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

Primary Purpose

Severe Hemophilia A

Status

Terminated

Phase

Phase 1

Locations

Bulgaria

Study Type

Interventional

Intervention

OCTA101

About this trial

This is an interventional treatment trial for Severe Hemophilia A focused on measuring Hemophilia A, Blood Coagulation Disorders, Inherited, Blood Coagulation Disorders, Hematologic Diseases, Coagulation Protein Disorders, Hemorrhagic Disorders, Genetic Diseases, Inborn, Factor VIII

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

Severe hemophilia A (<1% FVIII:C) as documented in medical records
Males ≥18 years of age
Subjects who have had ≥150 exposure days (EDs) with a FVIII product
Written informed consent for study participation obtained before undergoing any study specific procedures

Exclusion Criteria:

Previous participation in this trial
Use of an Investigational Medicinal Product within 30 days prior to the first OCTA101 injection
History of FVIII inhibitors titre ≥0.6 BU/mL defined by medical records
Inhibitors to FVIII (≥0.6 BU/mL) at screening measured by Nijmegen modified Bethesda method at central laboratory
Human immunodeficiency virus (HIV) positive subjects with a CD4+ count <200/mL
Clinically significant anemia at screening (hemoglobin <8 g/dL)
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
Any coagulation disorder other than hemophilia A
AST or ALT levels >3 times the upper limit of normal
Creatinine >120 μmol/L
Platelet count <100,000 μL
BMI ≥30 kg/m²
For Cohort 6, patients with a positive LumiTope test at screening will be excluded

Sites / Locations

Specialized Hospital for Active Treatment of Hematological Diseases EAD Clinic of Clinical Hematology

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 5

Cohort 6

Arm Description

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.

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.

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.

(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.

(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.

Outcomes

Primary Outcome Measures

Adverse Events

Dose-limiting toxicities (DLTs)

Thromboembolic events

Local injection site reactions

Inhibitor formation to FVIII

Secondary Outcome Measures

Efficacy: Area under the concentration-time curve (AUC) of FVIII:C

Efficacy: Maximum plasma concentration (Cmax) of FVIII:C

Efficacy: Time for reaching maximum plasma concentration (Tmax) of FVIII:C

Efficacy: In vivo recovery (IVR) of FVIII:C

Efficacy: Half-life (t1/2) of FVIII:C

Efficacy: Mean residence time (MRT) of FVIII:C

Efficacy: Area under the concentration-time curve (AUC) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)

Efficacy: Maximum plasma concentration (Cmax) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)

Efficacy: Time for reaching maximum plasma concentration (Tmax) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)

Efficacy: In vivo recovery (IVR) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)

Efficacy: Half life (t1/2) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)

Efficacy: Mean residence time (MRT) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)

Efficacy: Total annualized bleeding rate

Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6

Efficacy: Spontaneous annualized bleeding rate

Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6

Efficacy: Total annualized treated bleeding rate

Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6

Efficacy: Spontaneous annualized treated bleeding rate

Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6

Efficacy: Traumatic annualized bleeding rate

Traumatic annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6

Efficacy: Joint annualized bleeding rate

Joint annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6

Efficacy: FVIII:C trough and peak plasma levels

FVIII:C trough and peak plasma levels during daily dosing for cohorts 1, 2, 3 and 6

Efficacy: Efficacy of treatment of bleeding episodes using Score (4-point)

Score (4-point) to assess the efficacy of treatment of bleeding episodes with Human-cl rhFVIII. Treatment efficacy will be assessed using predefined criteria to score either 'Excellent', 'Good', 'Moderate' or 'None'. All efficacy ratings assessed as either 'excellent' or 'good' will be considered 'successfully treated'.

Safety: Antibody formation to OCTA12

Safety: OCTA12 plasma levels

OCTA12 plasma levels during daily dosing (cohorts 1 to 3)

Safety: Change in hemoglobin

Hemoglobin compared to baseline

Safety: change in alanine aminotransferase (ALT)

Alanine aminotransferase (ALT) compared to baseline, measured in U/L

Safety: change in aspartate transaminase (AST)

Aspartate transaminase (AST) compared to baseline, measured in U/l

Safety: Vital signs

Vitals signs compared to baseline

Safety: Physical examination results

Physical examination results compared to baseline

Full Information

NCT ID

NCT04046848

First Posted

July 18, 2019

Last Updated

March 31, 2022

Sponsor

Octapharma

1. Study Identification

Unique Protocol Identification Number

NCT04046848

Brief Title

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

Official 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 Type

Interventional

2. Study Status

Record Verification Date

March 2022

Overall Recruitment Status

Terminated

Why Stopped

Study was terminated due to SADRs

Study Start Date

July 3, 2019 (Actual)

Primary Completion Date

February 18, 2022 (Actual)

Study Completion Date

February 18, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Octapharma

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

Arm Title

Cohort 3

Arm Type

Experimental

Arm Description

Arm Title

Cohort 5

Arm Type

Experimental

Arm Description

(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 Title

Cohort 6

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

OCTA101

Intervention Description

OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).

Primary Outcome Measure Information:

Title

Adverse Events

Time Frame

Approximately 4 months; up to 11 months for cohort 6

Title

Dose-limiting toxicities (DLTs)

Time Frame

Approximately 4 months; up to 11 months for cohort 6

Title

Thromboembolic events

Time Frame

Approximately 4 months; up to 11 months for cohort 6

Title

Local injection site reactions

Time Frame

Approximately 4 months; up to 11 months for cohort 6

Title

Inhibitor formation to FVIII

Time Frame

5 days to approximately 4 months; up to 11 months for cohort 6

Secondary Outcome Measure Information:

Title

Efficacy: Area under the concentration-time curve (AUC) of FVIII:C

Time Frame