The Hemophilia Inhibitor Eradication Trial

Overview

This is a multi-center randomized phase III clinical trial, the Inhibitor Eradication Trial, in which Eloctate ITI plus Emicizumab will be compared with Eloctate ITI alone to eradicate inhibitors in severe hemophilia A.

Full Title of Study: “Phase III Multi-Center, Randomized, Controlled Inhibitor Eradication Trial, Comparing Eloctate Immune Tolerance Induction (ITI) Plus Emicizumab vs. Eloctate ITI Alone to Eradicate Inhibitor Formation in Severe Hemophilia A”

Study Type

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

Detailed Description

This is a multi-center randomized phase III clinical trial, the Inhibitor Eradication Trial, in which Eloctate ITI plus Emicizumab will be compared with Eloctate ITI alone to eradicate inhibitors in patients with severe hemophilia A This adaptive design is necessary as randomized trials in rare diseases are often 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 Eradication Trial is a 48-week randomized phase III trial, in which 90 previously treated patients (PTPs) with severe hemophilia A and high-responding inhibitors (anti-VIII > 0.6 B.U.), will be enrolled. Subjects will include individuals with severe hemophilia A who develop inhibitors during the linked Inhibitor Prevention Trial and adults or children at the same HTCs refractory to or never undergoing immune tolerance induction (ITI). Once enrolled, subjects who meet all the inclusion and none of the exclusion criteria, will be randomized to weekly Eloctate ITI plus weekly Emicizumab vs. weekly Eloctate ITI alone to eradicate inhibitor formation, defined as anti-FVIII<0.6 B.U. 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 Eradication 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 Eradication Trial (PRO19070080) is linked to the Inhibitor Prevention Trial (PRO19040140), as part of the INHIBIT Clinical Trials Platform, and 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 ITI
    • This is a factor VIII-Fc infusion protein.
  • Drug: Emicizumab
    • This is a bispecific monoclonal antibody FVIII mimic.

Arms, Groups and Cohorts

  • Experimental: Eloctate ITI plus Emicizumab
    • Arm A: Eloctate 100 IU/kg every other day by intravenous infusion plus Emicizumab 1.5 mg/kg subcutaneously (following 3 mg/kg/wk x 4 induction) in children and adults with severe hemophilia A and anti-FVIII inhibitor, continued up to 48 weeks.
  • Active Comparator: Eloctate ITI
    • Arm B: Eloctate 100 IU/kg every other day by intravenous infusion in children and adults with severe hemophilia A and anti-FVIII inhibitor, continued up to 48 weeks.

Clinical Trial Outcome Measures

Primary Measures

  • Inhibitor eradication
    • Time Frame: 48 weeks
    • The proportion eradicating 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 adults or children > 4 months of age. 2. Severe hemophilia A (FVIII < 0.01 U/ml). 3. Current or past high-responding inhibitor, anti-FVIII >= 5.0 B.U., ITI-refractory or ITI-naive. Exclusion Criteria:

1. Acquired hemophilia or any bleeding disorder other than hemophilia A. 2. Current use of Emicizumab, or if used, > 8 weeks since last treatment. 3. Use of an experimental drug(s). 4. Surgery anticipated in the next 48 weeks. 5. Life expectancy less than 5 years. 6. Patient/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, 8, 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: N/A

Maximum Age: N/A

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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