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

NCT04046848 | Terminated Phase 1 Results DMC

• 1 other identifier: SubQ8-01
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (5)

• Patients Experiencing Adverse Events

  Approximately 4 months; up to 11 months for cohort 6

• Participants Experiencing Dose-limiting Toxicities (DLTs)

  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

  Approximately 4 months; up to 11 months for cohort 6

• Patients Experiencing Thromboembolic Events

  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)

  Approximately 4 months; up to 11 months for cohort 6

• Patients Experiencing Local Injection Site Reactions of Any Grade

  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).

  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).

• Inhibitor Formation to FVIII

  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.

  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 (27)

• Efficacy: Area Under the Concentration-time Curve (AUC) of FVIII:C

  From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)

• Efficacy: Maximum Plasma Concentration (Cmax) of FVIII:C

  From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)

• Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of FVIII:C

  From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)

• In Vivo Recovery (IVR) of FVIII:C

  From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)

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

  From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)

Study Arms (5)

Cohort 1

EXPERIMENTAL

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.

Drug: OCTA101

Cohort 2

EXPERIMENTAL

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.

Drug: OCTA101

Cohort 3

EXPERIMENTAL

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.

Drug: OCTA101

Cohort 5

EXPERIMENTAL

(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.

Drug: OCTA101

Cohort 6

EXPERIMENTAL

(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.

Drug: OCTA101

Interventions

OCTA101 DRUG

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

Cohort 1; Cohort 2; Cohort 3; Cohort 5; Cohort 6

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Male patients only
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Octapharma: lead

Study Sites (1)

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

Sofia, Bulgaria

Location

Related Publications (5)

• Cannavo 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.

  PMID: 28034891 BACKGROUND

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

  BACKGROUND

• 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(R) (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.

  PMID: 28815880 BACKGROUND

• 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. doi: 10.1023/a:1026451721686.

  PMID: 11145235 BACKGROUND

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

  BACKGROUND

MeSH Terms

Conditions

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Sigurd Knaub, Senior VP CR&D Haematology
• Organization: Octapharma

Sigurd.Knaub@octapharma.com

01554512141

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 18, 2019
• First Posted: August 6, 2019
• Study Start: July 3, 2019
• Primary Completion: February 18, 2022
• Study Completion: February 18, 2022
• Last Updated: February 13, 2025
• Results First Posted: February 13, 2025

Record last verified: 2025-01

Locations

BU (1)