Phase 1/2 Study to Assess the Safety and Pharmacokinetics of Subcutaneous Injection of OCTA101 in Previously Treated Adult Patients With Severe Hemophilia A
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Octapharma
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Patients Experiencing Adverse Events
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: OCTA101 (Drug)
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.
干预措施: OCTA101 (Drug)
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.
干预措施: OCTA101 (Drug)
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.
干预措施: OCTA101 (Drug)
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.
干预措施: OCTA101 (Drug)
结局指标
主要结局
Patients Experiencing Adverse Events
时间窗: Approximately 4 months; up to 11 months for cohort 6
Participants Experiencing Dose-limiting Toxicities (DLTs)
时间窗: Approximately 4 months; up to 11 months for cohort 6
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
Patients Experiencing Thromboembolic Events
时间窗: Approximately 4 months; up to 11 months for cohort 6
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)
Patients Experiencing Local Injection Site Reactions of Any Grade
时间窗: 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).
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).
Inhibitor Formation to FVIII
时间窗: 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)
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.
次要结局
- 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))
- Efficacy: Mean Residence Time (MRT) of FVIII:C(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)(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)(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)(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)(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)(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)(From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2))
- Efficacy: Total 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 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(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(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(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(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(3 months; maximally 6 months for cohort 6)
- Efficacy: Efficacy of Treatment of Bleeding Episodes Using Score (4-point).(5 days to approximately 11 months)
- Safety: Antibody Formation to OCTA12(From 0 hours (pre-dose) to 72 hours (cohorts 1,2,3,5) or 96 hours (cohort 2).)
- Safety: OCTA12 Plasma Levels(3 months; maximally 6 months for cohort 6)
- Safety: Change in Hemoglobin(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)(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)(5 days to approximately 11 months)
- Patients With Changes to Vital Signs(5 days to approximately 11 months)
- Patients With Changes in Physical Examination Results(5 days to approximately 11 months)