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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

Primary Purpose

Hemophilia A With Inhibitors, Hemophilia B With Inhibitors

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
CSL689
Eptacog alfa (activated)
Sponsored by
CSL Behring
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia A With Inhibitors

Eligibility Criteria

12 Years - 65 Years (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

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).

Sites / Locations

  • Site Reference # 2680001
  • Site Reference # 3800023
  • Site Reference # 4580001
  • Site Reference # 6430026
  • Site Reference # 7100001
  • Site Reference # 7240007
  • Site Reference # 7640006
  • Site Reference # 7640004
  • Site Reference # 8040005
  • Site Reference # 8260008

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Active Comparator

Active Comparator

Arm Label

CSL689 low-dose

CSL689 high-dose

Eptacog alfa low-dose

Eptacog alfa high-dose

Arm Description

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

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

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

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

Outcomes

Primary Outcome Measures

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).
Incremental recovery
Incremental recovery of plasma factor VIIa activity (in Part 1 only)
Elimination half-life
Elimination half-life of plasma factor VIIa activity (in Part 1 only)
Total clearance
Total clearance of plasma factor VIIa activity (in Part 1 only)
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.
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
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

Secondary Outcome Measures

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.
Number of bleeding events requiring > 1 CSL689 injection
Outcome measure will be analyzed for Part 2 and for Part 3
Number of CSL689 injections per bleeding event
Outcome measure will be analyzed for Part 2 and for Part 3
Total dose of CSL689 per bleeding event
Outcome measure will be analyzed for Part 2 and for Part 3
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
Percentage of first bleeding events successfully treated with first CSL689 injection at population best dose in Part 3
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
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
Percentage of bleeding events with only "definite" or "abrupt" subject-reported pain relief at the population best dose
Percentage of bleeding events with "good" or "excellent" investigator-reported assessment of treatment response at the population best dose of CSL689
Proportion of recurrences
Recurrence defined as a bleeding in the same joint/anatomical location within 24 hours after an initial "good" or "excellent" response.
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
Proportion of bleeding events requiring post-hemostatic maintenance dosing
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
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
Number of subjects with an antibody response
Number of subjects with: Inhibitors against FVII Antibodies to CSL689
Percentage of subjects with an antibody response
Percentage of subjects with: Inhibitors against FVII Antibodies to CSL689
AUC(0-inf)
Area under plasma factor VIIa activity versus time curve from time 0 extrapolated to infinity
Maximum observed plasma FVIIa activity (Cmax)
Time of occurrence of maximum observed plasma FVIIa activity (Tmax)
Volume of distribution at steady state (Vss)
Mean residence time (MRT)

Full Information

First Posted
June 25, 2015
Last Updated
August 27, 2019
Sponsor
CSL Behring
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1. Study Identification

Unique Protocol Identification Number
NCT02484638
Brief Title
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

2. Study Status

Record Verification Date
August 2019
Overall Recruitment Status
Terminated
Why Stopped
Business decision non-safety related.
Study Start Date
July 23, 2015 (Actual)
Primary Completion Date
March 28, 2018 (Actual)
Study Completion Date
March 28, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
CSL Behring

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia A With Inhibitors, Hemophilia B With Inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CSL689 low-dose
Arm Type
Experimental
Arm Description
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
Arm Title
CSL689 high-dose
Arm Type
Experimental
Arm Description
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
Arm Title
Eptacog alfa low-dose
Arm Type
Active Comparator
Arm Description
Single injection of low-dose Eptacog alfa in Part 1 for PK evaluation
Arm Title
Eptacog alfa high-dose
Arm Type
Active Comparator
Arm Description
Single injection of high-dose Eptacog alfa in Part 1 for PK evaluation
Intervention Type
Drug
Intervention Name(s)
CSL689
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Eptacog alfa (activated)
Intervention Description
Recombinant activated coagulation factor VII. Two dose levels (low dose, high dose) will be studied in Part 1.
Primary Outcome Measure Information:
Title
Area under the curve (AUC0-t)
Description
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
Title
Incremental recovery
Description
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
Title
Elimination half-life
Description
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
Title
Total clearance
Description
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
Title
Treatment success with first CSL689 injection
Description
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
Title
Treatment success with first CSL689 injection at the population best dose
Description
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
Title
Treatment success with first or second CSL689 injection at the population best dose
Description
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 Outcome Measure Information:
Title
Treatment success with first or second CSL689 injection
Description
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
Title
Number of bleeding events requiring > 1 CSL689 injection
Description
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
Title
Number of CSL689 injections per bleeding event
Description
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
Title
Total dose of CSL689 per bleeding event
Description
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
Title
Treatment success with first CSL689 injection at the population best dose
Description
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
Title
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
Title
Treatment success at population best dose
Description
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
Title
Treatment success with CSL689 at the dose level that is not the population best dose
Description
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
Title
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
Title
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
Title
Proportion of recurrences
Description
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
Title
Proportion of bleeding events with ultrarapid progression.
Description
"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
Title
Proportion of bleeding events requiring post-hemostatic maintenance dosing
Time Frame
Up to 9 months
Title
Number of subjects with treatment-emergent adverse events (TEAEs)
Description
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
Title
Percentage of subjects with TEAEs
Description
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
Title
Number of subjects with an antibody response
Description
Number of subjects with: Inhibitors against FVII Antibodies to CSL689
Time Frame
Up to 16 months
Title
Percentage of subjects with an antibody response
Description
Percentage of subjects with: Inhibitors against FVII Antibodies to CSL689
Time Frame
Up to 16 months
Title
AUC(0-inf)
Description
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
Title
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
Title
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
Title
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
Title
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

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Physician
Organizational Affiliation
CSL Behring
Official's Role
Study Director
Facility Information:
Facility Name
Site Reference # 2680001
City
Tbilisi
ZIP/Postal Code
0179
Country
Georgia
Facility Name
Site Reference # 3800023
City
Milano
ZIP/Postal Code
20122
Country
Italy
Facility Name
Site Reference # 4580001
City
Kuala Lumpur
ZIP/Postal Code
50400
Country
Malaysia
Facility Name
Site Reference # 6430026
City
Kemerovo
ZIP/Postal Code
650061
Country
Russian Federation
Facility Name
Site Reference # 7100001
City
Johannesburg
ZIP/Postal Code
2193
Country
South Africa
Facility Name
Site Reference # 7240007
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Site Reference # 7640006
City
Bangkok
ZIP/Postal Code
10400
Country
Thailand
Facility Name
Site Reference # 7640004
City
Khon Kaen
ZIP/Postal Code
40002
Country
Thailand
Facility Name
Site Reference # 8040005
City
Lviv
ZIP/Postal Code
79044
Country
Ukraine
Facility Name
Site Reference # 8260008
City
London
ZIP/Postal Code
NW3 2 QG
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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