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

Primary Purpose

Hemophilia A, Hemophilia B, Hemophilia A With Inhibitor

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
MarzAA (marzeptacog alfa [activated])
Sponsored by
Catalyst Biosciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Hemophilia A

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • Medical Center "Hippocrates - N"
  • Specialized Hospital for Active Treatment of Hematological Diseases
  • Kirov Research Institute of Hematology and Blood Transfusion
  • National Medical Hematology Research Center
  • Municipal Policlinic # 37, City Center for Hemophilia Treatment

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Study Population

Arm Description

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)

Outcomes

Primary Outcome Measures

Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last
Comparative pharmacokinetics (PK) by dose level/stage based on examination of AUC frequencies of these for each of the dose groups
Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose
Comparative pharmacokinetics by dose level/stage based on examination of AUC frequency of these for each of the dose groups

Secondary Outcome Measures

Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax
Change in Cmax at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax
Change in Tmax at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα
Change in T1/2eqα at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z
Change in T1/2λ-z at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - CL
Change in CL at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1
Change in Vd1 at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs
Change in BAabs at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time
Change in Mean Residence Time at each stage for each dose group
Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC From T1 to T2 Norm by Dose
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)
Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc
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)
Change in Coagulation Parameters - Prothrombin Time (PT)
Maximum change in PT from pre-dose
Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT)
Maximum change in aPTT from pre-dose
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak
Maximum change in TGT parameter from pre-dose
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak
Maximum change in TGT parameters from pre-dose
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential
Maximum change in TGT parameter from pre-dose
Change in Thrombogenicity Parameter - Fibrinogen
Maximum change in thrombogenicity parameter from pre-dose
Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2
Maximum change in thrombogenicity parameter from pre-dose
Change in Thrombogenicity Parameter - Thrombin/Antithrombin
Maximum change in thrombogenicity parameter from pre-dose
Change in Thrombogenicity Parameter - D-Dimer
Maximum change in thrombogenicity parameter from pre-dose
Occurrence of an Antibody Response to MarzAA
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
Occurrence of Clinical Thrombotic Event
Occurrence of clinical thrombotic event not attributable to another cause

Full Information

First Posted
August 22, 2019
Last Updated
September 9, 2021
Sponsor
Catalyst Biosciences
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1. Study Identification

Unique Protocol Identification Number
NCT04072237
Brief Title
Study of Coagulation Faction VIIa Variant Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
September 24, 2019 (Actual)
Primary Completion Date
April 30, 2020 (Actual)
Study Completion Date
June 17, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Catalyst Biosciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia A, Hemophilia B, Hemophilia A With Inhibitor, Hemophilia B With Inhibitor, Hemophilia A Without Inhibitor, Hemophilia B Without Inhibitor

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Study Population
Arm Type
Experimental
Arm Description
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)
Intervention Type
Biological
Intervention Name(s)
MarzAA (marzeptacog alfa [activated])
Intervention Description
Single intravenous dose and ascending doses of subcutaneous injection of MarzAA (Coagulation Faction VIIa Variant)
Primary Outcome Measure Information:
Title
Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last
Description
Comparative pharmacokinetics (PK) by dose level/stage based on examination of AUC frequencies of these for each of the dose groups
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.
Title
Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose
Description
Comparative pharmacokinetics by dose level/stage based on examination of AUC frequency of these for each of the dose groups
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.
Secondary Outcome Measure Information:
Title
Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax
Description
Change in Cmax at each stage for each dose group
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.
Title
Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax
Description
Change in Tmax at each stage for each dose group
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.
Title
Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα
Description
Change in T1/2eqα at each stage for each dose group
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.
Title
Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z
Description
Change in T1/2λ-z at each stage for each dose group
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.
Title
Comparative MarzAA Activity of Intravenous and Subcutaneous - CL
Description
Change in CL at each stage for each dose group
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.
Title
Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1
Description
Change in Vd1 at each stage for each dose group
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.
Title
Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs
Description
Change in BAabs at each stage for each dose group
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.
Title
Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time
Description
Change in Mean Residence Time at each stage for each dose group
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.
Title
Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC From T1 to T2 Norm by Dose
Description
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)
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.
Title
Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc
Description
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)
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.
Title
Change in Coagulation Parameters - Prothrombin Time (PT)
Description
Maximum change in PT from pre-dose
Time Frame
From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-7 (SC).
Title
Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT)
Description
Maximum change in aPTT from pre-dose
Time Frame
From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
Title
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak
Description
Maximum change in TGT parameter from pre-dose
Time Frame
From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
Title
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak
Description
Maximum change in TGT parameters from pre-dose
Time Frame
From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
Title
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential
Description
Maximum change in TGT parameter from pre-dose
Time Frame
From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
Title
Change in Thrombogenicity Parameter - Fibrinogen
Description
Maximum change in thrombogenicity parameter from pre-dose
Time Frame
From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
Title
Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2
Description
Maximum change in thrombogenicity parameter from pre-dose
Time Frame
From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
Title
Change in Thrombogenicity Parameter - Thrombin/Antithrombin
Description
Maximum change in thrombogenicity parameter from pre-dose
Time Frame
From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
Title
Change in Thrombogenicity Parameter - D-Dimer
Description
Maximum change in thrombogenicity parameter from pre-dose
Time Frame
From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
Title
Occurrence of an Antibody Response to MarzAA
Description
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
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.
Title
Occurrence of Clinical Thrombotic Event
Description
Occurrence of clinical thrombotic event not attributable to another cause
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.

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Howard Levy, MD, PhD, MMM
Organizational Affiliation
Sponsor GmbH
Official's Role
Study Director
Facility Information:
Facility Name
Medical Center "Hippocrates - N"
City
Plovdiv
Country
Bulgaria
Facility Name
Specialized Hospital for Active Treatment of Hematological Diseases
City
Sofia
Country
Bulgaria
Facility Name
Kirov Research Institute of Hematology and Blood Transfusion
City
Kirov
Country
Russian Federation
Facility Name
National Medical Hematology Research Center
City
Moscow
Country
Russian Federation
Facility Name
Municipal Policlinic # 37, City Center for Hemophilia Treatment
City
Saint Petersburg
Country
Russian Federation

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing 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.

Learn more about this trial

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

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