The Hemophilia Inhibitor Eradication Trial

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

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.

Study Overview

• Status: Terminated
• Conditions: Hemophilia A With Inhibitor
• Intervention / Treatment: Drug: Eloctate ITI; Drug: Emicizumab

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.

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

Contacts and Locations

Study Locations

• United States
  • 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: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Eloctate ITI; This is a factor VIII-Fc infusion protein.; Other Names: rFVIIIFc; Drug: Emicizumab; This is a bispecific monoclonal antibody FVIII mimic.; Other Names: Hemlibra
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.	Drug: Eloctate ITI; This is a factor VIII-Fc infusion protein.; Other Names: rFVIIIFc

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inhibitor Eradication	The proportion eradicating anti-FVIII inhibitors	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of 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
Human Leukocyte Antigen (HLA) Haplotype	The number of HLA haplotype variants.	48 weeks
FVIII Mutation	The number of FVIII mutation variants.	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): November 1, 2021
• Primary Completion (Actual): June 27, 2022
• Study Completion (Actual): June 27, 2022

Study Registration Dates

• First Submitted: October 31, 2019
• First Submitted That Met QC Criteria: March 10, 2020
• First Posted (Actual): March 11, 2020

Study Record Updates

• Last Update Posted (Estimate): February 20, 2023
• Last Update Submitted That Met QC Criteria: January 25, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Emicizumab; hemophilia; Eloctate; inhibitor formation
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: PRO19070080; 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 the 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