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

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

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 Overview

• Status: Terminated
• Conditions: Hemophilia A With Inhibitors; Hemophilia B With Inhibitors
• Intervention / Treatment: Drug: CSL689; Drug: Eptacog alfa (activated)

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Georgia
  • Tbilisi, Georgia, 0179
    • Site Reference # 2680001
• Italy
  • Milano, Italy, 20122
    • Site Reference # 3800023
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • Site Reference # 4580001
• Russian Federation
  • Kemerovo, Russian Federation, 650061
    • Site Reference # 6430026
• South Africa
  • Johannesburg, South Africa, 2193
    • Site Reference # 7100001
• Spain
  • Madrid, Spain, 28046
    • Site Reference # 7240007
• Thailand
  • Bangkok, Thailand, 10400
    • Site Reference # 7640006
  • Khon Kaen, Thailand, 40002
    • Site Reference # 7640004
• Ukraine
  • Lviv, Ukraine, 79044
    • Site Reference # 8040005
• United Kingdom
  • London, United Kingdom, NW3 2 QG
    • Site Reference # 8260008

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 63 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CSL689 low-dose; 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; 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.
Experimental: CSL689 high-dose; 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 eventNote: All subjects in the high-dose arm will be treated with low-dose CSL689 for bleeding events 1-3 in Part 2	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.
Active Comparator: Eptacog alfa low-dose; Single injection of low-dose Eptacog alfa in Part 1 for PK evaluation	Drug: Eptacog alfa (activated); Recombinant activated coagulation factor VII. Two dose levels (low dose, high dose) will be studied in Part 1.
Active Comparator: Eptacog alfa high-dose; Single injection of high-dose Eptacog alfa in Part 1 for PK evaluation	Drug: Eptacog alfa (activated); Recombinant activated coagulation factor VII. Two dose levels (low dose, high dose) will be studied in Part 1.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: CSL Behring
• Investigators: Study Director: Study Physician, CSL Behring

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2015
• Primary Completion (Actual): March 28, 2018
• Study Completion (Actual): March 28, 2018

Study Registration Dates

• First Submitted: June 25, 2015
• First Submitted That Met QC Criteria: June 26, 2015
• First Posted (Estimate): June 29, 2015

Study Record Updates

• Last Update Posted (Actual): August 28, 2019
• Last Update Submitted That Met QC Criteria: August 27, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: CSL689_2001; 2012-001309-26 (EudraCT Number)