The Hemophilia Inhibitor Prevention Trial

Multicenter, Randomized Phase III Inhibitor Prevention Trial, Comparing Eloctate vs. Emicizumab to Prevent Inhibitor Formation in Severe Hemophilia A

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.

Study Overview

• Status: Terminated
• Conditions: Hemophilia A Without Inhibitor
• Intervention / Treatment: Drug: Eloctate Injectable Product; Drug: Emicizumab Injection [Hemlibra]

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • University of Arkansas Medical Sciences Childrens Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Hemophilia Center of Western PA
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh and Hemophilia Center Western PA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 4 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Eloctate Injectable Product; This is a factor VIII-Fc fusion protein.; Other Names: rFVIIIFc
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.	Drug: Emicizumab Injection [Hemlibra]; This is a bispecific monoclonal antibody FVIII mimic.; Other Names: Hemlibra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inhibitor Formation	The proportion developing anti-FVIII inhibitors.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Human Leukocyte Antigen (HLA) Haplotype	The number of HLA haplotype variants.	48 weeks
FVIII Mutation	The number of FVIII mutation variants.	48 weeks
Bleeding Events	The number of bleeding events:hematoma, joint, central nervous system, other bleeds.	48 weeks
FVIII Trough Level	The FVIII trough activity by chromogenic assay	48 weeks
Number of FVIII Exposures	Number of FVIII exposures,	48 weeks

Collaborators and Investigators

• Sponsor: Margaret Ragni
• Collaborators: Health Resources and Services Administration (HRSA)

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2021
• Primary Completion (Actual): April 6, 2022
• Study Completion (Actual): June 16, 2022

Study Registration Dates

• First Submitted: March 2, 2020
• First Submitted That Met QC Criteria: March 10, 2020
• First Posted (Actual): March 11, 2020

Study Record Updates

• Last Update Posted (Actual): April 11, 2023
• Last Update Submitted That Met QC Criteria: March 17, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Emicizumab; inhibitor; hemophilia A; eloctate
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Bispecific
• Other Study ID Numbers: PRO19040140; H30MC24050 (Other Grant/Funding Number: (HRSA) Health Resources and Services Administration)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: A biologic specimen and data repository for this trial will be available at the Graduate School of Public Health (GSPH) Data Center repository for investigators who make formal application request and is formally approved by the Coordinating Center (Pitt) and Data Center (GSPH).
• IPD Sharing Time Frame: Within one year of trial completion.
• IPD Sharing Access Criteria: Access will be determined by Study Team.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No