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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hemophilia A With Inhibitors, Hemophilia B With Inhibitors

Intervention / Treatment
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* Biological: Coagulation Factor VIIa (Recombinant)


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FVIIa: 75 µg/kg first, then 225 µg/kg<br>Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), repeat cycle until study completion. | Biological: Coagulation Factor VIIa (Recombinant)<br>* 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<br>|
| Experimental: FVIIa: 225 µg/kg first, then 75 µg/kg<br>Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), repeat cycle until study completion. | Biological: Coagulation Factor VIIa (Recombinant)<br>* 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<br>|

What is the study measuring?
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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 |