Study of Coagulation Factor VIIa Variant Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia A and B

• ClinicalTrials.gov Identifier: NCT03407651
• Recruitment Status: Completed
• First Posted: January 23, 2018
• Results First Posted: September 23, 2021
• Last Update Posted: September 23, 2021
• Sponsor: Catalyst Biosciences
• Information provided by (Responsible Party): Catalyst Biosciences

Study Description

Brief Summary:

Phase 2, multi-center, open-label study designed to evaluate the PK, bioavailability, PD, efficacy and safety of a daily subcutaneous [SC] treatment regimen with MarzAA for bleeding prophylaxis in 12 adult subjects with hemophilia A or B with an inhibitor and history of frequent spontaneous bleeding episodes.

Condition or disease	Intervention/treatment	Phase
Hemophilia A With Inhibitor; Hemophilia B With Inhibitor	Biological: Coagulation Factor VIIa variant	Phase 2

Detailed Description:

Multi-center, open-label Phase 2 study to evaluate the PK, bioavailability, PD, efficacy and safety of a daily SC treatment regimen with MarzAA for bleeding prophylaxis in adult subjects with hemophilia A or B with an inhibitor. The study will enroll and dose, both intravenously and subcutaneously, a total of 12 adult male subjects with severe congenital hemophilia A or B with an inhibitor, and history of frequent bleeding episodes during the 6 months prior to enrollment, as per the individual's bleeding and treatment records.

Once a subject is enrolled into the trial, the study will be conducted in three parts (occurring consecutively):

Part 1a (24 hours): Single IV administration of MarzAA; Part 1b (48 hours): Single SC administration of MarzAA; Part 2: Daily SC administration. Dose escalation in Part 2 will occur if breakthrough bleeding occurs. Subjects are treated for 50 days at the final dose level required.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 11 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study to Evaluate the Pharmacokinetics, Efficacy and Safety of a Daily Subcutaneous Treatment Regimen With Marzeptacog Alfa (Activated) for Bleeding Prophylaxis in Adult Subjects With Hemophilia A and B Subjects With an Inhibitor
• Actual Study Start Date: December 18, 2017
• Actual Primary Completion Date: March 15, 2019
• Actual Study Completion Date: April 13, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1a; Coagulation Factor VIIa variant, 18 µg/kg by intravenous route	Biological: Coagulation Factor VIIa variant; Single intravenous injection of MarzAA, followed by single subcutaneous injection of MarzAA, followed by daily subcutaneous injection of MarzAA for 50 days at final dose level required.
Experimental: Part 1b; Coagulation Factor VIIa variant, 30 µg/kg by subcutaneous route	Biological: Coagulation Factor VIIa variant; Single intravenous injection of MarzAA, followed by single subcutaneous injection of MarzAA, followed by daily subcutaneous injection of MarzAA for 50 days at final dose level required.
Experimental: Part 2; Coagulation Factor VIIa variant, 30, 60, 90, 120 µg/kg by subcutaneous route	Biological: Coagulation Factor VIIa variant; Single intravenous injection of MarzAA, followed by single subcutaneous injection of MarzAA, followed by daily subcutaneous injection of MarzAA for 50 days at final dose level required.

Outcome Measures

Primary Outcome Measures :

1. Bleeding Episode Prevention Success [ Time Frame: Day 1 of final MarzAA dose level - Day 50 ]
   Annualized bleed rate (ABR; spontaneous and total) during Part 2 when on final MarzAA dose level versus recorded historical ABR. The analysis of the primary endpoint (annualized bleeding rate ABR for spontaneous and traumatic bleeds) of the final dose of MarzAA each subject was treated was based on the 1-sample test compared to a predefined rate assumed for the on-demand therapy. The latter was assumed to be 12 (or 1 bleed per month), which was the minimum ABR for each subject according to inclusion criterion 2 (defined as the H0), with no maximum value. A higher score indicated a worse outcome. ABR is on a scale of 0 to 365, with a lower score reflective of a lower number of bleeding events in a year.

Secondary Outcome Measures :

1. Occurrence of Breakthrough Bleeding [ Time Frame: From Day 5 of dose level until occurrence of event ]
   Occurrence of breakthrough bleeds requiring escalation to higher dose level
2. Occurrence of Clinical Thrombotic Event [ Time Frame: From date of first dose until date of first occurrence of clinical event, assessed up to treatment Day 50 ]
   Occurrence of clinical thrombotic event not attributable to another cause
3. Coagulation Assessment - Prothrombin Time [ Time Frame: From date of pre-dose to 24 hours (Part 1a), pre-dose to 48 hours (Part 1b), and pre-dose to Day 50 (Part 2) ]
   Change in coagulation parameter (prothrombin time [PT]) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.
4. Coagulation Assessment - Activated Partial Thromboplastin Time [ Time Frame: From date of pre-dose to 24 hours (Part 1a), 48 hours (Part 1b), to Day 50/end of study (Part 2) ]
   Change in coagulation parameter (activated partial thromboplastin time [aPTT]) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.
5. Coagulation Assessment - Fibrinogen [ Time Frame: From date of pre-dose to 24 hours (Part 1a), 48 hours (Part 1b), or Day 50 (Part 2). ]
   Change in coagulation parameter (fibrinogen) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.
6. Number of Events of Antibody Formation [ Time Frame: From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to treatment Day 50 ]
   Occurrence of antibody formation resulting in a decreased endogenous level of coagulation Factor VII (FVII) or Factor VII activated (FVIIa)
7. Number of Events of an Antibody Response [ Time Frame: From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to treatment Day 50. ]
   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.
8. Thrombogenicity Assessment [ Time Frame: From time of pre-dose of MarzAA at Day 1 until date of first occurrence of thrombotic event, assessed up to treatment Day 50. ]
   Number of participants with clinically significant levels of thrombogenicity markers (D-dimer, Prothrombin fragment 1+2 (F1+2), and thrombin-antithrombin complex [TAT]), based on standard laboratory tests and clinical examination with a specific search for any signs of thrombosis

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Severe congenital hemophilia A or B with an inhibitor.
• History of frequent spontaneous bleeding episodes.
• Male, age 18 or older.
• Affirmation of informed consent with signature confirmation before any trial-related activities.

Exclusion Criteria:

• Receiving prophylaxis treatment.
• Previous participation in a clinical trial evaluating a modified rFVIIa agent.
• Known positive antibody to FVII or FVIIa detected by central laboratory at screening.
• Have a coagulation disorder other than hemophilia A or B.
• Significant contraindication to participation.

Contacts and Locations

Locations

Armenia

Hematology Center after Prof. R. Yeolyan

Yerevan, Armenia

Georgia

JSC "K.Eristavi National Center of Experimental and Clinical Surgery"

Tbilisi, Georgia

LTD M.Zodelava Hematology Centre

Tbilisi, Georgia

LTD Medinvest - Institute of Hematology and Transfusiology

Tbilisi, Georgia

Poland

Gabinet Lekarski, Bartosz Korczowski

Rzeszów, Poland

Russian Federation

Regional Clinical Hospital

Kemerovo, Russian Federation

FGU Kirov Scientific Research

Kirov, Russian Federation

Center for Hemophilia Treatment

Saint Petersburg, Russian Federation

South Africa

Haemophilia Comprehensive Care Centre

Johannesburg, South Africa

Sponsors and Collaborators

Catalyst Biosciences

Investigators

• Study Director: Howard Levy, MD, PhD, MMM; Catalyst Biosciences

  Study Documents (Full-Text)

Documents provided by Catalyst Biosciences:

Study Protocol  [PDF] August 25, 2018

Statistical Analysis Plan  [PDF] November 5, 2018

More Information

• Responsible Party: Catalyst Biosciences
• ClinicalTrials.gov Identifier: NCT03407651
• Other Study ID Numbers: MAA-201
• First Posted: January 23, 2018
• Results First Posted: September 23, 2021
• Last Update Posted: September 23, 2021
• Last Verified: June 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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