Hemophilia Adult Prophylaxis Study: Factor VIII in Severe Hemophilia A

Phase 3

Terminated

• Conditions: Severe Hemophilia A
• Interventions: Drug: rF.VIII

• Registration Number: NCT01405742
• Lead Sponsor: University of Pittsburgh

Brief Summary

The purpose of this pilot R34 trial is to determine the feasibility of a large single dose Phase III study of hemophilia adult prophylaxis comparing once weekly with thrice-weekly recombinant factor VIII. Efficacy will measured by bleeding frequency, factor usage, joint range of motion, cost, quality-of-life, F.VIII level, and inter-dose hypocoagulability by thrombin generation. Safety will be measured by inhibitor formation and bleeding events unresponsive to up to two rescue doses.

Detailed Description

The purpose of this 52-week pilot R34 randomized, open-label, non-inferiority, cross-over study is to determine the feasibility of a large single dose Phase III study of hemophilia adult prophylaxis. The primary efficacy endpoint will be bleeding frequency. Secondary endpoints will include factor usage, joint range of motion, cost, quality-of-life, and inter-dose hypocoagulability by thrombin generation time and F.VIII activity will also be determined. Safety will be measured by the frequency of bleeding unresponsive to up to two rescue treatments. Inhibitor formation by anti-F.VIII Bethesda assay, and clinical frequency of thrombosis and allergic reactions will also be assessed. Subject acceptance and adherence to the treatment interventions will be determined; and web-based data entry of case report forms, digital range-of-motion images, and quality-of-life instrument will be implemented. The relation of bleeding frequency to relative inter-dose hypocoagulability, will be assessed by inter-dose thrombin generation time (TGT), endogenous thrombin potential (ETP), and factor VIII levels. Optimal blood sample collection and shipping methods will be determined. For all tests, we will estimate and determine completeness and congruency, in order to determine adjustments or revisions required before initiating a large phase III Randomized clinical trial. All testing will be exploratory, so that we may determine if the test, approach are realistic, and to estimate standard deviations for future power analyses.

Study Timeline

• Study First Submitted: 2011-07-25
• Study First Submitted QC: 2011-07-28
• Study First Posted: 2011-07-29
• Study Start: 2012-07
• Primary Completion: 2013-11
• Study Completion: 2013-11
• Results First Submitted: 2016-06-08
• Results First Submitted QC: 2016-07-27
• Status Verified: 2016-09
• Last Update Submitted: 2016-09-16
• Results First Posted: 2016-09-19
• Last Update Posted: 2016-10-07

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Male
• Target Recruitment: 4

Inclusion Criteria

• Adult males 18 years or older
• Severe hemophilia A (F.VIII < 0.01 U/ml)
• At least 150 exposure days to F.VIII products
• No detectable inhibitor
• No history of allergic reaction
• Platelets at least 150,000/ul
• If HIV(+), CD4 at least 200/ul, HIV-VL <48 copies/ml,and cART compliant
• If HCV(+), no splenomegaly,varices,GI bleed,ascites,edema,encephalopathy
• Willingness to comply with cross-over design, randomization schema
• Willingness to keep a personal diary of bleeding frequency and factor use
• Willingness to make every 3 month visits, coagulation testing at wks 2, 28

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Exclusion Criteria

• Acquired hemophilia
• Any bleeding disorder other than hemophilia A
• Presence of an inhibitor to factor VIII
• Historic platelet count < 100,000
• Use of experimental drugs
• Surgery anticipate in the next 52 weeks
• Symptomatic HCV(splenomegaly,varices,GI bleed,ascites,edema,encephalopathy)
• Symptomatic HIV(CD4<200/ul or HIV VL 48 or more copy/ml,cART noncompliant)
• Life expectancy less than 5 years
• Investigational drug or study within 4 weeks prior to study
• Inability to comply with study requirements

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Arm B	rF.VIII	The intervention for Arm B is 40 IU/kg recombinant factor VIII (rFVIII) by thrice-weekly intravenous injection for 26 weeks. Cross-over will occur at 26 weeks after a 72 hour washout period, after which 40 IU/kg recombinant factor VIII (rFVIII) will be given once-weekly by intravenous injection until week 52, with up to two rescue doses per week for bleeds
Arm A	rF.VIII	The intervention for Arm A is 40 IU/kg recombinant factor VIII (rFVIII) by once-weekly intravenous injection for 26 weeks. Cross-over will occur at 26 weeks after a 72 hour washout period, after which 40 IU/kg recombinant factor VIII (rFVIII) will be given thrice-weekly by intravenous injection until week 52, with up to two rescue doses per week for bleeds.

Primary Outcome Measures

Name	Time	Method
Number of Bleeds	Weeks 26 (first intervention) and 52 (second intervention)	The primary outcome was bleed frequency. The data were total number of events for each Arm, and not per-participant.

Secondary Outcome Measures

Name	Time	Method
Inter-dose Hypocoagulability by Thrombin Generation	The time frame is 52 weeks per subject.	Thrombin generation was performed at week 8 and week 34, i.e. 8 weeks after initiation of factor dosing in Weeks 1-26, and 8 weeks after initiation of factor dosing in Weeks 27-52.
F.VIII Activity	The time frame is 52 weeks per subject.	F.VIII Activity (IU/mL) performed at week 8 and week 34, i.e. 8 weeks after initiation of factor dosing in Weeks 1-26, and 8 weeks after initiation of factor dosing in Weeks 27-52.

Trial Locations

Locations (6)

Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Hemophilia Center of Western Pennsylvania; 🇺🇸 Pittsburgh, Pennsylvania, United States

Georgetown University; 🇺🇸 Washington, District of Columbia, United States

Puget Sound Blood Center; 🇺🇸 Seattle, Washington, United States

Vanderbilt University; 🇺🇸 Nashville, Tennessee, United States