Trial Outcomes & Findings for Safety and Pharmacokinetics of Subcutaneous Injection of OCTA101 in Adult Patients With Severe Hemophilia A (NCT NCT04046848)

Results Overview

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

36 participants

Primary outcome timeframe

Approximately 4 months; up to 11 months for cohort 6

Results posted on

2025-02-13

Participant Flow

Participant milestones

Participant milestones
Measure	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 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	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 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 6 Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).
Overall Study STARTED	4	4	8	4	16
Overall Study Completed Initial PK Assessment	4	4	8	4	0
Overall Study Started Daily Prophylaxis With OCTA-101	4	4	8	0	10
Overall Study Completed 3-month Daily Prophylaxis With OCTA-101	4	2	0	0	10
Overall Study COMPLETED	4	2	0	4	1
Overall Study NOT COMPLETED	0	2	8	0	15

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Safety and Pharmacokinetics of Subcutaneous Injection of OCTA101 in Adult Patients With Severe Hemophilia A

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 2 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 n=8 Participants 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 5 n=4 Participants (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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 6 n=16 Participants (n≥16): following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Total n=36 Participants Total of all reporting groups
Age, Continuous	37.0 years STANDARD_DEVIATION 7.35 • n=5 Participants	40.5 years STANDARD_DEVIATION 11.82 • n=7 Participants	43.5 years STANDARD_DEVIATION 12.78 • n=5 Participants	29.5 years STANDARD_DEVIATION 5.51 • n=4 Participants	41.9 years STANDARD_DEVIATION 12.37 • n=21 Participants	38.8 years STANDARD_DEVIATION 11.15 • n=8 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 Participants	4 Participants n=4 Participants	16 Participants n=21 Participants	36 Participants n=8 Participants
Race/Ethnicity, Customized White/Non-Hispanic or Latino	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 Participants	4 Participants n=4 Participants	16 Participants n=21 Participants	36 Participants n=8 Participants
Region of Enrollment Bulgaria	4 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants	4 participants n=4 Participants	16 participants n=21 Participants	36 participants n=8 Participants
BMI	27.7 kg per m2 STANDARD_DEVIATION 2.79 • n=5 Participants	27.1 kg per m2 STANDARD_DEVIATION 3.14 • n=7 Participants	25.3 kg per m2 STANDARD_DEVIATION 3.89 • n=5 Participants	27.8 kg per m2 STANDARD_DEVIATION 3.59 • n=4 Participants	24.6 kg per m2 STANDARD_DEVIATION 5.03 • n=21 Participants	26.6 kg per m2 STANDARD_DEVIATION 3.42 • n=8 Participants
Haemophilia joint health score	24.3 units on a scale STANDARD_DEVIATION 19.65 • n=5 Participants	27.8 units on a scale STANDARD_DEVIATION 26.11 • n=7 Participants	23.3 units on a scale STANDARD_DEVIATION 12.61 • n=5 Participants	16.3 units on a scale STANDARD_DEVIATION 8.14 • n=4 Participants	21.25 units on a scale STANDARD_DEVIATION 11.38 • n=21 Participants	23.0 units on a scale STANDARD_DEVIATION 15.89 • n=8 Participants

PRIMARY outcome

Timeframe: Approximately 4 months; up to 11 months for cohort 6

Population: The population included all patients who received at least one dose of IMP.

Outcome measures

Outcome measures
Measure	Cohort 1 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 2 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 n=8 Participants 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 5 n=4 Participants (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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 6 n=10 Participants Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 2 - 6 Hours 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. In months 2 and 3 data could not be collected from all participants. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 Predose 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 - 3 Hours 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3.	Cohort 3 - 6 Hours 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3.	Cohort 6 Predose Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed, so in month 3 data could not be collected from all participants.	Cohort 6 - 8 Hours Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed, so in month 3 data could not be collected from all participants.
Patients Experiencing Adverse Events	0 Participants	2 Participants	1 Participants	0 Participants	3 Participants	—	—	—	—	—	—

PRIMARY outcome

Timeframe: Approximately 4 months; up to 11 months for cohort 6

Population: The population included all patients who received at least one dose of IMP.

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

Outcome measures

Outcome measures
Measure	Cohort 1 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 2 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 n=8 Participants 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 5 n=4 Participants (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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 6 n=10 Participants Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 2 - 6 Hours 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. In months 2 and 3 data could not be collected from all participants. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 Predose 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 - 3 Hours 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3.	Cohort 3 - 6 Hours 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3.	Cohort 6 Predose Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed, so in month 3 data could not be collected from all participants.	Cohort 6 - 8 Hours Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed, so in month 3 data could not be collected from all participants.
Participants Experiencing Dose-limiting Toxicities (DLTs)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	—	—	—	—	—	—

PRIMARY outcome

Timeframe: Approximately 4 months; up to 11 months for cohort 6

Population: The population included all patients who received at least one dose of IMP.

The definition of the cluster thromboembolic events was 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)

Outcome measures

Outcome measures
Measure	Cohort 1 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 2 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 n=8 Participants 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 5 n=4 Participants (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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 6 n=10 Participants Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 2 - 6 Hours 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. In months 2 and 3 data could not be collected from all participants. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 Predose 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 - 3 Hours 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3.	Cohort 3 - 6 Hours 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3.	Cohort 6 Predose Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed, so in month 3 data could not be collected from all participants.	Cohort 6 - 8 Hours Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed, so in month 3 data could not be collected from all participants.
Patients Experiencing Thromboembolic Events	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	—	—	—	—	—	—

PRIMARY outcome

Timeframe: Approximately 4 months; up to 11 months for cohort 6. Local injection site reactions were captured throughout the period where OCTA-101 was injected subcutaneously (sc).

Population: The population included all patients who received at least one dose of IMP.

Investigator (and patient in case of home treatment) assessed local injection reactivity directly after injection and at 15 ± 5 min post-injection as per the 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).

Outcome measures

Outcome measures
Measure	Cohort 1 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 2 n=4 Participants 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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 n=8 Participants 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 5 n=4 Participants (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. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 6 n=10 Participants Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 2 - 6 Hours 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. In months 2 and 3 data could not be collected from all participants. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 Predose 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3. OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).	Cohort 3 - 3 Hours 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3.	Cohort 3 - 6 Hours 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 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. The study was terminated before treatment could be completed, as a result, no data was collected in months 2 and 3.	Cohort 6 Predose Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed, so in month 3 data could not be collected from all participants.	Cohort 6 - 8 Hours Following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed, so in month 3 data could not be collected from all participants.
Patients Experiencing Local Injection Site Reactions of Any Grade	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	—	—	—	—	—	—

PRIMARY outcome

Timeframe: From first injection to 4 months after start of of daily injection (cohorts 1, 2 and 3), 4 weeks after last PK injection (cohort 5), monthly during the daily sc treatment period (cohort 6)

Population: The population included all patients who received at least one dose of IMP.

Development of an inhibitor was defined as a neutralizing antibody value of greater than or equal to (\>=) 0.6 Bethesda units per milliliter (BU/mL) identified and confirmed by a second test on an independent sample. In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample was to be performed, preferably within 15 days of becoming aware of the positive result. Both tests performed by the central laboratory using Nijmegen-modified Bethesda assay.