The Hemophilia Inhibitor Prevention 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 Prevention Trial, in which Eloctate will be compared with Emicizumab, using adaptive design, to prevent inhibitors in patients with severe hemophilia A.

Detailed Description
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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.

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

Conditions
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Hemophilia A Without Inhibitor

Intervention / Treatment
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* Drug: Eloctate Injectable Product
* Drug: Emicizumab Injection [Hemlibra]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male children >= 4 months and up to 4 years of age. Severe hemophilia A (FVIII < 0.01 U/ml). No evidence of an inhibitor i.e. anti-FVIII < 0.6 B.U. No more than 3 FVIII exposures (Factor VIII concentrate, cryoprecipitate, or fresh frozen plasma), including circumcision. Exclusion Criteria: Acquired hemophilia or any bleeding disorder other than hemophilia A. Treatment with clotting factor or emicizumab previously. Use of an experimental drug(s). Surgery anticipated in the next 48 weeks. Life expectancy less than 5 years. 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. Other illness, condition or reason in the opinion of the investigator that would make the patient unsuitable for the trial.

Ages Eligible for Study
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Minimum Age: 4 Months
Maximum Age: 4 Years

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a phase III open-label, randomized controlled trial comparing two drugs in the prevention of hemophilia inhibitor formation.
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| Number of FVIII Exposures | Number of FVIII exposures, | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemophilia A, eloctate, Emicizumab, inhibitor