Phase III Study of Coagulation FVIIa (Recombinant) in Congenital Hemophilia A or B Patients With Inhibitors

A Phase III Study on the Safety, Pharmacokinetics and Efficacy of Coagulation Factor VIIa (Recombinant) in Congenital Hemophilia A or B Patients With Inhibitors to Factor VIII or IX

The purpose of the study is to assess the safety, efficacy and pharmacokinetics of 2 separate dose regimens (75µg/kg and 225 µg/kg) of Coagulation Factor VIIa (Recombinant) for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII/IX

Study Overview

• Status: Completed
• Conditions: Hemophilia A With Inhibitors; Hemophilia B With Inhibitors
• Intervention / Treatment: Biological: Coagulation Factor VIIa (Recombinant)

Detailed Description

This was a global, multicenter, Phase III, prospective, open-label, randomized, crossover study. After obtaining informed consent and performance of screening procedures, patients who met all inclusion and exclusion criteria were randomized to one of two treatment regimens as follows:

• 75 µg/kg treatment regimen
• 225 µg/kg treatment regimen

For each treatment regimen there were two phases:

• Phase A (Initial phase)
• Phase B (Treatment phase)

The assigned treatment regimen was the dose administered in Phase A and was the starting dose in Phase B.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belarus
  • Gomel, Belarus
    • Republican Research Center for Radiation Medicine and Human Ecology
• Bulgaria
  • Sofia, Bulgaria
    • Specialized Hospital for Active Treatment of Hematological Diseases
• Georgia
  • Tbilisi, Georgia
    • LTD HEMA
• Israel
  • Ramat Gan, Israel, 5261
    • Chaim Sheba Medical Center, Tel-hashomer hospital
• Poland
  • Warsaw, Poland
    • Institute of Hematology and Transfusion Medicine
• Romania
  • Bucharest, Romania
    • Sandor SRL
• Russian Federation
  • Kirov, Russian Federation
    • Kirov Research Institute of Hematology and Blood Transfusion
  • Moscow, Russian Federation
    • Hematology Research Center
  • Saint-Petersburg, Russian Federation
    • City Outpatient Clinic #37
• Ukraine
  • Kyiv, Ukraine
    • Kyiv City Clinical Hospital #9
  • Lviv, Ukraine
    • Institute of Blood Pathology and Transfusion Medicine of Academy of Medical Sciences of Ukraine
• United Kingdom
  • Basingstoke, United Kingdom
    • Basingstoke and North Hampshire Hospital, Hemophilia, Hemostasis and Thrombosis Center
• United States
  • California
    • Los Angeles, California, United States, 90007
      • Orthopaedic Hemophilia Treatment Center
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hemophilia and Thrombosis Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center Fairview

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 75 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• be male with a diagnosis of congenital hemophilia A and/or B of any severity
• have one of the following:
• a positive inhibitor test Bethesda Unit (BU) ≥ 5 (as confirmed at screening by the institutional lab), OR
• a BU<5 but expected to have a high anamnestic response to FVIII or FIX, as demonstrated from the subject's medical history, precluding the use of Factor VIII or IX products to treat bleedings, OR
• a BU<5 but expected to be refractory to increased dosing of FVIII or FIX, as demonstrated from the subject's medical history, precluding the use of Factor VIII or IX products to treat bleedings
• be 12 years or older, up to and including 75 years of age (NOTE: different age restrictions may apply per local regulation and/or ethical considerations)
• have at least 3 bleeding episodes of any severity in the past 6 months be capable of understanding and willing to comply with the conditions of the protocol
• have read, understood and provided written informed consent (patient and/or parent(s)/legal guardian(s) if <18 years of age)

Exclusion Criteria:

• have any coagulation disorder other than hemophilia A or B
• be immuno-suppressed (i.e., the patient should not be receiving systemic immunosuppressive medication, cluster of differentiation 4 (CD4) counts at screening should be >200/µl)
• have a known allergy or hypersensitivity to rabbits
• have platelet count <100,000/mL
• have had within one month prior to first administration of the study drug in this study a major surgical procedure (e.g. orthopedic, abdominal)
• have received an investigational drug within 30 days of the first study drug administration, or is expected to receive such drug during participation in this study
• have a clinically relevant hepatic (AST and/or alanine aminotransferase (ALT) >3 times the upper limit of normal) and/or renal impairment (creatinine >2 times the upper limit of normal)
• have a history of arterial and/or venous thromboembolic events (such as myocardial infarction, ischemic strokes, transient ischemic attacks, deep venous thrombosis or pulmonary embolism) within 2 years prior to first dose of study drug, or current New York Heart Association (NYHA) functional classification score of stage II -IV
• have an active malignancy (those with non-melanoma skin cancer are allowed)
• have any life-threatening disease or other disease or condition which, according to the investigator's judgment, could imply a potential hazard to the patient, interfere with the trial participation or trial outcome (e.g., a history of non-responsiveness to bypassing products).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: FVIIa: 75 µg/kg first, then 225 µg/kg; Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), repeat cycle until study completion.	Biological: Coagulation Factor VIIa (Recombinant); A cross over design to assess the efficacy of 2 separate dose regimens (75µg/kg and 225 µg/kg) of Coagulation Factor VIIa (Recombinant) for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII/IX
EXPERIMENTAL: FVIIa: 225 µg/kg first, then 75 µg/kg; Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), repeat cycle until study completion.	Biological: Coagulation Factor VIIa (Recombinant); A cross over design to assess the efficacy of 2 separate dose regimens (75µg/kg and 225 µg/kg) of Coagulation Factor VIIa (Recombinant) for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII/IX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Successfully Treated Mild/Moderate Bleeding Episodes	For the primary efficacy endpoint, successful treatment of a bleeding episode was defined as a combination of the following: "Good" or "Excellent" response noted by the patient; Study drug treatment: No further treatment with study drug beyond timepoint for this bleeding episode; No other hemostatic treatment needed for this bleeding episode; No administration of blood products that would indicate continuation of bleeding beyond timepoint; No increase of pain beyond timepoint that could not otherwise be explained	12 hours after first administration of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Mild/Moderate Bleeding Episodes With Patient (Pt)-Reported "Good" or "Excellent" Responses at 12 Hours	Based on Patient-Reported "Good" or "Excellent" responses as per the below descriptions: Good: Symptoms of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage) had largely been reduced by the treatment, but had not completely disappeared. Symptoms had improved enough to not require more infusions of the study drug. Excellent: Full relief of pain and cessation of objective signs of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage). No additional infusion of study drug was required.	at 12 hours
Time to Assessment of a "Good" or "Excellent" Response of Mild/Moderate Bleeding Episodes by the Patient	Categories of Response to Treatment are Described as Follows: None: No noticeable effect of the treatment on the bleed or worsening of patient's condition. Continuation of treatment with the study drug was needed. Moderate: Some effect of the treatment on the bleed was noticed, e.g., pain decreased or bleeding signs improved, but bleed continued and required continued treatment with the study drug. Good: Symptoms of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage) had largely been reduced by the treatment, but had not completely disappeared. Symptoms had improved enough to not require more infusions of the study drug. Excellent: Full relief of pain and cessation of objective signs of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage). No additional infusion of study drug was required.	Within 24 hours of Bleeding Episode
Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode		Within 24 hours of Bleeding Episode
Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode		Through study completion

Collaborators and Investigators

• Sponsor: rEVO Biologics
• Collaborators: Laboratoire français de Fractionnement et de Biotechnologies
• Investigators: Principal Investigator: Jean Francois Schved, MD, Saint Eloi Hospital

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (ACTUAL): July 1, 2015
• Study Completion (ACTUAL): August 1, 2015

Study Registration Dates

• First Submitted: December 18, 2013
• First Submitted That Met QC Criteria: December 18, 2013
• First Posted (ESTIMATE): December 24, 2013

Study Record Updates

• Last Update Posted (ACTUAL): June 14, 2017
• Last Update Submitted That Met QC Criteria: May 15, 2017
• Last Verified: May 1, 2017

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: RB-FVIIa-006-13

Plan for Individual participant data (IPD)

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