Study of Recombinant Factor VIIa Fusion Protein (rVIIa-FP, CSL689) for On-demand Treatment of Bleeding Episodes in Patients With Hemophilia A or B With Inhibitors

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hemophilia A With Inhibitors, Hemophilia B With Inhibitors

Intervention / Treatment
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* Drug: CSL689
* Drug: Eptacog alfa (activated)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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 CSL689. 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).

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSL689 low-dose<br>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 | Drug: CSL689<br>* Recombinant fusion protein, linking activated coagulation factor VII with albumin. Two dose levels (low dose, high dose) will be studied in Parts 1, 2, and 3.<br>|
| Experimental: CSL689 high-dose<br>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 | Drug: CSL689<br>* Recombinant fusion protein, linking activated coagulation factor VII with albumin. Two dose levels (low dose, high dose) will be studied in Parts 1, 2, and 3.<br>|
| Active Comparator: Eptacog alfa low-dose<br>Single injection of low-dose Eptacog alfa in Part 1 for PK evaluation | Drug: Eptacog alfa (activated)<br>* Recombinant activated coagulation factor VII. Two dose levels (low dose, high dose) will be studied in Part 1.<br>|
| Active Comparator: Eptacog alfa high-dose<br>Single injection of high-dose Eptacog alfa in Part 1 for PK evaluation | Drug: Eptacog alfa (activated)<br>* Recombinant activated coagulation factor VII. Two dose levels (low dose, high dose) will be studied in Part 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC0-t) | Area under plasma factor VIIa activity versus time curve from time 0 to last sample with quantifiable activity (in Part 1 only). | 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 | Incremental recovery of plasma factor VIIa activity (in Part 1 only) | 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 | Elimination half-life of plasma factor VIIa activity (in Part 1 only) | 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 | Total clearance of plasma factor VIIa activity (in Part 1 only) | 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 | 
| Treatment success with first CSL689 injection | Percentage of bleeding events successfully treated with the first injection of CSL689 for each bleeding event in Part 2. | Up to 8 hours after first CSL689 injection for each bleeding event | 
| Treatment success with first CSL689 injection at the population best dose | 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 | Up to 8 hours after first CSL689 injection for each bleeding event | 
| Treatment success with first or second CSL689 injection at the population best dose | 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 | Up to 16 hours after first CSL689 injection for each bleeding event | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment success with first or second CSL689 injection | Percentage of bleeding events successfully treated with the first or second (if required) injection of CSL689 for each bleeding event in Part 2. | Up to 16 hours after first CSL689 injection for each bleeding event | 
| Number of bleeding events requiring > 1 CSL689 injection | Outcome measure will be analyzed for Part 2 and for Part 3 | Up to 8 hours after first CSL689 injection for each bleeding event | 
| Number of CSL689 injections per bleeding event | Outcome measure will be analyzed for Part 2 and for Part 3 | 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 | Outcome measure will be analyzed for Part 2 and for Part 3 | 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 | Percentage of bleeding events successfully treated with the first injection of CSL689 for each bleeding event at the population best dose in subjects participating in Part 3 | 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 | Percentage of bleeding events successfully treated with the: first or second injection first, second or third injection of the population best dose of CSL689 in Part 3 | 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 | Percentage of bleeding events successfully treated with the: first injection first or second injection first, second or third injection at the dose level that is not the population best dose of CSL689 in Part 3 | 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 | Recurrence defined as a bleeding in the same joint/anatomical location within 24 hours after an initial good or excellent response. | Up to 9 months | 
| Proportion of bleeding events with ultrarapid progression. | Ultrarapid progression is defined as overt, uncontrolled hemorrhage and / or progressive increase in pain and / or rapid progression in hematoma size | 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) | TEAEs are adverse events (AEs) that start on or after the date and time of the first injection of either CSL689 or Eptacog alfa. Number of subjects with TEAEs will be presented: Overall Related to CSL689 | Up to 16 months | 
| Percentage of subjects with TEAEs | TEAEs are AEs that start on or after the date and time of the first injection of either CSL689 or Eptacog alfa. Percentage of subjects with TEAEs will be presented: Overall Related to CSL689 | Up to 16 months | 
| Number of subjects with an antibody response | Number of subjects with: Inhibitors against FVII Antibodies to CSL689 | Up to 16 months | 
| Percentage of subjects with an antibody response | Percentage of subjects with: Inhibitors against FVII Antibodies to CSL689 | Up to 16 months | 
| AUC(0-inf) | Area under plasma factor VIIa activity versus time curve from time 0 extrapolated to infinity | 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 | 
| 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 |