Clinical trial NCT04046848: 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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
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
Lead sponsor: Octapharma
Sponsor class: INDUSTRY
First posted: 2019-08-06
Enrollment: 36
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

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:

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 titre ≥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

Primary outcomes:
measure: Patients Experiencing Adverse Events
timeFrame: Approximately 4 months; up to 11 months for cohort 6
measure: Participants Experiencing Dose-limiting Toxicities (DLTs)
timeFrame: Approximately 4 months; up to 11 months for cohort 6
measure: Patients Experiencing Thromboembolic Events
timeFrame: Approximately 4 months; up to 11 months for cohort 6
measure: Patients Experiencing Local Injection Site Reactions of Any Grade
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).
measure: Inhibitor Formation to FVIII
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)
Secondary outcomes:
measure: Efficacy: Area Under the Concentration-time Curve (AUC) of FVIII:C
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Maximum Plasma Concentration (Cmax) of FVIII:C
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of FVIII:C
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: In Vivo Recovery (IVR) of FVIII:C
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Half-life (t1/2) of FVIII:C
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Mean Residence Time (MRT) of FVIII:C
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Area Under the Concentration-time Curve (AUC(0-tz)) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Maximum Plasma Concentration (Cmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: In Vivo Recovery (IVR) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Half Life (t1/2) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Mean Residence Time (MRT) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
measure: Efficacy: Total Annualized Bleeding Rate
timeFrame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93).
measure: Efficacy: Spontaneous Annualized Bleeding Rate
timeFrame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
measure: Efficacy: Total Annualized Treated Bleeding Rate
timeFrame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
measure: Efficacy: Spontaneous Annualized Treated Bleeding Rate
timeFrame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
measure: Efficacy: Traumatic Annualized Bleeding Rate
timeFrame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
measure: Efficacy: Joint Annualized Bleeding Rate
timeFrame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
measure: Efficacy: FVIII:C Trough and Peak Plasma Levels
timeFrame: 3 months; maximally 6 months for cohort 6
measure: Efficacy: Efficacy of Treatment of Bleeding Episodes Using Score (4-point).
timeFrame: 5 days to approximately 11 months
measure: Safety: Antibody Formation to OCTA12
timeFrame: From 0 hours (pre-dose) to 72 hours (cohorts 1,2,3,5) or 96 hours (cohort 2).
measure: Safety: OCTA12 Plasma Levels
timeFrame: 3 months; maximally 6 months for cohort 6
measure: Safety: Change in Hemoglobin
timeFrame: 5 days to approximately 11 months. All routine lab parameters and vital signs were measured at various times, until end of PK and also monthly during daily prophylaxis.)
measure: Safety: Change in Alanine Aminotransferase (ALT)
timeFrame: 5 days to approximately 11 months. All routine lab parameters and vital signs were measured at various times, until end of PK and also monthly during daily prophylaxis.)
measure: Safety: Change in Aspartate Transaminase (AST)
timeFrame: 5 days to approximately 11 months
measure: Patients With Changes to Vital Signs
timeFrame: 5 days to approximately 11 months
measure: Patients With Changes in Physical Examination Results
timeFrame: 5 days to approximately 11 months
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Treatment of Hematological Diseases EAD Clinic of Clinical Hematology
Study officials:
References:
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