Clinical trial NCT04046848
Conditions: Severe Hemophilia A
Keywords: Hemophilia A Blood Coagulation Disorders, Inherited Blood Coagulation Disorders Hematologic Diseases Coagulation Protein Disorders Hemorrhagic Disorders Genetic Diseases, Inborn Factor VIII
Sponsor: Octapharma
Start date: 2019-07-03; Completion date: 2022-02-18
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This Phase 1/2 study will be a dose escalation study in adults in 5 cohorts (named cohorts 1, 2, 3, 5 and 6), with the main purpose to assess the safety of subcutaneous injection of OCTA101 (a human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer) in previously treated adult patients with severe hemophilia A. The study also aims to assess the pharmacokinetics (PK) characteristics, dose proportionality, and subcutaneous bioavailability of OCTA101 compared with intravenous administration of Nuwiq (Human-cl rh FVIII), in order to define the prophylactic treatment (dose and injection interval) that would result in protective trough levels of FVIII:C for future Phase 3 studies. Cohorts 1, 2, 3 and 5 will undergo a single injection of OCTA101, with cohorts 1, 2 and 3 proceeding to 3-month daily dosing prophylactic treatment for 3 months by Data Monitoring Committee recommendation. Cohorts 1 and 2 will undergo a further PK at the end of the daily injection period. A further cohort, cohort 6, will have an initial 4 to 6-week run-in treatment period with Nuwiq intravenous prophylaxis followed by 12.5 IU/kg OCTA101 subcutaneous daily prophylaxis for \>3 up to 6-7 months.

Detailed description:

Arms: arm 1: 50 IU/kg (n=4): single-period investigation with a single sc dose of 50 IU/kg OCTA101 profiled up to 72 hours after dosing in adult male patients with severe hemophilia A.

Following review of safety and tolerability data by Data Monitoring Committee, proceed with Cohort 2, alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. arm 2: 100 IU/kg (n=4): single-period investigation with a single sc dose of 100 IU/kg OCTA101 profiled up to 96 hours after dosing in adult male patients with severe hemophilia A.

Following review of safety and tolerability data by Data Monitoring Committee, proceed with Cohort 3, alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. arm 3: 50 IU/kg (n=8): two-period investigation of a single iv dose of 50 IU/kg Human-cl rhFVIII (Nuwiq) profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg OCTA101 profiled up to 72 hours in adult male patients with severe hemophilia A.

Treatments will be administered in fixed sequence, with Human-cl rhFVIII first.

Following review of safety and tolerability data by Data Monitoring Committee, proceed with Cohort 4 and 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. arm 4: (n=4): Three-period investigation of single sc doses of 20, 40, and 60 IU/kg OCTA101 profiled up to 72 hours after dosing. Treatments were to be administered in fixed dose-ascending sequence. arm 5: (n=16): Following an initial 4 to 6-week run-in period with Nuwiq iv prophylaxis, \>3-6 months daily prophylactic treatment with 12.5 IU/kg OCTA101 sc, then 25 IU/kg OCTA101 sc for a further 6-7 months (exact dosing depends on available vial sizes). In case of two spontaneous bleeding episodes, after having completed at least 3 months with 12.5 IU/kg OCTA101 daily treatment the individual treatment dose will be increased from 12.5 to 25 IU/kg. Site of administration (abdomen or thigh) to be chosen by the patient. A further treatment phase with 40 IU/kg OCTA101 will be discussed with the DMC, once results of earlier dosing phases are available.
Interventions: intervention 1: OCTA101
Intervention descriptions: intervention 1: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).

Protocol documents:
Prot_000.pdf: 
 
This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
090-CSP-SubQ8-01-V9_30JUL2021 FINAL/DOC ID 3383 
 
CLINICAL STUDY PROTOCOL 
STUDY TITLE 
Phase 1/2 study to assess the safety and pharmacokinetics of 
subcutaneous injection of OCTA101 in previously treated 
adult patients with severe hemophilia A 
Study Code: SubQ8-01 
Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Indication: 
Severe hemophilia A 
Study Design: 
Prospective, open-label study, dose-finding 
Sponsor: 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
Study Number: 
SubQ8-01 
EudraCT: 
2018-002776-40 
Development Phase: 
Phase 1/2 
Planned Clinical Start: 
Quarter 2 2019 
Planned Clinical End: 
Quarter 3 2022 
Date of Protocol: 
30-Jul-2021 
Version: 
9.0 
Revision of Protocol Version 8.0, dated 03-Mar-2021 
Co-ordinating Investigator: 
Dr. Toshko J. Lissitchkov,  
Specialized Hospital for Active Treatment of 
Hematological Diseases EAD 
Clinic of Clinical Hematology 
6, Plovdivsko pole str 
1756 Sofia 
Bulgaria 
 
Property of Octapharma. Do not copy or distribute without written permission.


Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021
Page 2 of 82 
STUDY OUTLINE 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021
Title of Study: Phase 1/2 study to assess the safety and pharmacokinetics of subcutaneous 
injection of OCTA101 in previously treated adult patients with severe hemophilia A. 
Indication: Severe hemophilia A 
Number of Study Centers: 1 center 
Objectives: 
Primary Objective: 
The primary objective is to assess the safety of various doses of OCTA101 after subcutaneous 
(sc) injection.  
Secondary Objectives: 
The secondary objectives of this study are to assess 
•
the pharmacokinetics of FVIII:C after single sc injection of OCTA101
•
the dose proportionality of FVIII:C after sc injections of different doses of OCTA101
•
the bioavailability of sc OCTA101 compared to iv injection of Nuwiq
•
the pharmacokinetics of OCTA12 (recombinant human von Willebrand Factor
fragment dimer) after single injection of OCTA101
•
plasma trough and peak levels of FVIII:C after daily injections of OCTA101
•
plasma trough and peak levels of OCTA12 after daily injections of OCTA101
•
the efficacy of sc injections of OCTA101 in preventing bleeding episodes.
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 3 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
Study Design: 
SubQ8-01 is a first-in-human, prospective, open-label Phase 1/2 study of OCTA101 
(Human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer), which 
consists of an eluate of an already authorized human recombinant coagulation factor FVIII 
product (Nuwiq®) along with OCTA12 (at a molar ratio of 1:6, with regards to FVIII binding 
sites in OCTA12), an investigational human recombinant VWF fragment dimer, which is 
expected to increase the bioavailability of FVIII on subcutaneous (sc) dosing. The trial was 
to be carried out in adult patients with severe hemophilia A according to a staged integrated 
design with five planned consecutive cohorts. No patient can receive treatment in more than 
1 cohort. One part of the study was to be a single ascending dose study in 4 cohorts (50, 100, 
200 and 400 IU/kg). The decision of going to the next higher dose was to be taken after each 
cohort by an external independent Data Monitoring Committee (DMC) after review of safety 
and tolerability data, FVIII:C plasma levels, and PK characteristics of FVIII:C and OCTA12. 
Any safety-relevant signals were also forwarded to the DMC for their review as they occurred. 
The reason(s) for not progressing to a higher dose level, e.g. dose-limiting toxicities (DLTs), 
were to be documented if such a decision was reached. 
Pre-defined DLTs for this study are: 
1. Severe allergic reactions at least possibly related to study drug. 
2. Severe vital organ toxicity at least possibly related to study drug that does not resolve 
to at least mild severity within 48 to 72 hours. 
3. Any treatment-emergent severe toxicity at least possibly related to study drug other 
than the toxicities referenced in 2) that does not decrease to mild or resolve within 
7 days. 
Based on the results from Cohorts 1 and 2, the sponsor and DMC decided that escalation to 
higher doses should not take place and that further characterization of 50 IU/kg and lower 
doses was warranted. Therefore, Cohort 3 received 50 IU/kg administered into the abdomen, 
Cohort 4 was to receive 50 IU/kg administered into the thigh (this was not proceeded with, as 
described below), and Cohort 5 investigated dose linearity at a lower dose range than initially 
planned (20, 40 and 60 IU/kg instead of 50, 100 and 200 IU/kg). 
Patients in Cohort 3 also received a single iv dose of 50 IU/kg Nuwiq in order to compare the 
bioavailability of sc OCTA101 with those of Nuwiq (the FVIII part of OCTA101) injected 
intravenously (iv). The treatment sequence was Nuwiq followed by OCTA101. Dose 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 4 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
proportionality of OCTA101 was evaluated after single sc administration of three different 
doses (20 IU/kg, 40 IU/kg and 60 IU/kg) in 4 additional patients (Cohort 5).  
A PK assessment was performed in patients from Cohorts 1 and 2 who completed their 
3-month daily injection period.  
Following completion of the PK assessments in Cohort 3 and 1-month into OCTA101 daily 
prophylaxis in this cohort, the study was put on hold due to inhibitor development in a second 
patient (in Cohort 2). 
Due to the study hold, patients in Cohort 3 were switched to prophylaxis with Nuwiq after 
having received 1-month of OCTA101 daily prophylaxis. Patients in Cohort 3 completed the 
study when their overall time on daily prophylaxis (OCTA101 + Nuwiq) reached 3 months. 
By the time of preparation of protocol version 8.0, Cohorts 1, 2 (with the exception of 1 patient 
with FVIII inhibitors who entered ITI treatment with Nuwiq), 3, and 5 were completed. 
With the agreement of the DMC, it was decided to proceed with the study, introducing the 
following changes to the study design. Cohort 4 was cancelled and Cohort 5 was cut from 8 
patients to 4.  
A new cohort (Cohort 6) was initiated for 16 evaluable patients. In this cohort, patients have 
an initial 4 to 6-week run-in treatment period with Nuwiq iv prophylaxis followed by 
12.5 IU/kg OCTA101 sc daily prophylaxis for >3 up to 6-7 months. With DMC agreement, 
the patients will then proceed to 25 IU/kg OCTA101 sc daily prophylaxis for 6-7 months. 
Based on the results of both dosing phases, a 40 IU/kg OCTA101 will be considered. Cohort 6 
is planned to proceed as follows:  
• Following completion of the run-in period with Nuwiq iv prophylaxis, 3 patients  
started daily dosing with 12.5 IU/kg OCTA101 sc. 
• After 3 months of treatment with OCTA101, the patients had their 3-month follow-up 
visit. During the 2 to 3 weeks waiting for all relevant results, especially FVIII inhibitor 
testing results, these patients continued on daily dosing with 12.5 IU/kg OCTA101 sc. 
• DMC agreed that further patients can start their daily prophylaxis with OCTA101, up 
to 16 patients proceeded with 12.5 IU/kg OCTA101. After further 3 months, 
following DMC data review, the first 3 patients of this cohort were planned to start on 
daily dosing with 25 IU/kg OCTA101 sc for 6-7 months. The remaining patients were 
planned to follow after a further 3 months, after DMC data review. 
• Patients reporting two spontaneous bleeding episodes will be switched to the next 
higher dose level after having completed at least 3 months with 12.5 IU/kg OCTA101 
daily treatment: they will start daily dosing with 25 IU/kg OCTA101 sc. 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 5 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
• Depending on the results of the 12.5 IU/kg and 25 IU/kg OCTA101 treatment phases, 
the initiation of a 40 IU/kg OCTA101 phase will be considered together with the 
DMC. 
• Bleeding episodes will be controlled with the use of Nuwiq during the entire duration 
of treatment in Cohort 6. 
The cohorts are summarized as follows: 
• Cohort 1: 50 IU/kg OCTA101 (n=4): Single-period investigation with a single sc 
dose of 50 IU/kg OCTA101 profiled up to 72 hours after dosing. 
DMC assessment after last patient of Cohort 1. If ok, proceed with Cohort 2, and also 
with daily prophylactic dosing (approximately 40-60 IU/kg) for 3 months (initially 
with Nuwiq but then with OCTA101 if advised by the DMC). Patients from Cohort 2 
and 3 may also start their daily prophylactic dosing for 3 months immediately after 
collection of the last PK sample.  
• Cohort 2: 100 IU/kg OCTA101 (n=4): Single-period investigation with a single sc 
dose of 100 IU/kg OCTA101 profiled up to 96 hours after dosing. 
DMC assessment after last patient of Cohort 2. If ok, proceed with Cohort 3. 
• Cohort 1 and 2: PK assessment after 3-month daily dosing (n=8): single-period 
investigation with a single sc dose of 50 IU/kg OCTA101 profiled up to 120 hours 
after dosing for FVIII and up to 21 days for OCTA12.   
• Cohort 3: 50 IU/kg OCTA101 (n=8): Two-period investigation of a single iv dose of 
50 IU/kg Nuwiq profiled for up to 72 hours after dosing followed by sc dose of 
50 IU/kg OCTA101 administered into the abdomen profiled up to 72 hours. 
Treatments were to be administered in fixed sequence, with Nuwiq first. 
DMC assessment after last patient of Cohort 3. If ok, proceed with Cohort 4 and 5. 
• Cohort 4: 50 IU/kg OCTA101 (n=4): Cancelled. 
• Cohort 5: (n=4) [8 had been planned]: Three-period investigation of single sc doses 
of 20, 40, and 60 IU/kg OCTA101 profiled up to 72 hours after dosing. Treatments 
were to be administered in fixed dose-ascending sequence. 
• Cohort 6 (n≥16): Following an initial 4 to 6-week run-in period with Nuwiq iv 
prophylaxis, >3-6 months daily prophylactic treatment with 12.5 IU/kg OCTA101 sc, 
then 25 IU/kg OCTA101 sc for a further 6-7 months (exact dosing depends on 
available vial sizes). In case of two spontaneous bleeding episodes, after having 
completed at least 3 months with 12.5 IU/kg OCTA101 daily treatment the individual 
treatment dose will be increased from 12.5 to 25 IU/kg. Site of administration 
Property of Octapharma. Do not copy or distribute without written permission.


Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 6 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
(abdomen or thigh) to be chosen by the patient. A further treatment phase with 
40 IU/kg OCTA101 will be discussed with the DMC, once results of earlier dosing 
phases are available. 
The DMC will review and assess the available results approximately every 3 months. 
 
By DMC-recommendation, patients enrolled in Cohorts 1, 2, and 3 proceeded to 3-month 
prophylactic treatment part of the study and received daily dosing using one injection 
(approximately 40-60 IU/kg; dose chosen to allow administration by single injection; it was 
permitted to daily alternate the vial size, e.g. 3000 IU on one day 1, 5000 IU on day 2, 3000 IU 
on day 3, 5000 IU on day 4 etc.) of OCTA101 for 3 months (home treatment). Patients from 
Cohort 1 received prophylactic Nuwiq (home treatment) until the DMC had confirmed that 
OCTA101 can be used as daily prophylaxis. Bleeding events during the study were treated 
with Nuwiq. Throughout this part of the study, FVIII inhibitors, plasma concentrations of 
FVIII:C, and OCTA12 were measured repeatedly.  
Independent expert evaluation by the DMC has steered study progress for the stepwise dosage 
increments by cohort and the progression of patients from the first three cohorts to 3-month 
daily dosing. In addition, the DMC has advised on changes of the proposed dosage for the 
assessment of bioavailability (Cohort 3) and dose-proportionality (Cohort 5) and changes in 
the schedule of PK blood sampling and/or the duration of profiling without substantially 
increasing the total amount of blood to be sampled. Based on the observation of a second 
patient with inhibitors in Cohort 2, the DMC recommended placing the study on hold. The 
DMC recommended restarting the study with the implementation of Amendment 3, which 
cancelled Cohort 4, cut Cohort 5 to 4 patients instead of the planned 8, and introduced 
Cohort 6 investigating OCTA101 sc prophylaxis over 6-7 months of treatment per dose level 
following a run-in period with Nuwiq iv prophylaxis. The DMC will continue to be involved 
in the further conduct of the study. 
This study started in Q2 2019 and is planned to be completed by Q3 2022. 
Number of Patients: N = 36 evaluable in total (16 evaluable patients in Cohort 6)  
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 7 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
Patient Selection Criteria: 
Inclusion Criteria: 
Patients who meet all of the following criteria are eligible for the study: 
1. Severe hemophilia A (<1% FVIII:C) as documented in medical records 
2. Males ≥18 years of age 
3. Subjects who have had ≥150 exposure days (EDs) with a FVIII product 
4. Written informed consent for study participation obtained before undergoing any 
study specific procedures 
Exclusion Criteria: 
Patients who meet any of the following criteria are not eligible for the study: 
1. Previous participation in this trial 
2. Use of an Investigational Medicinal Product within 30 days prior to the first OCTA101 
injection 
3. History of FVIII inhibitors titer ≥0.6 BU/mL defined by medical records 
4. Inhibitors to FVIII (≥0.6 BU/mL) at screening measured by Nijmegen modified 
Bethesda method at central laboratory  
5. Human immunodeficiency virus (HIV) positive subjects with a CD4+ count <200/mL  
6. Clinically significant anemia at screening (hemoglobin <8 g/dL) 
7. Presence of any significant comorbidity (at the discretion of the investigator) that 
might confound the interpretation of the study data and/or that might put the patient 
at undue risk by participating in the trial 
8. Any coagulation disorder other than hemophilia A 
9. AST or ALT levels >3 times the upper limit of normal 
10. Creatinine >120 µmol/L 
11. Platelet count <100,000 µL 
12. BMI ≥30 kg/m² 
13. For Cohort 6, patients with a positive LumiTope test at screening will be excluded. 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 8 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
Test Product, Dose, and Mode of Administration: 
OCTA101 is composed of rFVIII (derived from commercial Nuwiq) and the recombinant 
VWF fragment dimer OCTA12, at a molar ratio of 1:6 (with regards to FVIII binding sites in 
OCTA12).  
OCTA101 will be injected sc at doses as described above. OCTA101 will be provided as 
lyophilized powder in vials containing 500 IU, 750 IU, 1000 IU and 2000 IU (plus 3000 IU 
and 5000 IU in cohorts 1-5). Each vial needs to be reconstituted with 1.0 mL of Water for 
Injection. The site of sc injection (abdomen or thigh) must be documented. 
In all cases, the minimum number of injections required to provide the required dose must be 
administered. 
Nuwiq is a human cell line derived recombinant FVIII concentrate for iv use. Vials contain 
500°IU, 1000 IU, 2000 IU or 3000 IU of freeze-dried FVIII concentrate, each to be reconstituted 
in 2.5 mL water for injections. Nuwiq should be injected iv by bolus injection at a maximum rate 
of 4 mL/min.  
Duration of Treatment (as planned): 
Cohort 1: Single injection of OCTA101 50 IU/kg sc with 72 hours of observation.   
Cohort 2: Single injection of OCTA101 100 IU/kg sc with 96 hours of observation.   
Cohort 1 and 2: At the end of the daily injection period and after a wash-out of at least 
72 hours after the last OCTA101 injection, or any other FVIII injection, the PK of FVIII:C 
and OCTA12 was to be assessed with an OCTA101 dose of 50 IU/kg. FVIII:C and OCTA12 
levels were to be measured up to 120 hours; thereafter, additional samples will be taken to 
measure OCTA12 at the following time points: 7, 14 and 21 days. After the 120 hour time 
point patients could use Nuwiq for prophylaxis or treatment of bleeding episodes until the last 
sampling time point.  
Cohort 3: Single injection of Nuwiq 50 IU/kg iv with 72 hours of observation, followed by 
single injection of OCTA101 50 IU/kg sc into the abdomen with 72 hours of observation. 
Cohorts 1, 2 and 3: Daily injections of OCTA101 approximately 40-60 IU/kg sc for 3 
months. 
Cohort 4: (Cancelled) Single injection of OCTA101 50 IU/kg sc into the thigh with 72 hours 
of observation.   
Cohort 5: Single injection of OCTA101 20 IU/kg sc with 72 hours of observation, followed 
by single dose of OCTA101 40 IU/kg sc with 72 hours of observation, followed by single 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 9 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
dose of OCTA101 60 IU/kg sc with 72 hours of observation (4 patients into the abdomen, 4 
patients into the thigh). 
Cohort 6: Following an initial 4 to 6-week run-in period with Nuwiq iv prophylaxis, >3-
6 months daily prophylactic treatment with 12.5 IU/kg OCTA101 sc, then 25 IU/kg 
OCTA101 sc for a further 6-7 months. In case of two spontaneous bleeding episodes, after 
having completed at least 3 months with 12.5 IU/kg OCTA101 daily treatment the individual 
treatment dose will be increased from 12.5 to 25 IU/kg. Depending on the results of the first 
two treatment phases, a further treatment phase with 40 IU/kg OCTA101 will be considered. 
Reference Therapy, Dose, Mode of Administration:  
None. 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Safety Parameters: 
Primary: 
- 
Adverse events 
- 
DLTs 
- 
Thromboembolic events 
- 
Local injection site reactions 
- 
Inhibitor formation to FVIII  
Secondary: 
- 
Antibody formation to OCTA12 
- 
LumiTope assay results 
- 
OCTA12 plasma levels during daily dosing 
- 
Routine lab tests compared to baseline 
- 
Vital signs compared to baseline 
- 
Physical examination results compared to baseline 
Efficacy Parameters: 
Secondary: 
- 
PK parameters of FVIII:C (AUC, Cmax, Tmax, IVR, t1/2, MRT, CL [iv dosing only], Vd 
[iv dosing only]) 
- 
PK parameters of OCTA12, same parameters as above 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 10 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
- 
Total annualized bleeding rate during daily sc treatment with OCTA101 
- 
Spontaneous annualized bleeding rate during daily sc treatment with OCTA101 
- 
Total annualized treated bleeding rate during daily sc treatment with OCTA101 
- 
Spontaneous annualized treated bleeding rate during daily sc treatment with 
OCTA101 
- 
Traumatic annualized treated bleeding rate during daily sc treatment with OCTA101 
- 
Annualized joint bleeding rate during daily sc treatment with OCTA101 
- 
FVIII:C trough and peak plasma levels during daily dosing 
- 
Score (4-point rating scale) to assess efficacy of treatment of bleeding episodes with 
Nuwiq  
Study Procedures: 
Screening Visit – all patients  
The following assessments will be performed:  
• Informed consent  
• Eligibility criteria 
• Demographics: age, ethnic origin 
• Blood type (ABO) 
• CD4+ count 
• Medical history  
• Previous and concomitant medication, including FVIII treatment details in previous 
6 months and bleeding frequency 
• Body weight 
• Height 
• Physical examination  
• Hemophilia Joint Health Score (HJHS) 
• Target joint(s) (defined as three or more spontaneous bleeding episodes into a single joint 
within 6 consecutive months preceding screening visit) 
• Vital signs: systolic and diastolic blood pressure, body temperature, pulse (before blood 
sample collection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay)  
• Routine safety lab: Hematology: red blood cell count, white blood cell count, hemoglobin, 
hematocrit, platelet count. Clinical chemistry: total bilirubin, ALT, AST, urea, serum 
creatinine, lactate dehydrogenase 
• Start of monitoring of adverse events (AEs) 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 11 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
• Cohort 6: LumiTope assay (negative test result required) 
 
Any bleeding episodes occurring between the Screening Visit and the first exposure with 
OCTA101 (or Nuwiq in Cohort 6 patients) should be treated with the patient’s previously 
used FVIII concentrate.  
 
Following screening, eligible patients will receive a patient diary after the first treatment. 
The investigator will explain to the patient how to fill in the diary and will emphasize the 
importance of carefully documenting all treatment details, adverse events, and concomitant 
medications. 
PK assessments should be performed after a washout period of at least 72 h, if possible, 
from the last FVIII injection. Patients must not be experiencing any bleeding.  
 
Cohort 1 patients – single dose PK, OCTA101 50 IU/kg sc 
The following assessments will be performed:  
• Body weight (before injection) 
• Vital signs (before injection, 0.5 h, 8 h, 24 h, 48 h and 72 h after injection) 
• Routine safety lab (before injection, 0.5 h, 8 h, 24 h, 48 h and 72 h after injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before injection)  
• Blood sample for anti-OCTA12 measurement (before injection) 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before 
injection and 0.5 h, 2 h, 4 h, 8 h, 24 h, 48 h and 72 h after injection).  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
 
Cohort 2 patients – single dose PK, OCTA101 100 IU/kg sc 
The following assessments will be performed:  
• Body weight (before injection) 
• Vital signs (before injection, 0.5 h, 8 h, 24 h, 48 h, 72 h and 96 h after injection) 
• Routine safety lab (before injection, 0.5 h, 8 h, 24 h, 48 h, 72 h and 96 h after injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before injection)  
• Blood sample for anti-OCTA12 measurement (before injection) 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 12 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before 
injection and 0.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h and 96 h after injection).  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
 
Cohort 3 patients – single dose PK, Nuwiq 50 IU/kg iv, followed by single PK OCTA101 50 
IU/kg sc into the abdomen  
The following assessments will be performed:  
Nuwiq injection (iv) 
• Body weight (before injection) 
• Vital signs (before injection, 0.5 h, 8 h, 24 h, 48 h, and 72 h after injection) 
• Routine safety lab (before injection, 0.5 h, 8 h, 24 h, 48 h, and 72 h after injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before injection)  
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) before 
injection and 0.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, and 72 h after injection 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
OCTA101 injection (sc into the abdomen) 
• Blood sample for anti-OCTA12 measurement (before injection) 
• Vital signs (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after injection) 
• Routine safety lab (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after injection) 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) before 
injection and 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after injection  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
 
Cohort 4 patients – single dose PK, OCTA101 50 IU/kg sc into the thigh 
Cancelled 
 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 13 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
Cohort 5 patients – single dose PK of OCTA101 20 IU/kg, followed by single PK of 
OCTA101 40 IU/kg sc, followed by single dose PK of OCTA101 60 IU/kg sc 
The following assessments will be performed:  
OCTA101 injection 20 IU/kg into the abdomen (4 patients) 
• Body weight (before injection) 
• Vital signs (before injection, 8 h, 12 h, 24 h, 48 h and 72 h after the injection) 
• Routine safety lab (before injection, 8 h, 12 h, 24 h, 48 h and 72 h after the injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before the first injection)  
• Blood sample for anti-OCTA12 measurement (before the injection) 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before the 
injection and 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection)  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period  
• Documentation of concomitant medication throughout the study period 
OCTA101 injection 40 IU/kg into the abdomen (4 patients)  
• Vital signs (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection) 
• Routine safety lab (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection) 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before the 
injection and 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection)  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period  
• Documentation of concomitant medication throughout the study period 
OCTA101 injection 60 IU/kg into the abdomen (4 patients)  
• Vital signs (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection) 
• Routine safety lab (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay) 
4 weeks after injection 
• Blood sample for anti-OCTA12 measurement 4 weeks after injection 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before the 
injection and 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection) 
• Blood samples for measurement of OCTA12, as above for FVIII:C 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 14 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period  
• Documentation of concomitant medication throughout the study period 
 
Cohort 1, 2 and 3 patients – daily injections for 3 months, OCTA101 40 - 60 IU/kg sc 
Patients entering the 3-month daily prophylactic part will be trained in sc self-administration 
of study medication. Patients in Cohort 1 will be required to return to the study site for their 
first daily dose; patients in Cohorts 2 and 3 will still be present at the study site at the time 
of their first daily dose. The following assessments will be performed:  
• Vital signs (before and 3 h and 6 h after the injection at the beginning of the 3-month daily 
dosing and 0.5, 1, 2, and 3 months thereafter) 
• Routine safety lab (before and 3 h and 6 h after the injection at the beginning of the 3-
month daily dosing and 0.5, 1, 2, and 3 months thereafter) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before the first injection and 0.5, 1, 2 and 3 months thereafter)  
• Blood sample for anti-OCTA12 measurement, (before the first injection and 0.5, 1, 2 and 
3 months thereafter)  
• Blood sample for FVIII:C measurement (one-stage and chromogenic assay), (before and 
3 h  and 6 h after the injection at the beginning and 0.5, 1, 2, and 3 months thereafter) 
• Blood sample for OCTA12 measurement, (before and 3 h and 6 h after the injection at the 
beginning and 0.5, 1, 2, and 3 months thereafter)  
• Physical examination (at End of Study) (Cohort 3 only) 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection, for each injection) 
• Adverse event monitoring throughout the study period  
• Documentation of concomitant medication throughout the study period 
 
PK assessment following 3-month daily prophylaxis in Cohort 1 and 2 patients  
Patients completing the 3-month daily prophylactic part will attend the study site. The 
following assessments will be performed:  
• After a wash-out of at least 72 hours after the last OCTA101 injection, or any other FVIII 
injection, a dose of 50 IU/kg OCTA101 sc will be administered 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before and at 21 days after the injection)  
• Blood sample for anti-OCTA12 measurement, (before and at 21 days after the injection)  
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 15 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
• Blood sample for FVIII:C measurement (one-stage and chromogenic assay), (before and 
2°h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, and 120 h after the injection) 
• Blood sample for OCTA12 measurement, (before and, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 
96 h, 120 h, 7 days, 14 days, and 21 days after the injection)  
• Physical examination (at End of Study)  
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period  
• Documentation of concomitant medication throughout the study period 
 
Cohort 6: Following 4 to 6-week run-in with Nuwiq iv prophylaxis, patients are 
prophylactically treated for 6-7 months with 12.5 IU/kg OCTA101 sc daily, then 25 IU/kg 
OCTA101 sc daily, again for 6-7 months. Depending on the results, a treatment phase with 
40 IU/kg OCTA101 may be added 
Patients in Cohort 6 will have their first Nuwiq administered at the study site. After the run-
in period, patients will be trained in sc OCTA101 self-administration for subsequent home 
administration.  
The following assessments will be performed:  
Start of 4 to 6 week Nuwiq run-in: 
• Documentation of bleeding episodes and their treatment throughout the run-in period  
• Adverse event monitoring throughout the run-in period  
• Documentation of concomitant medication throughout the run-in period 
Daily OCTA101 treatment periods: 
• Vital signs (before and 8 h after the injection OCTA101 at the beginning of each dosing 
period and 0.5, 1, 2, 3, 4, 5 and 6 months thereafter) 
• Routine safety lab (before and 8 h after the OCTA101 injection at the beginning of each 
dosing period and 0.5, 1, 2, 3, 4, 5 and 6 months thereafter) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before the first injection of OCTA101 and 0.5, 1, 2, 3, 4, 5 and 6 months thereafter for each 
of the 6-7 month OCTA101 daily prophylaxis treatment periods)  
• Blood sample for anti-OCTA12 measurement, (before the first injection of OCTA101 and 
0.5, 1, 2, 3, 4, 5 and 6 months thereafter for each of the 6-7 month OCTA101 daily 
prophylaxis treatment periods) 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 16 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
• Blood sample for FVIII:C measurement (one-stage and chromogenic assay), (before and 
8°h after the OCTA101 injection at the beginning of the 6-7 month dosing periods and 0.5, 
1, 2, 3, 4, 5 and 6 months thereafter) 
• Blood sample for OCTA12 measurement, (before the first injection of OCTA101 and 0.5, 
1, 2, 3, 4, 5 and 6 months thereafter for each dosing period)  
• Physical examination (at End of Study)  
• LumiTope assay (before the first injection of OCTA101 and 0.5, 1, 2, 3, 4, 5 and 6 months 
thereafter for each dosing period)  
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection, for each injection) 
• Documentation of bleeding episodes and their treatment throughout the study period 
• Adverse event monitoring throughout the study period  
• Documentation of concomitant medication throughout the study period 
 
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. 
Stopping rules  
A single death event (with the exception of death from underlying disease or any other death 
clearly unrelated to OCTA101) that occurs within 30 days of administration of study drug. 
According to the revised stopping rules implemented by Amendment 2, the study was to be 
put on hold until a further DMC recommendation for further conduct of the study was made, 
if more than one patient met the following criteria:  
• Exhibits a consistently high titer FVIII inhibitor (≥5 BU), as determined by central 
laboratory tests including a retest as detailed in Section 6.1.9. 
or  
• Exhibits a low titer FVIII inhibitor (≥0.6 BU and <5 BU), as determined by central 
laboratory test, including a retest as detailed in Section 6.1.9, and a standard recovery test 
using intravenous factor VIII shows a recovery below 66%. A formal half-life study with 
determination of the terminal half-life (t½) associated with the recovery study is encouraged 
with the patient in a non-bleeding state and free of any intercurrent illness.  
 
As a further patient with FVIII inhibitors in Cohort 2 subsequently met these criteria, the 
study was put on hold and patients stopped OCTA101 treatment. The ongoing patients in 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 17 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
Cohort 3 were switched to Nuwiq prophylaxis for the remainder of the planned 3-month 
prophylaxis period. 
Once Cohort 6 has been initiated, all patients will immediately stop treatment with OCTA101, 
if another patient develops a confirmed FVIII inhibitor (≥0.6 BU). 
In this case, all FVIII inhibitor negative patients will switch to prophylactic treatment with 
Nuwiq comparable to the run-in phase, and will come for a final follow-up visit after treatment 
change. During the final follow-up visit the following should be done: 
• Routine safety lab 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay) 
• Blood sample for anti-OCTA12 measurement 
• Blood sample for OCTA12 measurement 
• Physical examination 
• LumiTope assay 
• Documentation of bleeding episodes and their treatment 
• Adverse event monitoring 
• Documentation of concomitant medication 
Summary of status at the time of finalizing the amended study protocol version 9.0: 
At the time of finalizing the amended study protocol version 9.0, the following had been 
completed: 
• Cohort 1: 50 IU/kg: single-period investigation with a single sc dose of 50 IU/kg 
OCTA101 profiled up to 72 hours after dosing – completed as planned in 4 patients. 
3-month OCTA101 daily dosing – completed as planned in 4 patients. PK assessment 
after 3-month daily dosing – completed as planned in 4 patients. 
• Cohort 2: 100 IU/kg: single-period investigation with a single sc dose of 100 IU/kg 
OCTA101 profiled up to 96 hours after dosing – completed as planned in 4 patients. 
3-month OCTA101 daily dosing – completed as planned in 2 patients; 2 patients with 
inhibitors in Cohort 2 discontinued daily OCTA101 prophylaxis and started ITI 
treatment with Nuwiq. PK assessment after 3-month daily dosing – completed as 
planned in 1 patient; not performed in the 2 inhibitor patients switched to ITI treatment 
and a patient with low levels of FVIII. One patient who developed FVIII inhibitors 
and started ITI died due to a fatal serious adverse event (retroperitoneal hematoma). 
The second patient undergoing ITI after FVIII inhibitor development is continuing 
treatment with Nuwiq. 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 18 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
• Cohort 3: 50 IU/kg (n=8): two-period investigation of a single iv dose of 50 IU/kg 
Nuwiq profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg 
OCTA101 administered into the abdomen profiled up to 72 hours – completed as 
planned in 8 patients. 3-month OCTA101 daily dosing – due to the study hold, patients 
in Cohort 3 were switched to prophylaxis with Nuwiq after having received about 1-
month of OCTA101 daily prophylaxis; the 8 patients in Cohort 3 completed the study 
when their overall time on daily prophylaxis (OCTA101 + Nuwiq) reached 3 months. 
• Cohort 4: 50 IU/kg (n=4): cancelled. 
• Cohort 5 (n=4): three-period investigation of single sc doses of 20, 40, and 60 IU/kg 
OCTA101 profiled up to 72 hours after dosing with 4-week follow-up visit – 
completed in 4 patients instead of the originally planned 8 patients. 
• Cohort 6 (n≥16): Nineteen patients were screened for Cohort 6 since autumn 2020, of 
whom two failed inclusion-/exclusion criteria, and two withdrew consent. Ten patients 
started daily treatment with 12.5 IU/kg OCTA101 after a 4-6 weeks prophylactic 
treatment run-in phase with Nuwiq, 3 times weekly. Further five patients started the 
4-6 weeks run-in phase, but they have not yet started treatment with OCTA101. 
After six month daily treatment with OCTA101 a positive FVIII inhibitor result 
(0.8°BU/mL) was reported for patient C6-Q1-01-02 on 14-Jul-2021. After 
consultation and in agreement with the DMC the sponsor decided to put the study on-
hold with immediate effect: all patients with OCTA101 treatment were switched back 
to prophylactic treatment with Nuwiq, 3 times weekly. On 27-Jul-2021 a further low-
titer FVIII inhibitor was reported for patient C6-Q1-01-10 (1.6 BU/mL). 
It was decided to stop all further treatment with OCTA101, but to offer all enrolled 
patients access to Nuwiq prophylactic treatment until they are integrated into the 
National Health Insurance program for haemophilia A patients, again, but no longer 
than until the end of September 2021 + 2 weeks time window. 
Patients who developed FVIII inhibitors during treatment within cohort 6 are followed 
up as originally planned in the study protocol. 
Statistical Analysis Plan: 
Safety and tolerability data will first be analyzed for each cohort after the first dose(s) and 
evaluated by an external DMC. Two separate analyses will be performed: the first one will 
include all available data of enrolled patients in Cohorts 1, 2, 3, and 5 and the second one will 
include all data of the newly defined Cohort 6. Analyses based on data from repeat dosing 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 19 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
from Cohort 1, 2, and 3 with OCTA101 for 3 months will be analyzed separately from data 
related to the first doses. In these analyses, data will be presented by cohort and overall. 
Analysis based on Cohort 6 data will be presented by period (run-in period with Nuwiq and 
OCTA101 treatment period) and by planned OCTA101 daily dose. 
For each cohort  
• Descriptive analysis of demographic and baseline variables. 
• Safety analyses 
The number and percentage of patients with AEs and the number of AEs will be summarized 
by primary MedDRA System Organ Class (SOC) and Preferred Term (PT). Separate tables 
showing all AEs, all serious AEs and all AEs at least possibly related to IMP will be generated. 
Further a summary of AEs by severity, presenting the most severe event per patient overall 
and within each SOC and PT will be generated.  
For thromboembolic events and local injection site reactions, appropriate clusters of 
MedDRA terms will be defined and such events will be presented within these clusters, using 
the summaries detailed above. 
The frequencies of local injection reactivity ratings by the investigator and the patient will be 
summarized over time periods. The frequencies (including percentages) of any inhibitor 
formation to FVIII and antibody formation to OCTA12 will be presented. Vital sign and safety 
laboratory parameters will be analyzed using descriptive statistics for measured values and 
for changes from pre-dose values to each single injection. 
• Individual non-compartmental individual PK analyses (NCA) of the time courses of 
FVIII:C (after administration of OCTA101 and Nuwiq) and OCTA12 (administration 
of OCTA101) including terminal half-life (t½), incremental in-vivo recovery (IVR), 
maximum plasma concentration (Cmax), time for reaching maximum plasma 
concentration (tmax), mean residence time (MRT), quantifiable and total area under the 
concentration time curve (AUC), apparent clearance (CL), apparent distribution 
volume (Vd). In addition, for descriptive purposes, the time courses of FVIII:C and 
OCTA12 may be analyzed compartmentally assuming a linear, open, one- or two-
compartment model. Exposure levels will be reported untransformed and standardised 
for dose and body weight. 
• In addition, for patients from Cohorts 1 to 3 and Cohort 6: FVIII:C trough and peak 
levels during, and after for Cohorts 1 and 2, the 3-month daily dosing will be 
graphically displayed and listed by patient. 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 20 of 82 
Name of Sponsor/Company: 
Octapharma AG 
Name of Investigational Product: 
OCTA101 (Human-cl rhFVIII and recombinant 
human von Willebrand Factor fragment dimer) 
Protocol Identification Code: 
SubQ8-01 
Name of Active Ingredient: 
Coagulation factor VIII 
Date of Final Protocol: 
30-Jul-2021 
 
• In addition, for patients from Cohort 3: Estimation of relative bioavailability of 
FVIII:C by the ratios of AUC after sc administration over AUC after iv administration. 
• Data from Cohort 5 covering the pharmacokinetics after single sc doses of 20, 40 and 
60 IU/kg OCTA101 will be used to derive estimates of the dose-proportionality of the 
pharmacokinetics of FVIII:C and OCTA12. 
• Quantifiable and λz-extrapolated time courses of the concentrations after single doses 
(all cohorts) will be used to simulate the time courses when defined doses would be 
administered repeatedly at specified interval. 
The total annualized bleeding rate, the spontaneous annualized bleeding rate, the traumatic 
annualized bleeding rate, the total annualized treated bleeding rate, the spontaneous 
annualized treated bleeding rate, and the annualized joint bleeding rate during the daily sc 
treatment with OCTA101 will be presented for patients in the FAS and PP set in Cohort 6, 
grouped by dose level of daily OCTA101 dosing. These bleeding rates will be compared 
descriptively to those derived from the bleeding frequencies in the previous 6 months prior to 
the study. For the daily dosing period of Cohorts 1 to 3, no bleeding rates were calculated, 
because none occurred during daily prophylaxis with OCTA101. The observation period was 
considerably shorter than planned due to the study stop. 
 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 21 of 82 
FLOW CHART OF ASSESSMENTS 
Flow Chart 1: 
Screening Visit Assessments – all patients 
Informed consent 
X 
Eligibility criteria 
X 
Demographics 
X 
AB0 blood type 
X 
CD4+ count 
X 
Medical history 
x 
Details on medications taken within one month before screening, including FVIII 
dosing in the previous 6 months, and any concomitant medications. 
x 
Body weight 
x 
Height 
x 
Physical examination 
x 
Hemophilia Joint Health Score (HJHS) 
x 
Target joints 
x 
Vital signs 
x 
Routine safety laboratory 
x 
FVIII inhibitor* 
x 
AEs 
x 
Cohort 6: LumiTope assay* 
x 
* needs to be negative 
 
 
Flow Chart 2: 
Cohort 1: Single PK, OCTA101 50 IU/kg sc 
 
Prior to 
injection 
0.5 h 
2 h 
4 h 
8 h 
24 h 
48 h  
72 h 
Body weight 
x 
 
 
 
 
 
 
 
FVIII:C 
x 
x 
x 
x 
x 
x 
x 
x 
OCTA12 
x 
x 
x 
x 
x 
x 
x 
x 
FVIII inhibitor 
x 
 
 
 
 
 
 
 
Anti-OCTA12 
x 
 
 
 
 
 
 
 
Routine lab 
x 
x 
 
 
x 
x 
x 
x 
Vital signs 
x 
x 
 
 
x 
x 
x 
x 
Assessment 
of local 
injection site 
reactions 
 
Directly 
after 
injection 
and 15 ± 5 
min post-
injection 
 
 
 
 
 
 
AEs and 
concomitant 
medication 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 22 of 82 
Flow Chart 3: 
Cohort 2: Single PK, OCTA101 100 IU/kg sc 
 
Prior to 
injection 
0.5 h 
2 h 
4 h 
8 h 
24 h 
48 h  
72 h 
96 h 
Body weight 
x 
 
 
 
 
 
 
 
 
FVIII:C 
x 
x 
x 
x 
x 
x 
x 
x 
x 
OCTA12 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FVIII 
inhibitor 
x 
 
 
 
 
 
 
 
 
Anti-
OCTA12 
x 
 
 
 
 
 
 
 
 
Routine lab 
x 
x 
 
 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
 
 
x 
x 
x 
x 
x 
Assessment 
of local 
injection 
site 
reactions 
 
Directly 
after 
injection 
and 15 ± 5 
min post-
injection 
 
 
 
 
 
 
 
AEs and 
concomitant 
medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Flow Chart 4a: 
Cohort 3: Single PK, Nuwiq 50 IU/kg iv 
 
Prior to 
injection of 
Nuwiq 
0.5 h 
2 h 
4 h 
8 h 
24 h 
48 h  
72 h 
Body weight 
x 
 
 
 
 
 
 
 
FVIII:C 
x 
x 
x 
x 
x 
x 
x 
x 
FVIII inhibitor 
x 
 
 
 
 
 
 
 
Routine lab 
x 
x 
 
 
x 
x 
x 
x 
Vital signs 
x 
x 
 
 
x 
x 
x 
x 
AEs and 
concomitant 
medication 
x 
x 
x 
x 
x 
x 
x 
x 
 
Flow Chart 4b: 
Cohort 3: Single PK, OCTA101 50 IU/kg sc into the abdomen 
 
Prior to injection 
of OCTA101 
 
2 h 
4 h 
8 h 
12 h 
24 h 
48 h  
72 h 
Body weight 
x 
 
 
 
 
 
 
 
 
FVIII:C 
x 
 
x 
x 
x 
x 
x 
x 
x 
OCTA12 
x 
 
x 
x 
x 
x 
x 
x 
x 
Anti-
OCTA12 
x 
 
 
 
 
 
 
 
 
Routine lab 
x 
 
 
 
x 
x 
x 
x 
x 
Vital signs 
x 
 
 
 
x 
x 
x 
x 
x 
Assessment 
of local 
injection 
site 
reactions 
 
Directly after 
injection and 
15 ± 5 min 
post-injection 
 
 
 
 
 
 
 
AEs and 
concomitant 
medication 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
30-Jul-2021 
 
 
Page 23 of 82 
Flow Chart 5  
Cohort 4: Single PK, OCTA101 50 IU/kg sc into the thigh 
Cancelled 
 
Flow Chart 6a: 
Cohort 5: Single PK, OCTA101 20 IU/kg sc 
 
Prior to 
injection 
 
2 h 
4 h 
8 h 
12 h 
24 h 
48 h  
72 h 
Body weight 
x 
 
 
 
 
 
 
 
 
FVIII:C 
x 
 
x 
x 
x 
x 
x 
x 
x 
OCTA12 
x 
 
x 
x 
x 
x 
x 
x 
x 
FVIII 
inhibitor 
x 
 
 
 
 
 
 
 
 
Anti-
OCTA12 
x 
 
 
 
 
 
 
 
 
Routine lab 
x 
 
 
 
x 
x 
x 
x 
x 
Vital signs 
x 
 
 
 
x 
x 
x 
x 
x 
Assessment 
of local 
injection 
site 
reactions 
 
Directly after 
injection and 
15 ± 5 min 
post-
injection 
 
 
 
 
 
 
 
AEs and 
concomitant 
medication 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
Flow Chart 6b: 
Cohort 5: Single PK, OCTA101 40 IU/kg sc 
 
Prior to 
injection 
 
2 h 
4 h 
8 h 
12 h 
24 h 
48 h  
72 h 
Body weight 
x 
 
 
 
 
 
 
 
 
FVIII:C 
x 
 
x 
x 
x 
x 
x 
x 
x 
OCTA12 
x 
 
x 
x 
x 
x 
x 
x 
x 
FVIII inhibitor 
 
 
 
 
 
 
 
 
 
Anti-OCTA12 
 
 
 
 
 
 
 
 
 
Routine lab 
x 
 
 
 
x 
x 
x 
x 
x 
Vital signs 
x 
 
 
 
x 
x 
x 
x 
x 
Assessment 
of local 
injection site 
reactions 
 
Directly after 
injection and 
15 ± 5 min 
post-injection 
 
 
 
 
 
 
 
AEs and 
concomitant 
medication 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
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Flow Chart 6c: 
Cohort 5: Single PK, OCTA101 60 IU/kg sc 
 
Prior to 
injection 
 
2 h 
4 h 
8 h 
12 h 
24 h 
48 h  
72 h 
4 
weeks 
Body weight 
x 
 
 
 
 
 
 
 
 
 
FVIII:C 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
OCTA12 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
FVIII inhibitor 
 
 
 
 
 
 
 
 
 
x 
Anti-OCTA12 
 
 
 
 
 
 
 
 
 
x 
Routine lab 
x 
 
 
 
x 
x 
x 
x 
x 
 
Vital signs 
x 
 
 
 
x 
x 
x 
x 
x 
 
Assessment of 
local injection site 
reactions 
 
Directly after 
injection and 
15 ± 5 min 
post-injection 
 
 
 
 
 
 
 
 
AEs and 
concomitant 
medication 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Flow Chart 7: 
Cohorts 1, 2 and 3, daily injections of OCTA101 approximately 40-
60 IU/kg sc for 3 months 
 
Start of daily 
treatment with 
OCTA101 
Month 0.5 
Month 1 
 
Month 2  
 
Month 3 
Body weight 
x1 
 
 
 
 
Vital signs 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
Routine safety laboratory 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
FVIII inhibitor 
x1 
x1 
x1 
x1 
x1 
Anti-OCTA12 
x1 
x1 
x1 
x1 
x1 
FVIII:C  
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
OCTA12 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
Physical examination (Cohort 3 
only) 
 
 
 
 
x3 
Assessment of local injection site 
reactions 
Directly after injection and 15 ± 5 min post-injection, for each injection 
Adverse events 
x 
x 
x 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
1, before injection  
2, 3 h and 6 h after injection 
3, 6 h after injection  
 
 
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Flow Chart 8: 
Cohorts 1 and 2, PK assessment following 3-month daily 
administration 
 
Prior to 
injection 
 
2 h 
4 h 
8 h 
12 h 
24 h 
48 h 
72 h 
96 h 
120 
h 
7 
day
s 
14 
day
s 
21 
day
s 
Body weight 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
FVIII:C 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
OCTA12 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FVIII 
inhibitor 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Anti-
OCTA12 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Assessment 
of local 
injection site 
reactions 
 
Directly after 
injection and 
15 ± 5 min 
post-
injection 
 
 
 
 
 
 
 
 
 
 
 
 
AEs and 
concomitant 
medication 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
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Flow Chart 9: 
Cohort 6: 6-7 months daily prophylactic treatment with 12.5 IU/kg OCTA101 sc, then 6-7 months 25 IU/kg 
OCTA101 sc, probably followed by 40 IU/kg OCTA101 – depending on the results of earlier dosing phases 
 
 
 
For each 6-7 months daily prophylactic treatment period with OCTA101 
 
 
Screening 
Nuwiq iv 
Prophylaxis 
(4 to 6 weeks) 
Start of daily 
treatment with 
OCTA101 
Month 0.5 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Final Visit 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
 
 
 
 
 
 
Demographics (age, ethnic 
origin) 
x 
 
 
 
 
 
 
 
 
 
 
Blood type (AB0) 
x 
 
 
 
 
 
 
 
 
 
 
CD4+ count 
x 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
Previous concomitant 
medication, incl. FVIII during 
last 6 months 
x 
 
 
 
 
 
 
 
 
 
 
Body weight 
x 
 
x 
x 
x 
x 
x 
X 
x 
x 
 
Vital signs 
x 
 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
 
Routine safety laboratory 
x 
 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x 
FVIII inhibitor 
x 
 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x 
Anti-OCTA12 
x 
 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x 
FVIII:C level 
 
 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
x1,2 
 
OCTA12 
x 
 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x 
Physical examination, incl. 
HJHS and target joint 
assessment 
x 
 
 
 
 
 
 
 
 
x 
x 
LumiTope assay 
x1 
 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x 
Assessment of local injection 
site reactions 
 
 
Directly after injection and 15 ± 5 min post-injection, for each injection 
 
Bleeding episodes, including 
respective Nuwiq treatment, if 
any 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1, before injection; 2, 8 h after injection 
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Study Protocol No. SubQ8-0l, Version 9.0 CONFIDENTIAL 
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PROTOCOL SIGNATURES 
Signature of the Sponsor's Representative 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
Dr. Sigurd Knaub 
Senior Vice President 
Clinical R& D Haematology 
Octapharma AG 
on behalf of the Sponsor 
Signature 
Date 
Page 27 of82 
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Page 28 of 82 
 
 
 
Signature of the Author of the Protocol/Clinical Project Manager 
 
This study is intended to be conducted in compliance with the protocol, Good Clinical 
Practice and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
Martina Jansen 
___________________________________________________________________________ 
Author of the Protocol 
 
 
Signature 
 
 
 
Date 
Senior Clinical Project Manager Haematology 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
Oberlaaerstrasse 235 
A-1100 Vienna 
Austria 
 
 
 
01 Aug 2021 | 15:14:01 CE
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Signature of the Biostatistician 
 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
Dorothea Wessiepe 
___________________________________________________________________________ 
Biostatistician 
 
 
 
Signature 
 
 
 
Date 
Metronomia Clinical Research GmbH 
Paul-Gerhardt-Allee 42 
D-81245 München 
Germany 
 
 
 
02 Aug 2021 | 09:07:02 C
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Signature of the Coordinating Investigator 
 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
Dr. Toshko J. Lissitchkov 
___________________________________________________________________________ 
Coordinating Investigator  
 
Signature 
 
 
 
Date 
Specialized Hospital for Active Treatment of Hematological Diseases EAD 
Clinic of Clinical Hematology 
6, Plovdivsko pole str 
1756 Sofia 
Bulgaria 
  
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TABLE OF CONTENTS 
STUDY OUTLINE .................................................................................................................................2 
FLOW CHART OF ASSESSMENTS ................................................................................................21 
PROTOCOL SIGNATURES ..............................................................................................................27 
TABLE OF CONTENTS .....................................................................................................................31 
LIST OF ABBREVIATIONS ..............................................................................................................34 
1 
INTRODUCTION .......................................................................................................................36 
1.1 
BACKGROUND ........................................................................................................ 36 
1.2 
INVESTIGATIONAL MEDICINAL PRODUCT – OCTA101........................................... 37 
1.3 
RATIONALE FOR CONDUCTING THE STUDY ............................................................. 37 
1.4 
DOSE RATIONALE ................................................................................................... 37 
1.5 
BENEFIT-RISK STATEMENT..................................................................................... 38 
2 
STUDY OBJECTIVES ...............................................................................................................41 
2.1 
PRIMARY OBJECTIVE .............................................................................................. 41 
2.2 
SECONDARY OBJECTIVES ....................................................................................... 41 
3 
INVESTIGATIONAL PLAN .....................................................................................................41 
3.1 
PRIMARY AND SECONDARY ENDPOINTS ................................................................. 41 
3.1.1 
Primary Endpoints ................................................................................................41 
3.1.2 
Secondary Endpoints ............................................................................................41 
3.2 
OVERALL STUDY DESIGN AND PLAN ...................................................................... 42 
3.3 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S) .................... 46 
3.3.1 
Study Design .........................................................................................................46 
3.3.2 
Control Group ......................................................................................................47 
3.3.3 
Study Parameters ..................................................................................................47 
4 
STUDY POPULATION ..............................................................................................................47 
4.1 
POPULATION BASE ................................................................................................. 47 
4.1.1 
Inclusion Criteria ..................................................................................................47 
4.1.2 
Exclusion Criteria .................................................................................................48 
4.2 
PRIOR AND CONCOMITANT THERAPY ..................................................................... 48 
4.2.1 
Permitted Concomitant Therapy ...........................................................................48 
4.2.2 
Forbidden Concomitant Therapy ..........................................................................48 
4.3 
WITHDRAWAL AND REPLACEMENT OF PATIENTS ................................................... 49 
4.3.1 
Patient Withdrawal ...............................................................................................49 
4.3.2 
Patient Replacement Policy ..................................................................................49 
4.4 
ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS .............................................. 49 
4.5 
RELEVANT PROTOCOL DEVIATIONS ....................................................................... 49 
4.6 
SUBSEQUENT THERAPY .......................................................................................... 50 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS .................................................................50 
5.1 
CHARACTERIZATION OF INVESTIGATIONAL PRODUCTS .......................................... 50 
5.1.1 
OCTA101 ..............................................................................................................50 
5.1.2 
Nuwiq ....................................................................................................................50 
5.2 
PACKAGING AND LABELLING ................................................................................. 50 
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5.3 
CONDITIONS FOR STORAGE AND USE...................................................................... 50 
5.4 
DOSE AND DOSING SCHEDULE ................................................................................ 50 
5.5 
PREPARATION AND METHOD OF ADMINISTRATION ................................................. 52 
5.6 
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND .............. 52 
5.7 
TREATMENT COMPLIANCE ...................................................................................... 52 
5.7.1 
Drug Dispensing and Accountability ....................................................................52 
5.7.2 
Assessment of Treatment Compliance ..................................................................53 
6 
STUDY CONDUCT ....................................................................................................................53 
6.1 
OBSERVATIONS BY VISIT ........................................................................................ 53 
6.1.1 
Screening Visit – All Patients ...............................................................................53 
6.1.2 
Cohort 1 patients – single dose PK, OCTA101 50 IU/kg sc .................................54 
6.1.3 
Cohort 2 patients – single dose PK, OCTA101 100 IU/kg sc ...............................55 
6.1.4 
Cohort 3 patients – single dose PK, PK Nuwiq 50 IU/kg iv, followed by OCTA101 
50 IU/kg sc into the abdomen ...............................................................................55 
6.1.5 
Cohort 4 patients – single dose PK, OCTA101 50 IU/kg sc into the thigh ...........56 
6.1.6 
Cohort 5 patients – single dose PK of OCTA101 20 IU/kg sc, followed by single 
dose PK of OCTA101 40 IU/kg sc, followed by single dose PK of OCTA101 
60 IU/kg sc ............................................................................................................56 
6.1.7 
Cohort 1, 2 and 3 patients – daily injections for 3 months, OCTA101 40 - 60 
IU/kg sc .................................................................................................................57 
6.1.8 
Cohort 1 and 2 patients – PK assessment following 3-month daily prophylaxis..57 
6.1.9 
Cohort 6: Following a 4-6 week prophylactic treatment phase with ~30 IU/kg 
Nuwiq iv 3 x weekly, patients start 6-7 months daily treatment with 12.5 IU/kg 
OCTA101 sc, then 6-7 months daily 25 IU/kg OCTA101 sc (and probably 
40 IU/kg OCTA101 sc, depending on the results of earlier treatment phases) ....58 
6.1.10 Unscheduled visits ................................................................................................59 
6.1.11 Final visits ............................................................................................................59 
6.1.12 Time Windows Used in this Study, including Tolerances .....................................59 
6.2 
DURATION OF STUDY ............................................................................................. 60 
6.2.1 
Planned Duration for an Individual Patient .........................................................60 
6.2.2 
Planned Duration for the Study as a Whole .........................................................60 
6.2.3 
Premature Termination of the Study .....................................................................60 
7 
ASSESSMENTS AND METHODS ...........................................................................................61 
7.1 
DEMOGRAPHIC AND BASELINE INFORMATION ........................................................ 61 
7.1.1 
Demographic and baseline characteristics ..........................................................61 
7.1.2 
Medical history and prior/concomitant medications ............................................62 
7.2 
EFFICACY ASSESSMENTS ........................................................................................ 62 
7.2.1 
Assessments for Secondary Efficacy Endpoints ....................................................62 
7.3 
SAFETY ASSESSMENTS ........................................................................................... 64 
7.3.1 
Assessments for Safety Endpoints .........................................................................64 
7.3.2 
Adverse Events (AEs) ............................................................................................64 
7.3.3 
Serious Adverse Events (SAEs) .............................................................................66 
7.3.4 
SAE Reporting Timelines ......................................................................................67 
7.3.5 
Laboratory Tests ...................................................................................................68 
7.3.6 
Vital Signs and Physical Examination ..................................................................69 
7.3.7 
Other Relevant Safety Information .......................................................................70 
7.4 
OTHER ASSESSMENTS ............................................................................................. 70 
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7.4.1 
Local injection site reactions ................................................................................70 
7.5 
APPROPRIATENESS OF MEASUREMENTS ................................................................. 71 
8 
DATA HANDLING AND RECORD KEEPING......................................................................71 
8.1 
DOCUMENTATION OF DATA .................................................................................... 71 
8.1.1 
Source Data and Records .....................................................................................71 
8.1.2 
Case Report Forms ...............................................................................................72 
8.1.3 
Changes to Case Report Form (eCRF) Data ........................................................72 
8.2 
INFORMATION TO INVESTIGATORS .......................................................................... 72 
8.3 
RESPONSIBILITIES ................................................................................................... 73 
8.4 
INVESTIGATOR’S SITE FILE ..................................................................................... 73 
8.5 
PROVISION OF ADDITIONAL INFORMATION ............................................................. 74 
8.6 
INDEPENDENT DATA MONITORING COMMITTEE ..................................................... 74 
9 
STATISTICAL METHODS AND SAMPLE SIZE .................................................................74 
9.1 
DETERMINATION OF SAMPLE SIZE .......................................................................... 74 
9.2 
STATISTICAL ANALYSIS .......................................................................................... 74 
9.2.1 
Populations for Analysis .......................................................................................75 
9.2.2 
Efficacy Analysis Plan ..........................................................................................75 
9.2.3 
Safety Analysis Plan..............................................................................................77 
9.2.4 
Handling of Missing Data .....................................................................................78 
9.3 
RANDOMIZATION, STRATIFICATION, AND CODE RELEASE ...................................... 78 
9.4 
INTERIM ANALYSIS ................................................................................................. 78 
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ......................78 
10.1 ETHICAL/REGULATORY FRAMEWORK .................................................................... 78 
10.2 APPROVAL OF STUDY DOCUMENTS ........................................................................ 79 
10.3 PATIENT INFORMATION AND INFORMED CONSENT ................................................. 79 
10.4 PROTOCOL AMENDMENTS ...................................................................................... 79 
10.5 CONFIDENTIALITY OF PATIENT DATA ..................................................................... 79 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................................80 
11.1 PERIODIC MONITORING .......................................................................................... 80 
11.2 AUDIT AND INSPECTION .......................................................................................... 80 
12 
REPORTING AND PUBLICATION ........................................................................................80 
12.1 CLINICAL STUDY REPORT ....................................................................................... 80 
12.2 PUBLICATION POLICY ............................................................................................. 80 
13 
LIABILITIES AND INSURANCE ............................................................................................81 
14 
REFERENCES ............................................................................................................................81 
15 
APPENDICES..............................................................................................................................82 
A. 
APPENDIX 1: DIAGRAM OF SUBCUTANEOUS INJECTION SITES ................................ 82 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate transaminase 
AUC 
Area Under the Concentration-Time Curve 
BE 
Bleeding episode 
BMI 
Body mass index 
BU 
Bethesda unit 
CHMP 
Committee for Medicinal Products for Human Use 
CL 
Apparent clearance 
Cmax 
Maximum Plasma Concentration 
CRO 
Contract Research Organisation 
CV 
Coefficient of variation 
CVAD 
Central venous access device 
DLT 
Dose-limiting toxicities 
DMC 
Independent Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
ED 
Exposure day 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration (USA) 
FVIII 
Coagulation factor VIII 
FVIII:C 
Factor VIII coagulation activity 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
Human-cl rhFVIII 
Human-derived recombinant FVIII protein product 
IB 
Investigator Brochure 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITI 
Immune tolerance induction 
ITT 
Intention-To-Treat 
IU 
International Unit 
iv 
Intravenous 
IVR 
In vivo recovery 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
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MRT 
Mean residence time 
NCA 
Non-compartmental individual PK analyses 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PT 
Preferred term 
PTP 
Previously-treated patient 
PUP 
Previously-untreated patient 
r(h)FVIII 
Recombinant (human) FVIII 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
sc 
Subcutaneous 
SDV 
Source data verification 
SOC 
System organ class 
tmax 
time for reaching maximum plasma concentration 
Vd 
Apparent distribution volume 
VWF 
Von Willebrand Factor 
 
 
 
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1 
INTRODUCTION 
1.1 Background 
Hemophilia A is a serious coagulation disorder caused by a deficiency in FVIII that predisposes 
sufferers to recurrent bleeding, particularly in the joints. Hemophilia A is associated with 
significant morbidity and, if left untreated, can be life-threatening, particularly in patients who 
develop neutralizing FVIII inhibitors to FVIII replacement therapy. Hemophilia A is currently 
treated with replacement FVIII therapy with plasma-derived products or rFVIII products, such 
as simoctocog alfa, either prophylactically or on-demand. Prophylaxis is the gold-standard 
treatment for patients with severe hemophilia, and should be implemented as early as possible. 
Prophylaxis has been shown to significantly reduce bleeding rates, preserve joint health, and 
reduce the risk of intracranial hemorrhages (the most serious bleeding event for babies) and 
inhibitors, compared with on-demand treatment. Adherence to a prophylactic regimen is 
essential to ensure that the prevention of bleeding is realized. 
All currently available FVIII replacement products are administered via intravenous (iv) 
infusion, which usually involves infusion three times per week or every other day. The 
frequency/complexity of administration is one of many factors that influences adherence to 
hemophilia treatment. The iv route of administration is unpleasant for patients, often requires 
trained medical assistance, and is potentially damaging to the structure of the vein in the long 
term. In small babies, venous access is often particularly challenging, hindering the use of 
prophylaxis in children at a very young age despite the benefit for bleed protection. These 
drawbacks can result in reduced compliance by patients and are not very conducive to the 
development of regular, prophylactic care regimes, leaving patients open to the danger of bleeds 
and the resulting detrimental health consequences. In many patients, particularly children, a 
central venous access device (CVAD) is implanted, which is however associated with a risk of 
thrombosis, infection, and mechanical failure.  
Subcutaneous (sc) administration of rFVIII opens new perspectives for the treatment of 
hemophilia with the potential to change current care paradigms. sc delivery provides a more 
convenient, low-volume and less intensive mode of delivery for patients, and avoids CVAD-
related complications. This will most likely improve compliance with treatment and the care of 
patients with hemophilia A. In addition, early prophylaxis in very young children will become 
feasible and patients on episodic treatment may be encouraged to switch to a prophylaxis 
regimen that will improve joint outcomes and quality of life.  To be clinically viable, sc delivery 
for FVIII therapy in hemophilia A must overcome the limitation of poor FVIII bioavailability 
and ensure that the desired plasma level of FVIII is achieved. Von Willebrand factor (VWF), 
which naturally protects FVIII from proteolytic degradation, represents a promising candidate 
to increase the sc bioavailability of rFVIII. FVIII is naturally associated with VWF in the 
circulation and this increases the half-life of FVIII from 2-3 hours to 12-14 hours. When 
administered alone sc, the recovery of FVIII that reaches circulation is too low for an economic 
and effective treatment. One major cause for low recovery is the binding of FVIII to 
phospholipids that are present on cell surfaces at the site of injection. 
The concept for development of OCTA101 is to combine recombinant FVIII with a fragment 
of recombinant VWF that includes the FVIII-binding domains and thereby shields the FVIII 
phospholipid-binding domain. By building on more than 50 years of experience using iv FVIII 
to correct the FVIII deficiency in patients with hemophilia A, OCTA101 has the potential to 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
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Page 37 of 82 
provide the first and only self-administered, sc “true FVIII” therapy for hemophilia based on a 
human cell-line derived rFVIII for direct replacement.  
1.2 Investigational Medicinal Product – OCTA101 
OCTA101 (Human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer) 
is composed of OCTA8 (Human-cl rhFVIII – Nuwiq Intermediate 2 Q-Eluate) and OCTA12 
(recombinant human VWF fragment dimer), mixed in a defined molar ratio of approximately 
1:3 (1:6 with regards to FVIII binding sites in OCTA12, as one OCTA12 dimer contains two 
FVIII binding sites).  
The rFVIII in OCTA101, OCTA8, is derived from the commercial Nuwiq (simoctocog alfa) 
manufacturing process. Nuwiq is manufactured in a human cell line and was approved by EMA 
in 2014 and by the FDA in 2015 for the treatment of hemophilia A based on data in previously 
treated patients (PTPs). Interim data for 66 previously untreated patients (PUPs) treated for ≥20 
exposure days in the meanwhile completed NuProtect study have subsequently been published 
(Liesner et al. 2018). The cumulative inhibitor rate with Nuwiq was 20.8% (12.8% high titer), 
which compares with 44.5% (28.4% high titer) for rFVIII products produced in hamster cell 
lines reported in the recently published SIPPET study (Cannavò et al. 2017).  
Studies in minipigs indicate a sc bioavailability of 46% and an apparent terminal half-life of 
25.3 hours, approximately 3.6-fold longer than after iv administration. In a hemophilia A dog 
model, similar results were obtained (bioavailability: 30.3%; 3.3-fold half-life prolongation). 
In both animal models, peak levels of FVIII:C were observed after approximately 6 hours. 
Clinically relevant in-vivo hemostatic function of OCTA101 was demonstrated in an animal 
model. For a summary of non-clinical results, please refer to the Investigator Brochure (IB).  
1.3 Rationale for Conducting the Study 
To initiate clinical development of OCTA101, this study will be a dose escalation study in 
adults with the main purpose to assess the safety of OCTA101, but also to gain knowledge 
about its PK characteristics, the dose proportionality, and the sc bioavailability compared with 
iv administration of Nuwiq, in order to define the prophylactic treatment (dose per injection 
and injection interval) that would result in protective trough levels of FVIII:C for future Phase 
3 studies in adolescents/adults and children.  
This Phase 1/2 study will provide data regarding safety, the time course of FVIII:C plasma and 
OCTA12 concentration after repeated daily sc injections of a fixed dose for 6-7 months (at 2, 
probably 3, different dose levels in Cohort 6), and whether these FVIII:C levels protect against 
bleeding episodes. The experience gained in this study may lead to an adaption of the PK-based 
dose calculations for the pivotal Phase 3 studies. 
This study will be conducted according to ICH-GCP. 
1.4 Dose Rationale 
One part of the study was to be a single ascending dose study in 4 cohorts: 
• Cohort 1: 50 IU/kg 
• Cohort 2: 100 IU/kg 
• Cohort 3: 200 IU/kg 
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• Cohort 4: 400 IU/kg 
Based on the results of the animal studies, the proposed doses (50, 100, 200, and 400 IU/kg) 
were expected to result in measurable FVIII:C plasma levels up to approximately 2 to 4 days 
after injection. The highest dose planned to be tested (400 IU/kg) would certainly be 
significantly higher than the highest prophylactic dose earlier assumed to be tested in the pivotal 
Phase 3 studies (based on simulations derived from animal data an initial dose of approximately 
114 IU/kg followed by daily doses of approximately 60 IU/kg would be needed to maintain a 
trough level of at least 10%) and would provide a safety margin in case of inadvertent 
administration of higher prophylactic doses in the later stages of clinical development. In 
addition, based on the available animal data, a conservative IVR of around 0.17 [IU/dL]/[IU/kg] 
was expected. Thus, with a dose of 400 IU/kg, FVIII plasma level of around 70% was expected. 
These levels would not pose a risk to patients. On the contrary, depending on tmax or time to 
80% tmax, also break-through bleeds during prophylaxis might possibly be treated with 
OCTA101 with no further need of iv FVIII infusions for the patient. 
Dose proportionality of OCTA101 was evaluated after single sc administration of three 
different doses (50 IU/kg, 100 IU/kg and 200 IU/kg) in 4 additional patients (Cohort 5).  
The DMC assessed the data after each cohort and recommend continuation, modification or 
stopping of the study. Based on the results from Cohorts 1 and 2, the sponsor and DMC decided 
that escalation to higher doses should not take place and that further characterization of 50 
IU/kg and lower doses was warranted. Therefore, Cohort 3 received 50 IU/kg administered into 
the abdomen, Cohort 4 was cancelled, and Cohort 5 investigated dose linearity at a lower dose 
range than initially planned (20, 40 and 60 IU/kg instead of 50, 100 and 200 IU/kg). Patients in 
Cohort 3 also received a single iv dose of 50 IU/kg Nuwiq in order to compare the 
bioavailability of sc OCTA101 with those of Nuwiq injected iv. In Cohort 5, four patients each 
were consistently injected with OCTA101 either in the abdomen or in the thigh at all three dose 
levels.  
In order to evaluate the safety, efficacy, and PK of OCTA101 after repeated doses, with the 
revised study design, patients from Cohort 1, 2, and 3 received daily dosing (approximately 40-
60 IU/kg, with the dose chosen to allow administration by a single injection; it was permitted 
to daily alternate the vial size, e.g. 3000 IU on one day 1, 5000 IU on day 2, 3000 IU on day 3, 
5000 IU on day 4 etc.) of OCTA101 for 3 months. A new cohort will also investigate 12.5 IU/kg 
OCTA101 sc daily for 6-7 months and with DMC agreement at each stage, the patients will 
then proceed to 25 IU/kg (and probably 40 IU/kg) OCTA101 sc daily for a further 6-7 months. 
Throughout the prophylaxis parts of the study, FVIII inhibitors (including LumiTope assay), 
plasma concentrations of FVIII:C, and OCTA12 will be measured repeatedly. Bleeding 
episodes should be treated with Nuwiq.  
As discussed in the Benefit-Risk Statement below, based on the accumulated data from the 
study, an additional cohort, Cohort 6, will investigate lower doses of 12.5 and 25 IU/kg (and 
probably 40 IU/kg) OCTA101 sc daily for 6-7 months each, based on DMC recommendations. 
1.5 Benefit-Risk Statement 
The nonclinical program has shown that rFVIII combined with OCTA12 effectively enters the 
circulation, that it has a prolonged half-life and a clinically relevant in-vivo hemostatic function. 
No overt toxicity or adverse effects were observed, with a safety margin of at least 10 times the 
clinical dose. See the IB for details. 
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Patients would benefit if the clinical development of OCTA101 was to prove successful as sc 
delivery of FVIII provides a more convenient and less intrusive mode of administration for 
patients, and may improve treatment compliance. 
As OCTA101 consists of Nuwiq-process-derived rhFVIII (Q-eluate, the penultimate step of the 
Nuwiq drug substance manufacturing process) and the recombinant VWF fragment dimer, 
OCTA12, the risks that can be expected in patients consist of those known for Nuwiq, with 
further possible risks those associated with OCTA12 and with sc administration.  
The risks for Nuwiq have been well established and are outlined in the Nuwiq Investigator 
Brochure. The most frequently occurring adverse reactions (>0.5%) in clinical trials were 
paresthesia, headache, injection site inflammation, injection site pain, non-neutralizing anti-
factor VIII, inhibitor formation (only in PUPs), back pain, vertigo, dry mouth, hemorrhagic 
anemia, dizziness, malaise, and dyspnea. Hypersensitivity reactions, including anaphylaxis, are 
possible. 
There are no known risks associated with OCTA12. OCTA12 per se has no hemostatic function 
except that it binds to FVIII with a Kd comparable to endogenous VWF. There was no evidence 
of adverse effects attributable to OCTA12 in Cynomolgus monkeys after repeated sc injections 
of OCTA101. 
Subcutaneous administration has generally proven to have fewer risks as compared to iv 
administration. The most common adverse reactions related to sc administration consist of local 
injection site reactions, with pain, bruising, bleeding, itching, redness, or swelling at the 
injection site. Repeated injections at the same spot can cause scarring and hardening of fatty 
tissue that may interfere with uptake of sc-administered medication. Nevertheless, no relevant 
local intolerance reactions were observed in a repeated dose toxicity study in Cynomolgus 
monkeys. 
To minimize risk in this first-in-human study, one part of the study planned to include a single 
ascending dose portion in 4 cohorts. This part of the study was to identify a safe and effective 
dose for testing in further clinical trials. The results from Cohort 1 showed that a dose of 
50 IU/kg OCTA101 was effective in raising FVIII:C plasma levels while no safety issues were 
observed. In Cohort 2 (100 IU/kg), FVIII inhibitor formation was observed in 2 patients, one 
after 1 month and one after 2 months of daily treatment with OCTA101, without the occurrence 
of bleeding episodes, resulting in the study being placed on study hold. Immune tolerance 
induction (ITI) treatment was initiated with Nuwiq and the patients were followed-up. One 
patient died in summer 2020, after a fatal adverse event, the second patient is still undergoing 
ITI treatment. 
One patient from Cohort 3 also developed low titer transient FVIII inhibitors after 3 months of 
prophylaxis with OCTA101 (first month) and Nuwiq (second and third month). This FVIII 
inhibitor was transient. The patient returned to his previous FVIII concentrate and wasn’t tested 
being inhibitor positive, again. Based on the results from Cohorts 1, 2, and 3, the sponsor and 
DMC decided that escalation to higher doses should not take place and that further 
characterization of the 50 IU/kg dose and lower doses for daily prophylaxis was instead 
warranted. The stopping rules for the study were amended to add detailed instructions on how 
inhibitor formation should be monitored and how any further inhibitor formation will impact 
study conduct. The study design was amended accordingly with protocol Amendments 2 and 
3. Data will be continuously monitored, and the DMC consulted, where required throughout 
the remainder of the study.  
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It was noted that a major difference between treatment of Cohort 1 and Cohort 2 patients was 
the iv treatment with Nuwiq of all patients of Cohort 1 during the period between the first PK 
with sc OCTA101 and the start of daily prophylactic sc administration of OCTA101 at a dose 
of 50 IU/kg. In contrast, all patients of Cohort 2 underwent sc treatment with OCTA101 directly 
after the first PK assessment, without any interim Nuwiq dosing. It was also noted that patients 
from both cohorts were treated mainly on-demand with a plasma-derived product before 
entering the study. 
Immune response upon sc application of FVIII with or without iv pre-treatment with FVIII as 
applied for Cohorts 1, 2, and 3 respectively, has been evaluated in a humanized hemophilic 
mouse model described by Reedtz-Runge et al. (2018). The applied humanized hemophilic E17 
HLA-DRB1*1501 mice model carries a knockout of the entire murine MHC class II complex. 
It expresses a chimeric murine-human MHC class II complex, which contains the sequences of 
the human HLA-DRA*0101 and HLADRB1*1501 proteins responsible for peptide binding, 
and the murine binding sides for the murine CD4 protein (T-cell surface glycoprotein, 
coreceptor for MHC class II molecule:peptide complex). This humanized hemophilic mice was 
characterized by Steinitz et al. (2012) and appeared to be very sensitive against sc treatment 
using a full-length recombinant FVIII: all mice treated sc with FVIII developed anti-FVIII 
antibodies. Upon iv administration of FVIII, only a fraction of mice developed anti-FVIII 
antibodies (between 30%-80%).  
Reedtz-Runge et al. (2018) used this mice model to evaluate the hypothesis, if iv administration 
of recombinant FVIII (Advate) generates immune tolerance to sc administered glycopegylated 
FVIII (N8GP). The humanized hemophilic mice were treated sc with N8GP with or without iv 
pre-treatment with Advate. They administered iv Advate to 10 mice at a dose of 500 IU/kg once 
weekly over an 8-week period. After this they started an 8-week challenge period with sc N8GP, 
also 500 IU/kg (but only in mice who did not develop antibodies to iv FVIII; n=5). Mice that 
did not develop antibodies to iv FVIII therapy, did not develop any antibodies to N8GP upon 
sc-treatment. 
These data from a humanized hemophilic mouse model suggest that iv pre-treatment of patients 
with Nuwiq may have induced tolerance for subsequent sc treatment with OCTA101. 
Therefore, for the newly added Cohort 6, all patients will receive a 4 to 6-week run-in period 
with 3 x weekly ~30 IU/kg Nuwiq iv prophylaxis. Patients will also have to have a negative 
LumiTope test result at screening. This will exclude patients who have non-inhibitory 
antibodies, which can play a role in subsequent development of inhibitory antibodies. 
Patients with FVIII inhibitors had received OCTA101 doses of 100 IU/kg sc for PK 
determination followed by 50 IU/kg daily dosing. With 50 IU/kg OCTA101, a mean trough 
FVIII plasma level of more than 10% was achieved and protected patients from breakthrough 
bleeds. PK modelling based on the PK data obtained from Cohorts 1 and 3, indicate that doses 
lower than 50 IU/kg should provide sufficient bleeding control. With 12.5 IU/kg, FVIII trough 
plasma levels of more than 1% are expected based on modelling, which should protect the 
patients from breakthrough bleeds. Therefore, following the Nuwiq iv prophylaxis run-in, 
Cohort 6 will investigate daily prophylaxis with 12.5 IU/kg for 6-7 months, followed by 
25 IU/kg (and probably 40 IU/kg) for 6-7 months, based on DMC recommendations. 
By introducing a run-in with Nuwiq iv prophylaxis and testing lower doses of OCTA101 
sequentially in ≥16 patients in total, the risk of inhibitor formation should be substantially 
reduced. However, inhibitor formation will be monitored carefully in Cohort 6, and the study 
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will be terminated if one more patient develops a confirmed FVIII inhibitor (≥0.6 BU) as 
determined by the central lab. 
In conclusion, the existing nonclinical data and the clinical data from Cohorts 1,2, 3 and 5, 
together with the risk minimization steps implemented in this protocol, indicate that 
participating in this study should not represent any additional risk to the included patients 
beyond the possibility of inhibitor formation, for which risk mitigation steps have been taken.  
 
2 
STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is to assess the safety of various doses of OCTA101 after sc injection. 
2.2 Secondary Objectives 
The secondary objectives of this study are to assess 
• the pharmacokinetics of FVIII:C after single sc injection of OCTA101 
• the dose proportionality of FVIII:C after sc injections of different doses of OCTA101 
• the bioavailability of sc OCTA101 compared to iv injection of Nuwiq 
• the pharmacokinetics of OCTA12 (recombinant human von Willebrand Factor fragment 
dimer) after single injection of OCTA101 
• plasma trough and peak levels of FVIII:C after daily injections of OCTA101 
• plasma trough and peak levels of OCTA12 after daily injections of OCTA101 
• the efficacy of sc injections of OCTA101 in preventing bleeding episodes. 
 
3 
INVESTIGATIONAL PLAN 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoints 
The following safety endpoints are the primary endpoints in this study: 
• Adverse events 
• DLTs 
• Thromboembolic events 
• Local injection site reactions 
• Inhibitor formation to FVIII 
3.1.2 Secondary Endpoints 
Efficacy: 
• PK parameters of FVIII:C (AUC, Cmax, Tmax, IVR, t1/2, MRT, CL [iv dosing only], Vd 
[iv dosing only]) 
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• PK parameters of OCTA12 (same parameters as for FVIII:C above) 
• Total annualized bleeding rate during daily sc treatment with OCTA101 
• Spontaneous annualized bleeding rate during daily sc treatment with OCTA101 
• Total annualized treated bleeding rate during daily sc treatment with OCTA101 
• Spontaneous annualized treated bleeding rate during of daily sc treatment with 
OCTA101 
• Traumatic annualized bleeding rate during of daily sc treatment with OCTA101 
• Annualized joint bleeding rate during daily sc treatment with OCTA101 
• FVIII:C trough and peak plasma levels during daily dosing 
• Score (4-point rating scale) to assess efficacy of treatment of bleeding episodes with 
Nuwiq  
Safety:  
• Antibody formation to OCTA12 
• LumiTope assay results 
• OCTA12 plasma levels during daily dosing 
• Routine lab tests compared to baseline 
• Vital signs compared to baseline 
• Physical examination results compared to baseline 
3.2 Overall Study Design and Plan 
SubQ8-01 is a first-in-human, prospective, open-label Phase 1/2 study of OCTA101, which 
consists of an eluate of an already authorized human recombinant coagulation factor FVIII 
product (Nuwiq®) along with OCTA12 (at a molar ratio of 1:6, with regards to FVIII binding 
sites in OCTA12), a recombinant human VWF fragment dimer, which is expected to increase 
the bioavailability of FVIII on sc dosing. The trial will be carried in adult patients with severe 
hemophilia A according to a staged integrated design with five planned consecutive cohorts. 
No patient can receive treatment in more than 1 cohort. 
One part of the study was to be a single ascending dose study in 4 cohorts (50, 100, 200 and 
400 IU/kg). The decision of going to the next higher dose was to be taken after each cohort by 
an external independent DMC after review of safety and tolerability data, FVIII:C plasma 
levels, and PK characteristics of FVIII:C and OCTA12. Any safety-relevant signals were also 
forwarded to the DMC for their review as they occurred. The reason(s) for not progressing to a 
higher dose level, e.g. dose-limiting toxicities (DLTs), were to be documented if such a decision 
was reached. 
Pre-defined DLTs for this study are: 
1. Severe allergic reactions at least possibly related to study drug. 
2. Severe vital organ toxicity at least possibly related to study drug that does not resolve 
to at least mild severity within 48 to 72 hours. 
3. Any treatment-emergent severe toxicity at least possibly related to study drug other 
than the toxicities referenced in 2) that does not decrease to mild or resolve within 
7 days 
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Definitions for mild, moderate and severe toxicity: 
Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living. 
Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living. 
Based on the results from Cohorts 1 and 2, the sponsor and DMC decided that escalation to 
higher doses should not take place and that further characterization of 50 IU/kg and lower doses 
was warranted. Therefore, Cohort 3 received 50 IU/kg administered into the abdomen, Cohort 4 
was to receive 50 IU/kg administered into the thigh (this was not proceeded with, as described 
below), and Cohort 5 investigated dose linearity at a lower dose range than initially planned 
(20, 40 and 60 IU/kg instead of 50, 100 and 200 IU/kg). 
Patients in Cohort 3 also received a single iv dose of 50 IU/kg Nuwiq in order to compare the 
bioavailability of sc OCTA101 with those of Nuwiq (the FVIII part of OCTA101) injected iv. 
The treatment sequence was Nuwiq followed by OCTA101. 
Dose proportionality of OCTA101 was evaluated after single sc administration of three 
different doses (20 IU/kg, 40 IU/kg and 60 IU/kg) in 4 additional patients (Cohort 5).  
Following completion of the PK assessments in Cohort 3 and 1-month into OCTA101 daily 
prophylaxis in this cohort, the study was put on hold due to inhibitor development in a second 
patient (in Cohort 2). 
Due to the study hold, patients in Cohort 3 were switched to prophylaxis with Nuwiq after 
having received 1-month of OCTA101 daily prophylaxis. Patients in Cohort 3, completed the 
study when their overall time on daily prophylaxis (OCTA101 + Nuwiq) reached 3 months. By 
the time of preparation of protocol version 8.0, Cohorts 1, 2 (with the exception of 1 patient 
with FVIII inhibitors who entered ITI treatment with Nuwiq), 3, and 5 were completed (in 
Cohort 5 only 4 of the planned 8 patients were treated). During study hold, at the 
recommendation of the DMC, detailed immunogenicity analyses were carried out, including 
the LumiTope assay, and all available data were presented to the DMC.  
With the agreement of the DMC, it was decided to proceed with the study introducing the 
following changes to the study design. Cohort 4 was cancelled and Cohort 5 was cut from 8 
patients to 4.  
A new cohort (Cohort 6) was planned with 16 evaluable patients. In this cohort, around 18-20 
patients (to compensate for possible early drop-outs) were planned to start with an initial 4 to 
6-week run-in treatment period with Nuwiq iv prophylaxis followed by 12.5 IU/kg OCTA101 
sc daily prophylaxis for >3 up to 6-7 months. With DMC agreement, the patients were planned 
to proceed to 25 IU/kg OCTA101 sc daily prophylaxis for 6-7 months. Based on the results of 
both dosing phases, a 40 IU/kg OCTA101 were planned to be considered.  
Cohort 6 was planned to proceed as follows:  
• Following completion of the run-in period with Nuwiq iv prophylaxis, 3 patients (one 
screened patient withdrew consent after Nuwiq run-in phase) started daily dosing with 
12.5 IU/kg OCTA101 sc. 
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• After 3 months of treatment with OCTA101, the patients will have their 3-month follow-
up visit. During the 2 to 3 weeks waiting for all relevant results, especially FVIII 
inhibitor testing results, these patients will continue on daily dosing with 12.5 IU/kg 
OCTA101 sc. 
• If the DMC determines that further patients can start their daily prophylaxis with 
OCTA101, at least 16 patients will proceed with 12.5 IU/kg OCTA101. After a further 
3 months, following DMC data review, the first 3 patients of this cohort will start on 
daily dosing with 25 IU/kg OCTA101 sc for 6-7 months. The remaining patients will 
follow after a further 3 months, after DMC data review. 
• Patients reporting two spontaneous bleeding episodes will be switched to the next higher 
dose level after having completed at least 3 months with 12.5 IU/kg OCTA101 daily 
treatment: they will start daily dosing with 25 IU/kg OCTA101 sc. 
• Depending on the results of the 12.5 IU/kg and 25 IU/kg OCTA101 treatment phases, 
the initiation of a 40 IU/kg OCTA101 phase will be considered together with the DMC. 
• Bleeding episodes will be controlled with the use of Nuwiq during the entire duration 
of treatment in Cohort 6. 
 
The cohorts are summarized as follows: 
• Cohort 1: 50 IU/kg (n=4): single-period investigation with a single sc dose of 50 IU/kg 
OCTA101 profiled up to 72 hours after dosing. 
• Cohort 2: 100 IU/kg (n=4): single-period investigation with a single sc dose of 
100 IU/kg OCTA101 profiled up to 96 hours after dosing. 
• Cohort 1 and 2 (n=8): single-period investigation with a single sc dose of 50 IU/kg 
OCTA101 profiled up to 120 hours after dosing for FVIII and up to 21 days for 
OCTA12. 
• Cohort 3: 50 IU/kg (n=8): two-period investigation of a single iv dose of 50 IU/kg 
Nuwiq profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg 
OCTA101 administered into the abdomen profiled up to 72 hours. Treatments were to 
be administered in fixed sequence, with Nuwiq first. 
• Cohort 4: 50 IU/kg (n=4): Cancelled. 
• Cohort 5 (n=4): three-period investigation of single sc doses of 20, 40, and 60 IU/kg 
OCTA101 profiled up to 72 hours after dosing, respectively. Treatments were to be 
administered in fixed dose-ascending sequence.  
• Cohort 6 (n ≥16): Following an initial 4 to 6-week run-in period with Nuwiq iv 
prophylaxis, >3-6 months daily prophylactic treatment with 12.5 IU/kg OCTA101 sc, 
then 25 IU/kg OCTA101 sc for a further 6-7 months (exact dosing depends on available 
vial sizes). In case of two spontaneous bleeding episodes, after having completed at least 
3 months with 12.5 IU/kg OCTA101 daily treatment the individual treatment dose was 
planned to be increased from 12.5 to 25 IU/kg. Site of administration (abdomen or thigh) 
to be chosen by the patient. A further treatment phase with 40 IU/kg OCTA101 was 
planned to be discussed with the DMC, once results of earlier dosing phases are 
available. 
The DMC will review and assess the available results approximately every 3 months. 
By DMC-recommendation, patients enrolled in Cohorts 1, and 2 proceeded to the 3-month 
prophylactic treatment part of the study and received daily dosing (approximately 40-60 IU/kg; 
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dose chosen to allow administration by single injection; it was permitted to daily alternate the 
vial, e.g. 3000 IU on one day 1, 5000 IU on day 2, 3000 IU on day 3, 5000 IU on day 4 etc.) of 
OCTA101 for 3 months (home treatment). Patients from Cohort 1 received prophylactic Nuwiq 
(home treatment) until the DMC had confirmed that OCTA101 could be used as daily 
prophylaxis. Bleeding events during the study were treated with Nuwiq. Throughout this part 
of the study, FVIII inhibitors, plasma concentrations of FVIII:C, and OCTA12 were measured 
repeatedly.  
A PK assessment was to be performed in all patients from Cohorts 1 and 2 who completed their 
3-month daily injection period; it was actually performed in all patients of Cohort 1 and in one 
patient of Cohort 2 (the two inhibitor patients as well as a patient whose FVIII levels were very 
low did not do the repeat PK assessment). 
Independent expert evaluation by the DMC has steered study progress for the stepwise dosage 
increments by cohort and the progression of patients from the first three cohorts to 3-month 
daily dosing. In addition, the DMC has advised on changes of the proposed dosage for the 
assessment of bioavailability (Cohort 3) and dose-proportionality (Cohort 5) and changes in the 
schedule of PK blood sampling and/or the duration of profiling. These changes have been 
implemented with Amendment 2 of the protocol. Based on the observation of a second patient 
with inhibitors in Cohort 2, the DMC recommended placing the study on hold. The DMC 
recommended restarting the study with the implementation of Amendment 3, which cancelled 
Cohort 4, cut Cohort 5 to 4 patients instead of the planned 8, and introduced Cohort 6 
investigating lower doses of OCTA101 sc daily prophylaxis per dose level following a run-in 
period with Nuwiq iv prophylaxis. The DMC will continue to be involved in the further conduct 
of the study. 
This study started in Q2 2019 and is planned to be completed by Q3 2022. 
 
Summary of status at the time of finalizing the amended study protocol version 9.0: 
At the time of finalizing the amended study protocol version 9.0, the following had been 
completed: 
• Cohort 1: 50 IU/kg: single-period investigation with a single sc dose of 50 IU/kg 
OCTA101 profiled up to 72 hours after dosing – completed as planned in 4 patients. 3-
month OCTA101 daily dosing – completed as planned in 4 patients. PK assessment 
after 3-month daily dosing – completed as planned in 4 patients. 
• Cohort 2: 100 IU/kg: single-period investigation with a single sc dose of 100 IU/kg 
OCTA101 profiled up to 96 hours after dosing – completed as planned in 4 patients. 3-
month OCTA101 daily dosing – completed as planned in 2 patients; 2 patients with 
inhibitors in Cohort 2 discontinued daily OCTA101 prophylaxis and started ITI 
treatment with Nuwiq. PK assessment after 3-month daily dosing – completed as 
planned in 1 patient; not performed in the 2 inhibitor patients switched to ITI treatment 
and a patient with low levels of FVIII. One patient who developed FVIII inhibitors and 
started ITI died after a fatal serious adverse event (retroperitoneal hematoma). The 
second patient undergoing ITI after FVIII inhibitor development is continuing treatment 
with Nuwiq.  
• Cohort 3: 50 IU/kg (n=8): two-period investigation of a single iv dose of 50 IU/kg 
Nuwiq profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg 
OCTA101 administered into the abdomen profiled up to 72 hours – completed as 
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planned in 8 patients. 3-month OCTA101 daily dosing – due to the study hold, patients 
in Cohort 3 were switched to prophylaxis with Nuwiq after having received about 1-
month of OCTA101 daily prophylaxis; the 8 patients in Cohort 3 completed the study 
when their overall time on daily prophylaxis (OCTA101 + Nuwiq) reached 3 months. 
• Cohort 4: 50 IU/kg (n=4): cancelled. 
• Cohort 5 (n=4): three-period investigation of single sc doses of 20, 40, and 60 IU/kg 
OCTA101 profiled up to 72 hours after dosing with 4-week follow-up visit – completed 
in 4 patients instead of the originally planned 8 patients. 
• Cohort 6 (n≥16): Nineteen patients were screened for Cohort 6 since autumn 2020, of 
whom two failed inclusion-/exclusion criteria, and two withdrew consent. Ten patients 
started daily treatment with 12.5 IU/kg OCTA101 after a 4-6 weeks prophylactic 
treatment run-in phase with Nuwiq, 3 times weekly. Further five patients started the 4-
6 weeks run-in phase, but they have not yet started treatment with OCTA101. 
After six month daily treatment with OCTA101 a positive FVIII inhibitor result 
(0.8°BU/mL) was reported for patient C6-Q1-01-02 on 14-Jul-2021. After consultation 
and in agreement with the DMC the sponsor decided to put the study on-hold with 
immediate effect: all patients with OCTA101 treatment were switched back to 
prophylactic treatment with Nuwiq, 3 times weekly. On 27-Jul-2021 a further low-titer 
FVIII inhibitor was reported for patient C6-Q1-01-10 (1.6 BU/mL). 
It was decided to stop all further treatment with OCTA101, but to offer all enrolled 
patients access to Nuwiq prophylactic treatment until they are integrated into the 
National Health Insurance program for haemophilia A patients, again, but no longer 
than until the end of September 2021 + 2 weeks time window. 
3.3 Discussion of Study Design and Choice of Control Group(s) 
3.3.1 Study Design 
The study evaluates i) the safety, tolerability and pharmacokinetics of single sc doses of 
OCTA101; ii) the absolute bioavailability of FVIII following sc dosing of OCTA101; iii) the 
dose relationship of the FVIII-exposure levels (20-60 IU/kg OCTA101); and iv) the safety, 
efficacy, tolerability and trough PK levels of a prophylactic 3-month treatment with once daily 
sc dosing of approximately 40-60 IU/kg OCTA101 (based on DMC recommendations). 
As discussed in Section 1.5 and implemented by Amendment 3 to this protocol, the study design 
has been adapted based on the observation of inhibitor formation in Cohort 2. In Cohort 6, 
12.5 IU/kg OCTA101, followed by 25 IU/kg (and probably 40 IU/kg) OCTA101 daily 
prophylaxis will be investigated in a cohort of ≥16 patients following a run-in period with 
Nuwiq iv prophylaxis. 
The bioavailability and dose proportionality comparisons, together with the PK data from the 
single ascending dose cohorts, will determine the prophylactic treatment (dose per injection and 
injection interval) that would result in protective trough levels of FVIII:C for Phase 3 studies 
in adolescents/adults and children. 
By DMC-recommendation, patients from Cohorts 1, 2 and 3 received daily dosing (home 
treatment) with approximately 40-60 IU/kg of OCTA101 for 3 months. Throughout this part of 
the study, FVIII inhibitors, plasma concentrations of FVIII:C, and OCTA12 will be measured 
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repeatedly. This part of the study will provide safety data for multiple doses and the time course 
of FVIII:C and OCTA12 plasma concentrations after repeated daily injections. These data will 
allow determination of whether these FVIII levels protect against bleeding episodes and of the 
dynamics of OCTA12.  
A PK assessment was performed in patients from Cohorts 1 and 2 who completed their 3-month 
daily injection period further characterizing the PK of FVIII:C and OCTA12. Blood samples 
will be collected up to 21 days in order to see a decline in OCTA12 plasma concentrations (and 
allow determination of half-life) as the initial PK period is not long enough to see a decline of 
OCTA12. Concomitant measurement of FVIII:C up to 120 h will allow evaluation of any 
interaction between OCTA12 plasma concentration and FVIII:C. The experience gained in this 
part of the study may lead to an adaption of the PK-based dose calculations for the Phase 3 
studies. 
3.3.2 Control Group 
Patients in Cohort 3 will also receive a single iv dose of 50±5 IU/kg Nuwiq in order to compare 
the bioavailability of sc OCTA101 with those of Nuwiq injected iv. To be clinically viable, sc 
delivery of FVIII therapy in hemophilia A must overcome the limitation of poor FVIII 
bioavailability and ensure that the desired plasma level of FVIII is achieved. As Nuwiq is the 
rFVIII component of OCTA101, it is the appropriate control for bioavailability of OCTA101. 
3.3.3 Study Parameters 
The safety and efficacy parameters selected for assessment in this study are well-established 
parameters that have been used in the Nuwiq clinical studies that led to marketing authorization 
of that product, and they will establish the safety and pharmacokinetics of sc administered 
OCTA101. 
Based on the observation of inhibitor formation during the study, further analysis of antibody 
formation using the LumiTope assay was introduced by Amendment 3. 
 
4 
STUDY POPULATION 
4.1 Population Base 
The study will include adult male patients with severe hemophilia A who have been previously 
treated with FVIII. 
4.1.1 Inclusion Criteria 
Patients who meet all of the following criteria are eligible for the study: 
1. Severe hemophilia A (<1% FVIII:C) as documented in medical records 
2. Males ≥18 years of age 
3. Subjects who have had ≥150 exposure days (EDs) with a FVIII product 
4. Written informed consent for study participation obtained before undergoing any study 
specific procedures 
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4.1.2 Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for the study: 
1. Previous participation in this trial  
2. Use of an Investigational Medicinal Product within 30 days prior to the first OCTA101 
injection 
3. History of FVIII inhibitors titer ≥0.6 BU/mL defined by medical records 
4. Inhibitors to FVIII (≥0.6 BU/mL) at screening measured by Nijmegen modified 
Bethesda method at central laboratory  
5. Human immunodeficiency virus (HIV) positive subjects with a CD4+ count <200/mL  
6. Clinically significant anemia at screening (hemoglobin <8 g/dL) 
7. Presence of any significant comorbidity (at the discretion of the investigator) that might 
confound the interpretation of the study data and/or that might put the patient at undue 
risk by participating in the trial 
8. Any coagulation disorder other than hemophilia A 
9. AST or ALT levels >3 times the upper limit of normal 
10. Creatinine >120 µmol/L 
11. Platelet count <100,000 µL 
12. BMI ≥30 kg/m² 
13. For Cohort 6, patients with a positive LumiTope test at screening will be excluded. 
4.2 Prior and Concomitant Therapy 
Details on medications taken within one month before screening, including FVIII dosing in the 
previous 6 months, and any concomitant medications taken during the study must be recorded 
in the eCRF. 
4.2.1 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 first exposure with 
OCTA101 (or Nuwiq in Cohort 6 patients) should be treated with the patient’s previously 
used FVIII concentrate.  
Similarly, prophylactic treatment between the Screening Visit and the first exposure with 
OCTA101 (or Nuwiq in Cohort 6 patients) should be treated with the patient’s previously 
used FVIII concentrate.  
4.2.2 Forbidden Concomitant Therapy 
With the exception of the Nuwiq run-in in Cohort 6, no FVIII concentrate other than OCTA101 
should be given for prophylaxis and no FVIII concentrate other than Nuwiq should be given 
for treatment of bleeding episodes (except for emergency situations).  
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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 concentrate 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 product available at home) 
4.3 Withdrawal and Replacement of Patients 
4.3.1 Patient Withdrawal 
Patients have the right to withdraw from the study at any time for any reason, without the need 
to justify their decision. The Investigator also has the right to withdraw patients in case of AEs, 
poor compliance, or other reasons. Since an excessive rate of withdrawals can render the study 
noninterpretable, any unnecessary withdrawal of patients should be avoided. 
For any withdrawals after study entry, the Investigator will obtain all the required details and 
document the reason(s) for discontinuation (Termination Visit). If the reason for withdrawal of 
a patient is an AE, the main specific event or laboratory test will be recorded, and the 
Investigator will make thorough efforts to clearly document the outcome. 
4.3.2 Patient Replacement Policy 
Patients who are to undergo more than 1 PK assessment but drop out before the entire PK 
assessment is completed (i.e. Cohorts 3 and 5) will be replaced. If data indicate that IMP was 
inadvertently administered iv instead of sc for the PK assessment, the patient will be replaced. 
Any replacement patient will be assigned to the same treatment sequence as the withdrawn 
patient. 
Patients withdrawn from the study for safety reasons will not be replaced. 
Patients who were screened but did not proceed to OCTA101 treatment can be included after 
re-screening. 
4.4 Assignment of Patients to Treatment Groups 
The Investigator will enter a unique identifier of each patient in both the eCRF and the 
confidential patient identification list. The numbers will be allocated sequentially in the order 
in which the patients are enrolled. Patients will be assigned to the next available treatment 
cohort in a sequential manner. The Investigator will inform the sponsor representative of new 
patients enrolled using a subject enrolment form and faxing or e-mailing it to the Clinical Study 
Monitor or to the Clinical Project Manager immediately.  
Under no circumstances are patients who enroll in the study permitted to re-enroll. 
4.5 Relevant Protocol Deviations 
In case of any major protocol deviation, the Investigator and Octapharma will decide on the 
further participation of the patient in this study after having discussed all relevant aspects. 
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4.6 Subsequent Therapy 
Any patient who discontinues from the study or completes study treatment as planned should 
continue medical treatment according to local standards.  
 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1 Characterization of Investigational Products 
5.1.1 OCTA101 
OCTA101 (Human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer) 
is composed of rFVIII (derived from commercial Nuwiq) and the recombinant VWF fragment 
dimer OCTA12, at a molar ratio of 1:6 (with regards to FVIII binding sites in OCTA12).  
OCTA101 will be provided as lyophilized powder in vials containing 500 IU, 750 IU, 1000 IU 
and 2000 IU (additional 3000 IU and 5000 IU vials were provided for the completed cohorts 
1°-°5) human recombinant coagulation factor FVIII. Each vial needs to be reconstituted with 
1.0 mL of Water for Injection, which will be provided in a pre-filled glass syringe. The batch 
number(s) used will be recorded. The final product will be released by the responsible 
Octapharma Quality Control Department, in accordance with a defined final product 
specification. 
5.1.2 Nuwiq  
Nuwiq will be used in this study and will be provided by Octapharma. Nuwiq will be provided 
as lyophilized powder in vials containing either 500, 1000, 2000, or 3000 IU. Each vial needs 
to be reconstituted with 2.5 mL of Water for Injection. Nuwiq should be injected iv by bolus 
injection at a maximum rate of 4 mL/min. The batch number(s) used will be recorded. 
5.2 Packaging and Labelling 
This open-label study design does not necessitate the blinding of study participants or study site 
personnel with respect to treatment information.  
OCTA101 and Nuwiq will be packed and labelled according to local regulations, ensuring that 
the final labelling will comply with the national requirements of each country where the study 
is conducted.  
5.3 Conditions for Storage and Use 
OCTA101 and Nuwiq have to be stored at 2-8°C protected from light. They must not be frozen. 
The Investigator/authorized personnel at the site will ensure that the IMP is stored in appropriate 
conditions with restricted access and in compliance with national regulations. 
5.4 Dose and Dosing Schedule 
The following will be administered at the study site by trained personnel: 
• Cohort 1: Single injection of OCTA101 50 IU/kg sc with 72 hours of observation.   
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• Cohort 2: Single injection of OCTA101 100 IU/kg sc with 96 hours of observation.   
• Cohort 1 and 2: PK assessment after 3-month daily dosing: Single injection of 
OCTA101 50 IU/kg sc with 120 hours of observation for FVIII and 21 days of 
observation for OCTA12.   
• Cohort 3: Single injection of Nuwiq 50 IU/kg iv with 72 hours of observation, followed 
by single injection of OCTA101 50 IU/kg sc administered into the abdomen with 
72 hours of observation.   
• Cohort 4: (Cancelled) Single injection of OCTA101 50 IU/kg sc administered into the 
thigh with 72 hours of observation.   
• Cohort 5: Single injection of OCTA101 20 IU/kg sc with 72 hours of observation, 
followed by single dose of OCTA101 40 IU/kg sc with 72 hours of observation, 
followed by single dose of OCTA101 60 IU/kg sc with 72 hours of observation.  
• Cohort 6: 4-6 weeks prophylactic run-in treatment phase with ~30 IU/kg Nuwiq iv, 
given 3 x weekly, followed by 2 (probably 3) phases of 6-7 months daily injection with 
OCTA101, first 12.5 IU/kg, followed by 25 IU/kg daily (and probably 40 IU/kg). No 
wash-out periods are required between the treatment phases. Patients reporting two 
spontaneous bleeding episodes during the 12.5 IU/kg treatment phase may immediately 
switch to the 25 IU/kg daily, if they have completed at least 3 months with 12.5 IU/kg. 
Nuwiq (according to SmPC) is used to control bleeding episodes, if any.  
In all cases, the minimum number of injections required to provide the required dose must be 
administered. If multiple injections are needed, then they should not be administered at the same 
spot. The PK doses were to be achieved as accurately as possible with the available vial 
strengths as a single injection; it was permitted to daily alternate the vial size, (e.g. 3000 IU on 
one day 1, 5000 IU on day 2, 3000 IU on day 3, 5000 IU on day 4 etc.).  
OCTA101 will be administered by sc injection into the abdomen or thigh (see Appendix 1 in 
Section 13.a), whereby for Cohorts 1 and 2 the choice is up to the investigator and patient, in 
Cohort 3 all administrations of OCTA101 will be into the abdomen, in Cohort 5, four patients 
each will consistently be injected with OCTA101 either in the abdomen or in the thigh at all 
three dose levels.  
In Cohort 6, the choice is up to the patient. It is recommended to alternate injection sites.  
Patients will be trained on the correct method for sc administration. In Cohort 1, 2 and 3, daily 
injections of OCTA101, approximately 40-60 IU/kg sc, were planned to be administered by the 
patient for 3 months.  
Cohort 6 will investigate 6-7 months daily prophylactic treatment with 12.5 IU/kg OCTA101 
sc, then 25 IU/kg OCTA101 sc for a further 6-7 months (and probably 40 IU/kg OCTA101), 
administered by the patients, unless the patient is attending a visit at the study site.  
At the end of the daily injection period in Cohorts 1 and 2, and after a wash-out of at least 
72 hours after the last OCTA101 injection, or any other FVIII injection, the PK of FVIII:C and 
OCTA12 was to be assessed with an OCTA101 dose of 50 IU/kg. FVIII:C and OCTA12 levels 
were to be measured up to 120 hours; thereafter, additional samples will be taken to measure 
OCTA12 at the following time points: 7, 14 and 21 days. After the 120 hour time point patients 
could use Nuwiq for prophylaxis or treatment of bleeding episodes until the last sampling time 
point. 
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Nuwiq was to be injected iv once for PK evaluation at a dose of 50 IU/kg in patients of 
Cohort 3.  
Patients in Cohort 1 who had completed their respective PK assessment used Nuwiq (iv) at the 
discretion of the investigator for prophylaxis until the DMC had adjudicated 50 IU/kg as safe, 
had advised to continue with Cohort 2, and had advised that Cohort 1 patients can start daily 
dosing with OCTA101.  
During study hold, the patients in Cohort 3 stopped OCTA101 daily prophylaxis after about 
1 month and were switched to Nuwiq prophylaxis during the study hold period. Patients in 
Cohort 3 completed the study when they had completed 3 months of daily prophylaxis in total 
(OCTA101 + Nuwiq). Two patients with inhibitors entered ITI treatment with Nuwiq and did 
not receive the planned treatment for Cohort 2. 
Bleeding events during the study will be treated with Nuwiq in accordance with the 
recommended doses given in the SmPC. 
5.5 Preparation and Method of Administration 
OCTA101 and Nuwiq will be provided in single-use vials to be reconstituted in Water for 
Injection. 
Prior to injection, the solution must have reached room temperature, without taking any specific 
warming-up measures. The preparation should be used immediately after reconstitution. The 
solution is a clear or slightly opalescent colorless solution. Solutions that are cloudy or have 
deposits must not be used.  
OCTA101 must be injected sc into the abdomen or thigh (see Appendix 1 in Section 13.a). The 
site of sc administration must be documented. The investigator and the patients will receive 
detailed Handling Instructions on how and where to perform the sc injections. 
Nuwiq must be injected iv by bolus injection (maximally 4 mL/minute) by using aseptic 
technique.  
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
Not applicable in this open-label study. 
5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
Any IMP provided to the site will be accounted for. This includes IMP received at the site and 
IMP dispensed to patients. A Drug Inventory and Dispensing Log will be kept current by the 
Investigator, detailing the dates and quantities of IMP received and dispensed to each patient 
and the remaining quantity.  
For their home treatment, a sufficient amount of OCTA101 and of Nuwiq will be handed out 
to the patients. The Investigator or his/her designee has to document the date, quantities and 
batch (lot) number(s) of IMP handed out including the corresponding patient number. The 
patients will be advised to return used or expired vials to the study site at their on-site visits, 
and to return used and unused vials at the (early) Termination Visit. 
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Patient returned IMP (used or unused) must not be used anymore and must be destroyed after 
completion of drug accountability.  
The inventory and dispensing log will be available to the monitor to verify drug accountability 
during the study.  
Unused IMP can be destroyed at the study site or returned to the Sponsor for destruction. 
Destruction can be initiated only after accountability has been verified and fully reconciled by 
the monitor and after the Sponsor has granted written approval of destruction. 
5.7.2 Assessment of Treatment Compliance 
Administration of IMP at the study site will be performed by trained personnel, who will 
document details of administration in the eCRF. 
At the first visit, the Investigator will provide eligible patients with a sufficient amount of trial 
medication (in cooling boxes, if appropriate). 
Eligible patients will receive a patient diary after the first injection of OCTA101 (after the first 
injection of Nuwiq for the run-in in Cohort 6). The investigator will explain to the patient how 
to fill in the diary and will emphasize the importance of carefully documenting all treatment 
details, adverse events, and concomitant medications. Furthermore, the efficacy rating criteria 
for treating a bleeding episode (Section 7.2.1.1) and the criteria for assessing the severity of a 
bleed will be explained. The Investigator will emphasize the necessity of careful documentation 
of all treatment details. The recording of at-home injections will include the date and time, dose, 
and batch number. IMP is provided with tear-off labels that must be placed in the diary.  
In case of treatment of BEs, the patients will document the site and severity of the bleed, the 
start and end dates and time, and carry out an efficacy assessment according to the explanation 
provided in the diary. The patients will be trained on how to administer Nuwiq to control 
bleeding, if required. 
Study product administrations that are overseen by the Investigator (e.g. treatment in case of 
severe BEs treated at the study site), are to be documented in the patient’s journal (by the 
Investigator), as well as in the patient's diary (by the patient). 
In addition, the patient will record any concomitant medications taken during the study period 
in their diaries. 
For each follow-up visit at the study site, the patients must bring all diaries to be reviewed and 
validated by site personnel. 
 
6 
STUDY CONDUCT  
The flow charts of assessments by study visit are given, starting on page 21. The flow chart of 
the recently ongoing Cohort 6 can be found on page 26. 
6.1 Observations by Visit 
6.1.1 Screening Visit – All Patients 
The following assessments will be performed during the Screening Visit, which should take 
place within 30 days before the first administration of IMP: 
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• Obtaining voluntarily given, written (signed and dated) informed consent 
• Check of inclusion and exclusion criteria 
• Demographics: age, ethnic origin 
• Blood type (ABO) 
• CD4+ count 
• Medical history  
• Details on medications taken within one month before screening, including FVIII 
dosing in the previous 6 months, and any concomitant medications. 
• Body weight  
• Height  
• Physical examination  
• Hemophilia Joint Health Score (HJHS)  
• Target joint(s) (defined as three or more spontaneous bleeding episodes into a single 
joint within 6 consecutive months preceding screening visit) 
• Vital signs: systolic and diastolic blood pressure, body temperature, pulse (before blood 
sample collection)  
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay)  
• Routine safety lab: Hematology: red blood cell count, white blood cell count, 
hemoglobin, hematocrit, platelet count; Clinical chemistry: total bilirubin, ALT, AST, 
urea, serum creatinine, lactate dehydrogenase 
• Start of monitoring of adverse events (AEs) 
• Cohort 6: LumiTope assay (negative test result required) 
Any bleeding episodes occurring between the Screening Visit and the first exposure to 
OCTA101 or Nuwiq should be treated with the patient’s previously used FVIII concentrate.  
Following screening, eligible patients will receive a patient diary after the first injection of 
OCTA101 or Nuwiq. The investigator will explain to the patient how to fill in the diary and 
will emphasize the importance of carefully documenting all treatment details, adverse events, 
and concomitant medications. 
PK assessments are to be performed after a washout period of at least 72 h, if possible, from 
the last FVIII injection. Patients must not be experiencing any bleeding.  
6.1.2 Cohort 1 patients – single dose PK, OCTA101 50 IU/kg sc 
The following assessments will be performed:  
• Body weight (before injection) 
• Vital signs (before injection, 0.5 h, 8 h, 24 h, 48 h and 72 h after injection) 
• Routine safety lab (before injection, 0.5 h, 8 h, 24 h, 48 h and 72 h after injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before injection)  
• Blood sample for anti-OCTA12 measurement (before injection) 
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• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before 
injection and 0.5 h, 2 h, 4 h, 8 h, 24 h, 48 h and 72 h after injection).  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
6.1.3 Cohort 2 patients – single dose PK, OCTA101 100 IU/kg sc 
The following assessments will be performed: 
• Body weight (before injection) 
• Vital signs (before injection, 0.5 h, 8 h, 24 h, 48 h, 72 h and 96 h after injection) 
• Routine safety lab (before injection, 0.5 h, 8 h, 24 h, 48 h, 72 h and 96 h after injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before injection)  
• Blood sample for anti-OCTA12 measurement (before injection) 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before 
injection and 0.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h and 96 h after injection).  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
6.1.4 Cohort 3 patients – single dose PK, PK Nuwiq 50 IU/kg iv, followed by OCTA101 
50 IU/kg sc into the abdomen 
NUWIQ injection (iv): the following assessments will be performed: 
• Body weight (before injection) 
• Vital signs (before injection, 0.5 h, 8 h, 24 h, 48 h, and 72 h after injection) 
• Routine safety lab (before injection, 0.5 h, 8 h, 24 h, 48 h, and 72 h after injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before injection) 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before 
injection and 0.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, and 72 h after injection.  
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
OCTA101 injection (sc into the abdomen): the following assessments will be performed: 
• Blood sample for anti-OCTA12 measurement (before injection) 
• Vital signs (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after injection) 
• Routine safety lab (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after injection) 
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• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before 
injection and 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after injection).  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
6.1.5 Cohort 4 patients – single dose PK, OCTA101 50 IU/kg sc into the thigh 
Cancelled. 
6.1.6 Cohort 5 patients – single dose PK of OCTA101 20 IU/kg sc, followed by single 
dose PK of OCTA101 40 IU/kg sc, followed by single dose PK of OCTA101 
60 IU/kg sc 
OCTA101 injection 20 IU/kg into the abdomen (4 patients): the following assessments will be 
performed: 
• Body weight (before injection) 
• Vital signs (before injection, 8 h, 12 h, 24 h, 48 h and 72 h after the injection) 
• Routine safety lab (before injection, 8 h, 12 h, 24 h, 48 h and 72 h after the injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before the first injection)  
• Blood sample for anti-OCTA12 measurement (before the injection) 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before 
the injection and 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection)  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
OCTA101 injection 40 IU/kg into the abdomen (4 patients): the following assessments will be 
performed: 
• Vital signs (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection) 
• Routine safety lab (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection) 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before 
the injection and 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection)  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
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OCTA101 injection 60 IU/kg into the abdomen (4 patients): the following assessments will be 
performed: 
• Vital signs (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection) 
• Routine safety lab (before injection, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay) 
4 weeks after injection 
• Blood sample for anti-OCTA12 measurement 4 weeks after injection 
• Blood samples for measurement of FVIII:C (one-stage and chromogenic assay) (before 
the injection and 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after the injection)  
• Blood samples for measurement of OCTA12, as above for FVIII:C 
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
6.1.7 Cohort 1, 2 and 3 patients – daily injections for 3 months, OCTA101 40 - 60 
IU/kg sc 
Patients entering the 3-month daily prophylactic part will be trained in sc self-administration of 
study medication. Patients in Cohort 1 will be required to return to the study site for their first 
daily dose; patients in Cohorts 2 and 3 will still be present at the study site at the time of their 
first daily dose. The following assessments will be performed:  
• Vital signs (before and 3 h and 6 h after the injection at the beginning of the 3-month 
daily dosing and 0.5, 1, 2, and 3 months thereafter) 
• Routine safety lab (before and 3 h and 6 h after the injection at the beginning and 2, 4, 
8 and 12 weeks thereafter) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before the first injection and 0.5, 1, 2 and 3 months thereafter)  
• Blood sample for anti-OCTA12 measurement, (before the first injection and 0.5, 1, 2 
and 3 months thereafter)  
• Blood sample for FVIII:C measurement (one-stage and chromogenic assay), (before and 
3 h and 6 h after the injection at the beginning and 0.5, 1, 2, and 3 months thereafter) 
• Blood sample for OCTA12 measurement, (before and 3 h and 6 h after injection at the 
beginning and 0.5, 1, 2, and 3 months thereafter)  
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection, for each injection) 
• Physical examination (at End of Study) (Cohort 3 only) 
• Adverse event monitoring throughout the study period 
• Documentation of concomitant medication throughout the study period 
6.1.8 Cohort 1 and 2 patients – PK assessment following 3-month daily prophylaxis 
Patients from Cohorts 1 and 2 completing the 3-month daily prophylactic part will attend the 
study site. The following assessments will be performed:  
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• After a wash-out of at least 72 hours after the last OCTA101 injection, or any other 
FVIII injection, a dose of 50 IU/kg OCTA101 sc will be administered 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before and at 21 days after the injection)  
• Blood sample for anti-OCTA12 measurement, (before and at 21 days after the injection)  
• Blood sample for FVIII:C measurement (one-stage and chromogenic assay), (before and 
2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, and 120 h after the injection) 
• Blood sample for OCTA12 measurement, (before and 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 
h, 120 h, 7 days, 14 days, and 21 days after the injection)  
• Physical examination (at End of Study)  
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection) 
• Adverse event monitoring throughout the study period  
• Documentation of concomitant medication throughout the study period 
6.1.9 Cohort 6: Following a 4-6 week prophylactic treatment phase with ~30 IU/kg 
Nuwiq iv 3 x weekly, patients start 6-7 months daily treatment with 12.5 IU/kg 
OCTA101 sc, then 6-7 months daily 25 IU/kg OCTA101 sc (and probably 
40 IU/kg OCTA101 sc, depending on the results of earlier treatment phases) 
Patients in Cohort 6 will have their first Nuwiq administered at the study site. After the run-in 
period, patients will be trained in sc OCTA101 self-administration for subsequent home 
treatment.  
The following assessments will be performed:  
Start of 4 to 6 week Nuwiq run-in: 
• Documentation of bleeding episodes and their treatment throughout the run-in period  
• Adverse event monitoring throughout the run-in period  
• Documentation of concomitant medication throughout the run-in period 
Daily OCTA101 treatment periods: 
• Vital signs (before and 8 h after the injection OCTA101 at the beginning of each dosing 
period and 0.5, 1, 2, 3, 4, 5 and 6 months thereafter) 
• Routine safety lab (before and 8 h after the OCTA101 injection at the beginning of each 
dosing period and 0.5, 1, 2, 3, 4, 5 and 6 months thereafter) 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay), 
(before the first injection of OCTA101 and 0.5, 1, 2, 3, 4, 5 and 6 months thereafter for 
each of the 6-7 month OCTA101 daily prophylaxis treatment periods)  
• Blood sample for anti-OCTA12 measurement, (before the first injection of OCTA101 
and 0.5, 1, 2, 3, 4, 5 and 6 months thereafter for each of the 6-7 month OCTA101 daily 
prophylaxis treatment periods) 
• Blood sample for FVIII:C measurement (one-stage and chromogenic assay), (before and 
8°h after the OCTA101 injection at the beginning of the 6-7 months dosing periods and 
0.5, 1, 2, 3, 4, 5 and 6 months thereafter) 
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• Blood sample for OCTA12 measurement, (before the first injection of OCTA101 and 
0.5, 1, 2, 3, 4, 5 and 6 months thereafter for each dosing period)  
• Physical examination (at End of Study)  
• LumiTope assay (before the first injection of OCTA101 and 0.5, 1, 2, 3, 4, 5 and 6 
months thereafter for each dosing period)  
• Assessment of local injection site reactions (directly after injection and 15 ± 5 min post-
injection, for each injection) 
• Documentation of bleeding episodes and their treatment throughout the study period 
• Adverse event monitoring throughout the study period  
• Documentation of concomitant medication throughout the study period 
6.1.10 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. 
6.1.11 Final visits 
All patients will immediately stop treatment with OCTA101, if another patient develops a 
confirmed FVIII inhibitor (≥0.6 BU). 
In this case, all FVIII inhibitor negative patients will switch to prophylactic treatment with 
Nuwiq comparable to the run-in phase, and will come for a final follow-up visit after treatment 
change. During the final follow-up visit the following should be done: 
• Routine safety lab 
• Blood sample for FVIII inhibitor measurement (modified Nijmegen Bethesda assay) 
• Blood sample for anti-OCTA12 measurement 
• Blood sample for OCTA12 measurement 
• Physical examination 
• LumiTope assay 
• Documentation of bleeding episodes and their treatment 
• Adverse event monitoring 
• Documentation of concomitant medication 
6.1.12 Time Windows Used in this Study, including Tolerances 
In this study, the following time windows and tolerances apply: 
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Table 2: 
Time Windows Used in this Study 
Time point 
Time stated 
Tolerance 
Interval between visits 
x-month daily prophylaxis part: at 0.5, 1, 
2, 3, 4, 5 and 6 months 
± 4 days 
Blood sampling 
before IMP administration 
≤ 30 minutes 
 
30 minutes after IMP administration 
± 10 minutes 
 
1–6 hours after IMP administration 
± 15 minutes 
 
7–12 hours 
± 1 hour 
 
13–24 hours 
± 2 hours 
 
> 24-120 hours 
± 3 hours 
 
7 days 
± 1 day 
 
14 days  
± 2 days 
 
21 days 
± 3 days 
Inhibitor testing 
4 weeks 
± 1 week 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Patient 
The duration of the entire study for an individual patient according to protocol will range from 
5 days (patients from Cohort 5) until up to approximately 10 months (patients from Cohort 6), 
not counting the time period between the screening visit and the first administration of IMP, or 
patients undergoing immune tolerance induction therapy. 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed when all patients have completed the planned 
observation period. 
The start of the study (enrolment of first patient) was Q2 2019, and the estimated end of the 
study (last visit of last patient) is Q3 2022. 
6.2.3 Premature Termination of the Study 
Both the Investigator and the Sponsor reserve the right to terminate the study at any time. In 
this event, any necessary procedures will be arranged on an individual study basis after review 
and consultation by both parties. In terminating the study, the Sponsor and the Investigator will 
ensure that adequate consideration is given to the protection of the patients’ interests. 
Regulatory authorities and IECs/IRBs should be informed in accordance with national 
regulations. 
Early termination of the study as a whole or by center may apply for the following reasons: 
6.2.3.1 Early Termination of the Entire Clinical Study 
At any time, the study as a whole will be terminated prematurely if: 
• New toxicological or pharmacological findings or safety reports invalidate the earlier 
positive benefit-risk-assessment. 
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• A single death event (with the exception of death from underlying disease or any other 
death clearly unrelated to OCTA101) that occurs within 30 days of administration of 
study drug. 
• If clinical development of OCTA101 is terminated for any reason. 
According to the revised stopping rules implemented by Amendment 2, the study was to be put 
on hold until a further DMC recommendation for further conduct of the study was made, if 
more than one patient met the following criteria:  
• Exhibits a consistently high titer inhibitor (≥5 BU), as determined by central laboratory 
tests including a retest as detailed in Section 0. 
or  
• Exhibits a low titer inhibitor (≥0.6 BU and <5 BU), as determined by central laboratory 
test, including a retest as detailed in Section 0, and a standard recovery test using 
intravenous factor VIII shows a recovery below 66%. A formal half-life study with 
determination of the terminal half-life (t½) associated with the recovery study is 
encouraged with the patient in a non-bleeding state and free of any intercurrent illness.  
As a further patient with inhibitors in Cohort 2 subsequently met these criteria, the study was 
put on hold and patients stopped OCTA101 treatment. The ongoing patients in Cohort 3 were 
switched to Nuwiq prophylaxis for the remainder of the planned 3-month prophylaxis period. 
The study will be terminated if another patient develops an inhibitor (≥0.6 BU). 
6.2.3.2 Early Termination at an Individual Study Center 
At any time, the study can be terminated at an individual center if: 
• The center cannot comply with the requirements of the protocol. 
• The center cannot comply with GCP standards. 
• The required recruitment rate is not met. 
Should the study be prematurely terminated, all study materials (IMPs, etc.) must be returned 
to the Sponsor. 
 
7 
ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
The following information will be recorded during the Screening Visit: 
7.1.1 Demographic and baseline characteristics 
The demographic and baseline characteristics are age, ethnic origin, height, weight, and Body 
Mass Index (BMI).  
Blood type (ABO) will be documented. If not available, this will be tested. 
CD4+ count will be determined. 
The Hemophilia Joint Health Score (HJHS) will be documented.  
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Target joint(s) will be documented (defined as three or more spontaneous bleeding episodes 
into a single joint within 6 consecutive months preceding screening visit). 
7.1.2 Medical history and prior/concomitant medications 
The medical history will be obtained by interviewing the patient. Records of past diseases and 
treatments (e.g., hospital discharge letters) will be obtained for the study files, if available. 
Prior and concomitant medications, including FVIII treatment details in previous 6 months and 
bleeding frequency will be documented. 
7.2 Efficacy Assessments 
7.2.1 Assessments for Secondary Efficacy Endpoints 
7.2.1.1 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 Nuwiq was injected, if applicable 
• Nuwiq dose(s) and batch number(s) 
• Assessment of the efficacy of treatment at the end of the BE; see 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. 
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. 
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 
hemorrhage. These additional infusions should be recorded in the diary (and eCRF) but will not 
be evaluated as treatments of the BE. 
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: 
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• Excellent: Abrupt pain relief and/or unequivocal improvement in objective signs of 
bleeding within approximately 8 hours after a single infusion 
• Good: Definite pain relief and/or improvement in signs of bleeding within 
approximately 8–12 hours after an infusion, requiring up to 2 infusions for complete 
resolution 
• Moderate: Probable or slight beneficial effect within approximately 12 hours after the 
first infusion, requiring more than 2 infusions for complete resolution 
• None: No improvement within 12 hours, or worsening of symptoms, requiring more 
than 2 infusions for complete resolution 
The proportion of BEs successfully treated with Nuwiq will be evaluated for all BEs together 
and by severity. All efficacy ratings assessed as either ‘excellent’ or ‘good’ will be considered 
‘successfully treated.’ 
7.2.1.2 FVIII:C plasma levels 
Blood samples for the assessment of FVIII:C (one-stage and chromogenic assays) plasma levels 
will be taken at the following timepoints: 
• Cohort 1: before injection of OCTA101 50 IU/kg sc, 0.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, and 
72 h after injection. 
• Cohort 2: before injection of OCTA101 100 IU/kg sc, 0.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, 
72 h and 96 h after injection. 
• Cohort 3: FVIII:C only, before injection of Nuwiq 50 IU/kg iv, 0.5 h, 2 h, 4 h, 8 h, 24 h, 
48 h, and 72 h after injection. 
• Cohort 3: before injection of OCTA101 50 IU/kg sc, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 
72 h after injection. 
• Cohort 5: before injection of OCTA101 20 IU/kg sc, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 
72 h after injection. 
• Cohort 5: before injection of OCTA101 40 IU/kg sc, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 
72 h after injection. 
• Cohort 5: before injection of OCTA101 60 IU/kg sc, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 
72 h after injection. 
• Cohort 1, 2, and 3 – daily sc injections for 3 months: before injection of OCTA101 
25 IU/kg sc and 3 and 6 h after injection, for the first injection and at 0.5, 1, 2 and 
3 months thereafter. 
• Cohort 1 and 2 patients – PK assessment following 3-month daily prophylaxis: before 
injection of OCTA101 50 IU/kg sc, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h 96 h, and 
120 h after injection. 
• Cohort 6 – daily sc injections for 6-7 months: before injection of OCTA101 12/25 IU/kg 
sc (and probably 40 IU/kg) and 8 h after injection, for the first injection and at 0.5, 1, 2, 
3, 4, 5 and 6 months thereafter in each dosing period. Samples will be shipped to the 
central laboratory for one-stage and chromogenic assay assessments (see Section 7.3.5). 
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7.3 Safety Assessments 
7.3.1 Assessments for Safety Endpoints 
Any of the following drug safety information shall be collected: 
• Adverse events (AEs) and serious adverse events (SAEs) associated with the 
administration of IMP (for definitions and reporting requirements, see Sections 7.3.2, 
7.3.3, and 7.3.4) 
• Drug overdose, interaction, medication error, lack of efficacy, and post-study SAEs (see 
Section 7.3.7) 
7.3.2 Adverse Events (AEs) 
7.3.2.1 Definitions 
• Adverse event (AE): An AE is any untoward medical occurrence in a study patient 
receiving an IMP and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an IMP, whether or not related to the IMP. 
• Adverse drug reaction (ADR): An ADR is any noxious and unintended response to an 
IMP related to any dose. The phrase ‘response to an IMP’ means that a causal 
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: AE/ADR leading to discontinuation of treatment with 
IMP. Any such events will be followed up by the Investigator until the event is resolved 
or until the medical condition of the subject/patient is stable. All follow-up information 
collected will be made available to the Sponsor. 
7.3.2.2 Collection of AEs 
The condition of the patient will be monitored throughout the study. At each visit, whether 
scheduled or unscheduled, AEs will be elicited using a standard nonleading question such as 
“How have you been since the last visit/during the previous study period?” In addition, the 
Investigator will check the patient diaries (if applicable) for any documented event. 
Any AE or ADR which occurs during the study will be noted in detail on the appropriate pages 
of the eCRF. If the patient reports several signs or symptoms representing a single syndrome or 
diagnosis, the diagnosis should be recorded in the eCRF. The Investigator will grade the 
severity of all AEs or ADRs (mild, moderate, or severe), the seriousness (non-serious or 
serious), and the causality as defined in Sections 7.3.2.3, 7.3.3, and 7.3.2.4. The Sponsor is 
responsible for assessing the expectedness of each ADR (expected or unexpected) as defined 
in Section 7.3.2.5. 
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In the event of clinically significant abnormal laboratory findings, the tests will be confirmed, 
and the patient followed up until the laboratory values have returned to normal and/or an 
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 Investigator will provide detailed information about any abnormalities and about the nature 
of and reasons for any action taken as well as any other observations or comments that may be 
useful for the interpretation and understanding of an AE or ADR. 
7.3.2.3 Severity of AEs 
The intensity/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 that is sufficiently discomforting to interfere with the patient’s routine 
activities 
• Severe: an AE that is incapacitating and prevents the pursuit of the patient’s routine 
activities 
The grading of an AE is up to the medical judgement of the Investigator and will be decided on 
a case-by-case basis. 
7.3.2.4 Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the Investigator: 
• Probable: reports including good reasons and sufficient documentation to assume a 
causal relationship, in the sense of plausible, conceivable, likely, but not necessarily 
highly probable. A reaction that follows a reasonable temporal sequence from 
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 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 etiology 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). 
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7.3.2.5 Classification of ADRs by Expectedness 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an ADR that is listed in the current edition of the Investigator’s Brochure. 
• Unexpected: an ADR that is not listed in the current edition of the Investigator’s 
Brochure, or that differs because of greater severity or greater specificity. 
7.3.2.6 Outcome of AEs 
The outcome of all reported AEs has to be documented as follows: 
1. Recovered, resolved 
2. Recovering, resolving 
3. Not recovered, not resolved 
4. Recovered, resolved with sequelae 
5. Fatal 
6. Unknown 
NOTE: A patient’s death per se is not an event, but an outcome. The event which resulted in 
the patient’s death must be fully documented and reported, even in case the death occurs within 
4 weeks after IMP treatment end and regardless of whether or not it is considered treatment-
related. 
7.3.2.7 Action(s) taken 
AEs requiring action or therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the patient. Appropriate resuscitation equipment and 
medicines must be available to ensure the best possible treatment in an emergency situation. 
The action taken by the Investigator must be documented: 
a) General actions taken in the event of an AE 
– None 
– Medication (other than IMP) or other (e.g., physical) therapy started 
– Test performed 
– Other (to be specified) 
b) IMP-related actions taken in the event of an AE 
– None 
– Product withdrawn 
– Dose reduced 
– Dose increased 
The Investigator will follow up on each AE until it has resolved or until the medical condition 
of the patient has stabilized. Any relevant follow-up information will be reported to the Sponsor. 
7.3.3 Serious Adverse Events (SAEs) 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
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• 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. 
NOTE: 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 death had it been more severe. 
In deciding whether an AE/ADR is serious, medical judgment should be exercised. Thus, 
important AEs/ADRs that are not immediately life-threatening or do not result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definitions above should also 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.  
7.3.4 SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to study treatment, are to be reported 
immediately by telephone, fax, or email to the Clinical Project Manager or designee: 
Martina Jansen 
Senior Clinical Project Manager Haematology 
Oberlaaerstrasse 235 
A – 1100 Vienna 
Austria 
Phone: 
+43 1 61032 1208 
Mobile: +43 664 80408208 
Fax: 
+43 1 61032 9249 
Email: 
martina.jansen@octapharma.com 
The contact details will also be communicated at the study initiation visit. 
In addition, within 24 hours after recognition of the event, an Octapharma Serious Adverse 
Event Report must be completed and submitted to: 
Octapharma’s Corporate Drug Safety Unit 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Fax: +43 1 61032-9949 
E-mail: cdsu@octapharma.com 
24 hours emergency telephone number: +43 1 40 80 500 
 
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Waivers the from SAE Reporting Requirement 
Waivers from the SAE reporting requirement include surgeries that are elective or 
prolongations of existing hospitalizations for economic or social, but not medical, reasons. Such 
surgeries or prolongations of hospitalizations should not be considered SAEs. 
7.3.5 Laboratory Tests 
7.3.5.1 Local Laboratory 
The routine safety laboratory tests (Hematology: red blood cell count, white blood cell count, 
hemoglobin, hematocrit, platelet count, CD4+ count. Clinical chemistry: total bilirubin, ALT, 
AST, urea, serum creatinine, lactate dehydrogenase) will be done by the local laboratory. The 
methods of determination and normal ranges for each parameter will be provided in the clinical 
study report.  
7.3.5.2 Central Laboratory 
FVIII:C (one-stage and chromogenic assays) and FVIII inhibitors will be assessed by the 
following central laboratory: 
 
Esoterix Inc (Coagulation)  
 
8490 Upland Drive, Suite 100  
 
Englewood, CO 80112, USA 
OCTA12 was measured by the following central laboratory (for cohorts 1-5): 
 
SYNLAB Analytics & Services Germany GmbH  
 
Bayerstr. 53  
 
80335 Munich, Germany 
Anti-OCTA12 was measured by the following central laboratory (for cohorts 1-5): 
 
SYNLAB Analytics & Services Switzerland AG  
 
Birsfelden, Switzerland 
OCTA12 and Anti-OCTA12 is measured by the following central laboratory (for Cohort 6): 
 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
 
Octapharma Clinical Laboratory 
 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
 
Clinical Laboratory: at1kliniklabor@octapharma.com 
 
Inhibitor activity will be determined by the modified Bethesda assay (Nijmegen modification) 
using plasma-derived FVIII as a test base. Inhibitor tests will be performed at the times specified 
in Section 6, and whenever inhibitor development is suspected. 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. Patients who develop a non-
transient inhibitor and do not agree to start an ITI will be withdrawn from the study. In case of 
confirmed positive inhibitor, ITI may be initiated with Nuwiq according to the investigator’s 
discretion. Patients developing an inhibitor and starting ITI will be closely monitored, once they 
have been informed about the ITI treatment details and gave their written consent before ITI 
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initiation. Depending on the development of the inhibitor, a bi-weekly (later on monthly to 3-
monthly) inhibitor titer testing is considered appropriate.  
Once the inhibitor is eliminated, a normalized recovery and half-life are expected during the 
continued ITI. Samples to test the recovery are recommended to be drawn at baseline and 15 
minutes post-injection. For the half-life evaluation, the following sampling time points are 
recommended: baseline, 15 minutes, 3, 6, 9, 12, (24) hours post-injection. 
Patients will complete study participation after a complete success of the ITI (inhibitor-free, 
normalized recovery and half-life), or after a maximum ITI period of 36 months. 
In case of development of antibodies to OCTA12, patients will be closely monitored for any 
clinically relevant signs and symptoms (e.g. lack of efficacy or unusual plasma concentrations 
of FVIII and/or OCTA12). 
 
The LumiTope assay will be performed by the following central laboratory: 
 
University Clinic Bonn 
 
Institute of Experimental Haematology and Transfusion Medicine  
 
Venusberg Campus 1 
 
53127 Bonn, Germany 
The LumiTope assay is a sensitive immunoassay based on the LuminexTM system for detection 
and characterization of anti-FVIII antibodies in patient plasma samples. The LuminexTM 
technology is a bead-based assay system using superparamagnetic microbeads. Specific 
proteins (e.g. full-length and BDD FVIII, several single- and multi-domain fragments of the 
FVIII molecule) are individually coupled to different magnetic bead regions. Each bead 
contains its own distinct dye ratio which will generate a unique fluorescence pattern to enable 
individual bead identity. Beads are mixed with the plasma samples and later incubated with a 
phytoerythrin-conjugated antibody that produces a fluorescence signal proportional to the 
amount of bound FVIII antibodies. A positive signal in the screening visit sample would 
exclude a patient from entering the study as the probability of later inhibitor development during 
OCTA101 treatment may be increased if antibodies are present. The cut-off to differentiate 
positive and negative LumiTope assay results will be determined according to the publication 
of Shankar et al (Shankar et al. 2008), which provides recommendations for the validation of 
immunoassays used for detection of host antibodies against biotechnology products. 
7.3.6 Vital Signs and Physical Examination 
The vital signs obtained at the time points specified in Section 6 are blood pressure, body 
temperature, pulse rate, and respiratory rate. 
Physical examinations will be performed at the visits specified in Section 6. Both height and 
weight will be measured at baseline. In addition, weight will be measured at all visits prior to 
dosing. 
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7.3.7 Other Relevant Safety Information 
a) Post-study related safety reports 
Any SAE which occurs up to 4 weeks after the last IMP administration should be reported by 
the Investigator to the Sponsor in case the Investigator becomes aware of it. Proactive 
monitoring for post-study SAEs is not required. 
In case a post-study SAE is identified, the Investigator should complete an SAE form and also 
state the relation to the clinical study in the report. 
Deaths occurring within 4 weeks after the last IMP administration should also be reported, 
regardless of whether or not they are considered treatment-related. 
Overdose, interaction, medication error and lack of efficacy 
The following safety relevant information should be reported as AE or, if the reaction fulfils 
one of the criteria for seriousness, as SAE. 
b) Drug overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol and higher than the known therapeutic dose that is of clinical relevance. 
The reaction must be clearly identified as an overdose. 
c) Drug interaction 
A drug interaction is a situation in which a substance or medicinal product affects the activity 
of an IMP, i.e., increases or decreases its effects, or produces an effect that none of the products 
would exhibit on its own. The reaction must be clearly identified as a drug interaction. 
d) Medication error 
A medication error involves the inadvertent administration or unintended use of a medicinal 
product which may be caused by the naming, presentation of pharmaceutical form/packaging, 
or instructions for use/labelling. The reaction must be clearly identified as a medication error. 
e) Lack of efficacy 
Lack of efficacy is suspected when the therapeutic result is not as expected. One example of a 
lack of efficacy may be continued bleeding in a patient with hemophilia following the correct 
administration of coagulation factors. 
7.4 Other Assessments 
7.4.1 Local injection site reactions 
Patients will evaluate injection site pain using a visual analog scale (VAS) (0 mm/no pain, 
100 mm/extreme pain) immediately after injection completion.  
Investigator (and patient in case of home treatment) should assess local injection reactivity 
directly after injection and 15 ± 5 min post-injection as described in ISO10999-10 standard: 
• 0=no skin reactivity;  
• 1=mild (subject is aware of the signs/symptoms, but finds it easily tolerated) 
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• 2=moderate (discomfort enough to cause interference with usual activities) 
• 3=severe (subject is incapacitated and unable to work or participate in many or all usual 
activities).   
7.5 Appropriateness of Measurements 
All measurements used for the assessment of the safety and efficacy of OCTA101 are in 
compliance with the requirements set up in the CHMP “Guideline on the clinical investigation 
of 
recombinant 
and 
human 
plasma-derived 
factor 
VIII 
products” 
(EMA/CHMP/BPWP/144533/2009”).  
All FVIII inhibitor and FVIII plasma level samples obtained in the course of this study will be 
evaluated by accredited central laboratories using validated methods and assays.  
All OCTA12 and anti-OCTA12 antibody samples obtained in the course of this study will be 
evaluated by a laboratory working according to EMA/INS/GCP/532137/2010, Feb 2012: 
“Reflection paper for laboratories that perform the analysis or evaluation of clinical trial 
samples”, using validated methods. 
If clinically indicated, FVIII and inhibitor testing can additionally be performed in the local 
laboratory. The results obtained locally will be recorded in the eCRFs. 
 
8 
DATA HANDLING AND RECORD KEEPING 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, observations, or other 
activities in the study, written down in original records or certified copies of original records, 
allowing reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (e.g., case histories or patient files for 
each patient enrolled). Source records should be preserved for the maximum period of time 
required by local regulations. 
For each patient enrolled, the Investigator will indicate in the source record(s) that the patient 
participates in this study. 
All data entered in the eCRF must be supported by source data in the patient records. 
The Investigator will permit study-related monitoring, audit(s), IEC/IRB review(s), and 
regulatory inspection(s), by providing direct access to the source data/records. 
The Investigator may authorize site staff (e.g., sub-investigators, nurses) to enter study data into 
the eCRF. This must be documented in the Delegation of Authority Log signed by the 
Investigator. 
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8.1.2 Case Report Forms 
For each patient enrolled, an electronic CRF (eCRF) will be completed within the Electronic 
Data Capture (EDC) system and approved by the Investigator or an authorized sub-investigator.  
Study site staff (e.g., research nurse) will be responsible for entering patient data into the 
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. 
The site is also provided with the approved eCRF Completion Guidelines which will assist in 
data entry and data issues/questions. The site will be notified once the database is active to 
begin data entry. Additional site training may be provided as refreshers throughout the study, if 
needed. All persons allowed to enter or change eCRF data must be listed in the Delegation of 
Authority Log. 
8.1.3 Changes to Case Report Form (eCRF) Data 
Monitors will perform source data verification (SDV) as defined for the study. 
If any errors or discrepancies in the eCRFs are found during data entry or review, discrepancies 
will be generated programmatically within the EDC system, and ‘manual’ queries will be 
generated by either a monitor or Data Management.  
Discrepancies and queries can only be corrected by the Investigator(s) or other authorized site 
personnel. An audit trail documents all changes to the data over the entire study period. The 
EDC system will require entering a reason for any change in data unless data is changed 
immediately after data entry, in which case “Immediate correction” will be written 
automatically into the audit trail. The study monitor should provide guidance to Investigator(s) 
and the Investigator(s)’ designated representatives on making such corrections.  
Once queries have been resolved by the site staff, the resolutions are assessed by Data 
Management. If the query response provided confirms the data as correct, the discrepancy will 
be closed. If the response does not adequately address the question raised, a new query will be 
issued for further clarification. 
Manual checks are performed and programs are run throughout the study until the data is clean 
and the database is ready for lock. All discrepancies will be resolved prior to database lock. 
There will be a final run of the programmed checks to ensure all discrepancies are closed out, 
SDV will be confirmed as complete by the monitor, and all eCRFs will be approved by the 
Investigator prior to database lock. 
8.2 Information to Investigators 
An Investigator’s Brochure (IB) will be handed out to the Investigator before the start of the 
study. The IB contains all information in the Sponsor’s possession necessary for the 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 and whenever relevant new 
information concerning the IMP becomes available. 
The Investigator will be informed about the methods for rating relevant study outcomes and for 
completing eCRFs to reduce discrepancies between participating Investigator and study sites. 
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The Investigator will be kept informed of important data that relate to the safe use of the IMP 
as the study proceeds. 
8.3 Responsibilities 
The Principal Investigator is accountable for the conduct of the clinical study. Responsibilities 
may be delegated to appropriately qualified persons. 
A Delegation of Authority Log will be filled in and signed by the Principal Investigator. In 
accordance with this authority log, study site staff (e.g., sub-investigators, nurses) is authorized 
to perform tasks relating to the study. 
The central laboratory for all coagulation parameters and inhibitor testing is Esoterix Inc 
(Coagulation), Englewood, USA.  
The central laboratory for measurement of OCTA12 (for cohorts 1-5) was SYNLAB Analytics 
& Services Germany GmbH, Bayerstr. 53, 80335 Munich, Germany 
The central laboratory for measurement of Anti-OCTA12 (for cohorts 1-5) was SYNLAB 
Analytics & Services Switzerland AG, Birsfelden, Switzerland 
The central laboratory for measurement of OCTA12 and anti-OCTA12 in Cohort 6 is 
Octapharma Clinical Laboratory, Octapharma Pharmazeutika Produktionsges.m.b.H., 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
The central lab for LumiTope analysis is University Clinic Bonn, Institute of Experimental 
Haematology and Transfusion Medicine, Venusberg Campus 1, Bonn, Germany. 
Study data management and statistics will be delegated under an agreement of transfer of 
responsibilities to Metronomia Clinical Research GmbH, Munich, Germany. 
All parties involved in the study are responsible to comply with local and international 
obligations, regulatory requirements and duties in accordance with local laws, using the 
principles of good clinical practice (GCP) and good laboratory practice (GLP) guidelines, 
respectively follow the EMA Reflection Paper 2012, SOPs and complying with all other 
applicable regulations. 
8.4 Investigator’s 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, site copies of all eCRFs, 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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8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating to the study, 
or copies of relevant source records, ensuring that the patient’s confidentiality is maintained. 
This is particularly important when 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. 
8.6  Independent Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established by the Sponsor. The 
DMC will be composed of recognized experts in the field of hemophilia who are not actively 
recruiting patients. 
The DMC will review relevant data at defined times during the study and will give advice on 
the continuation, modification, or termination of the study. Any safety-relevant signals will also 
be forwarded to the DMC for their review as they occur. A written study-specific procedure 
will define in detail the composition, responsibilities, and procedures of the DMC. 
 
9 
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. Two separate SAPs will be created: the first one for the final statistical 
analysis of all available data of enrolled patients in Cohorts 1, 2, 3, and 5 and the second one 
for the final analysis of the newly defined Cohort 6. 
9.1 Determination of Sample Size 
The sample size was determined based on pre-clinical findings and clinical reasoning, and was 
discussed with the FDA. No formal sample size calculation was performed. 
9.2 Statistical Analysis 
A formal statistical analysis plan (SAP) describing all details of the analyses to be performed 
will be prepared by the study statistician and approved by the Sponsor prior to the start of the 
statistical analysis. 
Data collected in this study will be summarized according to their nature as follows:  
• Continuous variables: arithmetic mean, standard deviation, minimum and maximum 
values, median and quartiles depending on the number of observations. 
• Categorical variables: absolute and relative frequencies.  
• The geometric mean and geometric CV will additionally be included in the descriptive 
analyses of pharmacokinetic parameters, except for Tmax. 
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9.2.1 Populations for Analysis 
The safety analysis set (SAF) will include all patients who received at least one dose of IMP. 
The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle will 
include all patients who received at least one dose of OCTA101 in the context of repeat daily 
prophylactic dose (approximately 40-60 IU/kg or 12.5/25 IU/kg (and probably 40 IU/kg)). 
The per-protocol (PP) set, i.e., a subset of the FAS, will exclude patients with major protocol 
deviations which may have an impact on the evaluation of the primary study outcome 
parameter(s). 
• Examples of major and minor protocol deviations will be described in the SAP. 
• A final decision about the classification of protocol deviations and their consequences 
regarding assignment of patients to analysis sets will be made during the data review 
meeting. Decisions and outcome will be approved by the Sponsor. 
Due to the stop of the daily dosing period because of antibody formation, no PP set was defined 
for the analysis of Cohorts 1 to 3.  
The PK analysis set will include all patients from the SAF who started the initial PK assessment 
with OCTA101.  
The PK–PP analysis set will be a subset of the PK analysis set. It will exclude patients not 
fully evaluable for PK endpoint. The criteria to exclude any patient from this analysis set will 
be described in the SAP.  A final decision about the inclusion into the PK-PP analysis set will 
be made during the data review meeting. Decisions and outcome will be approved by the 
Sponsor. 
The analysis of safety will be based on the safety set by cohort. 
The analysis of data from the repeat dosing will be based on the FAS as primary analysis and 
on the PP set as secondary analysis. This analysis will be performed by cohort and overall. 
The evaluation of PK data will be based on the PK and on the PK-PP analysis sets. 
9.2.2 Efficacy Analysis Plan 
Pharmacokinetic data will be analysed separately for each dose cohort. 
Blood for the determination of the concentrations of FVIII:C (one-stage and chromo-genic 
assays) and OCTA12 in plasma will be sampled at scheduled times. The time courses of the 
plasma concentrations will be analysed non-compartmentally using the following conventions: 
• The courses of the concentrations are analysed individually relative to the actual time 
of sampling (relative to the time of first injection). 
• For the analysis, non-quantifiable pre-dose levels will be set equal to zero. In the event 
of quantifiable levels prior to first dosing, the baseline level will be subtracted from the 
post-dosing values and the further analysis is focused on the post-dosing changes from 
baseline. 
• Post-dosing values that are either missing or not quantifiable will not be included in the 
analysis.  
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• Extrapolations beyond the last quantifiable plasma concentration will only be re-ported 
if the apparent terminal log-linearity used to this purpose is sufficiently well expressed 
for at least 3 data points. 
• The duration of profiling is adjusted by dose; based on the available experience with 
rFVIII it may be expected that the quantifiable area under the time course of the 
concentrations (AUC) is at least 80% of the total i.e. extrapolated AUC. 
• The time courses of the plasma concentrations will be summarised descriptively by 
means of the following non-compartmental metrics: 
– Cmax: maximum observed concentration 
– Tmax: time of occurrence of Cmax after dosing 
– AUC(0-tz): quantifiable area under the time course of the concentrations de-rived by 
means of the combined linear/log-linear trapezoidal rule 
– λz: apparent terminal log-linear rate constant 
– t½: apparent terminal log-linear half-life 
– AUC(tz-∞): AUC extrapolated beyond the last time point with quantifiable 
concentrations calculated as C*(tz)/λz in which C*(tz) is the concentration at time tz 
fitted according to λz 
– AUC(0-∞): total AUC = AUC(0-tz)+ AUC(tz-∞) 
– AUCextrapolated: extent of AUC extrapolation = AUC(tz-∞)/AUC(0-∞) 
– AUMC(0-tz) and AUMC(0-∞): quantifiable and total area under the statistical first 
moment curve 
– MRT: mean residence time = AUMC(0-∞)/AUC(0-∞) 
– IVR: in vivo recovery = dose- and body weight-normalised maximum gain in 
FVIII:C 
– CL: total clearance (iv dosing only) = Dose/AUC(0-∞) 
– Vd: estimated distribution volume (iv dosing only) = CL.MRT 
• Exposure levels will be reported untransformed and standardised for dose and body 
weight. 
The same conventions will be used for the plasma concentrations of FVIII:C and OCTA12 
sampled after the single dose administration of 50 IU/kg OCTA101 after the completion of the 
3 months daily dosing period of Cohort 1 and Cohort 2. 
Single-dose data from Cohort 3 comparing the pharmacokinetics after sc and iv dosing (Nuwiq) 
will be used to derive estimates of the absolute bioavailability after sc dosing and to assess route 
dependency of the further pharmacokinetic criteria. To this purpose, point and confidence 
interval estimates of the true ratio of the treatment mean for sc- relative to iv-dosing will be 
back-transformed from the ANOVA-derived estimates of the true difference of the treatment 
means of the log-transformed data. By means of a similar ANOVA, estimates of the differences 
of the treatment means will be derived for t½ and MRT. 
Data from Cohort 5 covering the pharmacokinetics after single sc doses of 20, 40 and 60 IU/kg 
OCTA101 will be used to derive estimates of the dose-proportionality of the pharmacokinetics 
of FVIII:C and OCTA12. To this purpose, methods as described by Smith et al. (2000) will be 
used. 
Quantifiable and λz-extrapolated time courses of the concentrations after single doses (all 
cohorts) will be used to simulate the time courses when defined doses would be administered 
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repeatedly at specified interval. To this purpose, the pharmacokinetics will be assumed to be 
linear i.e. dose-proportional, time-invariant and superimposable. A superposition cascade 
approach as described by Gibaldi (Biopharmaceutics and Clinical Pharmacokinetics – 4th 
edition, 1991, Lea & Febinger, Malvern, USA – Appendix II) will be used. 
If the smoothness of the time courses of the concentrations permits, estimates of the absorption 
rate on sc dosing will be derived by the Wagner-Nelson method and/or by compartmental 
analysis. If appropriate, the time courses of the plasma concentrations will be analysed 
compartmentally, i.e. fitted to an open mammillary 1-, 2- or 3-compartmental model, and 
further simulations of the time courses of the concentrations on repeated dosing may be derived. 
The total annualized bleeding rate, the spontaneous annualized bleeding rate, the traumatic 
annualized bleeding rate, the total annualized treated bleeding rate, the spontaneous annualized 
treated bleeding rate, and the annualized joint bleeding rate during daily sc treatment with 
OCTA101 will be presented for patients in the FAS and PP set in Cohort 6, grouped by dose 
level of daily OCTA101 dosing. For the daily dosing period of Cohorts 1 to 3, no bleeding rates 
were calculated. The observation period was considerably shorter than planned due to the study 
stop. Bleedings occurred only in patients who had developed antibodies or after the end of the 
daily dosing period. 
All other data collected for BEs, efficacy assessments at the end of BEs will be analyzed 
descriptively. The proportion of BEs successfully treated with Nuwiq will be presented. 
Summaries on patient levels will be detailed in the SAP as needed. All data collected will be 
listed. 
FVIII:C and OCTA12 trough and peak plasma levels during daily dosing will be analyzed 
descriptively. 
9.2.3 Safety Analysis Plan 
Safety and tolerability data will first be analyzed for each cohort after the first dose(s) and 
evaluated by an external DMC. 
All safety and tolerability parameters (adverse events, vital signs, laboratory monitoring, and 
physical examination results) will be listed by patient and cohort.  
Analyses based on data from repeat dosing from Cohort 1, 2, and 3 with OCTA101 for 3 months 
will be analyzed separately from data related to the first doses. In these analyses, data will be 
presented by cohort and overall. Data from single doses after the completion of the repeat 
dosing will be analyzed separately. All data will be presented together without reference to the 
original cohort. 
Data from Cohort 6 will be analyzed separately and will be split by period (run-in period with 
Nuwiq and OCTA101 treatment period) and by planned OCTA101 daily dose. 
All AEs reported during the study will analyzed and presented. AEs starting at or after the first 
dose of IMP will be presented separately from those starting prior to the first dose of IMP. For 
Cohort 6, AEs starting at or after the first dose of Nuwiq and prior to the first dose on OCTA101 
will be presented separately from AEs starting after the first dose of OCTA101. 
The number and percentage of patients with AEs and the number of AEs will be summarized 
by primary MedDRA System Organ Class and Preferred Term. Separate tables showing all 
AEs, all serious AEs and all AEs at least possibly related to IMP will be generated. Further a 
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summary of AEs by severity, presenting the most severe event per patient overall and within 
each SOC and PT will be generated.  
For thromboembolic events and local injection site reactions, appropriate clusters of MedDRA 
terms will be defined and such events will be presented within these clusters, using the 
summaries detailed above.  
The frequencies of local injection reactivity ratings by the investigator and the patient (see 
Section 7.4.1) directly after injection and 15 ± 5 min post-injection will be summarized over 
the whole daily treatment period using the number of injections as denominator. Further, the 
worst rating per patient and time period will be summarized. Visual analogue scale assessments 
of injection site pain will be summarized analogously. 
The frequencies (including percentages) of any inhibitor formation to FVIII and antibody 
formation to OCTA12 will be presented by cohort and overall. Inhibitor formation to FVIII will 
be considered if at least one result of neutralizing antibody was equal or greater than 
0.6 BU/mL. Antibody formation to OCTA12 will be defined as positive if at least one result of 
OCTA12 antibody was positive at any visit during the study. Results from LumiTope assay will 
be listed. 
Vital sign and safety laboratory parameters will be analyzed using descriptive statistics for 
measured values and for changes from pre-dose values to each single injection. 
9.2.4 Handling of Missing Data 
In general, missing data will not be imputed. Any specific rule or convention needed for the 
statistical analysis to account for possibly missing data will be detailed in the SAP. 
9.3 Randomization, Stratification, and Code Release 
Not applicable for this open-label study based on sequential cohorts. 
9.4 Interim Analysis  
After the completion of each cohort, PK and safety data were analyzed and discussed during a 
DMC meeting. Data from each cohort were analyzed separately. Safety data were compared 
descriptively and no adjustment of a significance level will be performed. These analyses will 
also be performed for Cohort 6 for safety and efficacy data. 
One separate interim analysis will be performed: this will include all available data of enrolled 
patients in Cohorts 1, 2, 3, and 5. 
 
10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Ethical/Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down in the 
Declaration of Helsinki. The study protocol and any subsequent amendment(s) will be 
submitted to an Independent Ethics Committee (IEC)/Institutional Review Board (IRB) and to 
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the Regulatory Authority. The study will be conducted in compliance with the protocol, GCP 
guidelines, and applicable regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by the Sponsor 
or designated third party (e.g., CRO) as required by national law. 
10.2 Approval of Study Documents 
The study protocol, a sample of the patient information and informed consent form, any other 
materials provided to the patients, and further requested information will be submitted by the 
Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory Authority. The study 
must be approved by the IEC/IRB and the Regulatory Authority before any IMP may be shipped 
to the study sites and any patient is exposed to a study-related procedure. 
The Sponsor, the Investigator, and any third party (e.g., CRO) involved in obtaining approval 
must inform each other in writing that all ethical and legal requirements have been met before 
the first patient is enrolled in the study. 
10.3 Patient Information and Informed Consent 
The Investigator will obtain freely given written consent from each patient after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspect 
of the study which is relevant to the patient’s decision to participate. The informed consent form 
must be signed, with name and date and time noted by the patient, before the patient is exposed 
to any study-related procedure, including screening tests for eligibility. 
The Investigator will explain that the patients are completely free to refuse to enter the study or 
to withdraw from it at any time, without any consequences for their further care and without 
the need to justify. The Investigator will complete the informed consent section of the eCRF 
for each patient enrolled. 
Each patient will be informed that his medical (source) records may be reviewed by the study 
monitor, a quality assurance auditor, or a health authority inspector, in accordance with 
applicable regulations, and that these persons are bound by confidentiality obligations. 
10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Investigator (Coordinating 
Investigator in multi-center studies) and the Sponsor prior to its implementation. Any such 
amendments will be submitted to the any competent IEC/IRB and/or competent authority 
responsible 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, the objective/design of the study, any increase in dosage or 
duration of exposure to the IMP, an increase in the number of patients treated, the addition of a 
new test or procedure, or the dropping of a test intended to monitor safety. 
10.5 Confidentiality of Patient Data 
The Investigator will ensure that the patient’s confidentiality is preserved. On eCRFs or any 
other documents submitted to the Sponsor, the patients will not be identified by their names, 
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but by a unique patient identifier. Documents not intended for submission to the Sponsor, i.e., 
the confidential subject identification code list, original consent forms, and source records, will 
be maintained by the Investigator in strict confidence. 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to review all study-related 
source data/records, verify the adherence to the protocol and the completeness, correctness and 
accuracy of all eCRF entries compared to source data. The Investigator will co-operate with the 
monitor to ensure that any discrepancies identified are resolved. 
For this study, the first monitoring visit shall take place shortly after the inclusion of the first 
patient. Thereafter, monitoring frequency will depend on study progress, whereby monitoring 
after completion of each cohort is mandatory. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyze, verify, and reproduce any 
records and reports that are important to the evaluation of the clinical study. Source data will 
be available for all data in the eCRFs, including all laboratory results. 
11.2 Audit and Inspection 
The Investigator will make all study-related source data and records available to a qualified 
quality assurance auditor mandated by the Sponsor, or to IEC/IRB/regulatory inspectors, after 
reasonable notice. The main purposes of an audit or inspection are to confirm that the rights 
and welfare of the patients have been adequately protected, and that all data relevant for the 
assessment of safety and efficacy of the IMP have been reported to the Sponsor. 
 
12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s SOPs) will be 
prepared by the Sponsor after completion of the study. The Co-ordinating Investigator will 
approve the final study report after review. 
12.2 Publication Policy 
The results of this study will 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. 
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In accordance with standard editorial and ethical practice, the Sponsor will support publication 
of multi-center studies only in their entirety and not as individual center data. Authorship will 
be determined by mutual agreement. 
 
13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in association with the 
IMP or participation in the study, the Sponsor will contract insurance in accordance with local 
regulations. 
The Investigator is responsible for dispensing the IMP according to this protocol and for its 
secure storage and safe handling throughout the study. 
 
14 REFERENCES 
Cannavò A, Valsecchi C, Garagiola I, Palla R, Mannucci PM, Rosendaal FR, Peyvandi F; 
SIPPET study group. Nonneutralizing antibodies against factor VIII and risk of inhibitor 
development in severe hemophilia A. Blood. 2017 Mar 9;129(10):1245-1250.  
Gibaldi M. (1991) Biopharmaceutics and Clinical Pharmacokinetics. 4th Edition, Lea and 
Febiger, Philadelphia, Appendix II. 
Liesner RJ, Abashidze M, Aleinikova O, et al. Immunogenicity, efficacy and safety of 
Nuwiq(®) (human-cl rhFVIII) in previously untreated patients with severe haemophilia A-
Interim results from the NuProtect Study. Haemophilia. 2018. Mar;24(2):211-220. 
Reedtz-Runge et al. Intravenous Administration of Recombinant Factor VIII Induces Immune 
Tolerance to Subcutaneous Turoctocog Alfa Pegol (SC N8-GP) in Humanized Hemophilia A 
Mice. Abstract. Blood (2018) 132 (Supplement 1): 1194. 
Shankar G, Devanarayan V, Amaravadi L, et al. Recommendations for the validation of 
immunoassays used for detection of host antibodies against biotechnology products. J Pharm 
Biomed Anal. 2008;48(5):1267-1281. 
Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment of 
dose proportionality. Pharm Res. 2000 Oct;17(10):1278-83. 
Steinitz KN, van Helden PM, Binder B, et al. CD4+ T-cell epitopes associated with antibody 
responses after intravenously and subcutaneously applied human FVIII in humanized 
hemophilic E17 HLA-DRB1*1501 mice. Blood. 2012 Apr 26;119(17):4073-82. 
Wagner JG (1975) Fundamentals of clinical pharmacokinetics. Drug Intelligence Publications, 
Inc. Hamilton, IL, USA 
 
 
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Study Protocol No. SubQ8-01, Version 9.0 CONFIDENTIAL 
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Page 82 of 82 
 
15 APPENDICES 
a. Appendix 1: Diagram of Subcutaneous Injection Sites 
To locate injection sites on the abdomen, use the areas shown in the diagram below, avoiding 
the belly button, ribs, and hip bones, scars or moles. 
 
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SAP_001.pdf: 
Statistical Analysis Plan 
This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
 
 
 
 
 
 
Date: 
4-Mar-2021 (based on protocol version 7.0, dated 
06-Jul-2020) 
Version: 
2.2 
Status: 
Final 
Author: 
D. Wessiepe 
Study Title: 
Phase 1/2 study to assess the safety and 
pharmacokinetics of subcutaneous injection of OCTA101 
in previously treated adult patients with severe 
hemophilia A (study code: SubQ8-01) 
Investigational Product: 
OCTA101 
Clinical Phase: 
1/2 
Enrolment of First Patient 
Quarter 2 2019 (planned) 
Last Patient Last Visit 
Quarter 3 2022 (planned) 
Sponsor: 
Octapharma AG 
Seidenstrasse 2 
8853 Lachen 
Switzerland 
Data Management and Statistics: 
Metronomia GmbH 
Paul-Gerhardt-Allee 42 
81245 München 
Germany 
Project Manager (Sponsor): 
Martina Jansen (Senior Clinical Project Manager) 
Project Manager (Metronomia): 
Ulrich Meyer (Senior Clinical Data Manager) 
Manager Biometrics (Sponsor): 
Laurenz Trawnicek (Manager Biometrics) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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04 Mar 2021 | 13:01:30 CET 
Date, Signature 
 
 
1 Signatures 
 
Authors: 
Dorothea Wessiepe, Director, Head of Biostatistics 
Metronomia 
 
 
08 Mar 2021 | 02:03:07 PST 
 
 
Date, Signature 
 
Mounira Schweizer, Lead Statistician 
Metronomia 
 
 
04 Mar 2021 | 05:37:05 PST 
 
 
Date, Signature 
 
 
 
 
Approval: 
Martina Jansen, Senior Clinical Project Manager Haematology, 
Octapharma Pharmazeutika Produktionsges.m.b.H 
 
 
 
 
 
 
 
 
 
Laurenz Trawnicek, Manager Biometrics 
Octapharma PPG 
 
 
04 Mar 2021 | 12:44:18 CET 
Date, Signature 
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2 Table of Contents 
1 
Signatures ............................................................................................................................ 2 
2 
Table of Contents ................................................................................................................ 3 
3 
List of Abbreviations ........................................................................................................... 5 
4 
General ................................................................................................................................ 7 
4.1 
Analyses planned and already performed .................................................................. 7 
4.2 
SOPs to be followed .................................................................................................. 7 
5 
Overview of the protocol ..................................................................................................... 7 
5.1 
Objectives of the study .............................................................................................. 7 
5.2 
Study design .............................................................................................................. 7 
5.3 
Sample size ................................................................................................................ 9 
5.4 
Endpoints ................................................................................................................. 10 
5.4.1 
Primary endpoints .............................................................................................. 10 
5.4.2 
Secondary endpoints .......................................................................................... 10 
6 
General Aspects of the Statistical analysis ........................................................................ 11 
6.1 
Analysis sets ............................................................................................................ 11 
6.2 
Protocol deviations .................................................................................................. 11 
6.3 
Changes or deviations from planned analyses ......................................................... 12 
7 
Definitions for statistical analysis ..................................................................................... 12 
7.1 
Handling of withdrawals (drop-outs), missing values and outliers ......................... 12 
7.2 
Baseline ................................................................................................................... 13 
7.3 
Reference day / Day 1 ............................................................................................. 13 
8 
Statistical analysis Specification ....................................................................................... 13 
8.1 
Specifications related to whole analysis .................................................................. 13 
8.1.1 
Tables ................................................................................................................. 13 
8.1.2 
Data listings ....................................................................................................... 14 
8.2 
Disposition of patients ............................................................................................. 14 
8.3 
Medical history and concomitant diseases .............................................................. 14 
8.4 
Previous and concomitant medication ..................................................................... 14 
8.5 
Previous FVIII treatment ......................................................................................... 14 
8.6 
Efficacy (bleeding episodes) ................................................................................... 15 
8.6.1 
Data collection ................................................................................................... 15 
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8.6.2 
Definition of BEs ............................................................................................... 15 
8.6.3 
Analysis of BEs .................................................................................................. 16 
8.7 
Diary data ................................................................................................................ 16 
8.8 
Safety ....................................................................................................................... 16 
8.8.1 
Study drug exposure .......................................................................................... 16 
8.8.2 
Inhibitor and antibody formation ....................................................................... 17 
8.8.3 
Adverse events ................................................................................................... 17 
8.8.4 
Local injection reactivity ................................................................................... 18 
8.8.5 
Safety laboratory ................................................................................................ 18 
8.8.6 
Vital signs .......................................................................................................... 19 
8.8.7 
Physical examination ......................................................................................... 19 
8.9 
Pharmacokinetic data ............................................................................................... 19 
8.9.1 
Descriptive summaries for all cohorts ............................................................... 19 
8.9.2 
Bioavailability analysis for Cohort 3 ................................................................. 20 
8.9.3 
Dose proportionality analysis for Cohort 5 ........................................................ 20 
8.9.4 
Plasma trough and peak levels after daily injections of OCTA101 ................... 22 
9 
Software and statistical programming ............................................................................... 22 
10 References ......................................................................................................................... 22 
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3 List of Abbreviations 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate transaminase 
AUC 
Area Under the Concentration-Time Curve 
BE 
Bleeding episode 
CL 
Apparent clearance 
Cmax 
Maximum Plasma Concentration 
DMC 
(Independent) Data Monitoring Committee 
DRM 
Data Review Meeting 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FVIII 
Coagulation factor VIII 
FVIII:C 
Factor VIII coagulation activity 
IMP 
Investigational Medicinal Product 
IU 
International Unit 
iv 
Intravenous 
IVR 
In vivo recovery 
MedDRA Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PT 
Preferred term 
r(h)FVIII 
Recombinant (human) FVIII 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
sc 
Subcutaneous 
SMQ 
Standardised MedDRA Query 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
tmax 
time for reaching maximum plasma concentration 
Vd 
Apparent distribution volume 
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VWF 
Von Willebrand factor 
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4 General 
This statistical analysis plan reflects study protocol SubQ8-01, version 7.0 dated 06-Jul-2020. It 
follows the principles of the Guidelines ICH Topic E3 and ICH Topic E9. 
It gives all details for the final statistical analysis of all available data of enrolled patients in 
cohorts 1, 2, 3 and 5, except one patient who is still on immune tolerance induction (ITI) 
treatment. For this patient, all data reported until the time of the database snapshot on 14-Jan- 
2021 will be used in this analysis. 
A separate statistical analysis plan will be created for the final analysis of the newly defined 
cohort 6. 
4.1 Analyses planned and already performed 
After the completion of each cohort, pharmacokinetic (PK) and safety data were analyzed and 
discussed during a Data Monitoring Committee (DMC) meeting. Data from each cohort were 
analyzed separately. This statistical analysis plan (SAP) covers the final analysis of the study as 
described above. 
4.2 SOPs to be followed 
The statistical analysis will be carried out according to Metronomia Standard Operation 
Procedures (SOPs). 
 
5 Overview of the protocol 
5.1 Objectives of the study 
The primary objective is to assess the safety of various doses of OCTA101 (human-cl rhFVIII 
and recombinant von Willebrand Factor dimer) after subcutaneous (sc) injection. 
The secondary objectives of this study are to assess 
• the pharmacokinetics of FVIII:C after single sc injection of OCTA101 
• the dose proportionality of FVIII:C after sc injections of different doses of OCTA101 
• the bioavailability of sc OCTA101 compared to iv injection of Human-cl rhFVIII 
• the pharmacokinetics of OCTA12 (recombinant human von Willebrand Factor fragment 
dimer) after single injection of OCTA101 
• plasma trough and peak levels of FVIII:C after daily injections of OCTA101 
• plasma trough and peak levels of OCTA12 after daily injections of OCTA101 
• the efficacy of sc injections of OCTA101 in preventing bleeding episodes (BEs) 
5.2 Study design 
SubQ8-01 is a first-in-human, prospective, open-label Phase 1/2 study of OCTA101, a novel 
combination product, which consists of an eluate of an already authorized human recombinant 
coagulation factor FVIII product (Human-cl rhFVIII = Nuwiq®) along with OCTA12 (at a molar 
ratio of 1:6, with regards to FVIII binding sites in OCTA12), an investigational recombinant 
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human VWF fragment dimer, which is expected to increase the bioavailability of FVIII on sc 
dosing. The trial was planned to be carried in adult patients with severe hemophilia A according 
to a staged integrated design with five planned consecutive cohorts. No patient can participate in 
more than one cohort. 
One part of the study was to be a single ascending dose study in 4 cohorts (50, 100, 200 and 400 
IU/kg). The decision of going to the next higher dose or not was to be taken after each cohort by 
an external independent DMC after review of safety and tolerability data, FVIII:C plasma levels, 
and PK characteristics of FVIII:C and OCTA12. Any safety-relevant signals were also 
forwarded to the DMC for their review as they occurred. The reason(s) for not progressing to a 
higher dose level, e.g. dose-limiting toxicities (DLTs), were to be documented if such a decision 
was reached. Based on the results from Cohorts 1 and 2, the sponsor and DMC decided that 
escalation to higher doses should not take place and that further characterization of the 50 IU/kg 
dose was warranted. Therefore, Cohort 3 received 50 IU/kg administered into the abdomen, 
Cohort 4 was to receive 50 IU/kg administered into the thigh (this was not proceeded), and 
Cohort 5 investigated dose linearity at a lower dose range than initially planned (20, 40 and 60 
IU/kg instead of 50, 100 and 200 IU/kg). 
Patients in Cohort 3 also received a single intravenous (iv) dose of 50 ± 5 IU/kg Human-cl 
rhFVIII (Nuwiq) in order to compare the bioavailability of sc OCTA101 with those of Human-cl 
rhFVIII (the FVIII part of OCTA101) injected iv. The treatment sequence was be Human-cl 
rhFVIII followed by OCTA101. 
Dose proportionality of OCTA101 was evaluated after single sc administration of three different 
doses (20 IU/kg, 40 IU/kg and 60 IU/kg) in 4 patients (Cohort 5). 
The cohorts are summarized as follows: 
• Cohort 1: 50 IU/kg (n=4): single-period investigation with a single sc dose of 50 IU/kg 
OCTA101 profiled up to 72 hours after dosing. 
• Cohort 2: 100 IU/kg (n=4): single-period investigation with a single sc dose of 100 IU/kg 
OCTA101 profiled up to 96 hours after dosing. 
• Cohort 3: 50 IU/kg (n=8): two-period investigation of a single iv dose of 50 IU/kg rFVIII 
(Human-cl rhFVIII) profiled for up to 72 hours after dosing followed by sc dose of 50 
IU/kg OCTA101 administered into the abdomen profiled up to 72 hours. Treatments 
were to be administered in fixed sequence, with Human-cl rhFVIII first. 
• Cohort 4: Cancelled. 
• Cohort 5 (n=4): three-period investigation of single sc doses of 20, 40, and 60 IU/kg 
OCTA101 profiled up to 72 hours after dosing. Treatments were to be administered in 
fixed dose-ascending sequence. 
• Cohort 1 and 2 PK assessment after 3-month daily dosing (n=8): single-period 
investigation with a single sc dose of 50 IU/kg OCTA101 profiled up to 120 hours after 
dosing for FVIII and up to 21 days for OCTA12. 
• Cohort 6 (n=16): following an initial 4 to 6-week run-in period with Human-cl rhFVIII iv 
prophylaxis, 3-month daily prophylactic treatment with 12.5 IU/kg OCTA101 sc, then 25 
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IU/kg OCTA101 sc, and then 40 IU/kg OCTA101 sc (exact dosing depends on vial 
strength). The analysis of this data is not in the scope of this SAP. 
By DMC-recommendation, patients enrolled in Cohorts 1, 2, and 3 proceeded to 3-month 
prophylactic treatment part of the study and received daily dosing using one injection 
(approximately 40-60 IU/kg; dose chosen to allow administration by single injection; it was 
permitted to daily alternate the vial size, e.g. 3000 IU on one day 1, 5000 IU on day 2, 3000 IU 
on day 3, 5000 IU on day 4 etc.) of OCTA101 for 3 months (home treatment). Patients from 
Cohort 1 received prophylactic Human-cl rhFVIII after the initial PK assessment (home 
treatment) until the DMC had confirmed that OCTA101 can be used as daily prophylaxis. 
Bleeding events during the study were to be treated with Human-cl rhFVIII. Throughout this part 
of the study, FVIII inhibitors, plasma concentrations of FVIII:C, and OCTA12 were measured 
repeatedly. 
A PK assessment was performed in all patients from Cohorts 1 and one patient from Cohort 2 
who completed their 3-month daily injection period for further characterizing the PK of FVIII:C 
and OCTA12. Blood samples were collected up to 21 days in order to see a decline in OCTA12 
plasma concentrations (and allow determination of half-life) as the initial PK period was not long 
enough to see a decline of OCTA12. Concomitant measurement of FVIII:C up to 120 h will 
allow evaluation of any interaction between OCTA12 plasma concentration and FVIII:C. 
Independent expert evaluation by the DMC has steered study progress for the stepwise dosage 
increments by cohort and the progression of patients from the first three cohorts to 3-month daily 
dosing. In addition, the DMC has advises on changes of the proposed dosage for the assessment 
of bioavailability (Cohort 3) and dose-proportionality (Cohort 5) and changes in the schedule of 
PK blood sampling and/or the duration of profiling without substantially increasing the total 
amount of blood to be sampled. Based on the observation of a second patient with inhibitors in 
Cohort 2, the DMC recommended placing the study on hold. the following changes were 
recommended for the restart of the study: cancel Cohort 4, cut Cohort 5 to 4 patients instead of 
the planned 8, and introduce Cohort 6. 
Therefore, only the following data is available and will be analyzed: 
1. Data of Cohorts 1, 2 and 3 including their 3-month daily injection period data as planned. 
For Cohort 3, the 3-month daily injection period was discontinued after about 4 weeks. 
2. Data of Cohort 5 (planned n=8) available for 4 patients only. 
3. Repeated PK assessments after 3-month daily injection period in Cohorts 1 and 2 
(planned n=8) available for 5 patients (4 in Cohort 1 and one patient in Cohort 2) 
 
 
5.3 Sample size 
The sample size was determined based on pre-clinical findings and clinical reasoning, and was 
discussed with the FDA. No formal sample size calculation was performed. 
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5.4 Endpoints 
5.4.1 Primary endpoints 
The following safety endpoints are the primary endpoints in this study: 
• Adverse events 
• DLTs 
• Thromboembolic events 
• Local injection site reactions 
• Inhibitor formation to FVIII 
5.4.2  Secondary endpoints 
Efficacy 
• PK parameters of FVIII:C (see below) 
• PK parameters of OCTA12 (see below) 
• Total annualized bleeding rate during 3 months of daily sc treatment with OCTA101 
• Spontaneous annualized bleeding rate during 3 months of daily sc treatment with OCTA101 
• Total annualized treated bleeding rate during 3 months of daily sc treatment with OCTA101 
• Spontaneous annualized treated bleeding rate during 3 months of daily sc treatment with 
OCTA101 
• Traumatic annualized bleeding rate during 3 months of daily sc treatment with OCTA101 
• Joint annualized bleeding rate during 3 months of daily sc treatment with OCTA101 
• FVIII:C trough and peak plasma levels during 3-month daily dosing 
• Score (4-point) to assess efficacy of treatment of BEs with Human-cl rhFVIII 
PK parameters 
• Cmax: maximum observed concentration 
• Tmax: time of occurrence of Cmax after dosing 
• AUC(0-tz): quantifiable area under the time course of the concentrations de-rived by 
means of the combined linear/log-linear trapezoidal rule 
• λz: apparent terminal log-linear rate constant 
• t½: apparent terminal log-linear half-life 
• AUC(tz-∞): AUC extrapolated beyond the last time point with quantifiable 
concentrations calculated as C*(tz)/λz in which C*(tz) is the concentration at time tz 
fitted according to λz 
• AUC(0-∞): total AUC = AUC(0-tz)+ AUC(tz-∞) 
• AUCextrapolated: extent of AUC extrapolation = AUC(tz-∞)/AUC(0-∞) 
• AUMC(0-tz) and AUMC(0-∞): quantifiable and total area under the statistical first 
moment curve 
• MRT: mean residence time = AUMC(0-∞)/AUC(0-∞) 
• IVR: in vivo recovery = dose- and body weight-normalised maximum gain in FVIII:C 
• 
CL: total clearance (iv dosing only) = Dose/AUC(0-∞) 
• Vd: estimated distribution volume (iv dosing only) = CL.MRT 
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Safety 
• Antibody formation to OCTA12 
• OCTA12 plasma levels during 3-month daily dosing 
• Routine lab tests compared to baseline 
• Vital signs compared to baseline 
• Physical examination results compared to baseline 
 
6 General Aspects of the Statistical analysis 
6.1 Analysis sets 
The safety analysis set (SAF) will include all patients who received at least one dose of IMP. 
The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle will 
include all patients who received at least one dose of IMP in the context of repeat daily 
prophylactic dose (40-60 IU/kg) for 3 months. 
The per-protocol (PP) set, i.e., a subset of the FAS, will exclude patients with major protocol 
deviations which may have an impact on the evaluation of the primary study outcome 
parameter(s). 
• Examples of major and minor protocol deviations are described in section 6.2 of this 
SAP. 
• A final decision about the classification of protocol deviations and their consequences 
regarding assignment of patients to analysis sets will be made during the data review 
meeting. Decisions and outcomes will be approved by the Sponsor. 
The PK analysis set will include all patients from the SAF who started the initial PK assessment 
with OCTA101. 
The PK–PP analysis set will be a subset of the PK analysis set. It will exclude patients not fully 
evaluable for PK endpoint. Examples of criteria to exclude any patient from this analysis set are 
described in section 6.2 of this SAP. A final decision about the inclusion into the PK-PP analysis 
set will be made during the data review meeting. Decisions and outcomes will be approved by 
the Sponsor. 
The analysis of safety will be based on the safety set by cohort. 
The analysis of data from the repeat dosing will be based on the FAS as primary analysis and on 
the PP set as secondary analysis. This analysis will be performed by cohort and overall. 
The evaluation of PK data will be based on the PK and on the PK-PP analysis sets. 
 
6.2 Protocol deviations 
The following protocol deviations are examples for major deviations with respect to the per- 
protocol analysis of efficacy related non-PK data. A final decision about the classification of 
protocol deviations and their consequences regarding assignment of patients to analysis sets will 
be made during the data review meeting (DRM). Decisions and outcomes will be documented in 
the DRM minutes, which will be approved by the Sponsor. 
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Table 6-1 Major protocol deviations leading to exclusion from the per protocol set 
 
Description 
Rationale 
Patient used other Factor VIII product than study medication for 
prophylaxis of bleeding. 
The analysis of annualized bleeding 
rates is biased if other products 
were used. 
Patient deviated substantially from the dose of study medication 
foreseen in the protocol. 
The analysis of annualized bleeding 
rates is biased if the study 
medication dosage did not follow 
the protocol defined dose. 
The following protocol deviations are examples for major deviations with respect to the per- 
protocol analysis of PK data. A final decision about the inclusion into the PK-PP analysis set will 
be made during the data review meeting. Decisions and outcomes will be approved by the 
Sponsor. 
Table 6-2 Major protocol deviations leading to exclusion from the PK per protocol set 
 
Description 
Rationale 
Missing PK samples due to sampling issues do not allow a reliable 
determination of the PK parameters 
Reliable estimates of the 
parameters are the basis for 
the statistical analysis 
The following protocol deviations are defined as minor. 
Table 6-3 Minor protocol deviations 
 
Description 
Rationale 
Patient had a secondary diagnosis that was excluded for safety 
reasons. Patient could complete the study without any problems. 
Does not affect the analysis of 
annualized 
BEs 
or 
other 
efficacy parameters 
Vital signs were not measured in the scheduled time frame and vital 
signs are not part of the primary efficacy endpoint. 
Does not affect the analysis of 
primary 
or 
secondary 
endpoints. 
All protocol deviations including classification and reasons for exclusion from any analysis set 
will be presented in by-patient listings. 
6.3 Changes or deviations from planned analyses 
As the study was discontinued, fewer data are available than planned. Therefore, the following 
changes from planned analyses will be implemented: 
All analysis based on per-protocol (PP) set will be not done as this was mainly intended for the 
bleeding rate analysis, and this will not be performed as originally planned. 
 
7 Definitions for statistical analysis 
7.1 Handling of withdrawals (drop-outs), missing values and outliers 
If not specified otherwise, missing values will not be displayed and no imputations will be 
performed. Patients who dropped out from the study will be analyzed with all data provided. 
In general, it is assumed that the quality of data for the 16 patients treated for 3 months on a daily 
basis in a single investigational site will be good and that questions related to BEs or treatment of 
BEs can be clarified prior to database lock. 
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The following rules will be applied for the analysis of BEs: 
If it is unclear whether any day or site with bleeding should be counted as a separate BE due to 
missing or unclear data, a conservative approach will be used to count unclear dates or sites as 
separate BEs. In a sensitivity analysis, these date and sites will not be counted as separate BEs. 
When the type of a BE cannot be determined due to missing data, the BE will be counted within 
the total annualized bleeding rate but not for the bleeding rates that require the type of bleeding. 
In a sensitivity analysis, such BEs will be counted within all possible types of bleeding. 
If missing data does not allow the assessment whether a BE was successfully treated or not, the 
BE will be omitted from the denominator for the proportion of successfully treated BEs. In a 
sensitivity analysis, such a BE will be analyzed as a not successfully treated BE. 
7.2 Baseline 
A baseline assessment is the last assessment prior to the first injection of OCTA101. A baseline 
assessment may take place on Day 1, prior to the actual sc injection. 
7.3 Reference day / Day 1 
The day of the first treatment with study medication OCTA101 will be Day 1 for all patients for 
the PK part in the study, except for Cohort 3, where the first treatment with Human-cl rhFVIII 
within the PK part of the study will be defined as Day 1. 
Patients who enter the 3-month daily prophylactic part will be assigned a second reference day, 
the day of first treatment with OCTA101 during the prophylactic part. 
 
8 Statistical analysis Specification 
8.1 Specifications related to whole analysis 
8.1.1 Tables 
If not explained differently below, summary tables will be stratified by cohort and by 
product/dose if applicable. 
Summary tables for single dose cohorts will be presented showing the result of each cohort in the 
same summary table. 
Summary tables related to data collected during the 3-month daily dosing period will be based on 
the overall FAS and will not be stratified by the previous cohort. 
For continuous data, the basic statistics sample size, (number of missing values), mean, and 
standard deviation; minimum, first quartile, median, third quartile and maximum will be shown. 
Categorical data will be displayed in frequency tables showing sample size and absolute and 
relative frequency. The time course of continuous data will be presented using the basic statistics 
for each visit and the differences from baseline to last value and relative differences from 
baseline to last value. 
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8.1.2 Data listings 
Electronic case report form (eCRF) and diary data will be listed as documented as well as all 
relevant generated and transformed variables next to the original data items. In all listings, cohort 
and analysis population for each patient will be included. The listings will be sorted by cohort 
and patient identifier. 
8.2 Disposition of patients 
The number and percentage of subjects screened, allocated to a cohort, received IMP, completed 
the full course of the trial and discontinued prematurely (incl. reasons for premature 
discontinuation) will be summarized by cohort and overall. 
Demographic data and all other baseline characteristics and tests performed to assess the 
eligibility of patients will be summarized by cohort and overall for the SAF and the FAS. 
8.3 Medical history and concomitant diseases 
Medical history and concomitant diseases will be coded using the MedDRA dictionary in the 
version and the update strategy as defined in the coding guideline for this study. A concomitant 
disease is defined as any diagnosis, for that either no stop date was documented or the stop date 
is later than day 1. Incomplete stop dates will be estimated using the last possible date in order to 
define whether a disease is concomitant. 
Summary tables presenting number and percentage of patients with medical history and with 
concomitant diseases by MedDRA system organ class (SOC) and MedDRA preferred term (PT) 
will be provided cohort and overall for the SAF and the FAS. In these tables, SOCs and PTs 
within SOCs will be ordered with decreasing frequency in the total column. 
8.4 Previous and concomitant medication 
Prior and concomitant medications excluding FVIII treatments will be coded using the WHO 
drug dictionary Enhanced Version, in the version and using the update strategy as specified in 
the coding guideline for this study. Previous medication is defined as medication that started and 
stopped prior to Day 1. Concomitant medication is defined as medication with at least one dose 
taken after Day 1. Incomplete start dates will be estimated using the first possible date, 
incomplete stop dates will be estimated using the last possible date in order to define whether a 
treatment was taken concomitantly. For missing start dates, a start prior to Day 1 will be 
assumed. 
Summary tables presenting number and percentage of patients with previous and concomitant 
medication (excluding FVIII treatments) will be summarized separately for the SAF and the 
FAS. In these tables, the medications will be decoded on the ATC level 2 (Therapeutic 
Subgroup). Previous and concomitant medication will be listed together with a flag indicating 
whether it is classified as previous medication or concomitant medication. 
8.5 Previous FVIII treatment 
The type of previous FVIII treatment will be summarized overall and by indication prophylactic, 
on demand). Further, the preferred term of the previous FVIII treatments will be summarized. 
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The summaries will be stratified by cohort and will be provided for the SAF and the FAS. 
 
8.6 Efficacy (bleeding episodes) 
All reported bleedings with all details (see below) will be listed. In addition, the relative time of 
onset of bleeding to the OCTA101 daily injection period will be determined and listed as 
“before/during/after” category. 
8.6.1 Data collection 
For any bleeding episode (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 (OCTA101 or Human-cl rhFVIII) was injected 
• Dates and times the IMP was injected, if applicable 
• IMP dose(s) and batch number(s) 
• Assessment of the efficacy of treatment at the end of the BE; see 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. 
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 infusion 
• Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8– 
12 hours after an infusion, requiring up to 2 infusions for complete resolution 
• Moderate: Probable or slight beneficial effect within approximately 12 hours after the first 
infusion, requiring more than 2 infusions for complete resolution 
• None: No improvement within 12 hours, or worsening of symptoms, requiring more than 2 
infusions for complete resolution 
8.6.2 Definition of BEs 
If the treatment of a BE at one site is interrupted for more than 48 hours, the events are recorded 
and will be analyzed as two separate BEs; if another than the original bleeding site is affected, 
the events are recorded and will be analyzed as separate BEs at any time. 
If there are several simultaneous bleeding sites, each bleeding site is recorded and will be 
analyzed as a separate BE. 
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 
hemorrhage. These additional treatments should be recorded in the diary (and eCRF) but will not 
be evaluated as treatments of the BE. 
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All efficacy ratings assessed as either ‘excellent’ or ‘good’ will be considered ‘successfully 
treated.’ 
8.6.3 Analysis of BEs 
For the current planned analysis of cohorts 1 to 5, the analysis as described below will not be 
performed since the daily dosing period had to be interrupted and then fully stopped due to 
inhibitor formation. 
All bleeding episode will be presented for each patient in the trial, with a clear flag, whether the 
bleeding occurred prior to, during, or after the 3-month daily dosing period with OCTA101. 
All time periods of prophylactic treatment and all bleeding episodes during the 3-month daily 
prophylactic part will be pooled as y (number of BEs) and t (the pooled time intervals in days). 
The total annualized bleeding rate is defined as λyear = y*t/d, with d = 365.25 days, a 
standardized year. 
The spontaneous annualized bleeding rate, the traumatic annualized bleeding rate, the total 
annualized treated bleeding rate, the spontaneous annualized treated bleeding rate, and the joint 
annualized bleeding rate will be calculated in the same way, by restricting the count of bleedings 
to the respective type of bleeding. 
In addition, the prior total annualized bleeding rate of patients who entered the 3-month daily 
prophylactic treatment based on all bleedings reported during the 6 months prior to the first dose 
of OCTA101 will be calculated in the same way and presented. 
All other data collected for BEs and the efficacy assessments at the end of BEs will be analyzed 
descriptively. The analysis will be stratified by the product that was used to treat the bleeding, if 
applicable. 
The proportion of BEs successfully treated with Human-cl rhFVIII and (if applicable) 
successfully treated with OCTA101 will be presented. 
8.7 Diary data 
All diary data collected will be analyzed as described in the other sections of the SAP. Data from 
diaries will be merged together with the data from the eCRF prior to the statistical analysis. 
8.8 Safety 
Safety and tolerability data will first be analyzed for each cohort after the first dose(s) and 
evaluated by an external DMC. 
All safety and tolerability parameters (adverse events, vital signs, laboratory monitoring, and 
physical examination results) will be listed by patient and cohort. 
Analyses based on data from repeat dosing from Cohort 1, 2, and 3 with OCTA101 for 3 months 
will be analyzed separately from data related to the first doses. In these analyses, data will be 
presented by cohort and overall. The analyses will thus be based on the SAF and the FAS. 
8.8.1 Study drug exposure 
Study drug exposure during the PK part of the study will be analyzed by cohort and by study 
drug for cohort 3. 
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Summary tables of number of injections, total dose applied in IU and in IU/kg will be presented 
by cohort and PK visit. 
The following data will be presented for the treatment with OCTA101 during the daily 3-month 
treatment period by cohort and overall: 
• Duration of the OCTA101 daily treatment period in days 
• Number of OCTA101 exposure days 
• Number of OCTA101 injections per exposure day 
• Average dose (in IU/kg) and in absolute IU per week of OCTA101 
• Average dose (in IU/kg) and in absolute IU per injection of OCTA101 
• Average dose (in IU/kg) and in absolute IU per injection for each visit during the daily 3- 
month treatment period 
 
The number of injections per exposure day during the daily 3-month treatment period will be 
calculated as the number of injection sites when one vial was used and as the number of vials 
when more than one vial was used. Further, summary tables of total dose applied in IU and in 
IU/kg will be presented by cohort and overall for each visit during the daily 3-month treatment 
period. 
All available data of study drug exposure will be listed. 
 
8.8.2 Inhibitor and antibody formation 
The frequencies (including percentages) of any inhibitor formation to FVIII and antibody 
formation to OCTA12 will be presented in summary table by cohort and overall and all available 
data will be listed. 
Inhibitor formation to FVIII will be considered if at least one result of neutralizing antibody was 
equal or greater than 0.6 BU/ml. Antibody formation to OCTA12 will be defined as positive, if 
after a positive assay at screening, a confirmatory test is also positive. 
 
 
8.8.3 Adverse events 
Adverse events (AEs) will be coded using the MedDRA dictionary in the version and using the 
update strategy as specified in the coding guideline for this study. 
All AEs reported during the study will be analyzed and presented. AEs starting at or after the first 
dose of OCTA101 (treatment emergent AE [TEAEs]) will be presented separately from those 
starting prior to the first dose of OCTA101 (pre-treatment AEs). 
A TEAE related to OCTA101 is defined as any TEAE considered by the investigator to have at 
least a “possible” relationship with the study medication, this will also include TEAEs reported 
with a relationship to study medication of “Unclassified” or with a missing relationship. The 
relationship with the study medication will be also assessed by the Sponsor. This assessment will 
be listed. 
The number and percentage of patients with TEAEs and the number of TEAEs will be summarized 
by primary MedDRA SOC and PT. Separate tables showing all TEAEs, all serious TEAEs, all 
non-serious TEAEs and all TEAEs related to OCTA101 will be generated. Further a summary of 
TEAEs by severity, presenting the most severe event per patient overall and within each SOC and 
PT will be generated. 
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Thromboembolic events and local injection site reactions will be presented within these clusters, 
using the summaries detailed above. 
The definition of the cluster thromboembolic events will be based on the standardised MedDRA 
query (SMQ) “Embolic and thrombotic events”: 
Definition: Thrombotic disorders are diseases characterized by formation of a thrombus that 
obstructs vascular blood flow locally or detaches and embolizes to occlude blood flow 
downstream. Embolism is the sudden blocking of a vessel by a clot or foreign material which has 
been brought to its site of lodgment by the blood current. (Thrombo-)phlebitis is an inflammation 
of a vein (phlebitis) associated with thrombus formation (thrombosis). 
This SMQ includes 3 sub-SMQ: 
• Embolic and thrombotic events, venous (SMQ) 
• Embolic and thrombotic events, arterial (SMQ) 
• Embolic and thrombotic events, vessel type unspecified and mixed arterial and venous 
(SMQ) 
Local injection site reactions will be identified directly via the CRF entry (tickbox). 
8.8.4 Local injection reactivity 
Patients will evaluate injection site pain using a visual analog scale (VAS) from “0 mm/no pain” 
to “100 mm/extreme pain” immediately after injection completion. The local injection reactivity 
after single injections in the PK part will be summarized descriptively by cohort and PK visit and 
by overall for the follow-up PK visits. 
The summaries will be provided stratified by injection site (abdomen or thigh) and by number of 
daily injections and overall. 
Investigator (and patient in case of home treatment) shall assess local injection reactivity directly 
after injection and at 15 ± 5 min post-injection as described in ISO10999-10 standard: 
• 0=no skin reactivity; 
• 1=mild (subject is aware of the signs/symptoms, but finds it easily tolerated) 
• 2=moderate (discomfort enough to cause interference with usual activities) 
• 3=severe (subject is incapacitated and unable to work or participate in many or all usual 
activities). 
For the injections during the daily 3-month treatment with OCTA101, the frequencies of local 
injection reactivity ratings by the investigator and the patient directly after injection and 15 ± 5 
min post-injection will be summarized over the whole 3-month period using the number of 
injections as denominator. Visual analogue scale assessments of injection site pain will be 
summarized analogously. 
8.8.5 Safety laboratory 
Safety laboratory parameters will be analyzed using descriptive statistics for measured values at 
each visit and time point and for changes from pre-dose values prior to each single injection of 
OCTA101 for the SAF and the FAS. 
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8.8.6 Vital signs 
Vital sign parameters will be analyzed using descriptive statistics for measured values at each 
visit and time point and for changes from pre-dose values prior to each single injection of 
OCTA101 for the SAF and the FAS. 
8.8.7 Physical examination 
Physical examination data will be displayed in patient data listings only. 
 
8.9 Pharmacokinetic data 
In general for the analysis, non-quantifiable pre-dose levels will be set equal to zero. In the event 
of quantifiable levels prior to dosing, the baseline level will be subtracted from the post-dosing 
values and the further analysis is focused on the post-dosing changes from baseline. 
All data collected at unscheduled visits will be not used in the PK analysis. 
 
8.9.1 Descriptive summaries for all cohorts 
For each of the investigation periods after 20, 40, 60, 50 and 100 IU/kg sc of OCTA101 and for 
the investigation period after 50 IU/kg iv of Human-cl rhFVIII in Cohort 3, the concentrations of 
each analyte will be analyzed with geometric means, geometric coefficient of variation, 
arithmetic mean, standard deviation, minimum, maximum and median by time point (and visit) 
for the PK and PK-PP analysis set. 
For each of the investigation periods after 20, 40, 60, 50 and 100 IU/kg sc of OCTA101 and for 
the investigation period after 50 IU/kg iv of Human-cl rhFVIII in Cohort 3, the PK parameters of 
each analyte (see section 5.4) will be analyzed with geometric means, geometric coefficient of 
variation, arithmetic mean, standard deviation, minimum, maximum and median for the PK and 
PK-PP analysis set. 
Graphical displays of individual and of summarized data by cohort will support the summary 
tables. 
In general, the dose-adjusted PK parameters will be determined using the “actual” dose in IU 
that was administered to a patient. The actual dose will be derived from the nominal dose and the 
actual potencies determined by the central laboratory for each batch separately. 
The same analyses will be performed for the plasma concentrations of FVIII:C and OCTA12 
samples and for the PK parameters of each analyte (see section 5.4) after the single dose 
administration of 50 IU/kg OCTA101 after the completion of the 3-months daily dosing period 
of Cohort 1 and Cohort 2. 
These analyses will be reported in the relevant PK reports. 
Summary tables of non-compartmental PK parameters of FVIII:C and OCTA12 will be 
additionally created for each cohort (cohorts 1, 2 and 3) and each period (cohort 5). 
Summary tables of plasma concentrations of FVIII:C and OCTA12 will be created by cohort and 
overall for all visits during the 3-months daily dosing period. 
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8.9.2 Bioavailability analysis for Cohort 3 
Single-dose data from Cohort 3 comparing the pharmacokinetics after sc and iv dosing (Human- 
cl rhFVIII) will be used to derive estimates of the absolute bioavailability after sc dosing and to 
assess route dependency of the further pharmacokinetic criteria. 
Mixed effects models will be estimated for the PK-PP analysis set for each parameter of FVIII:C 
(dose-adjusted AUC(0-∞), AUC(0-tz), IVR and Cmax) with the natural logarithm of the dose- 
adjusted PK parameter as outcome and route (sc versus iv) as explanatory variable and a random 
intercept for each subject. Point and 95% confidence interval estimates of the ratio of the 
treatment means (sc versus iv) will be derived by back-transforming the model estimates of the 
difference of the treatment means on the log scale to the original scale. The SAS code will be 
similar to the following statements: 
proc mixed; 
class route(ref=”"IV") subjid; 
model logauc_adj = route; 
lsmeans route / diff alpha=0.05; 
random subjid; 
run; 
By means of a similar mixed effects model, estimates of the differences of the treatment means 
will be derived for t½ and MRT of FVIII:C. The SAS code will be similar to the following 
statements: 
proc mixed; 
class route(ref=”"IV") subjid; 
model t12 = route; 
lsmeans route / diff alpha=0.05; 
random subjid; 
run; 
Point and 95% confidence interval estimates for the difference will be directly obtained from the 
model output. Further, summary tables of non-compartmental PK parameters used in the mixed 
model will be created for each analyte. 
8.9.3 Dose proportionality analysis for Cohort 5 
Data from Cohort 5 covering the pharmacokinetics after single sc. doses of 20, 40 and 60 IU/kg 
OCTA101 will be used to derive estimates of the dose-proportionality of the pharmacokinetics of 
FVIII:C and OCTA12. 
Since the sample size for this cohort was reduced to 4 subjects, the planned statistical analysis 
may not be feasible due to non-convergence of the calculated model. 
Analysis of Cmax and AUC 
To this purpose, the power model as described by e.g. Smith et al. (2000) will be used. A mixed 
effects model will be estimated for the PK-PP analysis set for each analyte and parameter 
(FVIII:C Cmax and AUC(0-∞) and OCTA12 Cmax, AUC(0-∞) and AUC(0-tz)) with natural logarithm 
of the parameter of interest as outcome variable and the natural logarithm of the planned dose as 
(continuous) explanatory variable and a random intercept per subject. The SAS code will be 
similar to the following statements: 
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proc mixed; 
class subjid; 
model logauc = logdose / alpha=0.1; 
random subjid; 
run; 
This corresponds to the following model equation: 
ln(𝐴𝐴𝐴𝐴𝐴𝐴𝑖𝑖𝑖𝑖) = (𝛽𝛽0 + 𝜂𝜂1𝑖𝑖) + 𝛽𝛽1 ∗ ln(𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑖𝑖) + 𝜀𝜀𝑖𝑖𝑖𝑖 
where AUCij is the dose-adjusted AUC under jth dose (j=1, 2, 3 corresponding to doses 20 IU/kg 
sc, 40 IU/kg sc, 60 IU/kg sc of OCTA101) for the ith subject (i=1,...,4) and 𝜂𝜂1 is the vector of 
subjects random intercepts. 
The parameter estimate for logdose (natural logarithm of dose) 𝛽𝛽1and its 90% confidence 
interval will be presented and compared to the critical region based on the following formula: 
ln(𝛩𝛩𝐿𝐿) 
1 + 
ln(𝑟𝑟) 
 
; 1 + ln(𝛩𝛩𝐻𝐻) 
ln(𝑟𝑟) 
where ΘL and ΘH are set to 0.5 and 2.0 and r is the ratio of the highest and the lowest target dose 
(60 IU/kg sc / 20 IU/kg sc = 3). This yields the following critical region for 𝛽𝛽1 and its confidence 
interval: 
0.4 ; 1.6 
Additionally, mixed effects models as specified above will be estimated for each analyte and 
parameter with the additional inclusion of a random slope per subject into the mixed model. The 
SAS code will be similar to the following statements: 
proc mixed; 
class subjid; 
model logauc = logdose / alpha=0.1; 
random intercept logdose / sub=subjid; 
run; 
This corresponds to the following model equation: 
ln(𝐴𝐴𝐴𝐴𝐴𝐴𝑖𝑖𝑖𝑖) = (𝛽𝛽0 + 𝜂𝜂1𝑖𝑖) + (𝛽𝛽1 + 𝜂𝜂2𝑖𝑖) ∗ ln(𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑖𝑖) + 𝜀𝜀𝑖𝑖𝑖𝑖 
where AUCij is the dose-adjusted AUC under jth dose (j=1, 2, 3 corresponding to doses 20 IU/kg 
sc, 40 IU/kg sc, 60 IU/kg sc of OCTA101) for the ith subject (i=1,...,4), 𝜂𝜂1 is the vector of 
subjects random intercepts and 𝜂𝜂2 is the vector of subjects random slopes. 
The fixed parameter estimate for logdose (natural logarithm of dose) 𝛽𝛽1 and its 90% confidence 
interval will be presented and compared to the above mentioned critical region, only if the 
variance-covariance matrix of the random effects (“G matrix”) is found to be positive-definite. 
Analysis of t½ and MRT 
In order to check for a potential dose-dependency of t½ and MRT, mixed models with outcome t½ 
and MRT will be estimated for the PK-PP analysis set. The SAS code will be similar to the 
following statements: 
proc mixed; 
class subjid; 
model t12 = dose / alpha=0.1; 
random subjid; 
run; 
This corresponds to the following model equation: 
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𝑡𝑡12𝑖𝑖𝑖𝑖 = (𝛽𝛽0 + 𝜂𝜂1𝑖𝑖) + 𝛽𝛽1 ∗ 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑖𝑖 + 𝜀𝜀𝑖𝑖𝑖𝑖 
where 𝑡𝑡12𝑖𝑖𝑖𝑖 is the t1/2 under jth dose (j=1, 2, 3 corresponding to doses 20 IU/kg sc, 40 IU/kg sc, 
60 IU/kg sc of OCTA101) for the ith subject (i=1,...,4) and 𝜂𝜂1 is the vector of subjects random 
intercepts. Further, summary tables of non-compartmental PK parameters used in the mixed 
model will be created by period for each analyte. 
8.9.4 Plasma trough and peak levels after daily injections of OCTA101 
FVIII:C and OCTA12 trough and peak plasma levels during 3-month daily dosing period will be 
analyzed with geometric means, geometric coefficient of variation, arithmetic mean, standard 
deviation, minimum, maximum and median for the FAS. Graphical displays by visit of individual 
and average trough and peak levels of FVIII-C and OCTA12 will support the summary tables. 
Also, individual graphical displays of both analytes by time point of measurement will be 
provided. 
This analysis will be included in the relevant PK report. 
 
9 Software and statistical programming 
The derivation of PK parameters will be performed using PCModfit v6.0. 
The statistical analysis will be performed using the SAS® statistical software package, version 
9.4 or higher. 
SAS programming will be performed according to Metronomia standards as defined in BM-08- 
SOP “Statistical Analysis and Programming” and related work instructions. Special attention 
will be paid to planning and performance of quality control measures as documented in the QC 
plan for the analysis of this study (see also BM-08-WIN03 “How to Plan and Document QC for 
Statistical Analysis”). 
 
10 References 
ICH Topic E9: Statistical Principles for Clinical Trials5 February 1998, adopted by CPMP, 
March 1998, issued as CPMP/ICH/363/96 
ICH Topic E3: Structure and Content of Clinical Study Reports, adopted by CPMP, December 
1995, issued as CPMP/ICH/137/95 
SAS Institute Inc. 2017. Base SAS® 9.4 Procedures Guide, Seventh Edition. Cary, NC: SAS 
Institute Inc. 
https://documentation.sas.com/?cdcId=pgmsascdc&cdcVersion=9.4_3.4&docsetId=pgmsasho 
me&docsetTarget=home.htm&locale=en 
Smith BP et al (2000), Confidence Interval Criteria for Assessment of Dose Proportionality, 
Pharmaceutical Research, Vol. 17, No. 10, pp. 1278-83 
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