Clinical trial NCT02484638: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Hemophilia A With Inhibitors
Hemophilia B With Inhibitors
Lead sponsor: CSL Behring
Sponsor class: INDUSTRY
First posted: 2015-06-29
Enrollment: 25
Sex: MALE
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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).

Primary outcomes:
measure: Area under the curve (AUC0-t)
timeFrame: 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
measure: Incremental recovery
timeFrame: 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
measure: Elimination half-life
timeFrame: 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
measure: Total clearance
timeFrame: 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
measure: Treatment success with first CSL689 injection
timeFrame: Up to 8 hours after first CSL689 injection for each bleeding event
measure: Treatment success with first CSL689 injection at the population best dose
timeFrame: Up to 8 hours after first CSL689 injection for each bleeding event
measure: Treatment success with first or second CSL689 injection at the population best dose
timeFrame: Up to 16 hours after first CSL689 injection for each bleeding event
Secondary outcomes:
measure: Treatment success with first or second CSL689 injection
timeFrame: Up to 16 hours after first CSL689 injection for each bleeding event
measure: Number of bleeding events requiring > 1 CSL689 injection
timeFrame: Up to 8 hours after first CSL689 injection for each bleeding event
measure: Number of CSL689 injections per bleeding event
timeFrame: Up to 16 hours (Part 2) or up to 24 hours (Part 3) after first CSL689 injection for each bleeding event
measure: Total dose of CSL689 per bleeding event
timeFrame: Up to 16 hours (Part 2) or up to 24 hours (Part 3) after first CSL689 injection for each bleeding event
measure: Treatment success with first CSL689 injection at the population best dose
timeFrame: Up to 8 hours after first CSL689 injection for each bleeding event
measure: Percentage of first bleeding events successfully treated with first CSL689 injection at population best dose in Part 3
timeFrame: Up to 8 hours after first CSL689 injection for first bleeding event
measure: Treatment success at population best dose
timeFrame: Up to 24 hours after first CSL689 injection for each bleeding event
measure: Treatment success with CSL689 at the dose level that is not the population best dose
timeFrame: Up to 24 hours after first CSL689 injection for each bleeding event
measure: Percentage of bleeding events with only "definite" or "abrupt" subject-reported pain relief at the population best dose
timeFrame: Up to 24 hours after CSL689 injection for each bleeding event
measure: Percentage of bleeding events with "good" or "excellent" investigator-reported assessment of treatment response at the population best dose of CSL689
timeFrame: Up to 9 months
measure: Proportion of recurrences
timeFrame: Up to 9 months
measure: Proportion of bleeding events with ultrarapid progression.
timeFrame: Up to 9 months
measure: Proportion of bleeding events requiring post-hemostatic maintenance dosing
timeFrame: Up to 9 months
measure: Number of subjects with treatment-emergent adverse events (TEAEs)
timeFrame: Up to 16 months
measure: Percentage of subjects with TEAEs
timeFrame: Up to 16 months
measure: Number of subjects with an antibody response
timeFrame: Up to 16 months
measure: Percentage of subjects with an antibody response
timeFrame: Up to 16 months
measure: AUC(0-inf)
timeFrame: 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
measure: Maximum observed plasma FVIIa activity (Cmax)
timeFrame: 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
measure: Time of occurrence of maximum observed plasma FVIIa activity (Tmax)
timeFrame: 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
measure: Volume of distribution at steady state (Vss)
timeFrame: 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
measure: Mean residence time (MRT)
timeFrame: 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
Other outcomes:
Locations:
city: Tbilisi
country: Georgia
facility: Site Reference # 2680001
city: Milano
country: Italy
facility: Site Reference # 3800023
city: Kuala Lumpur
country: Malaysia
facility: Site Reference # 4580001
city: Kemerovo
country: Russian Federation
facility: Site Reference # 6430026
city: Johannesburg
country: South Africa
facility: Site Reference # 7100001
city: Madrid
country: Spain
facility: Site Reference # 7240007
city: Bangkok
country: Thailand
facility: Site Reference # 7640006
city: Khon Kaen
country: Thailand
facility: Site Reference # 7640004
city: Lviv
country: Ukraine
facility: Site Reference # 8040005
city: London
country: United Kingdom
facility: Site Reference # 8260008
Study officials:
affiliation: CSL Behring
name: Study Physician
role: STUDY_DIRECTOR
References: