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Study of Coagulation Faction VIIa Variant Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04072237
Recruitment Status : Completed
First Posted : August 28, 2019
Results First Posted : July 16, 2021
Last Update Posted : September 13, 2021
Sponsor:
Information provided by (Responsible Party):
Catalyst Biosciences

Brief Summary:
This multi-center, open label Phase 1 study will evaluate the pharmacokinetics, pharmacodynamics, and safety of a single IV dose of MarzAA followed by ascending single SC doses of MarzAA in adult subjects with moderate or severe Hemophilia A or B, with or without an inhibitor.

Condition or disease Intervention/treatment Phase
Hemophilia A Hemophilia B Hemophilia A With Inhibitor Hemophilia B With Inhibitor Hemophilia A Without Inhibitor Hemophilia B Without Inhibitor Biological: MarzAA (marzeptacog alfa [activated]) Phase 1

Detailed Description:
This multi-center, open label Phase 1 study will evaluate the pharmacokinetics, pharmacodynamics, and safety of a single IV dose of MarzAA followed by ascending single SC doses of MarzAA in adult subjects with moderate or severe Hemophilia A or B, with or without an inhibitor. The study will enroll at least 8 adult male subjects with moderate or severe Hemophilia A or B with or without an inhibitor, in each dosing stage. Each subject will receive escalating doses of MarzAA for each stage of the study (except for Stage 5, where subjects receive the same dose as in Stage 4 split between two anatomical sites).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Phase 1 Study to Evaluate the Pharmacokinetics, Pharmacodynamics, and Safety of Ascending Doses of Subcutaneous Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia
Actual Study Start Date : September 24, 2019
Actual Primary Completion Date : April 30, 2020
Actual Study Completion Date : June 17, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Study Population
MarzAA (Coagulation Factor VIIa variant) 18 µg/kg intravenously (Stage 1) followed by MarzAA 30 µg/kg subcutaneously (SC) (Stage 2), MarzAA 45 µg/kg SC (Stage 3), MarzAA 60 µg/kg SC (Stage 4), MarzAA 2x30 µg/kg SC (Stage 5), MarzAA 90 µg/kg SC (Stage 6), MarzAA 120 µg/kg SC (Stage 7), MarzAA 2×60 µg/kg SC (Stage 8), MarzAA 3x60 µg/kg SC (Stage 9)
Biological: MarzAA (marzeptacog alfa [activated])
Single intravenous dose and ascending doses of subcutaneous injection of MarzAA (Coagulation Faction VIIa Variant)




Primary Outcome Measures :
  1. Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Comparative pharmacokinetics (PK) by dose level/stage based on examination of AUC frequencies of these for each of the dose groups

  2. Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Comparative pharmacokinetics by dose level/stage based on examination of AUC frequency of these for each of the dose groups


Secondary Outcome Measures :
  1. Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Change in Cmax at each stage for each dose group

  2. Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Change in Tmax at each stage for each dose group

  3. Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Change in T1/2eqα at each stage for each dose group

  4. Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Change in T1/2λ-z at each stage for each dose group

  5. Comparative MarzAA Activity of Intravenous and Subcutaneous - CL [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Change in CL at each stage for each dose group

  6. Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Change in Vd1 at each stage for each dose group

  7. Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Change in BAabs at each stage for each dose group

  8. Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]
    Change in Mean Residence Time at each stage for each dose group

  9. Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC From T1 to T2 Norm by Dose [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]

    PK analysis by route of administration, dose level/stage of the study based on examination of AUC for each of the dose groups.

    Split dose (2*30 µg/kg) vs. (60 µg/kg)


  10. Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc [ Time Frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. ]

    PK analysis by route of administration, dose level/stage of the study based on examination of AUC for each of the dose groups.

    Split dose (2*30 µg/kg) vs. (60 µg/kg)


  11. Change in Coagulation Parameters - Prothrombin Time (PT) [ Time Frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-7 (SC). ]
    Maximum change in PT from pre-dose

  12. Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) [ Time Frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). ]
    Maximum change in aPTT from pre-dose

  13. Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak [ Time Frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). ]
    Maximum change in TGT parameter from pre-dose

  14. Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak [ Time Frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). ]
    Maximum change in TGT parameters from pre-dose

  15. Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential [ Time Frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). ]
    Maximum change in TGT parameter from pre-dose

  16. Change in Thrombogenicity Parameter - Fibrinogen [ Time Frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). ]
    Maximum change in thrombogenicity parameter from pre-dose

  17. Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 [ Time Frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). ]
    Maximum change in thrombogenicity parameter from pre-dose

  18. Change in Thrombogenicity Parameter - Thrombin/Antithrombin [ Time Frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). ]
    Maximum change in thrombogenicity parameter from pre-dose

  19. Change in Thrombogenicity Parameter - D-Dimer [ Time Frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). ]
    Maximum change in thrombogenicity parameter from pre-dose

  20. Occurrence of an Antibody Response to MarzAA [ Time Frame: From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to End of Study. Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing. ]
    Occurrence of an antibody response to MarzAA and whether it is inhibitory and cross-reactive to wild-type recombinant coagulation FVII (wt-rFVII) or wt-FVIIa

  21. Occurrence of Clinical Thrombotic Event [ Time Frame: From the date of first dose of MarzAA until date of first occurrence of clinical event, assessed up to End of Study. Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing. ]
    Occurrence of clinical thrombotic event not attributable to another cause



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Moderate or severe congenital Hemophilia A or B, with or without an inhibitor
  • Male, age 18 or older
  • Affirmation of informed consent with signature confirmation before any trial related activities

Exclusion Criteria:

  • Inability to discontinue and washout prophylaxis treatment 72 hours prior to dosing.
  • Previous participation in a trial involving SC Administration of rFVIIa or any trial using a modified amino-acid sequence FVIIa
  • Known positive antibody to FVII or FVIIa detected by central laboratory at screening
  • Have a coagulation disorder other than hemophilia A or B, with or without an inhibitor
  • Significant contraindication to participate

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): NCT04072237


Locations
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Bulgaria
Medical Center "Hippocrates - N"
Plovdiv, Bulgaria
Specialized Hospital for Active Treatment of Hematological Diseases
Sofia, Bulgaria
Russian Federation
Kirov Research Institute of Hematology and Blood Transfusion
Kirov, Russian Federation
National Medical Hematology Research Center
Moscow, Russian Federation
Municipal Policlinic # 37, City Center for Hemophilia Treatment
Saint Petersburg, Russian Federation
Sponsors and Collaborators
Catalyst Biosciences
Investigators
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Study Director: Howard Levy, MD, PhD, MMM Sponsor GmbH
  Study Documents (Full-Text)

Documents provided by Catalyst Biosciences:
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Responsible Party: Catalyst Biosciences
ClinicalTrials.gov Identifier: NCT04072237    
Other Study ID Numbers: MAA-102
First Posted: August 28, 2019    Key Record Dates
Results First Posted: July 16, 2021
Last Update Posted: September 13, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: This is an open label study so each investigator will have full access to all study subject data that is entered into the database.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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