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.
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
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
11
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.
Hematology Center after Prof. R. Yeolyan
Yerevan, Armenia
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
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.
Time frame: Day 1 of final MarzAA dose level - Day 50
Occurrence of Breakthrough Bleeding
Occurrence of breakthrough bleeds requiring escalation to higher dose level
Time frame: 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
Time frame: 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.
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)
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.
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Tbilisi, Georgia
Gabinet Lekarski, Bartosz Korczowski
Rzeszów, Poland
Regional Clinical Hospital
Kemerovo, Russia
FGU Kirov Scientific Research
Kirov, Russia
Center for Hemophilia Treatment
Saint Petersburg, Russia
Haemophilia Comprehensive Care Centre
Johannesburg, South Africa
Time frame: 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.
Time frame: 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)
Time frame: 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.
Time frame: 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
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.