on the analysis of 
individual PK data obtained at the Initial PK Visit with the one-stage assay. The final 
decision on the prophylactic scheme will be taken by the investigator after consultation 
with the patient and Sponsor. 
Based on an appropriate PK model, various dosing intervals (usually 12-hour intervals) 
and corresponding doses (in IU/kg) will be calculated, which hypothetically lead to 
FVIII:C plasma concentrations of at least 0.01 IU/mL at the end of the respective injection 
interval. 

Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
The goal is to use the maximum regular prophylactic dosing interval that can be achieved 
with a maximum dose of not more than 65 IU/kg and that maintains a trough level of 
≥ 0.01 IU/mL. 
This recommendation may change in certain situations. For example, 
• If the maximum calculated dosing interval is ≤ 2.5 days, the recommendation may 
be to continue with the dose and dosing interval as used in Prophylactic 
Treatment—Phase I, provided that this treatment scheme was considered effective 
by both the treating physician and the patient. 
• If the maximum calculated dosing interval is > 3.5 days and the dose > 65 IU/kg, the 
recommendation may be to reduce the dosing interval by 0.5 days and use the 
corresponding lower dose. 
• If the maximum calculated dosing interval is ≥ 4.5 days, the recommendation may 
be to reduce the dosing interval by 0.5 days and use the corresponding dose. 
In general, the recommendation will take into account both the interpretation of the PK 
data as well as practical and economic aspects (i.e., consumption of FVIII). The final 
decision on the prophylactic scheme will be taken by the investigator after consultation 
with the patient and Sponsor. 
At the 4-Month Visit in Prophylactic Treatment—Phase II, the dose per injection for the 
remainder of the study may be reduced provided that FVIII:C trough levels (one-stage 
assay) obtained at the 2-Month Visit were ≥ 0.01 IU/mL and the patient has not 
experienced any spontaneous bleed up to the 4-Month Visit. 
In case of unacceptable frequent and/or severe spontaneous breakthrough bleedings, the 
dose should be increased by approximately 5 IU/kg (depending on the entire content of 
vial(s) that needs to be reconstituted additionally). However, the maximum dose should 
not exceed 65 IU/kg. If, after a dose increase, patients still experience unacceptable 
bleeding episodes, the dosing interval should be shortened. 
Treatment of Bleeding Episodes 
The dosage and duration of treatment of spontaneous or traumatic breakthrough bleeding 
episodes (BEs) will depend on the location and extent of bleeding and on the clinical 
situation of the patient. 

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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
Surgical Prophylaxis 
The dosage and duration of treatment with Human-cl rhFVIII will depend on the type of 
surgery and the patient’s individual incremental recovery. 
“Sub-Study Extension Phase” to GENA-21b (Japan) 
Patients will continue to be treated prophylactically after the completion of 6 months in 
Treatment-Phase II in GENA-21b. Prophylactic doses and dosing intervals will remain the 
same in the “Sub-Study Extension Phase” as in the last 2 months of Prophylactic 
Treatment-Phase II. 
In case of unacceptable frequent and/or severe spontaneous breakthrough bleedings, the 
dose should be increased by approximately 5 IU/kg (depending on the entire content of 
vial(s) that needs to be reconstituted additionally). However, the maximum dose should 
not exceed 65 IU/kg. If, after a dose increase, patients still experience unacceptable 
bleeding episodes, the dosing interval should be shortened. 
In addition, if the body weight of the patient during follow up visits fluctuates +/- 10% 
compared to the screening visit of the “Sub-Study Extension Phase”, the investigator 
should verify if the dosing is still within the prescribed range and adapt accordingly, if 
necessary. 
Duration of Treatment: The study duration for each patient in GENA-21b will be 
approximately 7–9 months. 
The duration of the “Sub-Study Extension Phase” for each patient will be approximately 
between 2.5 and 3.5 years depending upon the completion date of the GENA-21b study. 
Reference Therapy, Dose, and Mode of Administration: Not applicable; this is an 
open-label uncontrolled study. 
Outcome Parameters 
Primary Endpoint 

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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
• 
Reduction of the annualised total bleeding rate* observed in the GENA-01 study 
(58.1 total bleeding episodes per patient per year) by 50% during individually 
tailored prophylaxis 
Secondary Endpoints 
1. Reduction of the annualised spontaneous bleeding rate* observed in the GENA-01 
study (38.5 spontaneous bleeding episodes per patient per year) by 50% during 
individually tailored prophylaxis 
2. Reduction of the annualised bleeding rate* observed in GENA-01 by 50% in 
patients with 2x/week prophylaxis or less 
3. Median prophylactic dosing interval during individually tailored prophylaxis 
4. Safety and tolerability of Human-cl rhFVIII by monitoring adverse events (AEs) 
throughout the study 
Additional Endpoints 
1. Descriptive efficacy of Human-cl rhFVIII in the treatment of breakthrough BEs 
2. Descriptive efficacy of Human-cl rhFVIII in surgical prophylaxis 
3. Correlation between VWF antigen concentration and half-life of Human-cl 
rhFVIII 
4. Association between ABO blood type and half-life of Human-cl rhFVIII 
5. Human-cl rhFVIII consumption data (FVIII IU/kg per month per patient) during 
individually tailored prophylaxis 
Study Endpoints of the “Sub-Study Extension Phase” (Japan) 
1. Safety of Human-cl rhFVIII by monitoring adverse events (AEs) and inhibitors 
against FVIII throughout the “Sub-Study Extension Phase” 
2. The efficacy of Human-cl rhFVIII under prophylactic treatment will be assessed 
descriptively for the patients included in the “Sub-Study Extension Phase” by 
 
 
 
 
 
* Total bleeding rate or bleeding rate refers to all types of bleeding (spontaneous, traumatic and other). A 
specific type of bleed is always described in text. 

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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
calculating the frequency of total and spontaneous break-through bleeds under 
individually tailored prophylaxis 
3. Descriptive efficacy of Human-cl rhFVIII in the treatment of breakthrough BEs 
4. Descriptive efficacy of Human-cl rhFVIII in surgical prophylaxis 

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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
Study Procedures 
Screening Visit 
The following assessments will be performed: 
• Informed consent 
• Eligibility criteria 
• Demographic data: age, ethnic origin and blood type (ABO) 
• Medical history 
• Body weight 
• Height 
• Physical examination 
• Vital signs (before blood sample collection) 
• Routine safety lab 
• CD4+ 
• Previous and concomitant medication (within one month before screening), 
including FVIII dosing in previous 6 months 
• Hemophilia Joint Health Score (HJHS) (HJHS evaluation done in the 3 months prior 
to screening is acceptable) 
• Target joint(s) (defined as three or more spontaneous bleeding episodes into a single 
joint within 6 consecutive months preceding screening visit) 
Eligible patients agreeing to enter the study 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. 
If possible, the Screening Visit may coincide with the Initial PK Visit. If it does not, any 
bleeding episodes occurring between the Screening Visit and the Initial PK Visit should 
be treated with the patient’s previously used FVIII product. Similarly, prophylactic 
treatment between the Screening Visit and the Initial PK Visit should be done with the 
patient’s previously used FVIII product. This has to be documented as concomitant 
medication in the diary and eCRF. 
Initial PK Visit 

Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
Patients meeting the study entry criteria will receive Human-cl rhFVIII at a dose of 
60 ± 5 IU/kg (labelled dose) after a washout period of at least 96 hours from their last 
FVIII injection. A washout period of at least 72 hours would be acceptable only if a 
patient is at a high risk of bleeding. Patients must not be experiencing any bleeding. The 
following assessments will be performed: 
• Blood samples will be taken for the following purposes and at the following time 
points: 
– FVIII:C plasma concentration (one-stage and chromogenic assays): before 
injection (within 1 h before injection) and 0.5 h (± 5 min), 1 h (± 5 min), 3 h 
(± 15 min), 6 h (± 30 min), 9 h (± 1 h), 24 h (± 2 h), 30 h (± 2 h), 48 h (± 2 h), 
and 72 h (± 2 h), after the end of injection 
– VWFAg plasma concentration: before injection 
– FVIII inhibitor: before injection 
• Body weight before injection 
• Vital signs before injection as well as 1 and 72 hours after the end of injection 
• Information in the patient diary (if applicable) will be reviewed by the 
Investigator. 
• IMP for home treatment will be given to patients. They will be re-supplied 
whenever necessary during the study. 
Prophylactic Treatment—Phase I 
The 72-hour sampling time point of the Initial PK Visit marks the beginning of 
Prophylactic Treatment—Phase I, in which patients will be treated prophylactically every 
other day or 3x/week with a dose of 30–40 IU/kg BW for about 1–3 months until PK data 
have been analysed and discussed with the investigator. Throughout Prophylactic 
Treatment—Phase I, visits will take place according to the following schedule: 
Day 14 Visit: will take place 14-21 days after the administration of the first dose of 
Human-cl rhFVIII on initial PK Visit day 1. 
Day 30 Visit: will take place 30 days (± 3 days) after the administration of the first dose 
of Human-cl rhFVIII on initial PK Visit day 1. 

Study Protocol 
No. GENA-21b 
CONFIDENTIAL 
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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
• Blood samples for the determination of FVIII inhibitor will be obtained at these 
visits. Blood draw for inhibitor testing should be performed, preferably, when 
FVIII level has reached baseline. 
End-of-Phase I Visit: At the end of Prophylactic Treatment—Phase I, the prophylactic 
dose and dosing interval will be determined for each patient based on the analysis of 
individual PK data as outlined in the dosing section. A blood sample will be taken for 
FVIII inhibitor testing during this visit, only if the End-of-Phase I Visit does not coincide 
with the Day 30 Visit. 
Prophylactic Treatment—Phase II 
Patients will be treated prophylactically for 6 months starting with the dose and dosing 
interval determined at the End-of-Phase I Visit. Extra prophylactic dosing prior to risky 
activities is permitted, but should be kept to a necessary minimum. Throughout 
Prophylactic Treatment—Phase II, visits will take place every 2 months. 
2- Month Visit in Phase II: The 2-Month Visit will take place 2 months (± 1 week) after 
the start of Prophylactic Treatment—Phase II. 
Note: To allow the patient’s true trough levels to be determined, patients should be 
advised to present for blood sampling at the end of a regular treatment interval, i.e., within 
3 hours before injection of the next scheduled dose. 
The following assessments will be performed: 
• Blood samples for the determination of FVIII:C trough levels (one-stage and 
chromogenic assays) and FVIII inhibitor will be obtained within 3 hours before 
injection of the next scheduled FVIII dose. Whenever an extra dose of FVIII has to 
be administered between scheduled prophylactic doses (e.g., for on-demand 
treatment of a bleeding episode), blood sampling for the determination of FVIII:C 
trough levels has to be delayed until the end of the next regular treatment interval. 
• Information in the patient diary will be reviewed by the Investigator. For this 
purpose, the patient diaries will be collected and the data from completed diary 
pages transcribed to the eCRF. 

Study Protocol 
No. GENA-21b 
CONFIDENTIAL 
Version 10 
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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
4- Month Visit in Phase II: The 4-Month Visit will take place 4 months (± 1 week) after 
the start of Prophylactic Treatment—Phase II and the same assessments will be done 
as at the 2-Month Visit in Phase II. 
The dose per injection may be reduced for the remainder of the study provided that FVIII:C 
trough levels (one-stage assay) obtained at the 2-Month Visit were ≥ 0.01 IU/mL and the 
patient has not experienced any spontaneous bleed up to the 4-Month Visit. 
Monthly Compliance Checks 
During Prophylactic Treatment—Phases I and II, monthly compliance checks (± 1 week) 
will be performed by telephone or during personal visits by the patient. The 1 month 
compliance check in Phase-I will be combined with the Day 30 Visit. During these 
checks, the investigator will determine whether the patient has adhered to the prescribed 
dose and dosing interval and whether the dose and dosing interval are adequate. 
Study Completion Visit 
The Study Completion Visit will take place 6 months (± 1 week) after the start of 
Prophylactic Treatment—Phase II 
The following assessments will be performed: 
• Blood samples will be taken: 
– FVIII:C plasma concentration (one-stage and chromogenic assays) for the 
determination of trough levels. Blood samples will again be obtained within 
3 hours before injection of the next scheduled FVIII dose. Whenever an extra 
dose of FVIII has to be administered between scheduled prophylactic doses 
(e.g., for on-demand treatment of a bleeding episode), blood sampling for the 
determination of FVIII:C trough levels has to be delayed until the end of the 
next regular treatment interval. The next scheduled FVIII dose will no longer 
be considered study treatment. 
– FVIII inhibitor 
• Physical examination 

Study Protocol 
No. GENA-21b 
CONFIDENTIAL 
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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
• Information in the patient diary will be reviewed by the Investigator. For this 
purpose, the patient diaries will be collected and the data from completed diary 
pages transcribed to the eCRF. 
• All used and unused IMP vials will be returned by the patient. 
Unscheduled visits 
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. Other reasons for unscheduled visits may be the occurrence of serious AEs or 
hospitalizations due to severe bleeding episodes or surgical interventions. 
Study Visits in the “Sub-Study Extension Phase” (Japan) 
Screening Visit 
Patients will be informed about the “Sub-Study Extension Phase” details and will be 
required to give a separate written informed consent before any investigations and any 
assessments can be performed. The screening visit should be performed in conjunction 
with the study completion visit of the GENA-21b study. The majority of data required will 
be available from the preceding GENA-21b completion visit, so that only the following 
information needs to be documented/assessed in addition: 
• Check of inclusion- and exclusion criteria 
• Body weight 
The Investigator will hand out a patient diary and instruct the patient how to document 
details of treatment with Human-cl rhFVIII, bleeds, AEs and concomitant medication. 
6-Monthly (± 2 weeks) Follow-Up Visits 
These visits will include assessment of FVIII inhibitor, FVIII:C trough levels, and body 
weight. 
At such visits, each patient’s body weight will be checked, and blood samples will be 
obtained for FVIII inhibitor screen and FVIII:C plasma concentration (one-stage and 
chromogenic assays) for the determination of trough levels. Blood samples will be 
obtained within 3 hours before injection of the next scheduled FVIII dose. The patient 

Study Protocol 
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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
diary will be reviewed and data will be transferred into the CRF. The occurrence of AEs 
and changes in concomitant medication will be checked and documented. 
Completion Visit 
For each patient, the “Sub-Study Extension Phase” is planned to be completed in the 4th 
quarter of 2020. 
At this visit, patient’s body weight will be checked, and blood samples will be obtained 
for FVIII inhibitor screen and FVIII:C plasma concentration (one-stage and chromogenic 
assays) for the determination of trough levels. A physical examination will be performed. 
The occurrence of AEs and changes in concomitant medication will be checked and 
documented. 
At this visit, the patient diary will be reviewed and data transferred into the CRF. 
In addition, all used and unused IMP vials will be returned by the patient. 
Unscheduled visits 
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. Other reasons for unscheduled visits may be the occurrence of serious AEs or 
hospitalizations due to severe bleeding episodes or surgical interventions. 
Assessments and methods 
Efficacy assessments 
Bleeding episode (BE) data to be documented 
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) 
• Date and time the BE first occurred or was first noticed 
• Date and time the BE ended 
• Dates and times the IMP was injected 

Study Protocol 
No. GENA-21b 
CONFIDENTIAL 
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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
• IMP dose(s) and batch number(s) 
• Assessment of the efficacy of treatment at the end of the BE 
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- 
threatening BE should be treated at the study site. 
At the end of a BE, treatment efficacy will be assessed by the patient (together with the 
investigator in case of on-site treatment) using the following predefined criteria: 
• 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 injections 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.’ 
Surgical prophylaxis 
For any surgical procedure performed during the study, a predefined set of parameters will 
be recorded. Efficacy will be assessed at the end of surgery by the surgeon and at the end 
of the postoperative period by the haematologist. In addition, there will be an overall 
assessment of efficacy jointly made by the surgeon and the haematologist at the end of the 
postoperative period. 
Efficacy of prophylactic treatment in the “Sub-Study Extension Phase” (Japan) 
The efficacy of Human-cl rhFVIII in the prophylactic treatment will be assessed based on 
the frequency of total and spontaneous break-through bleeds under prophylactic treatment. 
The dates and times of study drug infusions, details of dose(s) and product batch numbers 

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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
used for the prophylactic treatment will be documented. Details of any BEs occurring 
under prophylactic treatment will be documented. Study drug consumption data (FVIII 
IU/kg per month, per year) per patient and in total will be evaluated. 
Safety assessments 
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 
• Other relevant safety information, including post-study safety reports, instances of 
drug overdose, drug-drug interactions, abuse, misuse, medication error, or lack of 
efficacy 
The severity of AEs will be graded as mild, moderate, or severe. The relationship of AEs 
to the administered IMP will be assessed by the responsible investigator and classified as 
probable, possible, unlikely, not related, or unclassified. 
Laboratory assessments 
The routine safety laboratory tests (as well as any FVIII:C measurements in case of 
surgery that may become necessary) will be done by the local laboratory. FVIII:C (one- 
stage and chromogenic assays), FVIII inhibitor, and VWFAg will be assessed by a 
central laboratory. 
Statistical Analysis 
Efficacy of individually PK tailored prophylactic regimen will be evaluated statistically 
based on comparison to 50% of the annualised total bleeding rate and the annualised 
spontaneous bleeding rate under on-demand treatment (data from study GENA-01). A 
confirmative one-sided one-sample Poisson-test will test whether the annualised total 
bleeding rate in patients with individual prophylaxis is at least 50% below the mean 
annualised total bleeding rate in the GENA-01 trial (i.e., if it is < 29). 
As a secondary analysis of bleeding rates, the individual annualised bleeding rate will be 
analysed with a Poisson regression model and a Negative Binomial regression model. In 

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Name of Sponsor/Company: 
Octapharma AG, 8853 Lachen, Switzerland 
Name of Investigational Medicinal Product: 
Human-cl rhFVIII 
Protocol Identification Code: 
GENA-21b 
Name of Active Ingredient: 
Coagulation FVIII 
Date of Final Protocol: 
Version 10, 24-Jul-2019 
 
 
addition, GENA-21b individualised annualised bleeding rate data will be compared with 
GENA-01 individualised annualised bleeding rate data in these models; the estimated rate 
ratio comparing the individualised annual bleeding rates of the two trials will be provided 
with its 95% CI. This will be done for spontaneous, traumatic, and all BEs. 
The statistical analysis of other secondary, additional, and safety endpoints will be 
descriptive. 
Statistical Analysis for the “Sub-Study Extension Phase” (Japan) 
No inferential analysis involving formal testing will be planned in this “Sub-Study 
Extension Phase”. The patients are offered to continue treatment after the completion of the 
GENA-21b evaluation study in accordance with the study protocol; no formal sample size 
estimation is performed. The statistical analyses of the endpoints will be descriptive. 

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Schematic representation of the study by study phase and visit 
  
Study phase 
 
 
Screening Visit 
 
 
Initial PK Visit 
(may coincide with the Screening Visit) 
 
 
 
 
 
 
 
 
 
Day 14 Visit 
 
Day 30 Visit / Monthly compliance check at 1 month 
 
Monthly compliance check at 2 month 
 
End-of-Phase-I Visit 
(and beginning of Phase II) 
 
 
 
 
 
Monthly compliance check at 1 month 
 
2-Month Visit 
 
Monthly compliance check at 3 months 
 
4-Month Visit* 
 
Monthly compliance check at 5 months 
 
Study Completion Visit/ 
Sub-Study Extension Phase 
Screening Visit 
 
 
 
 
 
 
Sub-Study Extension Phase 6-monthly 
Visit/Sub-Study Extension Phase 
Completion Visit 
* possibility for dose reduction based on FVIIII 
trough level at the 2M visit and bleeding status 
up to 4M visit in Phase II 
Sub-Study Extension Phase for Japan 
Duration: 2.5-3.5 years 
Dose and dosing interval: personalised 
Trough levels (FVIII:C), inhibitor test and BW every 6 months 
Prophylactic Treatment—Phase II 
Duration: 
6 months 
Dose and dosing interval: personalised 
Trough levels (FVIII:C) and inhibitor test at 2 months 
Trough levels (FVIII:C) and inhibitor test at 4 months 
Trough levels (FVIII:C) and inhibitor test at 6 months 
Prophylactic Treatment—Phase I 
Duration: 1–3 months 
Dose and dosing interval: 30–40 IU/kg every other day or 3x/week 
Inhibitor test at Day 14 
Inhibitor test at Day 30 
Inhibitor test at End of Phase I 
Initial PK Evaluation Phase 
Duration:  72 hours 
Dose:  60 ± 5 IU FVIII/kg 
Screening 

 
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PROTOCOL SIGNATURES 
 
Signature of the Sponsor's Representative 
 
 
This study is to be conducted in compliance with this protocol, 
Good Clinical Practice, and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
Sigurd Knaub, PhD 
 
Senior Vice President, Clinical R&D Haematology 
on behalf of the Sponsor 
Octapharma AG 
Seidenstrasse 2 
CH-8853 Lachen 
Signature 
Date 

2 
 
 
Study Protocol 
No. GENA-2th 
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Signature of the Author of the Protocol & Clinical Project Manager 
 
 
This study is to be conducted in compliance with this protocol, 
Good Clinical Practice, and applicable regulatory requirement s. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sylvia Werner, M.S. 
gw)Jw-£ 
Author of the Protocol 
Director Clinical Operations - Haematology 
Octapharma USA, In c. 
1 21 River Street, Suite 1 201 
Hoboken , NJ 07030 USA 
Signaturr 

3 
 
 
 
 
 
 
 
 
 
 
 
 
Study Protocol 
No. GENA-21b 
 
CONFIDENTIAL 
Versi on 10 
24-Jul-2019 
 
 
 
 
 
 
 
 
Signature of the Biostatist ician 
 
 
This study is to be conducted in compliance with this protocol, 
Good Clinical Practice , and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
m1 ttJ 
 
 
Accovion GmbH 
Softwarecenter 3 
D-35037 Marburg 
Germany 
Heinz-Otto Keinecke 
i 
Principal Statistician 

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TABLE OF CONTENTS 
1 
INTRODUCTION ....................................................................................................... 9 
1.1 
BACKGROUND ................................................................................................................................ 9 
1.2 
STUDY RATIONALE ................................................................................................................... 10 
1.3 
DOSE RATIONALE ...................................................................................................................... 11 
1.3.1 
Initial PK Assessment ........................................................................... 11 
1.3.2 
Prophylactic Dose ................................................................................. 12 
1.3.3 
Treatment of Bleeding Episodes and Surgical Prophylaxis .................. 12 
1.3.4 
Treatment with Human-cl rhFVIII during the “Sub-Study Extension 
Phase” (Japan) ..................................................................................... 12 
1.4 
BENEFIT-RISK STATEMENT .................................................................................................... 13 
2 
STUDY OBJECTIVES ............................................................................................. 14 
2.1 
PRIMARY OBJECTIVE ................................................................................................................ 14 
2.2 
SECONDARY OBJECTIVES ........................................................................................................ 14 
2.3 
ADDITIONAL OBJECTIVES ....................................................................................................... 14 
2.4 
OBJECTIVES OF THE “SUB-STUDY EXTENSION PHASE” TO GENA-21B (JAPAN) 15 
3 
INVESTIGATIONAL PLAN ................................................................................... 16 
3.1 
PRIMARY ENDPOINT ................................................................................................................. 16 
3.2 
SECONDARY ENDPOINTS ......................................................................................................... 16 
3.3 
ADDITIONAL ENDPOINTS ......................................................................................................... 16 
3.4 
ENDPOINTS OF THE SUB-STUDY (JAPAN) ........................................................... 16 
4 
OVERALL STUDY DESIGN ................................................................................... 18 
4.1 
DISCUSSION OF STUDY DESIGN ............................................................................................. 21 
4.1.1 
Assays used to determine the response to FVIII treatment ................... 21 
4.1.2 
Effectiveness of prophylactic treatment with Human-cl rhFVIII: 50% 
reduction in the number of bleeding episodes per patient per year 
compared with on-demand treatment in GENA-01 ............................... 21 
4.1.3 
Rationale for Treatment Duration ........................................................ 23 
5 
STUDY POPULATION ............................................................................................ 24 
5.1 
INCLUSION CRITERIA ................................................................................................................ 24 
5.2 
EXCLUSION CRITERIA............................................................................................................... 24 
5.3 
CONCOMITANT THERAPY ........................................................................................................ 25 
5.3.1 
Permitted Concomitant Therapy ........................................................... 25 
5.3.2 
Prohibited Concomitant Therapy .......................................................... 25 
5.4 
PREMATURE PATIENT WITHDRAWAL ................................................................................. 26 
5.4.1 
Patient Replacement Policy ................................................................... 26 
5.5 
ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS .................................................... 26 

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5.6 
RELEVANT PROTOCOL DEVIATIONS .................................................................................... 26 
5.7 
SUBSEQUENT THERAPY ........................................................................................................... 26 
6 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................. 27 
6.1 
CHARACTERISATION OF INVESTIGATIONAL MEDICINAL PRODUCT .......................... 27 
6.2 
PACKAGING AND LABELLING ................................................................................................ 27 
6.3 
CONDITIONS FOR STORAGE AND USE ................................................................................. 27 
6.4 
DOSE AND DOSING INTERVAL ............................................................................................... 27 
6.4.1 
Initial PK Visit 
28 
6.4.2 
Prophylactic Treatment—Phase I ......................................................... 28 
6.4.3 
Prophylactic Treatment—Phase II........................................................ 28 
6.4.4 
Treatment of Bleeding Episodes ........................................................... 29 
6.4.5 
Surgical Prophylaxis ............................................................................. 30 
6.5 
PREPARATION AND METHOD OF ADMINISTRATION ....................................................... 31 
6.6 
BLINDING, EMERGENCY ENVELOPES AND BREAKING THE STUDY BLIND ............. 31 
6.7 
TREATMENT COMPLIANCE ..................................................................................................... 31 
6.7.1 
Drug Dispensing and Accountability .................................................... 31 
6.7.2 
Assessment of Treatment Compliance ................................................... 32 
7 
STUDY CONDUCT ................................................................................................... 33 
7.1 
FLOW CHART OF ASSESSMENTS ........................................................................................... 33 
7.2 
OBSERVATIONS BY VISIT ........................................................................................................ 35 
7.2.1 
Screening Visit 
35 
7.2.2 
Initial PK Visit 
36 
7.2.3 
Prophylactic Treatment—Phase I, including End-of-Phase-I Visit ...... 37 
7.2.4 
Prophylactic Treatment—Phase II........................................................ 37 
7.2.5 
Monthly Compliance Checks ................................................................ 38 
7.2.6 
Study Completion Visit .......................................................................... 39 
7.2.7 
Unscheduled Visits ................................................................................ 39 
7.2.8 
Study visits of “Sub-Study Extension Phase” ....................................... 40 
7.3 
STUDY DURATION ..................................................................................................................... 42 
7.3.1 
Planned Duration for an Individual Patient .......................................... 42 
7.3.2 
Planned Duration for the Study as a Whole .......................................... 42 
7.3.3 
Premature Termination of the Study ..................................................... 42 
8 
ASSESSMENTS AND METHODS .......................................................................... 44 
8.1 
BASELINE INFORMATION ........................................................................................................ 44 
8.2 
EFFICACY ASSESSMENTS ........................................................................................................ 44 
8.2.1 
Bleeding Episodes (BEs) ....................................................................... 44 
8.2.2 
Efficacy Assessment of prophylaxis treatment in the “Sub-Study 
Extension Phase” .................................................................................. 46 
8.2.3 
Surgical Prophylaxis 47 
8.3 
SAFETY ASSESSMENTS ............................................................................................................. 51 
8.3.1 
Safety Endpoints 
51 
8.3.2 
Adverse Events 
51 

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8.3.3 
Serious Adverse Events (SAEs) ............................................................. 55 
8.3.4 
SAE Reporting Timelines ....................................................................... 56 
8.3.5 
Other Relevant Safety Information ........................................................ 56 
8.4 
LABORATORY ASSESSMENTS ................................................................................................ 58 
8.5 
APPROPRIATENESS OF MEASUREMENTS ............................................................................ 58 
9 
DATA HANDLING AND RECORD KEEPING ................................................... 60 
9.1 
DOCUMENTATION OF DATA ................................................................................................... 60 
9.1.1 
Source Data and Records ..................................................................... 60 
9.1.2 
Case Report Forms ............................................................................... 60 
9.1.3 
Changes to eCRF Data ......................................................................... 61 
9.2 
INFORMATION PROVIDED TO INVESTIGATORS ................................................................. 61 
9.3 
RESPONSIBILITIES ...................................................................................................................... 62 
9.4 
INVESTIGATOR SITE FILE ........................................................................................................ 62 
9.5 
PROVISION OF ADDITIONAL INFORMATION ...................................................................... 63 
10 STATISTICAL METHODS AND SAMPLE SIZE ............................................... 64 
10.1 
DETERMINATION OF SAMPLE SIZE ........................................................... 64 
10.1.1 
Power .................................................................. 64 
10.1.2 
Method of power calculation .............................. 65 
10.2 
POPULATIONS FOR ANALYSIS .................................................................... 65 
10.3 
EFFICACY ANALYSIS PLAN ........................................................................ 70 
10.3.1 Primary Objective ................................................................................. 70 
10.3.2 Secondary Objectives ............................................................................ 72 
10.3.3 Additional Objectives ............................................................................ 74 
10.3.4 Efficacy Analysis Plan for the “Sub-Study Extension Phase” .............. 75 
10.3.5 Safety Analysis Plan .............................................................................. 76 
10.3.6 Safety Analysis Plan for the “Sub-Study Extension Phase” ................. 77 
10.3.7 Handling of Missing Data ..................................................................... 77 
10.4 RANDOMIZATION, STRATIFICATION, AND CODE RELEASE .......................................... 77 
11 ETHICAL, REGULATORY, LEGAL, AND ADMINISTRATIVE ASPECTS . 78 
11.1 ETHICAL AND REGULATORY FRAMEWORK ....................................................................... 78 
11.2 APPROVAL OF STUDY DOCUMENTS ..................................................................................... 78 
11.3 PATIENT INFORMATION AND INFORMED CONSENT ........................................................ 78 
11.4 PROTOCOL AMENDMENTS ...................................................................................................... 79 
11.5 CONFIDENTIALITY OF PATIENTS DATA .............................................................................. 79 
12 QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 80 
12.1 PERIODIC MONITORING ........................................................................................................... 80 
12.2 AUDIT AND INSPECTION .......................................................................................................... 80 
13 REPORTING AND PUBLICATION ...................................................................... 81 
13.1 CLINICAL STUDY REPORT ....................................................................................................... 81 

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13.2 PUBLICATION POLICY ............................................................................................................... 81 
14 LIABILITIES AND INSURANCE .......................................................................... 81 
15 REFERENCES .......................................................................................................... 82 

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LIST OF ABBREVIATIONS 
 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve (from baseline to infinity) 
BE 
bleeding episode 
BU 
Bethesda Unit 
BW 
body weight 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum plasma concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
eCRF 
electronic Case Report Form 
ED 
exposure day 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FVIII 
factor VIII 
FVIII:C 
FVIII coagulant activity 
GCP 
Good Clinical Practice 
HJHS 
Hemophilia Joint Health Score 
IB 
Investigator’s Brochure 
IEC 
Independent Ethics Committee 
IMP 
investigational medical product 
ITT 
intention to treat 
IU 
International Unit 
IVR 
in-vivo recovery 
MRT 
mean residence time 
PK 
pharmacokinetic 
PP 
per protocol 
PTPs 
previously treated patients 
rFVIII 
recombinant FVIII 
rhFVIII 
recombinant human factor VIII 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
t1/2 
half-life 
Tmax 
time to reach maximum plasma concentration 
Vss 
volume of distribution at steady state 
VWFAg 
von Willebrand factor antigen 

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1 
INTRODUCTION 
 
1.1 Background 
 
Haemophilia A is an inherited sex-linked coagulation disorder in which affected males do 
not produce functional coagulation factor VIII (FVIII) in sufficient quantities to achieve 
satisfactory haemostasis, leading to bleeding diathesis. Most bleeding episodes (BEs) occur 
in the patient’s joints and muscles. Without adequate treatment, repeated haemarthroses 
and haematoma lead to long-term sequelae with severe disability. Other bleeding sites, 
although less frequent but more severe, are the central nervous system, the urinary or 
gastrointestinal tract, the eyes, and the retroperitoneum. In addition, patients with 
haemophilia A are at high risk of developing major and life-threatening bleeding even after 
minor surgical interventions, such as tooth extractions. 
The optimal treatment of haemophilia A is replacement of FVIII using FVIII product either 
obtained by fractionation of human plasma or manufactured by recombinant DNA 
technology. The transmission of viruses by plasma-derived coagulation factor concentrates 
in the 1970s and early 1980s sparked increased interest in producing FVIII products by 
recombinant DNA technology. The structure of the FVIII gene was elucidated in 1984, 
followed by the isolation of cDNA clones encoding the complete FVIII sequence and the 
in vitro expression of human FVIII in tissue culture. Since the early 1990s, recombinant 
FVIII products have been commercially available [1]. 
Thus far, hamster cells have been used for the expression of commercial recombinant 
unmodified full-length or B-domain deleted FVIII (rFVIII) product. However, products 
derived from hamster cells may contain contaminants of non-human origin that may cause 
immune reactions. Also, the post-translational modifications of these proteins expressed in 
hamster cells are not identical to those of native human FVIII, potentially leading to 
immunogenic reactions and the development of inhibitors against rFVIII [2,3]. 
Human-cl rhFVIII is a fourth-generation recombinant human factor VIII (rhFVIII)  
product developed by Octapharma for the control and prevention of bleeding episodes and 
for surgical prophylaxis in patients with haemophilia A. It is a B-domain deleted rhFVIII 
produced in human embryonic kidney cells (HEK 293F) [4]. Human-cl rhFVIII has been 
shown to be highly pure, with host-cell protein and DNA traces comparable to, or lower 
than, currently marketed rFVIII products [5]. Human-cl rhFVIII has a high specific FVIII 
activity and characteristics similar to full-length rFVIII products. In functional tests, 
Human-cl rhFVIII exhibited physiological thrombin generation and a normal rate of 
inactivation by activated protein C. Human-cl rhFVIII displayed a higher binding capacity 
with von Willebrand factor (VWF) than comparator products, theoretically minimizing 

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circulating unbound FVIII and further reducing the potential risk of inhibitor 
development [5]. 
For rhFVIII, glycosylation and sulfation are vital for functionality and VWF binding 
affinity. Human-cl rhFVIII has been shown to be sulfated and glycosylated in ways 
comparable to human-plasma-derived FVIII. Most importantly, Human-cl rhFVIII is 
devoid of the antigenic Neu5Gc or alpha-Gal epitopes observed in Chinese Hamster 
Ovary- and Baby Hamster Kidney-derived rFVIII products. Both the avoidance of non- 
human glycan structures and the achievement of complete sulfation are proposed to lower 
the intrinsic immunogenicity of Human-cl rhFVIII compared with current rFVIII 
products [6]. 
Several clinical studies in a total of 201 previously treated adult and paediatric patients 
with severe haemophilia A have demonstrated the safety and efficacy of preventing and 
treating BEs with Human-cl rhFVIII. In particular, none of the patients developed an 
inhibitor against Human-cl rhFVIII. 
 
 
 
1.2 Study Rationale 
 
Prophylactic therapy is aimed at keeping the trough FVIII level above 1% between doses 
[7]. Traditionally, FVIIIproduct has been administered on alternate days or 3x/week for 
severe haemophilia A [8]. It was shown that trough FVIII concentrations and time per 
week with FVIII <0.01 IU per mL are mainly determined by the half-life and the dosing 
frequency [9]. To optimise prophylactic treatment, there is a call to individualise therapy in 
haemophilia, requiring knowledge of each patient’s PK parameters in response to 
replacement factor, which is known to vary considerably between patients [10]. 
Individual differences between patients’ PK parameters have also been observed in studies 
with Human-cl rhFVIII. For example, in adults, the mean ± SD half life of Human-cl 
rhFVIII as analysed using the one-stage assay for FVIII:C plasma concentrations was 
17.1 ± 11.2 hours, the median half-life was 13.7 hours, and the 75% quantile was 
17.5 hours. Efficient prophylaxis in adults, with a mean annualised bleeding rate of 2.3, 
was achieved with a mean ± SD dose of 32.8 ± 2.8 IU/kg, which in most cases (93.6%) 
was given every other day as stipulated by the study protocol. 
The study GENA-21 was designed to investigate the efficacy and safety of personalised 
prophylaxis with Human-cl rhFVIII in previously treated adult patients (n=66) with severe 
haemophilia A in Europe with the aim to prolong the prophylactic injection intervals based 

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on analyses of individual patient’s PK data. Results show that, in more than half of the 
patients, twice-weekly prophylactic injection was sufficient. 
The current phase 3b study, GENA-21b, is also designed to investigate the efficacy and 
safety of personalised prophylaxis with Human-cl rhFVIII in previously treated adult 
patients with severe haemophilia A. The design of GENA-21b closely resembles that of 
GENA-21, and the study will collect further important data on the individualised 
prophylaxis approach worldwide. 
 
“Sub-Study Extension Phase” to GENA-21b (Japan) 
Once patients from treatment centres in Japan complete the study after 6 months in 
Prophylactic Treatment-Phase II and after performing the assessments of the completion 
visit, participants can decide to continue on the same treatment regimen and same product 
in a “Sub-Study Extension Phase” to GENA-21b. 
The aim of the “Sub-Study Extension Phase” is to investigate the long-term safety and 
efficacy of Human-cl rhFVIII in patients included into the preceding study GENA-21b. 
 
1.3 Dose Rationale 
 
1.3.1 Initial PK Assessment 
 
The PK dose of 60 ± 5 IU/kg in this study is the same as that used in the GENA-21 study 
and higher than in previous PK studies with Human-cl rhFVIII, in which the PK dose had 
been 50 IU/kg and the blood sampling period 48 hours. Considering the relatively long 
mean and median half-life of Human-cl rhFVIII as seen in GENA-01, it is expected that 
the higher dose in GENA-21b will result in measurable FVIII:C plasma concentrations 
after 72 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 
technically and might result in dosing errors. 

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1.3.2 Prophylactic Dose 
The dosing recommendations for the Prophylactic Treatment—Phase I (30–40 IU/kg 
every other day or 3x/week) are the same as in GENA-21 as well as in previous studies in 
adults (GENA-08, treatment every other day) and children (GENA-03, treatment every 
other day or 3x/week). 
In Prophylactic Treatment—Phase II, the PK-tailored dose and dosing interval will be 
determined individually for each patient. The goal is to determine the maximum regular 
prophylactic dosing interval that can be achieved with a dose not exceeding 65 IU/kg and 
capable of maintaining a trough level of ≥ 0.01 IU/mL. 
By comparison, the goal of GENA-21 had been to determine the maximum regular 
prophylactic dosing interval that can be achieved with a dose of up to 80 IU/kg. The reason 
for changing the wording of the dosing recommendation from ‘up to 80 IU/kg’ in GENA- 
21 to a dose ‘not exceeding 65 IU/kg’ in GENA-21b is to motivate a further dose 
optimization with a view to further economizing on FVIII use. 
 
1.3.3 Treatment of Bleeding Episodes and Surgical Prophylaxis 
The dosing recommendations for the treatment of bleeding episodes and surgical 
prophylaxis in this study (see Section 6.4) are the same as in the preceding studies with 
adult patients (GENA-21, GENA-01, GENA-08). 
 
 
1.3.4 Treatment with Human-cl rhFVIII during the “Sub-Study Extension Phase” 
(Japan) 
Patients will continue to be treated prophylactically after the completion of 6 months in 
Treatment-Phase II in GENA-21b. Prophylactic doses and dosing intervals will remain the 
same in the “Sub-Study Extension Phase” as in the last 2 months of Prophylactic 
Treatment-Phase II. 
In case of unacceptable frequent and/or severe spontaneous breakthrough bleedings, the 
dose should be increased by approximately 5 IU/kg (depending on the entire content of 
vial(s) that needs to be reconstituted additionally). However, the maximum dose should not 
exceed 65 IU/kg. If, after a dose increase, patients still experience unacceptable bleeding 
episodes, the dosing interval should be shortened. 
In addition, if the body weight of the patient during follow up visits fluctuates +/- 10% 
compared to the screening visit, the investigator should verify if the dosing is still within 
the prescribed range and adapt accordingly, if necessary. 

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Dosing recommendations for the treatment of bleeding episodes and for surgical 
prophylaxis are the same as in the preceding study (see section 6.4). 
 
1.4 Benefit-Risk Statement 
 
Based on the available clinical evidence, Human-cl rhFVIII is safe and effective in the 
prevention and treatment of BEs and during surgical prophylaxis in patients with inherited 
FVIII deficiency. 
The following adverse drug reactions (ADRs) have been observed with commercially 
available rFVIII preparations and may also occur with Human-cl rhFVIII: 
• Hypersensitivity or allergic type of reactions. Observed symptoms may include 
hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and 
anaphylaxis. Rarely, such reactions may progress to severe anaphylaxis, including 
shock. 
• Development of antibodies (inhibitors) against FVIII. 
Considering all currently available nonclinical and clinical observations, including 
pharmacokinetic (PK) data, it may be assumed that participation in this study does not 
present any additional risk. 

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2 
STUDY OBJECTIVES 
 
2.1 Primary Objective 
 
The primary objective of this clinical study is to compare the annualised total bleeding rate 
of individually tailored prophylaxis with the historical bleeding rate observed in patients 
having received on-demand treatment with Human-cl rhFVIII from study GENA-01. 
 
2.2 Secondary Objectives 
 
The secondary objectives of this clinical study are 
1. To compare the annualised spontaneous bleeding rate of individually tailored 
prophylaxis with the historical bleeding rate observed in patients having received 
on-demand treatment with Human-cl rhFVIII 
2. To compare the annualised total bleeding rate in patients with 2x/week (or less) 
prophylaxis with the historical bleeding rate observed in patients having received 
on-demand treatment with Human-cl rhFVIII 
3. To assess the median prophylactic dosing interval 
4. To assess the PK of Human-cl rhFVIII in terms of FVIII:C 
5. To assess the safety of Human-cl rhFVIII 
 
2.3 Additional Objectives 
 
Additional objectives of this clinical study are 
1. To assess the efficacy of Human-cl rhFVIII in the treatment of breakthrough 
bleeding episodes (BEs) 
2. To assess the efficacy of Human-cl rhFVIII in surgical prophylaxis 
3. To assess the correlation of VWF antigen concentration and half-life of Human-cl 
rhFVIII 
4. To assess the association between ABO blood type and half-life of Human-cl 
rhFVIII 
5. To assess Human-cl rhFVIII consumption data (exploratory) 

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2.4 Objectives of the “Sub-Study Extension Phase” to GENA-21b (Japan) 
 
1. To investigate the long-term safety of Human-cl rhFVIII in patients with severe 
haemophilia A who participated in the GENA-21b study 
2. To assess the long-term efficacy of Human-cl rhFVIII during prophylactic treatment 
(based on the frequency of total and spontaneous break-through bleeds) 
3. To assess the efficacy of Human-cl rhFVIII during treatment of bleeding episodes 
(BEs) 
4. To assess the efficacy of Human-cl rhFVIII in surgical prophylaxis 

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3 
INVESTIGATIONAL PLAN 
 
3.1 Primary Endpoint 
 
The primary endpoint of this study is the reduction of the annualised total bleeding rate 
observed in the GENA-01 study (58.1 total bleeding episodes per patient per year) by 50% 
during individually tailored prophylaxis. 
 
3.2 Secondary Endpoints 
 
1. Reduction of the annualised spontaneous bleeding rate observed in the GENA-01 
study (38.5 spontaneous bleeding episodes per patient per year) by 50% during 
individually tailored prophylaxis 
2. Reduction of the annualised bleeding rate observed in GENA-01 by 50% in patients 
with 2x/week prophylaxis or less 
3. Median prophylactic dosing interval during individually tailored prophylaxis 
4. Safety and tolerability of Human-cl rhFVIII by monitoring adverse events (AEs) 
throughout the study 
 
3.3 Additional Endpoints 
 
1. Descriptive efficacy of Human-cl rhFVIII in the treatment of breakthrough BEs 
2. Descriptive efficacy of Human-cl rhFVIII in surgical prophylaxis 
3. Correlation between VWF antigen concentration and the half-life of Human-cl 
rhFVIII 
4. Association between ABO blood type and half-life of Human-cl rhFVIII 
5. Human-cl rhFVIII consumption data (FVIII IU/kg per month per patient) during 
individually tailored prophylaxis 
 
3.4 Endpoints of the Sub-Study (Japan) 
 
1. Safety of Human-cl rhFVIII by monitoring adverse events (AEs) and inhibitors 
against FVIII throughout the “Sub-Study Extension Phase” 
2. The efficacy of Human-cl rhFVIII under prophylactic treatment will be assessed 
descriptively for the patients included in the “Sub-Study Extension Phase” by 
calculating the frequency of total and spontaneous break-through bleeds under 
individually tailored prophylaxis treatment 

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3. Descriptive efficacy of Human-cl rhFVIII in the treatment of breakthrough BEs 
4. Descriptive efficacy of Human-cl rhFVIII in surgical prophylaxis 

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4 
OVERALL STUDY DESIGN 
This is a prospective, open-label, multicentre phase 3b study investigating the efficacy and 
safety of individually tailored prophylaxis with Human-cl rhFVIII in previously treated 
adult patients with severe haemophilia A. 
Approximately 55 male subjects ≥ 18 years of age will be enrolled with the aim to have 
evaluable data on 50 subjects. Subjects will be recruited from about 30 haemophilia 
treatment centres worldwide. 
The study consists of three (3) phases, i.e., the PK Evaluation Phase, the Prophylactic 
Treatment—Phase I, and the Prophylactic Treatment—Phase II. After Prophylactic 
Treatment-Phase II a “Sub-Study Extension Phase” to continue the treatment with Human- 
cl rhFVIII and to investigate long-term safety and efficacy will be offered to patients from 
study centres in Japan. 
• The PK Evaluation Phase will last for 72 hours (i.e., 3 days). 
• The purpose of Prophylactic Treatment—Phase I, which will last for 1–3 months, 
is to treat the patients prophylactically every other day or 3x/week with a dose of 
30–40 IU/kg BW until individual PK data have been analysed and discussed with the 
investigator . 
• In Prophylactic Treatment—Phase II, Prophylactic doses and dosing intervals will 
be recommended by the Sponsor for each patient based on the analysis of individual 
PK data obtained at the Initial PK Visit with the one-stage assay. The final decision 
on the prophylactic scheme will be taken by the investigator after consultation with 
the patient and Sponsor. 
The study duration for each patient will be approximately 7–9 months, and the GENA-21b 
study duration will be about 3 years. The investigator will inform the monitor of any 
recruitment difficulty or delay in the anticipated completion date. The end of the GENA- 
21b study is defined as the last visit of the last patient participating in the study. 
“Sub-Study Extension Phase” to GENA-21b (for Japan) 
After completing the GENA-21b study which is defined as 6 months of prophylactic 
treatment in Treatment-Phase II and after performing the assessments of the completion 
visit, participants can decide to continue on the same treatment regimen with Human-cl 
rhFVIII in a “Sub-Study Extension Phase” to GENA-21b. 
This “Sub-Study Extension Phase” will be offered to patients from study centres in Japan. 
Approximately 10 patients from Japan are expected to enrol into the GENA-21b study. 
Therefore approximately 10 patients may continue treatment in the “Sub-Study Extension 
Phase”. 

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The “Sub-Study Extension Phase” will start individually for each patient with the completion 
visit of GENA-21b and the screening visit for the “Sub-Study Extension Phase”, which 
should occur on the same day. The treatment is planned until the 4th quarter in 2020. 
While in the “Sub-Study Extension Phase”, patients will be monitored every 6 months for 
FVIII inhibitors and FVIII:C trough levels. Patients will be handed a diary to continue 
recording adverse events, concomitant medications, treatment of bleeding episodes, 
prophylactic treatments, and the use of Human-cl rhFVIII within surgeries, if needed. 
Patients are eligible to participate in the “Sub-Study Extension Phase” if they completed 
the GENA-21b study with 6 months of prophylactic treatment in Treatment-Phase II and 
voluntarily gave fully informed written and signed consent before any Sub-Study related 
procedures are conducted. 
The completion visit of the GENA-21b study and the screening visit for the “Sub-Study 
Extension Phase” should occur on the same day. 
The patients should not have received any other FVIII product than Human-cl rhFVIII 
between completion visit of GENA-21b study and start of “Sub-Study Extension Phase” 
(except emergency cases). 
 
 
The study will be stopped if more than 3 patients develop a neutralizing antibody 
(inhibitor) to Human-cl rhFVIII. 
 
 
A schematic representation of the study by study phase and visit is given in Figure 1. 

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Dose
 
 
 
Figure 1 
Schematic representation of the study by study phase and visit 
 
  
Study phase 
Study visits 
 
 
Screening Visit 
 
 
Initial PK Visit 
(may coincide with the Screening Visit) 
 
 
 
 
 
 
 
 
Day 14 Visit 
 
Day 30 Visit / Monthly compliance check at 1 month 
 
Monthly compliance check at 2 month 
 
End-of-Phase-I Visit 
(and beginning of Phase II) 
 
 
 
 
 
 
Monthly compliance check at 1 month 
 
2-Month Visit 
 
Monthly compliance check at 3 months 
 
4-Month Visit* 
 
Monthly compliance check at 5 months 
 
 
 
 
 
 
 
 
 
Sub-Study Extension Phase 6-monthly 
Visit 
Sub-Study Extension Phase Completion 
Visit 
*possibility for dose reduction based on FVIII:C 
trough level at the 2M visit and bleeding status 
up to 4M visit in Phase II. 
Sub-Study Extension Phase for Japan 
Duration: 2.5-3.5 years 
Dose and dosing interval: personalised 
Trough levels (FVIII:C), inhibitor test and BW every 6 months 
Prophylactic Treatment—Phase II 
Duration:  6 months 
Dose and dosing interval: personalised 
Trough levels (FVIII:C) and inhibitor test at 2 months 
Trough levels (FVIII:C) and inhibitor test at 4 months 
Trough levels (FVIII:C) and inhibitor test at 6 months 
Prophylactic Treatment—Phase I 
Duration: 1–3 months 
Dose and dosing interval: 30–40 IU/kg every other day or 3x/week 
Inhibitor test at Day 14 
Inhibitor test at Day 30 
Inhibitor test at End of Phase I 
Initial PK Evaluation Phase 
Duration:  72 hours 
60 ± 5 IU FVIII/kg 
Screening 

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4.1 Discussion of Study Design 
 
The rationale of this study is to further fine-tune and individualise prophylactic treatment 
of patients with severe haemophilia A (see Section 1.2). 
The treatment needs of patient with haemophilia A are highly variable due to the 
heterogeneity of their bleeding phenotype, joint status, and type and intensity of physical 
activity [11]. Ideally, a multi-dimensional approach should be adopted in tailoring and 
monitoring prophylactic regimens, taking into account bleeding symptoms, laboratory data 
(factor trough levels, PK), joint status, quality of life, and treatment costs [11]. 
Because trough FVIII levels are likely to be important predictors of the efficacy of 
prophylaxis, the focus in this study is on PK data. The time spent below a certain factor 
level and trough FVIII levels depend on the dose and frequency of FVIII injections and on 
the individual PK parameters in response to injected FVIII. For the calculation of 
individual prophylactic dosing and dosing interval, we assume that effective prophylaxis 
against bleeding is maintained if plasma FVIII coagulant activity (FVIII:C) is kept above 
1%, although it is known that some patients do not bleed despite a trough level < 1%, 
whereas other patients bleed with trough levels > 3% [12]. 
In addition, the rationale for the “Sub-Study Extension Phase” is to investigate the long- 
term safety and efficacy of Human-cl rhFVIII in patients included into the preceding study 
GENA-21b. 
 
4.1.1 Assays used to determine the response to FVIII treatment 
In this study, two assays for the determination of FVIII plasma levels will be used, i.e., the 
one-stage assay and the chromogenic assay. 
For the PK analyses in the present study, we will use the results of FVIII:C one-stage 
measurements, because this is the more widely used assay in clinical practice. 
Discrepancies in factor half-life have been reported between one-stage and two- 
stage/chromogenic methods in clinical use [13]. In our previous PK study in adults 
(GENA-01), however, the discrepancies in the half-life between the two assays were not 
pronounced. 
 
4.1.2 Effectiveness of prophylactic treatment with Human-cl rhFVIII: 50% 
reduction in the number of bleeding episodes per patient per year compared 
with on-demand treatment in GENA-01 
In GENA-01, the efficacy and safety of on-demand treatment with Human-cl rhFVIII for 
at least 6 months and at least 50 exposure days (EDs) were evaluated in 22 adolescent and 

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adult PTPs with severe haemophilia A. The mean number of bleeding episodes per patient 
per year in GENA-01 was 58.1. 

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GENA-08 and GENA-09 determined the efficacy of prophylactic treatment with 
Human-cl rhFVIII every other day in 32 and 22 adult PTPs with severe haemophilia A for 
at least 6 months and at least 50 EDs. While GENA-08 was performed as a multicentre 
study in several, mainly Western European, countries, GENA-09 was a single-centre study 
in Russia in a patient population that had been inadequately treated since childhood. As 
agreed with the US Food and Drug Administration (FDA), prophylactic treatment with 
Human-cl rhFVIII in GENA-08 was to be considered effective if a 50% reduction in the 
total number of bleeding episodes per patient per year was observed compared to GENA- 
01 where on-demand treatment was used. The EMA Guideline gives no guidance as to 
how exactly assess the efficacy of prophylaxis. In the GENA-21 study, the same approach 
to demonstrate the effectiveness of prophylactic treatment with Human-cl rhFVIII as 
agreed with the FDA was chosen. 
 
4.1.3 Rationale for Treatment Duration 
EMA guideline EMA/CHMP/BPWP/144533/2009 states that for ‘the assessment of 
clinical efficacy of FVIII in long-term prophylaxis, patients should be treated for 6 months 
and assessed for bleeding episodes, bleeding intervals and number of treatments.’ As for 
previous studies with Human-cl rhFVIII (i.e., GENA-08 in adolescent/adult patients and 
GENA-03 in paediatric patients), the duration of the Prophylactic Treatment—Phase II in 
GENA-21b is 6 months. 
The Sub-Study is an extension to the GENA-21b study to allow patients in Japan to stay on 
Human-cl rhFVIII after completing the prophylactic treatment of 6 months in Prophylactic 
Treatment-Phase II and with the goal to investigate long-term safety and efficacy of 
Human-cl rhFVIII. 
Provided the inclusion- and exclusion criteria are met, all subjects wishing to continue the 
prophylaxis treatment with Human-cl rhFVIII will be included into the “Sub-Study 
Extension Phase”. The individual study participation period varies depending upon 
completion of Treatment-Phase II. 
The first patient in Japan completed Treatment-Phase-II of GENA-21b in June 2017 and 
the last completed Treatment-Phase-II in September 2018. The clinical study end of the 
“Sub-Study Extension Phase” is planned to be in the 4th Quarter of 2020. Thus, individual 
study duration in the “Sub-Study Extension Phase” may vary from approximately 2.5 to 
3.5 years. 
The overall study duration from start of the GENA-21b in the 2nd Quarter of 2015 until 
“Sub-Study Extension Phase” completion visit in the 4th Quarter of 2020 is approximately 
5.75 years. 

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5 
STUDY POPULATION 
The goal of the GENA-21b study is to collect data on 50 patients who complete the 6- 
month Prophylactic Treatment—Phase II of this study. Approximately 55 patients will be 
enrolled to compensate for potential drop-outs. 
The goal of the “Sub-Study Extension Phase” is to collect long-term safety and efficacy 
data from approximately 10 patients in Japan. Potential drop outs will not be replaced 
because only patients who completed the GENA-21b study will be eligible to participate in 
the “Sub-Study Extension Phase”. 
 
5.1 Inclusion Criteria 
 
Patients who meet all of the following criteria are eligible for the study: 
(a) Severe haemophilia A (FVIII:C < 1%) according to medical history 
(b) Male patients ≥ 18 years of age 
(c) Previous treatment with a FVIII product (regular prophylaxis with good 
compliance or on-demand treatment) for at least 150 EDs 
(d) Good documentation regarding dosing and bleeding frequency in the 6 months 
preceding study start 
(e) Immunocompetence (CD4+ count > 200/µL) 
(f) Freely given written informed consent 
 
Inclusion criteria for “Sub-Study Extension Phase” (Japan): 
(a) Patients who completed the GENA-21b study with 6 months of prophylactic 
treatment in Treatment Phase II 
(b) Voluntarily given, fully informed written and signed consent obtained before any 
”Sub-Study (Extension Phase)”-related procedures are conducted 
 
 
5.2 Exclusion Criteria 
 
Patients who meet any of the following criteria are not eligible for the study: 
(a) Any coagulation disorder other than haemophilia A 
(b) Present or past FVIII inhibitor activity (≥ 0.6 BU) according to medical history 
(c) Severe liver or kidney disease (ALT and AST levels > 5 times of upper limit of 
normal, creatinine > 120 µmol/L) 
(d) Treatment with any investigational medicinal product (IMP) except FVIII IMP 
within 14 days prior to the screening visit 

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Exclusion criteria for “Sub-Study Extension Phase” (Japan): 
(a) Other FVIII product than Human-cl rhFVIII was received between completion visit 
of GENA-21b study and start of “Sub-Study Extension Phase” (except emergency 
cases). 
 
 
5.3 Concomitant Therapy 
 
5.3.1 Permitted Concomitant Therapy 
Concomitant therapies not interfering with the objectives of the study are permitted. 
Details of any concomitant medication must be recorded in the electronic Case Report 
Form (eCRF). 
Any bleeding episodes occurring between the Screening Visit and the Initial PK Visit 
should be treated with the patient’s previously used FVIII product. Similarly, prophylactic 
treatment between the Screening Visit and the Initial PK Visit should be done with the 
patient’s previously used FVIII product. 
 
 
5.3.2 Prohibited Concomitant Therapy 
No other FVIII product should be given (except for emergency situations). 
Patients who switch to another FVIII product during their study participation will not be 
considered treatment failures in the efficacy analyses if: 
• the use of another FVIII product was due to an emergency (example: accident 
requiring treatment with FVIII without the patient (or intensive care unit personnel) 
having access to the IMP) 
• the IMP was not available to the patient in time (example: patient experiences severe 
bleed but has not enough IMP available at home) 
 
The switch to another FVIII product is allowed in case the IMP does not achieve the 
therapeutic results as expected e.g., when patients experience continued bleeding despite 
the correct administration of coagulation factors (lack of efficacy). In this case the patients 
will be considered treatment failures and their study participation will be discontinued. 
Lack of efficacy is considered an adverse event or serious adverse event, as applicable (see 
section 8.3.5). 

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5.4 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 or protocol violations or for other reasons. Because an excessive rate of 
withdrawals may render the study noninterpretable, unnecessary withdrawals of patients 
should be avoided. 
In case of any discontinuation after study entry, the investigator will collect all the required 
details and document the reason(s) for discontinuation in the eCRF. If the reason for 
withdrawal of a patient is an AE, the main specific event or laboratory test will be recorded 
in the eCRF, and the investigator will make every possible effort to clearly document the 
outcome. 
5.4.1 Patient Replacement Policy 
Patients withdrawn from the study will not be replaced. 
 
5.5 Assignment of Patients to Treatment Groups 
 
Not applicable; this is an uncontrolled study. 
 
5.6 Relevant Protocol Deviations 
 
In case of a major protocol deviation or violation, the investigator and Sponsor will decide 
on the further participation of the patient in this study after having considered all relevant 
aspects. 
 
5.7 Subsequent Therapy 
 
At the end of Treatment-Phase II of the GENA-21b study, patients will continue 
substitution therapy using a commercially available FVIII product or they can continue 
treatment with Human-cl rhFVIII in the “Sub-Study Extension Phase” after signing 
informed consent. 
At the end of the “Sub-Study Extension Phase” patients will continue substitution therapy 
using a commercially available FVIII product. 

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6 
INVESTIGATIONAL MEDICINAL PRODUCT 
 
6.1 Characterisation of Investigational Medicinal Product 
 
The IMP Human-cl rhFVIII is a human cell line derived B-domain deleted rFVIII product 
for intravenous use. Each vial contains either 250, 500, 1000, ;2000, 2500, 3000, or 4000 
international units (IU) of freeze-dried Human-cl rhFVIII product to be reconstituted in 2.5 
mL of water for injections (WFI) each. In this study, several batches of product will be 
used. 
 
6.2 Packaging and Labelling 
 
The IMP, i.e., the vial with Human-cl rhFVIII freeze-dried product, will be provided 
together with the diluent (2.5 mL of WFI in pre-filled syringe) and the necessary 
equipment to enable IMP administration. The final labelling will comply with the national 
requirements of each country where the study is conducted. 
 
6.3 Conditions for Storage and Use 
 
The product has to be stored at 2°C to 8°C and protected from light. Use the reconstituted 
solution immediately or within 3 hours after reconstitution. Keep the reconstituted solution 
at room temperature. Do not refrigerate after reconstitution. 
Do no freeze. Any remaining solution should be discarded. 
Do not use after the expiration date. 
The investigator or any authorised site personnel will ensure that the IMP is stored in 
appropriate conditions with restricted access and in compliance with national regulations. 
The investigator will advise the patient with regard to the necessary conditions for the 
storage of the IMP during home treatment. 
 
6.4 Dose and Dosing Interval 
 
The doses and dosing intervals used in this study vary with the study phase. For a 
schematic representation of the study by visit and study phase, see Figure 1. For a detailed 
description of the study visits, see Section 7.2. 

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6.4.1 Initial PK Visit 
At the Initial PK Visit, patients will receive Human-cl rhFVIII at a dose of 60 ± 5 IU/kg 
(labelled dose). 
 
6.4.2 Prophylactic Treatment—Phase I 
The 72-hour sampling time point of the Initial PK Visit marks the beginning of 
Prophylactic Treatment—Phase I, in which patients will be treated prophylactically every 
other day or 3x/week with a dose of 30–40 IU/kg BW for about 1–3 months until PK data 
have been analysed and discussed with the investigator. 
Dose escalations are allowed in case of an inadequate frequency and severity of 
breakthrough bleeding episodes in accordance with the institution’s standard clinical care. 
If patients receive a dose of 40 IU/kg BW and experience unacceptable frequent and/or 
severe spontaneous breakthrough bleedings only one further dose escalation is allowed for 
the maximum dose not to exceed 45 IU/kg BW. 
 
 
6.4.3 Prophylactic Treatment—Phase II 
In this phase, patients will be treated prophylactically for 6 months. 
The prophylactic dose and injection interval will be recommended by the Sponsor for each 
patient based on the analysis of individual PK data obtained with the one-stage assay at the 
Initial PK Visit. 
Based on an appropriate PK model, various dosing intervals (usually 12-hour intervals) 
and corresponding doses (in IU/kg) will be calculated, which theoretically lead to FVIII:C 
plasma concentrations of at least 0.01 IU/mL at the end of the respective injection interval. 
The goal is to use the maximum regular prophylactic dosing interval that can be achieved 
with a maximum dose of not more than 65 IU/kg and that maintains a trough level of 
≥ 0.01 IU/mL. 
This recommendation may change in certain situations. For example, 
• If the maximum calculated dosing interval is ≤ 2.5 days, the recommendation may be 
to continue with the dose and dosing interval as used in Prophylactic Treatment— 
Phase I, provided that this treatment scheme was considered effective by both the 
treating physician and the patient. 
• If the maximum calculated dosing interval is > 3.5 days and the dose > 65 IU/kg, the 
recommendation may be to reduce the dosing interval by 0.5 days and use the 
corresponding lower dose. 

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• If the maximum calculated dosing interval is ≥ 4.5 days, the recommendation may be 
to reduce the dosing interval by 0.5 days and use the corresponding dose. 
In general, the recommendation will take into account both the interpretation of the PK 
data as well as practical and economic aspects (i.e., consumption of FVIII). 
The final decision on the prophylactic scheme will be taken by the investigator after 
consultation with the patient and Sponsor. 
At the 4-Month Visit in Prophylactic Treatment—Phase II, the dose per injection for the 
remainder of the study may be reduced provided that FVIII:C trough levels (one-stage 
assay) obtained at the 2-Month Visit were ≥ 0.01 IU/mL and the patient has not 
experienced any spontaneous bleed up to the 4-Month Visit. 
Extra prophylactic dosing prior to risky activities is permitted and has to be documented. 
In case of unacceptable frequent and/or severe spontaneous breakthrough bleedings, the 
dose should be increased by approximately 5 IU/kg (depending on the entire content of 
vial(s) that needs to be reconstituted additionally). However, the maximum dose should not 
exceed 65 IU/kg. If, after a dose increase, patients still experience unacceptable bleeding 
episodes, the dosing interval should be shortened. 
 
 
6.4.3.1 Dosing in “Sub-Study Extension Phase” to GENA-21b 
In this “Sub-Study Extension Phase” patients will continue their prophylactic treatment as 
prescribed during the last 2 months in Treatment-Phase II. 
Extra prophylactic dosing prior to risky activities is permitted and has to be documented. 
In case of unacceptable frequent and/or severe spontaneous breakthrough bleedings, the 
dose should be increased by approximately 5 IU/kg (depending on the entire content of 
vial(s) that needs to be reconstituted additionally). However, the maximum dose should not 
exceed 65 IU/kg. If, after a dose increase, patients still experience unacceptable bleeding 
episodes, the dosing interval should be shortened. 
In addition, if the body weight of the patient during follow up visits fluctuates +/- 10% 
compared to the screening visit, the investigator should verify if the dosing is still within 
the prescribed range and adapt accordingly, if necessary. 
 
6.4.4 Treatment of Bleeding Episodes 
The dosage and duration of treatment of spontaneous or traumatic breakthrough bleeding 
episodes (BEs) will depend on the location and extent of bleeding and on the clinical 
situation of the patient. 

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The following general dosage recommendations are given: 
• Minor haemorrhage: 20–30 IU FVIII/kg every 12–24 hours until bleeding episode 
is resolved. 
• Moderate to major haemorrhage: 30–40 IU FVIII/kg. Repeat one dose every 12– 
24 hours until bleeding episode is resolved. 
• Major to life-threatening haemorrhage: initial dose of 50–60 IU FVIII/kg. Repeat 
dose of 20–25 IU FVIII/kg every 8–12 hours until bleeding episode is resolved. 
 
6.4.5 Surgical Prophylaxis 
The dosage and duration of treatment with Human-cl rhFVIII will depend on the type of 
surgery and the patient’s individual incremental recovery. 

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The following general dosage recommendations are given: 
• Minor surgeries, including tooth extractions: 25–30 IU FVIII/kg BW within 
3 hours prior to surgery to achieve an intended target peak level of about 50% to 
60%. Repeat one dose every 12–24 hours if needed. Trough levels should be 
maintained at approximately 30% (samples taken prior to the next injection of IMP). 
• Major surgeries: 50 IU FVIII/kg BW within 3 hours prior to surgery to achieve an 
intended target peak level of approximately 100%. Repeat if necessary after 6–12 
hours initially and for at least 6 days until healing is complete. Trough levels should 
be maintained at approximately 50% (samples taken prior to the next injection of the 
IMP). 
 
6.5 Preparation and Method of Administration 
 
Each vial of Human-cl rhFVIII will be reconstituted in 2.5 mL WFI. Detailed handling 
instructions will be provided. 
Before injection, the solution must reach room temperature without applying any specific 
warming-up measures. The solution should be administered within 3 hours after 
reconstitution on only one occasion. The solution is normally clear or slightly opalescent 
and colourless. Solutions which are cloudy or have deposits must not be used. 
Human-cl rhFVIII should be injected intravenously by bolus injection at a maximum rate 
of 4 mL/min using an aseptic technique. 
 
6.6 Blinding, Emergency Envelopes and Breaking the Study Blind 
 
Not applicable; this is an open-label study. 
 
6.7 Treatment Compliance 
 
6.7.1 Drug Dispensing and Accountability 
A drug dispensing log and the inventory will be kept current by the investigator, detailing 
the dates and quantities of IMP dispensed to each patient. The inventory will be available 
to the monitor to verify drug accountability during the study. Patients will be advised to 
return any used vials and expired IMP at each study visit and to return any used vials and 
unused IMP at the Study Completion Visit. Any unused IMP, either not dispensed or 
returned by the patient, will be accounted for. 

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Unused IMP will be returned to the Sponsor or can be destroyed at the study site after 
written approval from the Sponsor has been obtained. When required by local policies, 
unused IMP may be destroyed at the study site after drug accountability has been verified 
and fully reconciled and written approval from the Sponsor has been obtained. 
 
6.7.2 Assessment of Treatment Compliance 
Treatment compliance will be verified on the basis of patient diaries and monthly 
compliance checks in Treatment-Phases I and II. During the “Sub-Study Extension Phase” 
compliance will be checked during 6-monthly follow up visits. 
 
Patient diaries 
Patients will usually treat themselves at home, and they will therefore be provided with a 
sufficient amount of IMP and a patient diary. 
The patient diary will be handed to the patient during the Screening Visit after inclusion 
into the study. The investigator will explain to the patient how to fill in the diary and 
emphasize the importance of carefully documenting all treatment details. 
The following data will be recorded in the patient diary: 
• The recording of self-injections includes the date and time of administration as well 
as the dose, batch number, and reason for injection (i.e., prophylaxis, BE treatment). 
For BE data to be documented, see Section 8.2.1. 
• Concomitant medications 
• Adverse events (AEs) 
 
At each follow-up visit at the study site, the patient will bring along all diaries for review 
and validation by site personnel and return any used vials and unused expired IMP (see 
Section 6.7.1). 
During or after each follow-up visit, the information recorded in the patient diaries will be 
transcribed to the eCRFs. The patient diaries are classified as source data, and the originals 
will be included in the patient’s medical record. 
 
Monthly compliance checks 
 
During Prophylactic Treatment—Phases I and II, monthly compliance checks (± 1 week) 
will be performed by telephone or during personal visits by the patient. For more 
information on the monthly compliance checks, refer to Section 7.2.5. 

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7 
STUDY CONDUCT 
7.1 Flow Chart of Assessments 
 
The flow chart of assessments performed throughout the entire study is given in Table 1. 
Table 1 
Flow Chart of Assessments Performed Throughout the Study 
 
 
Asessments 
Screening 
Visit1 
Initial 
PK Visit1 
Day 
14 Visit 
Day 
30 Visit14 
End-of- Phase-I Visit 
(and beginning of 
Phase II) 
2-Month 
Visit2 
4-Month 
Visit2 
Study 
Completion 
Visit2/16 
after washout period 
of ≥ 96 h after last 
FVIII administration15 
(see Table 2) 
14-21 days 
after initial PK 
Visit day 
30 days 
(± 3 days) 
after initial PK 
Visit day 
1–3 months after 
Initial PK Visit 
2 months 
(± 1 week) 
after 
beginning of 
Prophylactic 
Treatment— 
Phase II 
4 months 
(± 1 week) 
after 
beginning of 
Prophylactic 
Treatment— 
Phase II 
6 months 
(± 1 week) 
after 
beginning of 
Prophylactic 
Treatment— 
Phase II 
Informed consent 
x 
Eligibility criteria 
x 
Demographics 
x 
Medical history 
x 
Body weight 
x 
x 
Height 
x 
Physical 
examination 
x 
x 
Vital signs3 
x 
x4 
Routine safety lab5 
x 
CD4+6 
x 
Previous 
medication 
x 
Hemophilia Joint 
Health Score 
(HJHS)12 
x 
FVIII:C plasma 
concentration7 
x 
x8 
x8 
x8 
von Willebrand 
factor antigen 
(VWFAg) 
x 
FVIII inhibitor 13 
x 
x 
x 
x 
x 
x 
x 
Review of patient 
diary 
x9 
x 
x 
x 
x 
Prophylactic dose 
and dosing 
interval 
x10 
x11 
Adverse event 
(AE) monitoring 
Throughout the study 
Concomitant 
medication 
Throughout the study 
Efficacy of Human- 
cl rhFVIII in the 
treatment of 
bleeding events 
(BEs) 
Throughout the study 
Efficacy of Human- 
cl rhFVIII in 
surgical prophy- 
laxis 
Throughout the study 
1 If possible, the Screening Visit may coincide with the Initial PK Visit. 
2 Throughout Prophylactic Treatment—Phase II, visits will take place every 2 months. 
3 Systolic and diastolic blood pressure, body temperature, pulse 
4 Before injection as well as 1 and 72 hours after the end of injection. 

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5 Haematology (local lab): red blood cell count, white blood cell count, haemoglobin, haematocrit, platelet count. 
Clinical chemistry (local lab): total bilirubin, ALT, AST, urea, serum creatinine, lactate dehydrogenase. 
6 Local lab. 
7 Central lab, using both one-stage and chromogenic assays. 
8 For the determination of FVIII:C trough plasma concentrations. Blood samples should be taken within 3 hours before injection of the next scheduled 
FVIII dose. Whenever an extra dose of FVIII has to be administered between scheduled prophylactic doses (e.g., for on-demand treatment of a 
bleeding episode), blood sampling for the determination of FVIII:C trough levels has to be delayed until the end of the next regular treatment interval. 
9 If the Screening Visit and the Initial PK Visit do not coincide. 
10 At the end of Prophylactic Treatment—Phase I, the prophylactic dose and dosing interval will be decided for each patient based on the analysis of 
individual PK data. 
11 The dose per injection may be reduced for the remainder of the study based FVIII:C trough levels (one-stage assay) obtained at the 2-Month Visit 
and provided the patient has not experienced any spontaneous bleed up to the 4-Month Visit. 
12 Version: HJHS 2.1 [14] 
13 Inhibitor testing should be performed, preferably, when FVIII level has reached baseline. 
14 Day 30 may coincide with End of Phase I Visit. 
15 A washout period of at least 72 hours would be acceptable only if a patient is at a high risk of bleeding. 
16 If patients continue treatment in the “Sub-Study Extension Phase” after the completion visit, the completion visit data will also be used as the 
screening data for the “Sub-Study Extension Phase”. If possible, both visits should occur on the same day. 
 
 
Table 2 Flowchart of Assessments in the “Sub-Study Extension Phase” 
 
Completion visit 
6-monthly (+/- 2 Completion visit 
GENA-21b/Screening 
weeks) follow up 
of “Sub-Study 
Visit “Sub-Study 
visits 
Extension 
Extension Phase” 
Phase” 
Written informed consent 
 
Inclusion/exclusion criteria check 
 
Body weight 
 
 
 
Physical Exam 
 
 
Diary & IMP instructions 
 
FVIII inhibitor/ FVIII:C (trough) 
 
 
 
Review of diary 
<throughout whole period> 
AE monitoring & changes in concomitant medication 
<throughout whole period> 
Efficacy of Human-cl rhFVIII in the treatment of bleeding 
events (BEs) 
throughout whole period 
Efficacy of Human-cl rhFVIII in surgical prophylaxis 
throughout whole period 

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7.2 Observations by Visit 
 
For a schematic representation of the study design by visit and study phase, see Figure 1. 
 
7.2.1 Screening Visit 
The following assessments will be performed: 
• Informed consent 
• Eligibility criteria 
• Demographic data: age, ethnic origin and blood type (ABO) 
• Medical history (including FVIII inhibitor history, HIV status, and bleeding 
frequency in the previous 6 months) 
• Body weight 
• Height 
• Physical examination 
• Vital signs (systolic and diastolic blood pressure, body temperature, pulse) before 
blood sample collection 
• Routine safety lab (haematology [red blood cell count, white blood cell count, 
haemoglobin, haematocrit, platelet count] and clinical chemistry [total bilirubin, 
ALT, AST, urea, serum creatinine, lactate dehydrogenase]) 
• CD4+ 
• Previous and concomitant medication (within one month before screening), 
including FVIII dosing in previous 6 months 
• Hemophilia Joint Health Score (HJHS) [14]. HJHS evaluation done in the 3 
months prior to screening is acceptable. HJHS 2.1 summary score sheet should be 
used [14] 
• Target joint(s) (defined as three or more spontaneous bleeding episodes into a single 
joint within 6 consecutive months preceding screening visit) 
 
Eligible patients agreeing to enter the study will receive a patient diary (see Section 6.7.2). 
The Screening Visit may coincide with the Initial PK Visit. If it does not, any bleeding 
episodes occurring between the Screening Visit and the Initial PK Visit should be treated 
with the patient’s previously used FVIII product. Similarly, prophylactic treatment 
between the Screening Visit and the Initial PK Visit should be done with the patient’s 
previously used FVIII product. This has to be documented as concomitant medication in 
the diary and eCRF. 

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7.2.2 Initial PK Visit 
Patients meeting the study entry criteria will receive Human-cl rhFVIII at a dose of 
60 ± 5 IU/kg (labelled dose) after a washout period of at least 96 hours from their last 
FVIII injection. A washout period of at least 72 hours would be acceptable only if a patient 
is at a high risk of bleeding. Patients must not be experiencing any bleeding. 
The following assessments will be performed: 
• Blood samples will be taken for the following purposes and at the following time 
points (see also Table 3): 
– FVIII:C plasma concentration (one-stage and chromogenic assays):* before 
injection (within 1 h before injection) and 0.5 h (± 5 min), 1 h (± 5 min), 3 h (± 
15 min), 6 h (± 30 min), 9 h (± 1 h), 24 h (± 2 h), 30 h (± 2 h), 48 h (± 2 h), and 
72 h (± 2 h), after the end of injection 
– VWFAg plasma concentration: before injection 
– FVIII inhibitor: before injection 
• Body weight before injection 
• Vital signs before injection as well as 1 and 72 hours after the end of injection 
• Information in the patient diary (if applicable) will be reviewed by the 
Investigator. For this purpose, the patient diaries will be collected and the data from 
completed diary pages transcribed to the eCRF. 
• IMP for home treatment will be given to patients. They will be re-supplied whenever 
necessary during the study. 
 
Table 3 
Flow Chart of Assessments of Initial PK Visit1 
 
Before 
injection 
(within 1 
hour) 
0.5 h 
±5 min 
1 h 
±5 min 
3 h 
±15 
min 
6 h 
±30 
min 
9 h 
±1 h 
24 h 
±2 h 
30 h 
±2 h 
48 h 
±2 h 
72 h 
±2 h 
FVIII:C plasma concentration2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
VWFAg 
x 
FVIII inhibitor 
x 
Body weight 
x 
Vital signs3 
x 
x 
x 
AE monitoring 
Throughout observation period 
1 After washout period of ≥ 96 h after last FVIII administration. A washout period of at least 72 hours would be acceptable only if a patient is 
at a high risk of bleeding . 
2 One-stage and chromogenic assays. 
 
 
 
 
 
 
* For PK analyses, data from the one-stage assay will be used (see Section 4.1 and Section 6.4.3). 

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3 Systolic and diastolic blood pressure, body temperature, pulse. 
 
 
 
7.2.3 Prophylactic Treatment—Phase I, including End-of-Phase-I Visit 
The 72-hour sampling time point of the Initial PK Visit marks the beginning of 
Prophylactic Treatment—Phase I, in which patients will be treated prophylactically every 
other day or 3x/week with a dose of 30–40 IU/kg BW for about 1–3 months until PK data 
have been analysed and discussed with the investigator. 
Dose escalations are allowed in case of an inadequate frequency and severity of 
breakthrough bleeding episodes in accordance with the institution’s standard clinical care. 
The maximum dose for a single infusion in Prophylaxis Treatment Phase I is 45 IU/kg 
BW. 
 
 
Throughout Prophylactic Treatment—Phase I, visits will take place according to the 
following schedule: 
 
Day 14 Visit: will take place 14-21 days after the administration of the first dose of 
Human-cl rhFVIII on initial PK Visit day 1. 
 
Day 30 Visit: will take place 30 days (± 3 days) after the administration of the first dose of 
Human-cl rhFVIII on initial PK Visit day 1. 
A blood sample will be taken for FVIII inhibitor testing. Blood draw for inhibitor testing 
should be performed, preferably, when FVIII level has reached baseline. 
 
End-of-Phase-I Visit 
At the end of Prophylactic Treatment—Phase I, the prophylactic dose and dosing interval 
will be determined for each patient based on the analysis of individual PK data as 
described in Section 6.4.3. A blood sample will be taken for FVIII inhibitor testing during 
this visit, only if the End-of-Phase I Visit does not coincide with the Day 30 Visit. The 
End-of-Phase-I Visit marks the beginning of Prophylactic Treatment—Phase II, in which 
patients will be treated prophylactically for 6 months using the dose and dosing interval 
determined during the End-of-Phase-I Visit as described in Section 6.4.3. 
 
 
7.2.4 Prophylactic Treatment—Phase II 
Throughout the Prophylactic Treatment—Phase II, visits will take place every 2 months. 

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2- Month Visit (± 1 week) in Phase II 
The 2-Month Visit will take place 2 months after the start of Prophylactic Treatment— 
Phase II. 
Note: To allow the patient’s true trough levels to be determined, patients should be advised 
to present for blood sampling at the end of a regular treatment interval, i.e., within 3 hours 
before injection of the next scheduled dose. 
The following assessments will be performed: 
• Blood samples for the determination of FVIII:C trough levels (one-stage and 
chromogenic assays) and FVIII inhibitor will be taken within 3 hours before 
injection of the next scheduled FVIII dose. Whenever an extra dose of FVIII has to 
be administered between scheduled prophylactic doses (e.g., for on-demand 
treatment of a bleeding episode), blood sampling for the determination of FVIII:C 
trough levels has to be delayed until the end of the next regular treatment interval. 
• Information in the patient diary will be reviewed by the Investigator. For this 
purpose, the patient diaries will be collected and the data from completed diary pages 
transcribed to the eCRF. 
 
4-Month Visit (± 1 week) in Phase II 
The 4-Month Visit will take place 4 months after the start of Prophylactic Treatment— 
Phase II. The assessments performed will be identical to those performed at the 2-Month 
Visit in Phase II. 
The dose per injection may be reduced for the remainder of the study provided that 
FVIII:C trough levels (one-stage assay) obtained at the 2-Month Visit were ≥ 0.01 IU/mL 
and the patient has not experienced any spontaneous bleed up to the 4-Month Visit. 
 
7.2.5 Monthly Compliance Checks 
Patient compliance will be closely monitored by the investigator or authorised study 
personnel on the basis of patient diaries and monthly compliance checks. 
For information on the use of patient diaries, refer to Section 6.7.2. 
During Prophylactic Treatment—Phases I and II, monthly compliance checks (± 1 week) 
will be performed by telephone or during personal visits by the patient. The 1 month 
compliance check in Phase-I will be combined with the Day 30 Visit. During these checks, 

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the investigator will determine whether the patient has adhered to the prescribed dose and 
dosing interval and whether the dose and dosing interval are adequate. 
 
7.2.6 Study Completion Visit 
The Study Completion Visit will take place 6 months (± 1 week) after the beginning of 
Prophylactic Treatment—Phase II. 
Note: To allow the patient’s true trough levels to be determined, patients should be advised 
to present for blood sampling at the end of a regular treatment interval, i.e., within 3 hours 
before injection of the next scheduled dose. 
The following assessments will be performed: 
• Blood samples will be taken: 
– FVIII:C plasma concentration (one-stage and chromogenic assays) for the 
determination of trough levels will be taken within 3 hours before injection of 
the next scheduled FVIII dose. Whenever an extra dose of FVIII has to be 
administered between scheduled prophylactic doses (e.g., for on-demand 
treatment of a bleeding episode), blood sampling for the determination of 
FVIII:C trough levels has to be delayed until the end of the next regular 
treatment interval. The next scheduled FVIII dose will no longer be considered 
study treatment. 
– FVIII inhibitor 
• Physical examination 
• Information in the patient diary will be reviewed by the Investigator. For this 
purpose, the patient diaries will be collected and the data from completed diary pages 
transcribed to the eCRF. 
All used and unused IMP vials will be returned to site. 
If patients continue treatment in the “Sub-Study Extension Phase” after the completion 
visit, the completion visit data will also be used as the screening data for the “Sub-Study 
Extension Phase”. If possible both visits should occur on the same day. 
 
 
7.2.7 Unscheduled Visits 
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. Other reasons for unscheduled visits may be the occurrence of serious AEs or 
hospitalizations due to severe BEs or surgical interventions. 

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The data that will be documented during BE or surgical visits are given in Sections 8.2.1 
and 8.2.3. 
 
7.2.8 Study visits of “Sub-Study Extension Phase” 
7.2.8.1 Screening Visit 
 
Patients have to be informed about the “Sub-Study Extension Phase” details and have to 
give their written informed consent before any investigations and assessments can be 
performed. The screening visit should be performed in conjunction with the study 
completion visit of the GENA-21b study. All test results that coincide with the study 
completion visit of GENA-21b, will be used for the screening visit of the “Sub-Study 
Extension Phase”. 
 
The following information will be documented/assessed in addition: 
 
• Check of inclusion- and exclusion criteria 
• Body weight 
 
The Investigator will hand out a patient diary and instruct the patients on how to document 
details of treatment with Human-cl rhFVIII, bleeds, AEs and concomitant medication. 
IMP for home treatment will be given to patients. They will be re-supplied whenever 
necessary during the “Sub-Study Extension Phase”. 
 
7.2.8.2 6-monthly (± 2 weeks) Follow Up Visits 
 
 
The 6-monthly follow up visit will take place every 6 months after the completion of 
Prophylactic Treatment—Phase II and the screening for the “Sub-Study Extension Phase”. 
The following assessments will be performed: 
• Blood samples for the determination of FVIII:C trough levels (one-stage and 
chromogenic assays) and FVIII inhibitor will be taken within 3 hours before 
injection of the next scheduled FVIII dose. Whenever an extra dose of FVIII has to 
be administered between scheduled prophylactic doses (e.g., for on-demand 
treatment of a bleeding episode), blood sampling for the determination of FVIII:C 
trough levels and inhibitor has to be delayed until the end of the next regular 
treatment interval. 

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• Information in the patient diary will be reviewed by the Investigator. For this 
purpose, the patient diaries will be collected and the data from completed diary pages 
transcribed to the eCRF. 
 
During these visits, the investigator will determine whether the patient has adhered to the 
prescribed dose and dosing interval and whether the dose and dosing interval are adequate. 
 
Note: To allow the patient’s true trough levels to be determined, patients should be advised 
to present for blood sampling at the end of a regular treatment interval, i.e., within 3 hours 
before injection of the next scheduled dose. 
 
 
7.2.8.3 Study Completion Visit 
The study completion visit is planned to take place within the 4th quarter of 2020. 
The following assessments will be performed: 
• Blood samples will be taken: 
– FVIII:C plasma concentration (one-stage and chromogenic assays) for the 
determination of trough levels and inhibitor will be taken within 3 hours before 
injection of the next scheduled FVIII dose. Whenever an extra dose of FVIII 
has to be administered between scheduled prophylactic doses (e.g., for on- 
demand treatment of a bleeding episode), blood sampling for the determination 
of FVIII:C trough levels and inhibitor has to be delayed until the end of the 
next regular treatment interval. 
• Physical examination 
• Body weight 
• Information in the patient diary will be reviewed by the Investigator. For this 
purpose, the patient diaries will be collected and the data from completed diary pages 
transcribed to the eCRF. 
All used and unused IMP vials will be returned to site. 
 
7.2.8.4 Unscheduled visit 
 
For Unscheduled visits during the “Sub-Study Extension Phase” see section 7.2.7 

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7.3 Study Duration 
 
7.3.1 Planned Duration for an Individual Patient 
The study duration for each patient will be approximately 7–9 months in the GENA-21b 
study. 
The duration of the “Sub-Study Extension Phase” for each patient will be approximately 
between 2.5 and 3.5 years depending upon the completion date of the GENA-21b study. 
The first patient in Japan completed Prophylactic Treatment-Phase II in June 2017 and the 
last patient completed Prophylactic Treatment-Phase II in September 2018. The clinical 
study end of the “Sub-Study Extension Phase” is planned to be in the 4th Quarter of 2020. 
Thus, individual study duration may vary from approximately 2.5 to 3.5 years. 
The overall study duration from start of the GENA-21b in the 2nd Quarter of 2015 until 
“Sub-Study Extension Phase” completion visit in the 4th Quarter of 2020 is approximately 
5.75 years. 
 
 
7.3.2 Planned Duration for the Study as a Whole 
This study started in the 2nd Quarter 2015, and the end of the GENA-21b study was in the 
3rd Quarter 2018, resulting in an overall study duration of about 3 years. 
The GENA-21b study was considered clinically completed when the last patient underwent 
the Study Completion Visit. 
The study start of the “Sub-Study Extension Phase” was in July 2017 and is planned to be 
completed in the 4th Quarter of 2020 with total study duration of about 3.5 years. The 
“Sub-Study Extension Phase” will be considered completed when the last patient has 
undergone the Study Completion Visit for the “Sub-Study Extension Phase”. 
The overall study duration from start of the GENA-21b in the 2nd Quarter of 2015 until 
“Sub-Study Extension Phase” completion visit in the 4th Quarter of 2020 is approximately 
5.75 years. 
 
 
7.3.3 Premature Termination of the Study 
Both the investigator and the Sponsor reserve the right to terminate the study at any time. 
Should this be necessary, the 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 
patients’ interests. 

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Furthermore, the Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs) will promptly be informed of the premature termination of the study and will be 
provided with a detailed written explanation. The pertinent regulatory authorities should be 
informed in accordance with national regulations. 
Early termination of the study as a whole or by study centre may occur for the following 
reasons: 
 
Clinical Study 
The study as a whole will be terminated prematurely as soon as new toxicological or 
pharmacological findings or SAEs invalidate the earlier positive benefit-risk-assessment. 
 
Study Centre 
The study can be terminated at any time at an individual centre if: 
• The centre cannot comply with the requirements of the protocol. 
• The centre cannot comply with GCP standards. 
• The required recruitment rate cannot be met. 
Should the study be prematurely terminated, all study materials (e.g., blank diaries, IMPs 
etc.) must be returned to the Sponsor. 

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8 
ASSESSMENTS AND METHODS 
A complete list of assessments performed throughout the study is given in Section 7.2. 
This section provides details on individual assessments performed as well as on the 
methods used. 
 
8.1 Baseline Information 
 
The patient’s baseline data (see Section 7.2.1) will be obtained by interviewing the patient, 
evaluating the patient’s medical record, and performing a physical examination and 
relevant laboratory tests. 
 
8.2 Efficacy Assessments 
8.2.1 Bleeding Episodes (BEs) 
BE data to be documented 
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) 
• Date and time the BE first occurred or was first noticed 
• Date and time the BE ended 
• Dates and times the IMP was injected 
• IMP dose(s) and batch number(s) 
• Assessment of the efficacy of treatment at the end of the BE; see item (c) below 
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- 
threatening BE should be treated at the study site. 
 
a) Definition of BE 
If the treatment of a BE at one site is interrupted for more than 48 hours, the events are 
recorded as two separate BEs; if another than the original bleeding site is affected, the 
events are recorded as separate BEs at any time. 
If there are several simultaneous bleeding sites, each bleeding site is recorded as a separate 
BE. 

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For certain major bleeding events, e.g., iliopsoas bleeds or bleeding into target joints, it 
may be necessary to continue treatment beyond the resolution of the acute phase to prevent 
recurrent haemorrhage. These additional injections should be recorded in the diary (and 
eCRF) but will not be evaluated as treatments of the BE. 
 
b) Assessment of the severity of a BE 
 
The following categorisation guide for severity of bleeding episodes is included in patient 
diary: 
• Minor: A bleeding that just starts and has little symptoms. For example: 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: A bleeding that involves swelling or pain including some decrease in 
range of motion of affected joint (if joint bleeding event) or moderate decrease in 
mobility and activity. For example: 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: A bleeding that causes significant pain, substantial decrease in range of 
motion of affected joint (if joint bleeding event), incapacity. For example: 
complicated joint bleeds, bleeds of the pelvic muscles, eyes. 
• Life-threatening: Bleedings in the cranium (skull), abdomen, digestive system or 
chest, central nervous system bleeds, bleedings in the area of the neck or throat or 
pharynx, head or other major trauma. 
 
c) Assessment of the efficacy of treatment at the end of a BE 
At the end of a BE, treatment efficacy will be assessed by the patient (together with the 
investigator in case of on-site treatment) using the following predefined criteria: 
• 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 

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• None: No improvement within 12 hours, or worsening of symptoms, requiring more 
than 2 injections for complete resolution 
The proportion of BEs successfully treated with IMP will be evaluated for all BEs 
together and by severity. All efficacy ratings assessed as either ‘excellent’ or ‘good’ will 
be considered ‘successfully treated’. 
 
8.2.2  Efficacy Assessment of prophylaxis treatment in the “Sub-Study Extension 
Phase” 
The efficacy of Human-cl rhFVIII in the prophylactic treatment will be assessed based on 
the frequency of total and spontaneous break-through bleeds under prophylactic treatment. 
The dates and times of study drug infusions, details of dose(s) and product batch numbers 
used for the prophylactic treatment will be documented. Details of any BEs occurring 
under prophylactic treatment will be documented. Study drug consumption data (FVIII 
IU/kg per month, per year) per patient and in total will be evaluated. 

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8.2.3 Surgical Prophylaxis 
For any surgical procedure performed during the GENA-21b study and the “Sub-Study 
Extension Phase”, the following data will be recorded: 
• Body weight within 12 hours before start of the surgery 
• Type of surgery (planned or emergency) 
• Location of surgery 
• Severity of surgery (minor, major); see item a) below 
• Expected duration of surgery 
• Actual duration of surgery (start and end times, i.e., skin to skin). 
• Details on dose(s) of Human-cl rhFVIII given pre-, intra-, or postoperatively; see 
item b) below 
• Pre-(within 3h before start of the surgery), intra-, and postoperative FVIII plasma 
levels; see item c) below 
• Expected and actual blood loss; see item d) below 
• Presence of wound haematomas and whether or not they require surgical evacuation 
• Safety lab tests (haematology, chemistry: within 12 hours before start of the surgery 
and 24 hours after the end of surgery) 
• Vital signs within 12 hours before start of the surgery (before blood sample 
collection) 
• Narrative describing the outcome and efficacy of the intervention 
• Efficacy assessment at the end of surgery by surgeon 
• Efficacy assessment at the end of the post-operative period by haematologist 
• Overall efficacy assessment at the end of surgical prophylaxis by the surgeon and the 
haematologist; see item e) below 
• Details on concomitantly administered products, including any blood or blood 
product transfusions but excluding drugs given for routine anaesthesia 
• Monitoring of AEs 
• Inhibitor test (central laboratory) with plasma sample obtained within 3 to 8 weeks 
after the end of the surgery. This visit can coincide with any other study visit where 
inhibitor testing is scheduled. 
 
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. 

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• The end of the postoperative period is the time the patient returns to his regular 
FVIII treatment regimen. 
 
a) Severity of surgery 
Surgeries are defined as major if any of the following criteria are met: 
• General or spinal anaesthesia required 
• Opening into the great body cavities required 
• Severe haemorrhage during surgery possible 
• Haemostatic therapy for at least 6 days required 
• Orthopaedic 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. 
 
b) Pre-, intra-, and postoperative doses of Human-cl rhFVIII 
Details on the pre-, intra-, and postoperative administration of Human-cl rhFVIII will be 
recorded and include the dates and times of administration as well as the batch numbers. 
In this study, only bolus injection is allowed. Continuous infusions are prohibited. 
 
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 
FVIII:C activity will be assessed at the local laboratory. In addition, samples will be 
shipped to the central laboratory for one-stage and chromogenic assay assessments (see 
Section 8.4). 
 
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 haemostasis of the same sex, age, and stature as the patient enrolled in 

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this study. After surgery, the surgeon will estimate the actual blood loss experienced by 
the patient. 
 
e) Assessment of the efficacy of surgical prophylaxis 
Efficacy will be assessed at the end of surgery by the surgeon and at end of the 
postoperative period by the haematologist. In both cases, predefined assessment criteria 
will be used. In addition, there will be an overall assessment of efficacy jointly made by 
the surgeon and the haematologist without predefined assessment criteria. 
 
At the end of surgery (by surgeon) 
• 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 haemostasis 
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 haemostasis. 
• Moderate: Intraoperative blood loss was higher than the maximum expected blood 
loss for the type of procedure performed in a patient with normal haemostasis, but 
haemostasis was controlled. 
• None: Haemostasis was uncontrolled, necessitating a change in the clotting factor 
replacement regimen. 
 
At the end of the postoperative period (by haematologist) 
• 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 Human-cl rhFVIII 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 Human-cl rhFVIII or additional injections not originally 
anticipated for the type of procedure. 
• Moderate: Some postoperative bleeding and oozing that was not due to 
complications of surgery. Control of postoperative bleeding required increased 
dosing with Human-cl rhFVIII or additional 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 product. 

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Overall efficacy assessment at the end of the postoperative period (by surgeon and 
haematologist) 
An overall efficacy assessment using the ‘excellent,’ ‘good,’ moderate,’ and ‘none’ scale 
(without any predefined criteria) taking both the intra- and postoperative assessment into 
account will be done jointly by the surgeon and the haematologist. 
Based on this overall efficacy assessment, all efficacy ratings assessed as either ‘excellent’ 
or ‘good’ will be considered ‘successfully treated’. 
Table 4 Flow Chart of Assessments Performed for Surgical Interventions During the Study Period 
 
 
 
Within 
12 hours 
before start 
Within 
3 hours 
before start 
Surgery 
POP 
day 1 
Any POP 
day 
At the end 
of POP 
periodb 
3-8 weeks 
after 
surgery* 
Intra- 
operatively 
Enda 
Body weight 
x 
Type of surgery 
x 
Location of surgery 
x 
Severity of surgery 
x 
Expected duration of surgery 
x 
Expected average and maximum blood 
loss during surgery 
x 
Actual duration of surgery 
x 
Actual blood loss during surgery 
x 
Administration of Human-cl rhFVIII 
x 
(x) 
(x) 
(x) 
(x) 
(x) 
FVIII plasma levels 
# 
(#) 
(#) 
#c 
# 
# 
Presence of wound haematomas 
x 
x 
x 
Safety lab tests 
x 
(x) 
(x) 
(x) 
Vital signs 
x 
x 
x 
Efficacy assessment 
S 
H 
Overall efficacy assessment 
SH 
FVIII Inhibitor  
x 
Narrative of outcome 
x 
Concomitant medications 
throughout observation period 
AE monitoring 
throughout observation period 
POP, postoperative; ( ) optional; # samples to be taken before (≤ 30 min) and 30 ± 15 min after IMP administration 
a time immediately after the last surgical suture. 
b time the patient returns to his regular FVIII treatment regimen 
c in case of major surgery, the determination of FVIII plasma levels is mandatory for the first 3 postoperative doses 
S, performed by surgeon; H, performed by haematologist; SH performed by surgeon and haematologist 

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8.3 Safety Assessments 
 
8.3.1 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 (definitions and reporting requirements see Section 8.3.2) 
• Other relevant safety information, including post-study safety reports, instances of 
drug overdose, drug-drug interactions, abuse, misuse, medication error, or lack of 
efficacy (see Section 8.3.5) 
8.3.2 Adverse Events 
Definitions 
• Adverse event (AE): An AE is any untoward medical occurrence in a study patient 
receiving an IMP and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable 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. 
• Adverse drug reaction (ADR): An ADR is any noxious and unintended response to 
an IMP related to any dose. “Response to an IMP” means that a causal relationship 
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: A patient whose treatment with IMP is discontinued 
because of an AE or ADR. Any such events will be followed up by the investigator 
until the event has resolved or until the medical condition of the patient has 
stabilized. Any follow-up information collected will be made available to the 
Sponsor. 
 
Collection of AEs 
The condition of the patient will be monitored throughout the study. At each scheduled or 
unscheduled study visit and at each monthly compliance check, AEs will be elicited using 
a standard non-leading question such as “How have you been since the last visit?”. In 
addition, the patient diaries will be checked by the investigator for any documented event. 

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Any AE or ADR which occurs during the study will be documented in detail on the 
appropriate pages of the eCRF. If the patient reports several signs or symptoms 
representing a single syndrome or diagnosis, the syndrome or diagnosis should be recorded 
in the eCRF. The investigator responsible will grade the severity of all AEs or ADRs 
(mild, moderate, or severe), the seriousness (non-serious or serious), and the causality as 
defined below. The Sponsor is responsible for assessing the expectedness of each ADR 
(expected or unexpected) as defined below. 
In the event of clinically significant abnormal laboratory findings, the tests will be repeated 
and the patient followed up until the laboratory values have returned to normal and/or an 
adequate 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 frequency (worsening) occurs. 
The responsible investigator will provide detailed information about any abnormalities and 
about the nature of and reasons for any action taken as well as any observations or 
comments that may be useful for the interpretation and understanding of an AEs or ADR. 
 
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 AEs is up to the medical judgement of the investigator and will be decided 
on a case-by-case basis. 
 
Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the responsible 
investigator. The causality of AEs will be classified as follows: 
• 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 
administration of the IMP; or that follows a known or expected response pattern to 
the suspected medicine; or that is confirmed by stopping or reducing the dosage of 

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the medicine and that could not reasonably be explained by known characteristics of 
the 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 
administration. An event which may have been produced by the 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 aetiology is unrelated to the IMP. 
• Unclassified: reports which for one reason or another are not yet assessable, e.g. 
because of outstanding information (can only be a temporary assessment). 
 
Classification of ADRs 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an AE that is listed in the current edition of the Investigator’s Brochure. 
• Unexpected: an AE that is not listed in the current edition of the Investigator’s 
Brochure, or that differs because of greater severity or greater specificity. 
 
Outcome of AEs 
The outcome of all reported AEs has to be documented as follows: 
(a) Recovered, resolved 
(b) Recovering, resolving 
(c) Not recovered, not resolved 
(d) Recovered, resolved with sequelae 
(e) Fatal 
(f) Unknown 
 
A patient’s death per se is not an event, but an outcome. The event having resulted in the 
patient’s death must be fully documented and reported. Deaths occurring within 4 weeks 
after IMP treatment end also have to be reported, regardless of whether or not they are 
considered treatment-related. 

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Action(s) taken 
AEs requiring action or therapy must be treated with recognised standards of medical care 
to safeguard the health and well-being of the patient. Appropriate resuscitation equipment 
and medicines must be available to ensure the best possible treatment of an emergency 
situation. 
The action taken by the investigator must be documented: 
• 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) 
• IMP-related actions taken in the event of an AE 
– None 
– Product withdrawn 
– Dose reduced 
– Dose increased 
 
The responsible investigator will follow up on each AE until it has resolved or until the 
medical condition of the patient has stabilised. Any relevant follow-up information will be 
reported to the Sponsor. 

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8.3.3 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). 
The term ‘life-threatening’ refers to an event in which the 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 the death of the patient if it had been 
more severe. 
In deciding whether a medical event is important enough to be considered a serious 
AE/ADR, medical judgment should be exercised. Thus, any event that is not immediately 
life-threatening or does not result in death or hospitalization but may jeopardise the health 
of the patient or require an intervention to prevent one of the other outcomes listed in the 
definitions above, should be considered ‘serious’. 
One such ‘important medical event’ is the development of FVIII inhibitors. Another is 
the suspected transmission of an infectious agent. These events, therefore, have to be 
reported as SAEs. 
A suspected virus transmission means that virus antigen has been detected in the patient. 
The passive transmission of antibodies alone does not constitute a suspected virus 
transmission. 

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8.3.4 SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to the study treatment, are to be 
reported immediately by telephone, fax, or email to the Clinical Project Manager: 
Sylvia Werner, MS 
Director Clinical Operations Haematology 
Octapharma USA Inc. 
121 River Street, 
Hoboken, NJ 07030 
Phone:   +1 201 604 1149 
Mobile:  +1 415 260 9577 
Fax: 
+1 415 520 9912 
Email: sylvia.werner@octapharma.com 
 
Within 24 hours after recognition of the event, an Octapharma ‘Serious Adverse Event 
Report’ must be completed and submitted. All SAEs should be reported to: 
Octapharma Central 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-hour emergency telephone number: +43 1 40 80 500 
 
Exemption from the SAE reporting requirement 
Exemptions from the SAE reporting requirement include surgeries that are elective or 
planned and prolongations of existing hospitalizations for economic or social rather than 
medical reasons. Such surgeries or prolongations of hospitalizations should not be 
considered SAEs. 
 
8.3.5 Other Relevant Safety Information 
Instances of drug overdose, drug-drug interactions, abuse, misuse, medication error, or lack 
of efficacy (items b) to g)) should be reported as AEs or SAEs, as applicable. 
 
a) Post-study safety reports 

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The investigator should also report any ADR (i.e., any AE with a suspected causal 
relationship to the IMP) occurring after completion of the study. The usual procedure for 
reporting post-marketing safety information should be followed, but the suspected causal 
relationship to the clinical study should be stated on the report. 
Deaths occurring within 4 weeks after IMP treatment end also have to be reported, 
regardless of whether or not they are considered treatment-related. 
 
b) Drug overdose 
An overdose is the deliberate or inadvertent administration of a treatment at a dose higher 
than that specified in the protocol and higher than the known therapeutic dose, and it must 
be of clinical relevance. The event must be clearly identified as an overdose. 
 
c) Drug-drug interactions 
A drug interaction is a situation where a substance/medicinal product affects the activity of 
an IMP, i.e. increases or decreases the effect(s) of an IMP, or produces an effect that none 
of the products would exhibit on their own. The event must be clearly identified as 
resulting from a drug-drug interaction. 
 
d) Abuse 
Abuse is the deliberate use of a medicinal product that may lead to addiction accompanied 
by harmful physical or psychological effects. 
 
e) Misuse 
Misuse is the deliberate administration or use of the medicinal product outside its 
described indication or outside the current state of the art medical practice (off-label-use). 
The reaction must be clearly identified as misuse. 
 
f) Medication error 
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, instructions for use/labelling. The reaction must be clearly identified as a 
medication error. 
 
g) Lack of efficacy 

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Lack of efficacy is suspected when the therapeutic result is not as expected, e.g., when 
patients with haemophilia experience continued bleeding despite the correct administration 
of coagulation factors. 
 
8.4 Laboratory Assessments 
 
The routine safety laboratory tests (as well as any FVIII:C measurements in case of 
surgery that may become necessary) will be done by the local laboratory. 
FVIII:C (one-stage and chromogenic assays), FVIII inhibitors, and VWFAg will be 
assessed by the following central laboratory: 
Colorado Coagulation 
Esoterix Inc. 
8490 Upland Drive, Suite 100 
Englewood, CO 80112, USA 
In surgical prophylaxis (see Section 8.2.3), FVIII:C activity will be assessed at the local 
laboratory. In addition, samples will be shipped to the central laboratory for one-stage and 
chromogenic assay assessments. 
Inhibitor activity will be determined by the modified Bethesda assay (Nijmegen 
modification) using congenital FVIII-deficient human plasma spiked with Human-cl 
rhFVIII as a test base. Inhibitor tests will be performed before the first injection of Human- 
cl rhFVIII, on Day 14 and Day 30 after the administration of the first dose of Human-cl 
rhFVIII, at the End-of-Phase-I Visit (this may coincide with Day 30 Visit), at the Phase II 
2-Month Visit and 4-Month Visit, at the Study Completion Visit, every 6 months during 
the “Sub-Study Extension Phase”, at Sub-Study completion visit, and whenever inhibitor 
development is suspected. Blood draw for inhibitor testing should be performed, 
preferably, when FVIII level has reached baseline. 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. 
 
8.5 Appropriateness of Measurements 
 
The criteria for assessing the efficacy of Human-cl rhFVIII in the treatment of BEs as well 
as in surgical prophylaxis are identical to those in the preceding studies with Human-cl 
rhFVIII, thus facilitating adequate comparison of results across studies. 
The measurements of the essential tolerability and immunogenicity parameters of Human- 
cl rhFVIII are identical to those used in the preceding studies with Human-cl rhFVIII. In 

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particular, inhibitor measurements are performed by a central laboratory using validated 
assays. 

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9 
DATA HANDLING AND RECORD KEEPING 
 
9.1 Documentation of Data 
 
9.1.1 Source Data and Records 
Source data are defined as 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, with 
exceptions listed in Section 9.1.2. 
The investigator will permit study-related monitoring, audit(s), IEC review(s) and 
regulatory inspection(s) by providing direct access to source data and records. 
The investigator may authorise site staff (e.g., sub-investigators, nurses) to enter study data 
into the eCRF. This must be documented in the ‘Delegation of Authority Log,’ which is to 
be filled in and signed by the responsible investigator. 
 
9.1.2 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 authorised 
sub-investigator. Monitors must provide a SDV flag to each of the eCRF pages in addition 
to the approval flag by the investigator. 
Study site staff (e.g., research nurse) will be responsible for entering all patient data into 
the validated 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, as defined in 
applicable SOPs. 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 appear on the delegation of authority log. 

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If any errors in the eCRFs are found during the data review process, discrepancies will be 
generated programmatically within the EDC system, and ‘manual’ queries will be 
generated by either a monitor or Data Management. The programmed checks fire 
automatically once an eCRF page is saved within the system. The output of the 
programmed checks are referred to as ‘discrepancies’. Discrepancies are generated by the 
input of illogical eCRF data. The purpose of these objects is to clarify the use, context, or 
insertion of illogical or missing data with the site or designee. 
All discrepancies (programmed and manual) will be submitted to the site personnel or 
monitor for the site within the EDC system. Once the site responds to a discrepancy, Data 
Management or the monitor will review the new or changed data to ensure an appropriate 
response and close the discrepancy within the system. 
 
9.1.3 Changes to eCRF Data 
Errors occurring on the EDC system can only be corrected by the investigator(s) or 
designated site personnel. An audit trail documents all changes to the data over the entire 
study period. If data is changed as a result of a query, a comment must be supplied within 
the query text, stating the reason for the change, prior to closing. The study monitor should 
provide guidance to investigators and the investigators’ designated representatives on 
making such corrections. In addition, any changes to a previously saved eCRF page that 
has not had a query generated will need to have a reason specified for the data change. This 
is handled within the EDC system, and relevant prompts appear once any changes are 
made. 
Once queries have been resolved by the site staff, the resolutions are assessed by Data 
Management for incomplete or ambiguous resolutions. If the query response provided 
confirms the data as correct, the discrepancy will be closed based on the query response. 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. 
 
9.2 Information Provided to Investigators 
 
An Investigator’s Brochure (IB) will be provided to the investigators before the start of the 
study. The IB contains all information in the Sponsor’s possession necessary for the 

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investigator 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 or whenever new information 
about the IMP becomes available. The investigators will be informed about the methods 
for rating relevant study outcomes and for completing eCRFs to reduce discrepancies 
between participating investigators 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. 
 
9.3 Responsibilities 
 
The investigator is accountable for the conduct of the clinical study. If any responsibilities 
are delegated, the investigator should maintain a list of appropriately qualified persons to 
whom he or she has delegated significant study-related duties. 
A ‘Delegation of Authority Log’ will be filled in and signed by the responsible 
investigator. Study site staff (e.g., sub-investigators, nurses) listed in the log will be 
authorised to perform study-related tasks and to enter specific data into the eCRF. 
 
9.4 Investigator Site File 
 
At each study site, the investigator is responsible for maintaining all records to enable the 
conduct 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 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 eCRF 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 
investigator 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. 

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9.5 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 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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10 STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities 
to an external Contract Research Organization (CRO). All Octapharma procedures and 
policies have to be met by this CRO. Discrepancies or exceptions are to be approved by the 
Sponsor’s Manager of Biometrics. 
A 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. 
The data collected in the GENA-21b and the “Sub-Study Extension Phase” will be stored 
in 2 separate databases and analysed separately. 
 
10.1 Determination of Sample Size 
 
10.1.1 Power 
With 50 patients with 6 months of treatment (300 person-months), one can show that the 
bleeding rate over all prophylactically treated patients (primary efficacy endpoint) is less 
than 29 per patient per year (α=0.0125 one-sided; adjusted for 2 multiple tests), assuming 
that BEs constitute a non-frequent event following a Poisson distribution and that the true 
bleeding rate is: 
• 2.3 per patient per year or lower with a power of > 99% (Scenario 1) 
• 6.7 per patient per year or lower with a power of > 99% (Scenario 2) 
• 13 per patient per year or lower with a power of > 99% (Scenario 3) 
An additional assumption for this statistical analysis is that the BEs occur at the same 
frequency independent from individual patients. 
Assuming that 20 patients will be treated with a 2x/week or less frequent prophylactic 
regimen, one can show that the bleeding rate over all patients treated with such a dosage 
regimen (secondary efficacy endpoint) is less than 29 per patient per year (α=0.0125 one 
sided; adjusted for 2 multiple tests), assuming that BEs constitute a non-frequent event 
following a Poisson distribution and that the true bleeding rate is: 
• 2.3 per patient per year or lower with a power of > 99% (Scenario 1) 
• 6.7 per patient per year or lower with a power of > 99% (Scenario 2) 
• 13 per patient per year or lower with a power of > 99% (Scenario 3) 

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Scenario 1 
assumes that the annualised bleeding rate equals the estimated mean annual 
bleeding rate in the GENA-08 trial 
Scenario 2 
assumes that the annualised bleeding rate equals the upper 2-sided 95% CI 
of study GENA-09 (i.e., 12*0.554) 
Scenario 3 
assumes that the annualised bleeding rate equals 2 times the upper 2-sided 
95% CI of study GENA-09 
 
For the “Sub-Study Extension Phase”, no inferential analysis including formal hypothesis 
testing is planned. The patients are offered to continue treatment after the completion of 
the GENA-21b evaluation study in accordance with the study protocol. Thus, neither 
formal sample size estimation nor power calculation is considered. 
 
10.1.2 Method of power calculation 
Assuming that the total number of BEs in 6 months in n patients is Poisson-distributed 
with λhalf year = n x 0.5 x λyear, where λhalf year is the expected number of BEs per 6 months 
for all patients and λyear is the expected individual bleeding frequency per year, the critical 
value c for the Poisson test is calculated as the last number before the first number for 
which the cumulative distribution function for the Poisson distribution with mean 
λhalf year,0 = n x 0.5 x 29 (null hypothesis λyear ≥ 29) is above α, the predefined nominal 
type I error. The power for this situation assuming λhalf year,1 = n x 0.5 x λyear,1 with a λyear,1 
< 29 (alternative hypothesis) is then calculated as the value of the cumulative distribution 
function for the Poisson distribution with mean λhalf year,1 at the critical value c. 
 
 
 
 
10.2 Populations for Analysis 
 
For the analysis of this study, several populations will be considered: 
• Safety analysis population: 
All patients who received at least one dose of Human-cl rhFVIII 
• Intent-to-Treat (ITT) analysis population: 
All patients in the safety analysis population for whom any data was collected after 
treatment with Human-cl rhFVIII 
• Efficacy Per Protocol (PP) analysis population: 
All patients in the ITT analysis population who completed the trial without 
significantly violating the inclusion/exclusion criteria or other aspects of the protocol 
considered to potentially affect the efficacy results. 

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Especially the following patients will be excluded from this population: 
– Patients who violate the following inclusion criteria: 
 Severe haemophilia A (FVIII:C <1%; according to medical history 
records) 
– Patients who fulfil the following exclusion criteria: 
 Other coagulation disorder than haemophilia A 
 Present or past FVIII inhibitor activity (≥ 0.6 BU), 
 Severe liver or kidney disease (ALT and AST levels > 5 times of upper 
limit of normal, creatinine >120 μmol/L), 
– Patients significantly noncompliant with the protocol, e.g., noncompliance in 
adequately completing the patient diary 
– Patients with dosing or treatment errors, e.g., the use of other FVIII products 
(except for emergencies as mentioned in Section 5.3.2) or several unexplained 
and significant deviations from the recommended dose regimen and/or dosing 
frequency 
• PK analysis population: 
All patients in the ITT population who started the initial PK assessment with Human- 
cl rhFVIII. 
• PK-PP analysis population: 
All patients in the PK analysis population who completed the initial PK sampling 
phase of the trial without significantly violating the inclusion/exclusion criteria or 
other aspects of the protocol considered to potentially affect the PK results: 
Especially the following patients will be excluded from this population: 
– Patients who violate the following inclusion criteria: 
 Severe haemophilia A (FVIII:C <1%; according to medical history 
records) 
– Patients who fulfil the following exclusion criteria: 
 Coagulation disorder other than haemophilia A 
 Present or past FVIII inhibitor activity (≥ 0.6 BU), 
 Severe liver or kidney disease (ALT and AST levels > 5 times of upper 
limit of normal, creatinine > 120 μmol/L) 
– Patients who use concomitant medication before or during the PK phase that 
may confound study results. 
– Patients who use FVIII treatment that may confound the PK results: 
resulting in baseline FVIII:C level ≥ 0.15 IU/mL 
– Patients who receive less than 80% or more than 120% of the planned dose 
– More than 2 consecutive blood samples missing for PK assessment 

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– More than 3 post-baseline blood samples missing for PK assessment 
• Population of patients on individual prophylactic treatment schedule (PROPH): 
All patients in the ITT population who enter the Prophylactic Treatment—Phase II of 
the study (i.e., have at least one prophylactic treatment in Phase II) 

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• PP population of patients on prophylactic treatment schedules (PROPH-PP): 
All patients in the PP population who enter the Prophylactic Treatment—Phase 
II 
of the study 
– who have evaluable initial PK results for the evaluation of the individual 
prophylactic treatment schedule 
– with at least 6 months (–2 weeks) of individual prophylactic treatment 
(Prophylactic Treatment—Phase II) with Human-cl rhFVIII 
– who have no significant dosing or treatment errors, e.g., several unexplained 
interruptions of individual prophylaxis with Human-cl rhFVIII, e.g., > 20% of 
prophylactic injections were not given within the prescribed treatment intervals 
(± 1 day) 
• Subpopulations of the PROPH populations: 
(1) patients with 2x/week (or less) individual prophylaxis in Prophylactic 
Treatment—Phase II (defined as patients on a 2x/week (or less) treatment 
schedule 80% of the time and without a decrease in the treatment interval in the 
last defined treatment schedule as compared to the previous one). 
(2) patients with more than 2x/week individual prophylaxis in Prophylactic 
Treatment—Phase II (all patients in the PROPH population who are not in 
subpopulation (1)). 
• Population of treated BEs (BLEED): 
All documented bleeds of patients in the ITT population for which 
– any amount of treatment with Human-cl rhFVIII is documented and which 
– starts between the start of Prophylactic Treatment—Phase I and the Study 
Completion Visit (or withdrawal) 
• PP population of treated BEs (BLEED-PP): 
All documented bleeds in the BLEED population of patients in the PP population for 
which no other FVIII product was documented. 
 
The patient disposition, i.e., the identification of significant violations to be considered for 
the PP populations and the assignment of each patient and bleeding to these analysis 
populations, will be the joint decision of the trial statistician and the responsible medical 
expert prior to database lock. 
The PROPH population is considered primary for analysis of efficacy data on prophylaxis; 
the BLEED population is considered primary for analysis of efficacy data on BEs. 

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To evaluate the robustness of the study results, efficacy analyses will also be done on basis 
of the respective PP populations. The PK-PP population is the primary analysis population 
for the PK data; however, any effort will be made to derive a calculation for the individual 
prophylactic scheme from the initial PK for all patients who start prophylaxis. 
The analysis of safety will be based on the safety analysis population. 
 
For a detailed description of patients included in the “Sub-Study Extension Phase”, the 
following population flags will be used: 
• Safety analysis population: All subjects who received at least one dose of Human-cl 
rhFVIII; 
• Intent to Treat (ITT) analysis population: All subjects in the safety analysis population 
for whom any data was collected post treatment with Human-cl rhFVIII; 
• Efficacy: Per Protocol (PP) analysis population: All subjects in the ITT analysis 
population 
who 
completed 
the 
trial 
without 
significantly 
violating 
the 
inclusion/exclusion criteria or other aspects of the protocol considered to potentially 
affect the efficacy results. 
Especially the following subjects will be excluded from this population: 
• Subjects who fulfill the following exclusion criteria: 
- other FVIII product than Human-cl rhFVIII was received between completion 
visit of GENA-21b and start of “Sub-Study Extension Phase” (except emergency 
cases) 
• Subjects with significant non-compliances with the protocol such as non-compliance 
to complete the diary in a proper manner or more than 30% of haemostatic efficacy 
assessments missing. 
• Subjects with dosing or treatment errors like e.g. the use of other FVIII products 
(except for emergencies as mentioned above) or several unexplained and significant 
deviations from the recommended dose regimen. 
• Population of subjects on prophylactic treatment schedule (PROPH): All subjects in the 
ITT population who have at least one prophylactic treatment 
• Per-protocol population of subjects on prophylactic treatment schedules (PROPH-PP): 
All subjects in the PP population who have no significant dosing or treatment errors, 
like e.g. unexplained interruptions of the prophylaxis with Human-cl rhFVIII 
• Population of bleedings (BLEED): All documented bleeds - except those occurring 
during and after surgery - of subjects in the ITT population for which 
• any amount of treatment with Human-cl rhFVIII is documented and which 
• start between first BE treated with Human-cl rhFVIII and the completion visit. 
• Population of bleedings per protocol (BLEED-PP): All documented bleeds in the 
BLEED population of subjects in the PP population. 
• Surgery population (SURG): All documented surgical interventions of subjects in the 

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ITT population for which 
• any amount of Human-cl rhFVIII prior to, during or after the surgery is 
documented and 
• no other FVIII product is documented within 24 hours prior to surgery. 
• Surgery per-protocol population (SURG-PP): All documented surgical interventions of 
subjects in the PP population for which 
• any amount of Human-cl rhFVIII prior to, during or after the surgery is 
documented and 
• no other FVIII product is documented within 72 hours prior to, during or after the 
surgery (until resuming regular prophylactic treatment or until discharge from 
hospital in case of a subject with on-demand treatment). 
The subject disposition, i.e. the identification of significant violations to consider for the 
PP populations and the assignment of each subject, bleeding and surgery to these analysis 
populations, will be the joined decision of the trial statistician and the responsible medical 
expert prior to database lock. 
Due to the limited sample size of patients in the “Sub-Study Extension Phase” the 
population flags will be used to describe patient characteristics in more detail within 
patient profiles or subject data listings. No subgroup analyses by use of these populations 
are planned. In case of extreme data constellations sensitivity analyses by excluding 
patients from the analysis or by focusing the analysis on patient populations as described 
above can be performed, if deemed reasonable with respect to sample size. 
 
10.3 Efficacy Analysis Plan 
 
10.3.1 Primary Objective 
 
The primary objective of this study is to compare the annualised total bleeding rate of 
individually tailored prophylaxis with the historical bleeding rate observed in patients 
having received on-demand treatment with Human-cl rhFVIII from study GENA-01. 
Primary endpoint: Reduction of the annualised total bleeding rate observed in the GENA- 
01 study (58.1 total bleeding episodes per patient per year) by 50% during individually 
tailored prophylaxis. 
a) Primary analysis 
Hypotheses and test procedures 
A confirmative one-sided one-sample Poisson test will test whether the annualised total 
bleeding rate in patients with individual prophylaxis is at least 50% below the mean 
annualised total bleeding rate in the GENA-01 trial (i.e., if it is < 29). 

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Assumption 
All BEs* and all months of prophylactic treatment will be pooled, each over all patients. 
The results will be denoted as y (number of BEs) and t (the pooled time frames in days). 
The total number of BEs y is assumed to be distributed with a Poisson distribution with 
parameter λyear. Assuming a standard year of 365 days, y weighted by d/t 
(d = 365 days, t = sum over all observed days) will follow a Poisson distribution. 
 
 
Tests on BE rates: 
H0: λyear ≥ 29 (1/2 of annualised mean bleeding rate in GENA-01) 
Ha: λyear < 29, 
where λyear  represents the annualised rate of BEs per patient through the 6-month 
efficacy period, assuming a Poisson distribution for the frequency of BEs. 
The annualised rate (λyear) of BEs will be estimated along with its 2-sided (1-2α) x 100% 
confidence limits: 
 
 
λ year = d y , 
t 
λ year, upper,1-2α = 
d x 0.5 
t 
 
2 
(1−α ),2 y+2 , 
λ year, lower,1-2α 
= 
d x 0.5 
t 
 
2 
α ,2 y 
 
 
with 
2 
(1−α ),ν 
representing the upper 1-α percentile of the Chi-Square distribution with ν degrees of 
freedom, y the total sum of BEs documented during the observed prophylactic treatment 
period total, t the sum of all observed individual prophylactic treatment periods in days, 
and the constant d = 365 the assumed number of days per year. 
H0 is rejected if λyear, upper,1-α < 29. Type one error, one-sided : α ≤ 0.0125. 
This confirmative test will be adjusted for a second test on the secondary efficacy variable 
‘annualised total bleeding rate in patients with 2x/week (or less) prophylaxis’ with the 
Bonferroni rule. The maximum overall type-one error for both tests therefore will be 
2 x α = 0.025. 
 
There will be no adjustments for covariates in this primary analysis. 
χ
χ
χ

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The individual annualised bleeding rate is estimated as follows: 
 
 
ATBRi,IP = 365 x (number of all documented BEs* in patients in the PROPH population 
between start of Prophylactic Treatment—Phase II and Study Completion Visit or 
withdrawal / (number of days between start of Prophylactic Treatment—Phase II and 
Study Completion Visit or withdrawal + 1) 
 
 
Notes: ATBRi,IP = annualised bleeding rate of patient i in study GENA-21b (individual 
prophylaxis scheme) 
*The number of all documented BEs includes BEs treated with Human-cl 
rhFVIII, treated with other FVIII, and not treated during Prophylactic 
Treatment—Phase II. 
 
a) Additional analysis 
As an additional analysis of bleeding rates, the individual annualised bleeding rate will be 
analysed with a Poisson regression model and a Negative Binomial regression model, both 
including a correction for overdispersion. In these models, the number of BEs is the 
dependent variable and the log time of the observed prophylactic treatment period is used 
as an offset variable. 
In addition, GENA-21b individualised annual bleeding rate data will be combined with 
GENA-01 individualised annual bleeding rate data in these models. The rate ratio 
comparing the individualised annual bleeding rates of the two trials and its corresponding 
95% CI will be estimated from the model. 
This will be done for spontaneous, traumatic, and all BEs. 
In addition, the distribution of individual annualised total bleeding rates will be shown with 
descriptive statistics. 
 
10.3.2 Secondary Objectives 
 
1. Comparison of annualised spontaneous bleeding rate of individualised tailored 
prophylaxis with the historical bleeding rate observed in patients having received on- 
demand treatment with Human-cl rhFVIII 
Endpoint: Reduction of the annualised spontaneous bleeding rate observed in the GENA- 
01 study (38.5 spontaneous bleeding episodes per patient per year) by 50% during 
individually tailored prophylaxis 

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This endpoint will be analysed in the same way as the primary endpoint (see 
Section 10.3.1), where the BEs are restricted to the spontaneous BEs. In case the upper 
limit of the 95% CI is below 19.25, the null hypothesis can be rejected. 
No adjustment for multiple testing will be made. 
In addition, descriptive analyses of individual bleeding rates (monthly, projected annually) 
will also be generated separately for the first 4 and the last 2 months (i.e., period starting 
with the 4-Month Visit) of Prophylactic Treatment—Phase II. 
 
2. Comparison of annualised total bleeding rate in patients with 2x/week (or less) 
prophylaxis with the historical bleeding rate observed in patients having received on- 
demand treatment with Human-cl rhFVIII 
Endpoint: Reduction of the annualised bleeding rate observed in GENA-01 by 50% in 
patients with 2x/week prophylaxis or less 
This endpoint will be analysed in the same way as the primary endpoint (see 
Section 10.3.1), where the patients are restricted to the subpopulation of patients with 
2x/week (or less) prophylaxis in Prophylactic Treatment—Phase II. 
The respective Poisson test will be adjusted for multiplicity with the Bonferroni rule as 
described for the primary endpoint. 
 
3. Assessment of the median prophylactic dosing interval 
Descriptive statistics will be provided on the distribution of the prophylactic dosing 
intervals overall and on the median prophylactic dosing interval per patient. 
 
4. Assessment of the PK of Human-cl rhFVIII in terms of the FVIII coagulant activity 
(FVIII:C) 
The initial PK will be used to determine an individual dosing scheme for Prophylactic 
Treatment—Phase II of the study. 
The calculations for the PK will be made by applying one- or two- compartmental PK 
methods (as individually appropriate) to plasma levels obtained at predefined time points 
as described in Section 7. 
The following PK parameters of Human-cl rhFVIII will be determined: 
• In vivo half-life (t1/2) (in case of two compartments both initial and terminal half-life) 
• In vivo incremental recovery (IVR) 
• Maximum plasma concentration (Cmax) 
• Time for reaching maximum plasma concentration (Tmax) 
• Mean residence time (MRT) 

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• Volume of distribution at steady state (Vss) 
• Clearance (CL) 
For these calculations, the actual potency of Human-cl rhFVIII, will be used. 
The calculations will be made by applying compartmental PK methods based on plasma 
levels obtained at pre-defined time points. FVIII:C chromogenic and the one-stage assay 
results will be determined. 
Descriptive statistics will be provided for all PK parameters for the treatment with Human- 
cl rhFVIII. 
 
Calculation of dose/dosing-interval for individual prophylaxis scheme 
Given the individual PK parameters and the respective one- or two-compartment model 
concentration time regression curve, it will be estimated for each patient for how long 
different doses are expected to provide FVIII:C plasma concentrations (one-stage assay) of 
≥ 0.01 IU/mL. 
The goal is to determine the maximum regular prophylactic dosing interval that can be 
achieved with a dose not exceeding 65 IU/kg and capable of maintaining a trough level of 
≥ 0.01 IU/mL. Simulations will support the individual determination of the prophylactic 
interval and dose; the final decision on the prophylactic scheme will be taken by the 
investigator after consultation with the patient and Sponsor. 
 
10.3.3 Additional Objectives 
 
1. Assessment of the efficacy of Human-cl rhFVIII in the treatment of bleeding episodes 
(BEs) 
Analyses will be performed on the BLEED and BLEED-PP populations. The efficacy will 
be evaluated by descriptive statistics on efficacy assessments per breakthrough bleeding, 
basic bleeding characteristics including severity, site, and type. The efficacy assessments 
will be presented in summary tables. 
A BE is considered successfully treated if the efficacy is assessed as at least ‘good.’ The 
rate of successfully treated BEs (all BEs, spontaneous BEs, traumatic BEs) will be 
provided with a 95% exact confidence interval. 
The frequency of BEs, the number of injections needed to treat a BE, the number of EDs, 
and study drug consumption data (FVIII IU/kg per injection, per BE, per month, per year) 
per patient and in total will be evaluated. 
In an alternative analysis, the frequency of successfully treated BEs will be analysed with a 
generalised estimation equations (GEE) model accounting for the within-subject 

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correlation of bleeding assessments. The analysis populations will be the subjects with any 
BE in the BLEED population and the subjects with any BE in the BLEED-PP population. 
2. Assessment of the efficacy of Human-cl rhFVIII in surgical prophylaxis 
The following will be presented in frequency tables or with descriptive statistics: 
• Efficacy evaluation by the surgeon and the haematologist (intra- and post-operatively 
and overall) 
• Number of patients undergoing surgeries and number of surgeries (minor, major, total) 
• Surgery characteristics (type and site, pre-planned (yes/no), reason, severity, expected 
and actual duration, expected and actual blood loss) 
• Details on treatment with Human-cl rhFVIII (before, during, and after the surgical 
procedure (number of injections, dosing details, amount of IMP) 
• Pre-, intra-, and post-operative FVIII plasma levels 
• Any wound hematomas and whether they require surgical evacuation 
 
3. Assessment of the correlation of VWF antigen concentration and half-life 
Both Pearson’s correlation coefficient and Spearman’s rank correlation coefficient will be 
presented. 
 
4. Assessment of the association between ABO type and half-life 
The descriptive statistics of terminal half-lives will be presented by ABO type; if 
appropriate, the number and percentage of patients with each combination of ABO type 
and classified terminal half-life will be presented in a contingency table in addition. 
 
5. Assessment of Human-cl rhFVIII consumption data (exploratory) 
 
Descriptive statistics will be provided on FVIII consumption data (FVIII IU/kg per week/ 
month/year per patient). 
 
 
 
10.3.4 Efficacy Analysis Plan for the “Sub-Study Extension Phase” 
Efficacy will be evaluated by descriptive statistics. 
• On bleeding rates (efficacy of prophylaxis) 
• On efficacy assessments per treatment of bleed, basic bleed characteristics including 
severity, site and type 
• On efficacy assessments per surgery 

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The frequency of bleeds, the number of infusions needed to treat a BE, the number of EDs, 
and study drug consumption data (FVIII IU/kg per infusion, per BE, per month, per year) 
per patient and in total will be evaluated. Furthermore, increased and decreased doses of 
Human-cl rhFVIII used to treat individual BEs (frequency and relative magnitude of dose 
changes) will be evaluated, as well as changes in the doses per infusion and changes in the 
total dose used to treat subsequent BEs of the same type (e.g. elbow, knee, etc.) in the same 
patient (frequency and relative magnitude of dose changes). 
 
10.3.5 Safety Analysis Plan 
Adverse events 
All AEs occurring after the initiation of study treatments (including events likely to be 
related to the underlying disease or a concomitant illness or medication as well as clinically 
significant abnormalities in laboratory parameters or vital signs) will be displayed in 
summary tables and listings. 
Incidences of AEs will be given as numbers and percentages of patients and injections 
with: 
• Any AE 
• Any serious AE 
• Any AE probably or possibly related to the IMP 
• Any AE that begins within 24 hours after the end of an injection 
• Any severe AE 
• Any withdrawal due to AE 
• Any AE by MedDRA Preferred Term (PT) 
• Any AE by MedDRA System Organ Class (SOC) 
Additionally, AEs will be summarised by severity and relationship to study treatment. 
These summary tables will feature total counts, prior exposure days to Human-cl rhFVIII, 
total amount of Human-cl rhFVIII used prior to the AE and the frequency of prophylactic 
treatment (up to 2x/week vs. 2x or more/week) to evaluate the need of further investigation 
of any apparent pattern or trend in AE rates. 
The MedDRA-coded terms and the corresponding original (verbatim) terms used by the 
investigator will be listed. 

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Vital signs 
Blood pressure (systolic/diastolic), pulse, and body temperature will be presented by time 
point. 
 
Routine laboratory data 
Routine laboratory parameters will be listed for all patients, using indicators for values 
outside the associated reference ranges. Shift tables will be provided where appropriate. 
 
Inhibitors against FVIII 
All recorded determinations of inhibitors against FVIII will be listed. If any, the 
occurrence and cumulative incidence of inhibitors (inhibitor titre ≥ 0.6 and ≥ 5 BU, 
respectively) will be presented in total, and as percentage of the analysis population. If any, 
the changes between start and end of study will be summarised in a shift table. 
 
 
10.3.6 Safety Analysis Plan for the “Sub-Study Extension Phase” 
Except for vital signs which are not monitored in the “Sub-Study Extension Phase” all 
analyses will be performed as outlined in section 10.3.5 
 
10.3.7 Handling of Missing Data 
In general, missing data will not be imputed, and calculations pertaining to person-year 
computations will be based on observed values only. 
Only in case of missing body weight will the last available weight measurement be used 
for calculating the dose per kg body weight or PK parameters (last observation carried 
forward). 
 
10.4 Randomization, Stratification, and Code Release 
 
Not applicable. 

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11 ETHICAL, REGULATORY, LEGAL, AND ADMINISTRATIVE 
ASPECTS 
 
11.1 Ethical and Regulatory Framework 
 
This study will be conducted in accordance with the ethical principles laid down in the 
Declaration of Helsinki. The study protocol and any subsequent amendment(s) will be 
submitted to an IEC/IRB and to the Regulatory Authority. The study will be conducted in 
compliance with the protocol, GCP regulations, 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. 
 
11.2 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 approval letter must be available before any patient 
undergoes any 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. 
 
11.3 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 aspects of the study that are relevant to the patient’s decision to participate. The 
informed consent form must be signed, with the patient’s name and the date and time 
added 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 
legal guardian (in the Netherlands, such patients are not allowed to participate in the 
study). 
If patients from Japan wish to continue treatment with Human-cl rhFVIII in the “Sub- 
Study Extension Phase” after the completion visit in GENA-21b they have to freely give 
legal, written consent for participation in the “Sub-Study Extension Phase”. 

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The investigator will explain that the patients are completely free to refuse to enter the 
study or the “Sub-Study Extension Phase”, to withdraw from them 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 applicable regulations and that these persons are bound by confidentiality obligations. 
 
11.4 Protocol Amendments 
 
Any prospective change to the protocol will be agreed between the co-ordinating 
investigator and the Sponsor before implementation. Any such amendments will be 
submitted to the IEC(s)/IRB(s) and/or competent authority as required 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 or the objective or design of the study, which is 
associated with an increase in the dosage, duration of exposure to the IMP, or number of 
patients treated, results in the addition of a new test or procedure, or which drops a test 
intended to monitor safety. 
 
11.5 Confidentiality of Patients Data 
 
The investigator will ensure that the patient's confidentiality is preserved. On eCRFs or any 
other documents submitted to the Sponsor, the patients will not be identified by their 
names but by a unique patient number. Documents not intended for submission to the 
Sponsor, i.e., the confidential patient identification code list, original consent forms, and 
source records, will be maintained by the investigator in strict confidence. 

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12 QUALITY CONTROL AND QUALITY ASSURANCE 
 
12.1 Periodic Monitoring 
 
The monitor will contact and visit the investigator periodically to review all study-related 
source data and 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, analyse, verify, and reproduce 
any records and reports that are important for the evaluation of the clinical study. Source 
data will be available for all data in the eCRFs, including all laboratory results. 
 
12.2 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/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 the safety and efficacy of the IMP have been reported to the Sponsor. 

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13 REPORTING AND PUBLICATION 
 
13.1 Clinical Study Report 
 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s SOPs) 
was prepared by the Sponsor after completion of the GENA-21b study and will be 
prepared after completion of the “Sub-Study Extension Phase”. The studies will be 
analysed separately and reported in 2 separate clinical study reports. The co-ordinating 
investigator will approve both final study reports after review. 
 
13.2 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-centre studies only in their entirety and not as individual centre data. 
Authorship will be determined by mutual agreement. 
 
14 LIABILITIES AND INSURANCE 
To cover any potential damage or injury occurring to a patient in association with the IMP 
or the participation in the study, Octapharma AG will contract insurance in accordance 
with local regulations. 
The investigator is responsible for dispensing the IMP according to this protocol as well as 
for the secure storage and safe handling of the IMP throughout the study. 

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