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

NCT02484638 | Terminated Phase 2 DMC

• 2 other identifiers: CSL689_20012012-001309-26
• Study Type: interventional
• Target: 25
• Locations: 9 countries
• Sites: 10

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.

Conditions

Hemophilia A With Inhibitors; Hemophilia B With Inhibitors

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (22)

• 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

• 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

Study Arms (4)

CSL689 low-dose

EXPERIMENTAL

* 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

CSL689 high-dose

EXPERIMENTAL

* 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

Eptacog alfa low-dose

ACTIVE COMPARATOR

Single injection of low-dose Eptacog alfa in Part 1 for PK evaluation

Drug: Eptacog alfa (activated)

Eptacog alfa high-dose

ACTIVE COMPARATOR

Single injection of high-dose Eptacog alfa in Part 1 for PK evaluation

Drug: Eptacog alfa (activated)

Interventions

CSL689 DRUG

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.

CSL689 high-dose; CSL689 low-dose

Eptacog alfa (activated) DRUG

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

Eptacog alfa high-dose; Eptacog alfa low-dose

Eligibility Criteria

• Age: 12 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• CSL Behring: lead

Study Sites (10)

Site Reference # 2680001

Tbilisi, 0179, Georgia

Location

Site Reference # 3800023

Milan, 20122, Italy

Location

Site Reference # 4580001

Kuala Lumpur, 50400, Malaysia

Location

Site Reference # 6430026

Kemerovo, 650061, Russia

Location

Site Reference # 7100001

Johannesburg, 2193, South Africa

Location

Site Reference # 7240007

Madrid, 28046, Spain

Location

Site Reference # 7640006

Bangkok, 10400, Thailand

Location

Site Reference # 7640004

Khon Kaen, 40002, Thailand

Location

Site Reference # 8040005

Lviv, 79044, Ukraine

Location

Site Reference # 8260008

London, NW3 2 QG, United Kingdom

Location

MeSH Terms

Interventions

Factor VII

Intervention Hierarchy (Ancestors)

Enzyme Precursors; Enzymes and Coenzymes; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Study Officials

• Study Physician

  CSL Behring

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2015
• First Posted: June 29, 2015
• Study Start: July 23, 2015
• Primary Completion: March 28, 2018
• Study Completion: March 28, 2018
• Last Updated: August 28, 2019

Record last verified: 2019-08

Locations

MY (1); IT (1); RU (1); ZA (1); ES (1); GE (1); TH (2); UA (1); GB (1)