The Hemophilia Inhibitor Prevention Trial

Overview

This is a multi-center randomized phase III clinical trial, the Inhibitor Prevention Trial, in which Eloctate will be compared with Emicizumab, using adaptive design, to prevent inhibitors in patients with severe hemophilia A.

Full Title of Study: “Multicenter, Randomized Phase III Inhibitor Prevention Trial, Comparing Eloctate vs. Emicizumab to Prevent Inhibitor Formation in Severe Hemophilia A”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: None (Open Label)
  • Study Primary Completion Date: August 2027

Detailed Description

This is a multi-center randomized phase III clinical trial, the Inhibitor Prevention Trial, in which consecutive hemostatic agents will be compared using adaptive design to prevent inhibitors in patients with severe hemophilia A. This adaptive design is necessary as randomized trials in rare diseases are otherwise not possible. This adaptive design is necessary as randomized trials in rare diseases are otherwise not possible. The INHIBIT Clinical Trials Platform includes two linked trials, the Inhibitor Prevention Trial (Prevention Trial) and the Inhibitor Eradication Trial (Eradication Trial) that will be conducted at up to 41 U.S. hemophilia treatment centers (HTCs) affiliated with universities. The Inhibitor Prevention Trial is a 48-week randomized phase III trial, in which 66 previously untreated patients (PUPs) with severe hemophilia A will be enrolled. Subjects will include children from 4 months of age up to 4 years of age who have not been previously treated with clotting factor. Once enrolled, subjects who meet all the inclusion and none of the exclusion criteria will be randomized to preemptive weekly Eloctate (rFVIIIFc) vs. weekly Emicizumab (Hemlibra) to prevent inhibitor formation, defined as anti-FVIII >= 0.6 BU. Blood draws will be minimized to 6 timepoints, pre, 4, 12, 24, 36, and 48 weeks, and validated for small volumes, 3.8 cc (¾ tsp) each. The Inhibitor Prevention Trial is considered greater than minimal risk as study drug is given before the first bleed and special inhibitor studies are obtained. (NB: The Inhibitor Prevention Trial (PRO19040140) is linked to the Inhibitor Eradication Trial (PRO19070080), as part of the INHIBIT Clinical Trials Platform, with both trials will be conducted efficiently in the same hemophilia treatment centers (HTCs), with the same MDs, coordinators, visit frequency, blood sampling, and assays.

Interventions

  • Drug: Eloctate Injectable Product
    • This is a factor VIII-Fc fusion protein.
  • Drug: Emicizumab Injection [Hemlibra]
    • This is a bispecific monoclonal antibody FVIII mimic.

Arms, Groups and Cohorts

  • Active Comparator: Eloctate
    • Arm A: Eloctate 65 IU/kg will be administered weekly by intravenous infusion in previously untreated children with severe hemophilia A beginning before the first bleed and continued up to 48 weeks.
  • Experimental: Emicizumab
    • Arm B: Emicizumab 1.5 mg/kg will be administered weekly by subcutaneous injection (following 3 mg/kg/wk x4 induction) in previously untreated children with severe hemophilia A beginning before the first bleed and continue up to 48 weeks.

Clinical Trial Outcome Measures

Primary Measures

  • Inhibitor formation
    • Time Frame: 48 weeks
    • The proportion developing anti-FVIII inhibitors.

Secondary Measures

  • Bleeding events
    • Time Frame: 48 weeks
    • The number of bleeding events:hematoma, joint, central nervous system, other bleeds.
  • FVIII trough level
    • Time Frame: 48 weeks
    • The FVIII trough activity by chromogenic assay
  • Human leukocyte antigen (HLA) haplotype
    • Time Frame: 48 weeks
    • The number of HLA haplotype variants.
  • FVIII mutation
    • Time Frame: 48 weeks
    • The number of FVIII mutation variants.

Participating in This Clinical Trial

Inclusion Criteria

1. Male children >= 4 months and up to 4 years of age. 2. Severe hemophilia A (FVIII < 0.01 U/ml). 3. No evidence of an inhibitor i.e. anti-FVIII < 0.6 B.U. 4. No more than 3 FVIII exposures (Factor VIII concentrate, cryoprecipitate, or fresh frozen plasma), including circumcision. Exclusion Criteria:

1. Acquired hemophilia or any bleeding disorder other than hemophilia A. 2. Treatment with clotting factor or emicizumab previously. 3. Use of an experimental drug(s). 4. Surgery anticipated in the next 48 weeks. 5. Life expectancy less than 5 years. 6. Parent/caretaker unable or unwilling to keep a personal diary of bleeding frequency and study drug treatment, make monthly visits and blood draws at weeks 4, 12, 24, 36, and 48. 7. Other illness, condition or reason in the opinion of the investigator that would make the patient unsuitable for the trial.

Gender Eligibility: Male

Minimum Age: 4 Months

Maximum Age: 4 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Margaret Ragni
  • Collaborator
    • Health Resources and Services Administration (HRSA)
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Margaret Ragni, Professor of Medicine and Clinical and Translational Research – University of Pittsburgh
  • Overall Official(s)
    • Margaret V Ragni, MD, MPH, Principal Investigator, University of Pittsburgh
  • Overall Contact(s)
    • Margaret V Ragni, MD, MPH, 412-209-7288, ragni@pitt.edu

References

Ragni MV, George LA; Members of Working Group 1, the NHLBI State of the Science Workshop on factor VIII inhibitors: Generating a national blueprint for future research. The national blueprint for future factor VIII inhibitor clinical trials: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors. Haemophilia. 2019 Jul;25(4):581-589. doi: 10.1111/hae.13717.

Ebbert PT, Xavier F, Malec LM, Seaman CD, Ragni MV. Observational study of recombinant factor VIII-Fc, rFVIIIFc, in hemophilia A. Thromb Res. 2020 Nov;195:51-54. doi: 10.1016/j.thromres.2020.07.004. Epub 2020 Jul 5.

Bertolet M, Brooks MM, Ragni MV. The design of a Bayesian platform trial to prevent and eradicate inhibitors in patients with hemophilia. Blood Adv. 2020 Nov 10;4(21):5433-5441. doi: 10.1182/bloodadvances.2020002789.

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