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

Severe Hemophilia A Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04046848
• Other study ID #: SubQ8-01
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: July 3, 2019
• Est. completion date: February 18, 2022

Study information

• Verified date: March 2022
• Source: Octapharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 30
• Est. completion date: February 18, 2022
• Est. primary completion date: February 18, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hemophilia A
• Severe Hemophilia A

Intervention

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

Locations

Country	Name	City	State
Bulgaria	Specialized Hospital for Active Treatment of Hematological Diseases EAD Clinic of Clinical Hematology	Sofia

Sponsors (1)

Lead Sponsor	Collaborator
Octapharma

Country where clinical trial is conducted

Bulgaria, 

References & Publications (5)

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. doi: 10.1182/blood-2016-06-720086. Epub 2016 Dec 29. Erratum in: Blood. 2017 Jul 13;130(2):232. — View Citation

Gibaldi M. (1991) Biopharmaceutics and Clinical Pharmacokinetics. 4th Edition, Lea and Febiger, Philadelphia, Appendix II.

Liesner RJ, Abashidze M, Aleinikova O, Altisent C, Belletrutti MJ, Borel-Derlon A, Carcao M, Chambost H, Chan AKC, Dubey L, Ducore J, Fouzia NA, Gattens M, Gruel Y, Guillet B, Kavardakova N, El Khorassani M, Klukowska A, Lambert T, Lohade S, Sigaud M, Turea V, Wu JKM, Vdovin V, Pavlova A, Jansen M, Belyanskaya L, Walter O, Knaub S, Neufeld EJ. 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. doi: 10.1111/hae.13320. Epub 2017 Aug 16. — View Citation

Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 2000 Oct;17(10):1278-83. — View Citation

Wagner JG (1975) Fundamentals of clinical pharmacokinetics. Drug Intelligence Publications, Inc. Hamilton, IL, USA

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse Events		Approximately 4 months; up to 11 months for cohort 6
Primary	Dose-limiting toxicities (DLTs)		Approximately 4 months; up to 11 months for cohort 6
Primary	Thromboembolic events		Approximately 4 months; up to 11 months for cohort 6
Primary	Local injection site reactions		Approximately 4 months; up to 11 months for cohort 6
Primary	Inhibitor formation to FVIII		5 days to approximately 4 months; up to 11 months for cohort 6
Secondary	Efficacy: Area under the concentration-time curve (AUC) of FVIII:C		Up to 120 hours after injection
Secondary	Efficacy: Maximum plasma concentration (Cmax) of FVIII:C		Up to 120 hours after injection
Secondary	Efficacy: Time for reaching maximum plasma concentration (Tmax) of FVIII:C		Up to 120 hours after injection
Secondary	Efficacy: In vivo recovery (IVR) of FVIII:C		Up to 120 hours after injection
Secondary	Efficacy: Half-life (t1/2) of FVIII:C		Up to 120 hours after injection
Secondary	Efficacy: Mean residence time (MRT) of FVIII:C		Up to 120 hours after injection
Secondary	Efficacy: Area under the concentration-time curve (AUC) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)		Up to 120 hours after injection
Secondary	Efficacy: Maximum plasma concentration (Cmax) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)		Up to 120 hours after injection
Secondary	Efficacy: Time for reaching maximum plasma concentration (Tmax) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)		Up to 120 hours after injection
Secondary	Efficacy: In vivo recovery (IVR) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)		Up to 120 hours after injection
Secondary	Efficacy: Half life (t1/2) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)		Up to 120 hours after injection
Secondary	Efficacy: Mean residence time (MRT) of OCTA12 (a recombinant von Willebrand Factor fragment dimer)		Up to 120 hours after injection
Secondary	Efficacy: Total annualized bleeding rate	Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6	3 months; approximately 11 months for cohort 6
Secondary	Efficacy: Spontaneous annualized bleeding rate	Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6	3 months; approximately 11 months for cohort 6
Secondary	Efficacy: Total annualized treated bleeding rate	Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6	3 months; approximately 11 months for cohort 6
Secondary	Efficacy: Spontaneous annualized treated bleeding rate	Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6	3 months; approximately 11 months for cohort 6
Secondary	Efficacy: Traumatic annualized bleeding rate	Traumatic annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6	3 months; approximately 11 months for cohort 6
Secondary	Efficacy: Joint annualized bleeding rate	Joint annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6	3 months; approximately 11 months for cohort 6
Secondary	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	3 months; approximately 11 months for cohort 6
Secondary	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'.	5 days to approximately 11 months
Secondary	Safety: Antibody formation to OCTA12		5 days to approximately 11 months
Secondary	Safety: OCTA12 plasma levels	OCTA12 plasma levels during daily dosing (cohorts 1 to 3)	3 months
Secondary	Safety: Change in hemoglobin	Hemoglobin compared to baseline	5 days to approximately 11 months
Secondary	Safety: change in alanine aminotransferase (ALT)	Alanine aminotransferase (ALT) compared to baseline, measured in U/L	5 days to approximately 11 months
Secondary	Safety: change in aspartate transaminase (AST)	Aspartate transaminase (AST) compared to baseline, measured in U/l	5 days to approximately 11 months
Secondary	Safety: Vital signs	Vitals signs compared to baseline	5 days to approximately 11 months
Secondary	Safety: Physical examination results	Physical examination results compared to baseline	5 days to approximately 11 months