Hemophilia Inhibitor Clinical Trials (INHIBIT) Platform

Study Overview
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Brief Summary
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This study will evaluate if Eloctate is superior to Emicizumab in reducing inhibitors in children with severe hemophilia when given before the first bleed (preemptive) and continued weekly to prevent bleeds (prophylaxis); and whether Eloctate immune tolerance induction (ITI) plus emicizumab is superior to Eloctate ITI alone in eradicating inhibitor formation in children and adults with severe hemophilia A.

Detailed Description
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This is a multi-center, randomized Phase III Clinical Trials Platform (INHIBIT) in which hemostatic agents will be compared using adaptive design to prevent and eradicate inhibitors in patients with severe hemophilia A. This adaptive design is necessary as randomized trials in rare diseases are otherwise not possible. The INHIBIT Trial Platform includes one Inhibitor Prevention Trial and one Inhibitor 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) (children < 6 yr) with severe hemophilia A will be enrolled and randomized to preemptive weekly Eloctate vs. Emicizumab to prevent inhibitor formation, defined as anti-FVIII > 5.0 BU. 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 >5.0 B.U.), including subjects developing inhibitors during the Prevention Trials and adults or children of any age at the same HTCs refractory to or never previously tolerated, will be enrolled and randomized to Eloctate ITI god plus weekly Emicizumab vs. 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 Inhibit Trials Platform is considered greater than minimal risk as study drug is given before the first bleed and special inhibitor studies are obtained.

Official Title
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Phase III INHIBIT Platform: Prevention Trial, Eloctate vs Emicizumab to Prevent Inhibitors; Eradication Trial: Eloctate Immune Tolerance (ITI) Plus Emicizumab vs vs Eloctate ITI Alone to Eradicate Inhibitors in Severe Hemophilia A

Conditions
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Severe Hemophilia A

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


Participation Criteria
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Eligibility Criteria
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Prevention Trial, Inclusion Criteria: Male children >/= 4 months of age. Severe hemophilia A (FVIII < 0.01 U/ml) No previous bleed or surgery requiring treatment (except circumcision) No previous factor VIII product (except for circumcision) Willingness to comply with weekly prophylaxis for 48 weeks Willingness of parent/caregiver to keep a personal diary of bleeding frequency and factor treatment. Willingness to make monthly visits and coagulation testing at weeks 4, 12, 24, 36, and 48 (end of study) Prevention Trial, Exclusion Criteria: Acquired hemophilia. Any bleeding disorder other than hemophilia A. Treatment with clotting factor previously, other than circumcision. Presence of an inhibitor to factor VIII. Use of an experimental drug(s). Surgery anticipated in the next 48 weeks. Life expectancy less than 5 years. Inability to comply with study requirements. Eradication Trial, Inclusion Criteria: Male adults or children with no age limitation. Severe hemophilia A (FVIII <0.01 U/ml). Presence of an inhibitor to FVIII (anti-FVIII > 5.0 B.U.) Willingness to comply with study drugs for up to 48 weeks. Willingness to keep a personal diary of bleed frequency and drug treatment. Willingness to make monthly visits and coagulation testing at weeks 4, 12, 24, 36, and 48 (end of study). Eradication Trial, Exclusion Criteria: Acquired hemophilia. 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. Inability to copy with study requirements.

Ages Eligible for Study
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Minimum Age: 4 Months
Maximum Age: 99 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two phase III randomized trials, each with two arms, including one inhibitor prevention trial and one inhibitor eradication trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eloctate Prophylaxis<br>Prevention Trial, Arm A: rFVIIIFc (Eloctate) 65 IU/kg weekly will be administered by intravenous infusion in previously untreated children with severe hemophilia A beginning before the first bleed and continued for up to 48 weeks. | Drug: Eloctate Prophylaxis<br>* Prevention Trial, Arm A: Eloctate (65 IU/kg) will be administered weekly by intravenous infusion for up to 48 weeks in previously untreated children with severe hemophilia A beginning before the first bleed.<br>* Other names: rFVIIIFc Prophylaxis;|
| Experimental: Emicizumab Prophylaxis<br>Prevention Trial, Arm B: Emicizumab 1.5 mg/kg weekly (following 4-wk induction at 3 mg/kg weekly) will be administered by subcutaneous injection in previously untreated children with severe hemophilia A beginning before the first bleed and continued for up to 48 weeks. | Drug: Emicizumab Prophylaxis<br>* Prevention Trial, Arm B: Emicizumab (1.5 mg/kg) will be administered weekly by subcutaneous injection for up to 48 weeks in previously untreated children with severe hemophilia A.<br>* Other names: Hemlibra Prophylaxis;|
| Experimental: Eloctate ITI plus Emicizumab<br>Eradication Trial, Arm A: Eloctate 100 IU/kg every other day will be administered by intravenous infusion as immune tolerance plus Emicizumab 1.5 mg/kg weekly by subcutaneous injection in previously treated children and adults with severe hemophilia A and high-titer inhibitors and continued for up to 48 weeks. | Drug: Eloctate ITI plus Emicizumab<br>* Eradication Trial, Arm A: Eloctate (100 IU/kg) ITI every other day by intravenous infusion plus Emicizumab (1.5 mg/kg) weekly by subcutaneous injection will be administered for up to 48 weeks as immune tolerance in children and adults with severe hemophilia A and high-titer inhibitors.<br>* Other names: rFVIIIFc ITI plus Hemlibra;|
| Active Comparator: Eloctate ITI Alone<br>Eradication Trial, Arm B: Eloctate 100 IU/kg every other day will be administered by intravenous infusion as immune tolerance alone in previously treated children and adults with severe hemophilia A and high-titer inhibitors and continued for up to 48 weeks. | Drug: Eloctate ITI<br>* Eradication Trial, Arm A: Eloctate (100 IU/kg) ITI every other day by intravenous infusion will be administered for up to 48 weeks as immune tolerance in children and adults with severe hemophilia A and high-titer inhibitors.<br>* Other names: rFVIIIFc ITI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention Trial: Time to inhibitor formation | Inhibitor formation is defined as anti-FVIII > / = 5.0 B.U. by chromogenic Nijmegen-modified Bethesda assay, performed on plasma, repeated for confirmation. | Up to 48 weeks | 
| Eradication Trial: Time to inhibitor eradication | Inhibitor eradication is defined as anti-FVIII < 0.6 B.U. by chromogenic Nijmegen Bethesda assay, performed on plasma, repeated for confirmation. | Up to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention & Eradication Trials: Bleeding events including hematoma, joint, central nervous system, other | Number of bleeding events | Up to 48 weeks | 
| Prevention & Eradication Trials: Factor VIII trough activity by chromogenic assay | FVIII activity | Up to 48 weeks | 
| Prevention & Eradication Trials: HLA type and factor VIII genotype | HLA haplotype and FVIII mutation | Up to 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe Hemophilia A, Hemophilia Inhibitor Formation, Eloctate, Emicizumab, Inhibitor Prevention, Inhibitor Eradication