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

Hemophilia A With Inhibitors Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02484638
• Other study ID #: CSL689_2001
• Secondary ID: 2012-001309-26
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: July 23, 2015
• Est. completion date: March 28, 2018

Study information

• Verified date: August 2019
• Source: CSL Behring
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 25
• Est. completion date: March 28, 2018
• Est. primary completion date: March 28, 2018
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 12 Years to 65 Years

Eligibility

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).

Related Conditions & MeSH terms

• Hemophilia A
• Hemophilia A With Inhibitors
• Hemophilia B
• Hemophilia B With Inhibitors

Intervention

Drug:
• CSL689
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)
Recombinant activated coagulation factor VII. Two dose levels (low dose, high dose) will be studied in Part 1.

Locations

Country	Name	City	State
Georgia	Site Reference # 2680001	Tbilisi
Italy	Site Reference # 3800023	Milano
Malaysia	Site Reference # 4580001	Kuala Lumpur
Russian Federation	Site Reference # 6430026	Kemerovo
South Africa	Site Reference # 7100001	Johannesburg
Spain	Site Reference # 7240007	Madrid
Thailand	Site Reference # 7640006	Bangkok
Thailand	Site Reference # 7640004	Khon Kaen
Ukraine	Site Reference # 8040005	Lviv
United Kingdom	Site Reference # 8260008	London

Sponsors (1)

Lead Sponsor	Collaborator
CSL Behring

Countries where clinical trial is conducted

Georgia,  Italy,  Malaysia,  Russian Federation,  South Africa,  Spain,  Thailand,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Proportion of bleeding events requiring post-hemostatic maintenance dosing		Up to 9 months
Secondary	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
Secondary	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
Secondary	Number of subjects with an antibody response	Number of subjects with: Inhibitors against FVII; Antibodies to CSL689	Up to 16 months
Secondary	Percentage of subjects with an antibody response	Percentage of subjects with: Inhibitors against FVII; Antibodies to CSL689	Up to 16 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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