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

Phase 3

Completed

Conditions: Hemophilia A With Inhibitors
Hemophilia B With Inhibitors

Interventions: Biological: Coagulation Factor VIIa (Recombinant)

Registration Number: NCT02020369

Lead Sponsor: rEVO Biologics

Brief Summary: 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

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 27

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
FVIIa: 225 µg/kg first, then 75 µg/kg	Coagulation Factor VIIa (Recombinant)	Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), repeat cycle until study completion.
FVIIa: 75 µg/kg first, then 225 µg/kg	Coagulation Factor VIIa (Recombinant)	Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), repeat cycle until study completion.

Primary Outcome Measures

Name	Time	Method
Proportion of Successfully Treated Mild/Moderate Bleeding Episodes	12 hours after first administration of study drug	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

Secondary Outcome Measures

Name	Time	Method
Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode	Through study completion
Proportion of Mild/Moderate Bleeding Episodes With Patient (Pt)-Reported "Good" or "Excellent" Responses at 12 Hours	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.
Time to Assessment of a "Good" or "Excellent" Response of Mild/Moderate Bleeding Episodes by the Patient	Within 24 hours of Bleeding Episode	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.
Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode	Within 24 hours of Bleeding Episode

Trial Locations

Locations (17): Republican Research Center for Radiation Medicine and Human Ecology
🇧🇾
Gomel, Belarus
Institute of Hematology and Transfusion Medicine
🇵🇱
Warsaw, Poland
Basingstoke and North Hampshire Hospital, Hemophilia, Hemostasis and Thrombosis Center
🇬🇧
Basingstoke, United Kingdom
LTD HEMA
🇬🇪
Tbilisi, Georgia
Kyiv City Clinical Hospital #9
🇺🇦
Kyiv, Ukraine
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
Specialized Hospital for Active Treatment of Hematological Diseases
🇧🇬
Sofia, Bulgaria
Chaim Sheba Medical Center, Tel-hashomer hospital
🇮🇱
Ramat Gan, Israel
University of Colorado Hemophilia and Thrombosis Center
🇺🇸
Aurora, Colorado, United States
Orthopaedic Hemophilia Treatment Center
🇺🇸
Los Angeles, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
University of Minnesota Medical Center Fairview
🇺🇸
Minneapolis, Minnesota, United States
Kirov Research Institute of Hematology and Blood Transfusion
🇷🇺
Kirov, Russian Federation
City Outpatient Clinic #37
🇷🇺
Saint-Petersburg, Russian Federation
Institute of Blood Pathology and Transfusion Medicine of Academy of Medical Sciences of Ukraine
🇺🇦
Lviv, Ukraine
Sandor SRL
🇷🇴
Bucharest, Romania
Hematology Research Center
🇷🇺
Moscow, Russian Federation