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

Phase 1/2 Study to Assess the Safety and Pharmacokinetics of Subcutaneous Injection of OCTA101 in Previously Treated Adult Patients With Severe Hemophilia A

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.

Study Overview

• Status: Terminated
• Conditions: Severe Hemophilia A
• Intervention / Treatment: Drug: OCTA101

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria
    • Specialized Hospital for Active Treatment of Hematological Diseases EAD Clinic of Clinical Hematology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: OCTA101; OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).
Experimental: 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.	Drug: OCTA101; OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).
Experimental: 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 4 and 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months.	Drug: OCTA101; OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).
Experimental: 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.	Drug: OCTA101; OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).
Experimental: Cohort 6; (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; OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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; mild (subject is aware of the signs/symptoms, but finds it easily tolerated); moderate (discomfort enough to cause interference with usual activities); 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: Area Under the Concentration-time Curve (AUC) of FVIII:C	Mean AUC of FVIII after PK injection of OCTA101 as measured by chromogenic assay.	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	Maximum observed concentration of FVIII:C after PK injection of OCTA101 as measured by chromogenic assay.	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	Time of occurrence of Cmax after PK injection of OCTA101 as measured by chromogenic assay.	From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
In Vivo Recovery (IVR) of FVIII:C	In vivo recovery (IVR) = dose-normalised and body weight-normalised maximum gain in FVIII:C (IU/dL per IU/kg)	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	Apparent terminal log-linear half-life of FVIII:C after PK injection of OCTA101 as measured by chromogenic assay.	From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Efficacy: Mean Residence Time (MRT) of FVIII:C	The average time at which the number of absorbed FVIII molecules reside in the body, after PK injection of OCTA101 as measured by chromogenic assay.	From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Efficacy: Area Under the Concentration-time Curve (AUC(0-tz)) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)	Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: OCTA12 was not determined for cohort 6 regarding PK assessment.	From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Efficacy: Maximum Plasma Concentration (Cmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)	Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: OCTA12 was not determined for cohort 6 regarding PK assessment.	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 OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)	Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: OCTA12 was not determined for cohort 6 regarding PK assessment.	From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Efficacy: In Vivo Recovery (IVR) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)	In vivo recovery (IVR) = dose-normalised and body weight-normalised maximum gain in OCTA-12 (ug/dL per ug/kg).	From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Efficacy: Half Life (t1/2) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)	Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: t(1/2) could not be determined for OTCA12 as the OCTA12 concentrations had not yet declined during the observation time prior to prior to end of sampling period.	From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Efficacy: Mean Residence Time (MRT) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)	Note: MRT could not be determined for OCTA12 as the OCTA12 concentrations had not yet declined during the observation time prior to end of sampling period.	From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Efficacy: Total Annualized Bleeding Rate	Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate for cohort 6.	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).
Efficacy: Spontaneous Annualized Bleeding Rate	Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total spontaneous annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate	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)
Efficacy: Total Annualized Treated Bleeding Rate	Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total annualized treated bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate.	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)
Efficacy: Spontaneous Annualized Treated Bleeding Rate	Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3. An estimated total spontaneous annualized treated bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate.	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)
Efficacy: Traumatic Annualized Bleeding Rate	Traumatic annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total traumatic annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate.	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)
Efficacy: Joint Annualized Bleeding Rate	Joint annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3. An estimated total joint annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate.	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)
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; maximally 6 months for cohort 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'.	5 days to approximately 11 months
Safety: Antibody Formation to OCTA12	Samples were checked for the presence of antibodies to OCTA12 by using a validated ELISA in a central lab.	From 0 hours (pre-dose) to 72 hours (cohorts 1,2,3,5) or 96 hours (cohort 2).
Safety: OCTA12 Plasma Levels	OCTA12 plasma levels during daily dosing (cohorts 1, 2, 3 and 6).	3 months; maximally 6 months for cohort 6
Safety: Change in Hemoglobin	Number of Participants with changes in hemoglobin levels that were considered as Adverse Events.	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.)
Safety: Change in Alanine Aminotransferase (ALT)	Alanine aminotransferase (ALT) compared to baseline, measured in U/L. Number of Participants with changes in ALT that were considered as Adverse Events.	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.)
Safety: Change in Aspartate Transaminase (AST)	Aspartate transaminase (AST) compared to baseline, measured in U/l. Number of Participants with changes in AST that were considered as Adverse Events.	5 days to approximately 11 months
Patients With Changes to Vital Signs	Vitals signs changes from baseline, reported as AEs. Number of Participants with changes to vital signs that were considered as Adverse Events.	5 days to approximately 11 months
Patients With Changes in Physical Examination Results	Number of Participants with changes to their physical examination results from baseline that were considered as Adverse Events	5 days to approximately 11 months

Collaborators and Investigators

• Sponsor: Octapharma

Publications and helpful links

General Publications

• 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(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.
• 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.
• Wagner JG (1975) Fundamentals of clinical pharmacokinetics. Drug Intelligence Publications, Inc. Hamilton, IL, USA
• 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. Erratum In: Blood. 2017 Jul 13;130(2):232. doi: 10.1182/blood-2017-05-787507.

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2019
• Primary Completion (Actual): February 18, 2022
• Study Completion (Actual): February 18, 2022

Study Registration Dates

• First Submitted: July 18, 2019
• First Submitted That Met QC Criteria: August 2, 2019
• First Posted (Actual): August 6, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 20, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Hematologic Diseases; Genetic Diseases, Inborn; Blood Coagulation Disorders; Factor VIII; Hemorrhagic Disorders; Hemophilia A; Coagulation Protein Disorders; Blood Coagulation Disorders, Inherited
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemophilia A
• Other Study ID Numbers: SubQ8-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No