The Hemophilia Inhibitor Eradication Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hemophilia A With Inhibitor

Intervention / Treatment
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* Drug: Eloctate ITI
* Drug: Emicizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male adults or children > 4 months of age. Severe hemophilia A (FVIII < 0.01 U/ml). Current or past high-responding inhibitor, anti-FVIII >= 5.0 B.U., ITI-refractory or ITI-naive. Exclusion Criteria: Acquired hemophilia or any bleeding disorder other than hemophilia A. Current use of Emicizumab, or if used, > 8 weeks since last treatment. Use of an experimental drug(s). Surgery anticipated in the next 48 weeks. Life expectancy less than 5 years. 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. Other illness, condition, or reason in the opinion of the investigator that would make the patient unsuitable for the trial.
Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a phase III open-label, randomized controlled trial comparing immune tolerance induction with one drug, with or without a second drug in the eradication of hemophilia inhibitors.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eloctate ITI plus Emicizumab<br>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<br>* This is a factor VIII-Fc infusion protein.<br>* Other names: rFVIIIFc;Drug: Emicizumab<br>* This is a bispecific monoclonal antibody FVIII mimic.<br>* Other names: Hemlibra;|
| Active Comparator: Eloctate ITI<br>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<br>* This is a factor VIII-Fc infusion protein.<br>* Other names: rFVIIIFc;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemophilia, inhibitor formation, Eloctate, Emicizumab