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

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

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia A With Inhibitor; Hemophilia B With Inhibitor
• Intervention / Treatment: Biological: Coagulation Factor VIIa variant

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 Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• Armenia
  • Yerevan, Armenia
    • Hematology Center after Prof. R. Yeolyan
• Georgia
  • Tbilisi, 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
• Poland
  • Rzeszów, Poland
    • Gabinet Lekarski, Bartosz Korczowski
• Russian Federation
  • Kemerovo, Russian Federation
    • Regional Clinical Hospital
  • Kirov, Russian Federation
    • FGU Kirov Scientific Research
  • Saint Petersburg, Russian Federation
    • Center for Hemophilia Treatment
• South Africa
  • Johannesburg, South Africa
    • Haemophilia Comprehensive Care Centre

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bleeding Episode Prevention Success	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.	Day 1 of final MarzAA dose level - Day 50

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Breakthrough Bleeding	Occurrence of breakthrough bleeds requiring escalation to higher dose level	From Day 5 of dose level until occurrence of event
Occurrence of Clinical Thrombotic Event	Occurrence of clinical thrombotic event not attributable to another cause	From date of first dose until date of first occurrence of clinical event, assessed up to treatment Day 50
Coagulation Assessment - Prothrombin Time	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.	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)
Coagulation Assessment - Activated Partial Thromboplastin Time	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.	From date of pre-dose to 24 hours (Part 1a), 48 hours (Part 1b), to Day 50/end of study (Part 2)
Coagulation Assessment - Fibrinogen	Change in coagulation parameter (fibrinogen) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.	From date of pre-dose to 24 hours (Part 1a), 48 hours (Part 1b), or Day 50 (Part 2).
Number of Events of Antibody Formation	Occurrence of antibody formation resulting in a decreased endogenous level of coagulation Factor VII (FVII) or Factor VII activated (FVIIa)	From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to treatment Day 50
Number of Events of an Antibody Response	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.	From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to treatment Day 50.
Thrombogenicity Assessment	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	From time of pre-dose of MarzAA at Day 1 until date of first occurrence of thrombotic event, assessed up to treatment Day 50.

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2017
• Primary Completion (Actual): March 15, 2019
• Study Completion (Actual): April 13, 2019

Study Registration Dates

• First Submitted: January 4, 2018
• First Submitted That Met QC Criteria: January 16, 2018
• First Posted (Actual): January 23, 2018

Study Record Updates

• Last Update Posted (Actual): September 23, 2021
• Last Update Submitted That Met QC Criteria: September 21, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: MAA-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No