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

• ClinicalTrials.gov Identifier: NCT02020369
• Recruitment Status: Completed
• First Posted: December 24, 2013
• Results First Posted: June 14, 2017
• Last Update Posted: June 14, 2017
• Sponsor: rEVO Biologics
• Collaborator: Laboratoire français de Fractionnement et de Biotechnologies
• Information provided by (Responsible Party): rEVO Biologics

Tracking Information

• First Submitted Date: December 18, 2013
• First Posted Date: December 24, 2013
• Results First Submitted Date: July 12, 2016
• Results First Posted Date: June 14, 2017
• Last Update Posted Date: June 14, 2017
• Study Start Date: April 2014
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 15, 2017)

Proportion of Successfully Treated Mild/Moderate Bleeding Episodes [ Time Frame: 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

Original Primary Outcome Measures (submitted: December 18, 2013)

Bleeding episode treatment success [ Time Frame: 12 hours after first administration of study drug ]

No additional hemostatic product required after12 hours of first dose.

Current Secondary Outcome Measures (submitted: May 15, 2017)

• Proportion of Mild/Moderate Bleeding Episodes With Patient (Pt)-Reported "Good" or "Excellent" Responses at 12 Hours [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Within 24 hours of Bleeding Episode ]
• Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode [ Time Frame: Through study completion ]

Original Secondary Outcome Measures (submitted: December 18, 2013)

Time to bleeding success [ Time Frame: at 12 hours ]

Patients shall rate the treatment of each bleeding episode. If treatment occurs under direct supervision of treating physician, then physician shall rate the response. Ratings based on a four point scale:Excellent, Good, Moderate, None

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: December 18, 2013)

• Immunogenicity assessment [ Time Frame: Pre-dose, 6 week, 12 weeks, 24 weeks then every 12 weeks and end of study visit ]
  Based on Coagulation Factor VIIa (Recombinant), binding antibody levels
• Pharmacokinetic assessment [ Time Frame: 7 timepoints from pre-dosing on Day 1 up to 8 hours ]
  Based on plasma concentrations of Coagulation Factor VIIa (Recombinant)

Descriptive Information

• Brief Title: Phase III Study of Coagulation FVIIa (Recombinant) in Congenital Hemophilia A or B Patients With Inhibitors
• Official Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Hemophilia A With Inhibitors
• Hemophilia B With Inhibitors

Intervention

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

Study Arms

• 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.
  Intervention: Biological: Coagulation Factor VIIa (Recombinant)
• 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.
  Intervention: Biological: Coagulation Factor VIIa (Recombinant)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 3, 2015): 27
• Original Estimated Enrollment (submitted: December 18, 2013): 25
• Actual Study Completion Date: August 2015
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 12 Years to 75 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belarus, Bulgaria, Georgia, Israel, Poland, Romania, Russian Federation, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT02020369
• Other Study ID Numbers: RB-FVIIa-006-13
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: rEVO Biologics
• Study Sponsor: rEVO Biologics
• Collaborators: Laboratoire français de Fractionnement et de Biotechnologies

Investigators

• Principal Investigator: Jean Francois Schved, MD; Saint Eloi Hospital

• PRS Account: rEVO Biologics
• Verification Date: May 2017