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

Phase 3TerminatedNCT02484638

CSL Behring25 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Hemophilia A With Inhibitors

Interventions

CSL689DRUG

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.

Eptacog alfa (activated)DRUG

Recombinant activated coagulation factor VII. Two dose levels (low dose, high dose) will be studied in Part 1.

Eligibility

Sex: MALEMin age: 12 YearsMax age: 65 Years

Medical Language ↔ Plain English

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).

Locations (10)

Site Reference # 2680001

Tbilisi, Georgia

Site Reference # 3800023

Milan, Italy

Site Reference # 4580001

Kuala Lumpur, Malaysia

Site Reference # 6430026

Kemerovo, Russia

Site Reference # 7100001

Johannesburg, South Africa

Site Reference # 7240007

Madrid, Spain

Site Reference # 7640006

Bangkok, Thailand

Site Reference # 7640004

Khon Kaen, Thailand

Site Reference # 8040005

Lviv, Ukraine

Site Reference # 8260008

London, United Kingdom

Outcomes

Primary Outcomes

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).

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: Up to 16 hours after first CSL689 injection for each bleeding event

Secondary Outcomes

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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Up to 24 hours after first CSL689 injection for each bleeding event

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: Up to 9 months

Proportion of bleeding events requiring post-hemostatic maintenance dosing

Time frame: 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

Time frame: 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

Time frame: Up to 16 months

Number of subjects with an antibody response

Number of subjects with: * Inhibitors against FVII * Antibodies to CSL689

Time frame: Up to 16 months

Percentage of subjects with an antibody response

Percentage of subjects with: * Inhibitors against FVII * Antibodies to CSL689

Time frame: Up to 16 months

AUC(0-inf)

Area under plasma factor VIIa activity versus time curve from time 0 extrapolated to infinity

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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