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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

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ClinicalTrials.gov Identifier: NCT02484638
Recruitment Status : Terminated (Business decision non-safety related.)
First Posted : June 29, 2015
Last Update Posted : October 30, 2018
Sponsor:
Information provided by (Responsible Party):
CSL Behring

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.

Condition or disease Intervention/treatment Phase
Hemophilia A With Inhibitors Hemophilia B With Inhibitors Drug: CSL689 Drug: Eptacog alfa (activated) Phase 2 Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 23, 2015
Actual Primary Completion Date : March 28, 2018
Actual Study Completion Date : March 28, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

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 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
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.




Primary Outcome Measures :
  1. Area under the curve (AUC0-t) [ 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 ]
    Area under plasma factor VIIa activity versus time curve from time 0 to last sample with quantifiable activity (in Part 1 only).

  2. Incremental recovery [ 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 ]
    Incremental recovery of plasma factor VIIa activity (in Part 1 only)

  3. Elimination half-life [ 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 ]
    Elimination half-life of plasma factor VIIa activity (in Part 1 only)

  4. Total clearance [ 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 ]
    Total clearance of plasma factor VIIa activity (in Part 1 only)

  5. Treatment success with first CSL689 injection [ Time Frame: Up to 8 hours after first CSL689 injection for each bleeding event ]
    Percentage of bleeding events successfully treated with the first injection of CSL689 for each bleeding event in Part 2.

  6. Treatment success with first CSL689 injection at the population best dose [ Time Frame: Up to 8 hours after first CSL689 injection for each bleeding event ]
    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

  7. Treatment success with first or second CSL689 injection at the population best dose [ Time Frame: Up to 16 hours after first CSL689 injection for each bleeding event ]
    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 :
  1. Treatment success with first or second CSL689 injection [ Time Frame: Up to 16 hours after first CSL689 injection for each bleeding event ]
    Percentage of bleeding events successfully treated with the first or second (if required) injection of CSL689 for each bleeding event in Part 2.

  2. Number of bleeding events requiring > 1 CSL689 injection [ Time Frame: Up to 8 hours after first CSL689 injection for each bleeding event ]
    Outcome measure will be analyzed for Part 2 and for Part 3

  3. Number of CSL689 injections per bleeding event [ Time Frame: Up to 16 hours (Part 2) or up to 24 hours (Part 3) after first CSL689 injection for each bleeding event ]
    Outcome measure will be analyzed for Part 2 and for Part 3

  4. Total dose of CSL689 per bleeding event [ Time Frame: Up to 16 hours (Part 2) or up to 24 hours (Part 3) after first CSL689 injection for each bleeding event ]
    Outcome measure will be analyzed for Part 2 and for Part 3

  5. Treatment success with first CSL689 injection at the population best dose [ Time Frame: Up to 8 hours after first CSL689 injection for each bleeding event ]
    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

  6. 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 ]
  7. Treatment success at population best dose [ Time Frame: Up to 24 hours after first CSL689 injection for each bleeding event ]

    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

  8. Treatment success with CSL689 at the dose level that is not the population best dose [ Time Frame: Up to 24 hours after first CSL689 injection for each bleeding event ]

    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

  9. 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 ]
  10. 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 ]
  11. Proportion of recurrences [ Time Frame: Up to 9 months ]
    Recurrence defined as a bleeding in the same joint/anatomical location within 24 hours after an initial "good" or "excellent" response.

  12. Proportion of bleeding events with ultrarapid progression. [ Time Frame: Up to 9 months ]
    "Ultrarapid progression" is defined as overt, uncontrolled hemorrhage and / or progressive increase in pain and / or rapid progression in hematoma size

  13. Proportion of bleeding events requiring post-hemostatic maintenance dosing [ Time Frame: Up to 9 months ]
  14. Number of subjects with treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 16 months ]

    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

  15. Percentage of subjects with TEAEs [ Time Frame: Up to 16 months ]

    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

  16. Number of subjects with an antibody response [ Time Frame: Up to 16 months ]

    Number of subjects with:

    • Inhibitors against FVII
    • Antibodies to CSL689

  17. Percentage of subjects with an antibody response [ Time Frame: Up to 16 months ]

    Percentage of subjects with:

    • Inhibitors against FVII
    • Antibodies to CSL689

  18. AUC(0-inf) [ 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 ]
    Area under plasma factor VIIa activity versus time curve from time 0 extrapolated to infinity

  19. 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 ]
  20. 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 ]
  21. 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 ]
  22. 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 ]


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Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02484638


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

Responsible Party: CSL Behring
ClinicalTrials.gov Identifier: NCT02484638     History of Changes
Other Study ID Numbers: CSL689_2001
2012-001309-26 ( EudraCT Number )
First Posted: June 29, 2015    Key Record Dates
Last Update Posted: October 30, 2018
Last Verified: October 2018

Additional relevant MeSH terms:
Hemophilia A
Hemophilia B
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked