A Multicenter, Open-label, Multiple-dose, Dose Escalation Study to Investigate the Pharmacokinetics, Efficacy, and Safety of rVIIa-FP (CSL 689) in Subjects With Hemophilia (A or B) and Inhibitors
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- CSL Behring
- 入组人数
- 25
- 试验地点
- 10
- 主要终点
- Area under the curve (AUC0-t)
研究概览
简要总结
The purpose of this study is to investigate the pharmacokinetics (PK), efficacy, and safety of rVIIa-FP (CSL689). The study will enroll approximately 54 male subjects, 12 to 65 years of age, with hemophilia types A or B who have developed inhibitors to FVIII or FIX. The study consists of 3 sequential parts (Parts 1, 2, 3): The purpose of Part 1 (PK part) is to evaluate the PK of a single treatment of CSL689 (low dose or high dose) and compare with the PK of a single treatment of Eptacog alfa (low dose or high dose). In Part 1, CSL689 and Eptacog alfa will be given by the doctor at the study center. The purpose of Part 2 (Dose-evaluation part) is to identify which of the 2 tested dose levels of CSL689 shows the best efficacy and safety in stopping acute bleeding events (this dose will be called the "population best dose"). The purpose of the final Part 3 (Repeated-dose part) is to confirm the efficacy and safety of the "population best dose" identified in Part 2. In Parts 2 and 3, subjects will self-administer a specified number of CSL689 infusions at home on-demand (ie, when a bleeding event occurs), will keep an electronic diary, and will visit the center at monthly intervals. This study is expected to last for up to 16 months for the subjects participating in all 3 parts, and up to 9 months for the subjects participating in Part 3 only.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male subjects with hemophilia A or B and inhibitors.
- •Age ≥ 12 and ≤ 65 years.
- •High responding inhibitor with documented historical inhibitor titer > 5 Bethesda Units/mL.
排除标准
- •Congenital or acquired coagulation disorders other than hemophilia A or B.
- •Ongoing immune tolerance induction therapy or planned during study.
- •Known or suspected hypersensitivity to activated recombinant human FVII or to any excipient of CSL
- •Body mass index > 30 kg/m².
- •Major surgery within 28 days before screening or scheduled major and / or orthopedic surgery during the study.
- •Advanced atherosclerotic disease (ie, known history of ischemic heart disease, or ischemic stroke).
- •Any clinical signs or known history of thromboembolic events, including known deep vein thrombosis.
- •Human immunodeficiency virus (HIV)-positive subjects who have low cluster of differentiation 4 (CD4)+ lymphocyte count (200/μL or less) at screening.
- •Use of the following within the screening period or planned during study: a) plasma or coagulation factor concentrates other than rescue therapy or therapy during Part 1, b) other platelet inhibitors, c) desmopressin, and d) fibrinolysis inhibitors, except if used as local treatment (eg, for oral bleeds).
研究组 & 干预措施
CSL689 low-dose
- Part 1: single injection of low-dose CSL689 for PK evaluation
- Part 2: up to 2 injections of low-dose CSL689 per bleeding event (bleeding events 1 to 3*)
- Part 3: up to 3 injections of low-dose CSL689 per bleeding event * Note: All subjects in the low-dose arm will be treated with high-dose CSL689 for bleeding events 4-6 in Part 2
干预措施: CSL689 (Drug)
CSL689 high-dose
-
Part 1: single injection of high-dose CSL689 for PK evaluation
-
Part 2: up to 2 injections of high-dose CSL689 per bleeding event (bleeding events 4 to 6*)
-
Part 3: up to 3 injections of high-dose CSL689 per bleeding event
-
Note: All subjects in the high-dose arm will be treated with low-dose CSL689 for bleeding events 1-3 in Part 2
干预措施: CSL689 (Drug)
Eptacog alfa low-dose
Single injection of low-dose Eptacog alfa in Part 1 for PK evaluation
干预措施: Eptacog alfa (activated) (Drug)
Eptacog alfa high-dose
Single injection of high-dose Eptacog alfa in Part 1 for PK evaluation
干预措施: Eptacog alfa (activated) (Drug)
结局指标
主要结局
Area under the curve (AUC0-t)
时间窗: Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until up to 120 hours after injection for CSL689
Area under plasma factor VIIa activity versus time curve from time 0 to last sample with quantifiable activity (in Part 1 only).
Incremental recovery
时间窗: Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until up to 120 hours after injection for CSL689
Incremental recovery of plasma factor VIIa activity (in Part 1 only)
Elimination half-life
时间窗: Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until up to 120 hours after injection for CSL689
Elimination half-life of plasma factor VIIa activity (in Part 1 only)
Total clearance
时间窗: Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until up to 120 hours after injection for CSL689
Total clearance of plasma factor VIIa activity (in Part 1 only)
Treatment success with first CSL689 injection
时间窗: Up to 8 hours after first CSL689 injection for each bleeding event
Percentage of bleeding events successfully treated with the first injection of CSL689 for each bleeding event in Part 2.
Treatment success with first CSL689 injection at the population best dose
时间窗: Up to 8 hours after first CSL689 injection for each bleeding event
Percentage of bleeding events successfully treated with the first injection of the population best dose of CSL689 in subjects participating only in Part 3, along with its 95% confidence interval
Treatment success with first or second CSL689 injection at the population best dose
时间窗: Up to 16 hours after first CSL689 injection for each bleeding event
Percentage of bleeding events successfully treated with the first or second injection of the population best dose of CSL689 in subjects participating in Part 3 only, along with its 95% confidence interval
次要结局
- Treatment success with first or second CSL689 injection(Up to 16 hours after first CSL689 injection for each bleeding event)
- Number of bleeding events requiring > 1 CSL689 injection(Up to 8 hours after first CSL689 injection for each bleeding event)
- Percentage of first bleeding events successfully treated with first CSL689 injection at population best dose in Part 3(Up to 8 hours after first CSL689 injection for first bleeding event)
- Treatment success at population best dose(Up to 24 hours after first CSL689 injection for each bleeding event)
- Treatment success with CSL689 at the dose level that is not the population best dose(Up to 24 hours after first CSL689 injection for each bleeding event)
- Percentage of bleeding events with only "definite" or "abrupt" subject-reported pain relief at the population best dose(Up to 24 hours after CSL689 injection for each bleeding event)
- Percentage of bleeding events with "good" or "excellent" investigator-reported assessment of treatment response at the population best dose of CSL689(Up to 9 months)
- Proportion of recurrences(Up to 9 months)
- Number of CSL689 injections per bleeding event(Up to 16 hours (Part 2) or up to 24 hours (Part 3) after first CSL689 injection for each bleeding event)
- Total dose of CSL689 per bleeding event(Up to 16 hours (Part 2) or up to 24 hours (Part 3) after first CSL689 injection for each bleeding event)
- Treatment success with first CSL689 injection at the population best dose(Up to 8 hours after first CSL689 injection for each bleeding event)
- Mean residence time (MRT)(Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until up to 120 hours after injection for CSL689)
- Proportion of bleeding events with ultrarapid progression.(Up to 9 months)
- Proportion of bleeding events requiring post-hemostatic maintenance dosing(Up to 9 months)
- Number of subjects with treatment-emergent adverse events (TEAEs)(Up to 16 months)
- Percentage of subjects with TEAEs(Up to 16 months)
- Number of subjects with an antibody response(Up to 16 months)
- Percentage of subjects with an antibody response(Up to 16 months)
- AUC(0-inf)(Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until up to 120 hours after injection for CSL689)
- Maximum observed plasma FVIIa activity (Cmax)(Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until up to 120 hours after injection for CSL689)
- Time of occurrence of maximum observed plasma FVIIa activity (Tmax)(Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until up to 120 hours after injection for CSL689)
- Volume of distribution at steady state (Vss)(Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until up to 120 hours after injection for CSL689)