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Hemophilia Inhibitor Clinical Trials (INHIBIT) Platform (INHIBIT)

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ClinicalTrials.gov Identifier: NCT02196207
Recruitment Status : Withdrawn (The trial was revised to be two protocols, one Prevention, one Eradication Trials.)
First Posted : July 21, 2014
Last Update Posted : August 20, 2019
Sponsor:
Information provided by (Responsible Party):
Margaret Ragni, University of Pittsburgh

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Severe Hemophilia A Drug: Eloctate Prophylaxis Drug: Emicizumab Prophylaxis Drug: Eloctate ITI plus Emicizumab Drug: Eloctate ITI Phase 3

Detailed Description:
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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : August 2020
Estimated Primary Completion Date : July 2027
Estimated Study Completion Date : July 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia
Drug Information available for: Emicizumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Eloctate Prophylaxis
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
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.
Other Name: rFVIIIFc Prophylaxis
Experimental: Emicizumab Prophylaxis
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
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.
Other Name: Hemlibra Prophylaxis
Experimental: Eloctate ITI plus Emicizumab
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
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.
Other Name: rFVIIIFc ITI plus Hemlibra
Active Comparator: Eloctate ITI Alone
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
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.
Other Name: rFVIIIFc ITI


Outcome Measures
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Primary Outcome Measures :
  1. Prevention Trial: Time to inhibitor formation [ Time Frame: Up to 48 weeks ]
    Inhibitor formation is defined as anti-FVIII > / = 5.0 B.U. by chromogenic Nijmegen-modified Bethesda assay, performed on plasma, repeated for confirmation.

  2. Eradication Trial: Time to inhibitor eradication [ Time Frame: Up to 48 weeks ]
    Inhibitor eradication is defined as anti-FVIII < 0.6 B.U. by chromogenic Nijmegen Bethesda assay, performed on plasma, repeated for confirmation.


Secondary Outcome Measures :
  1. Prevention & Eradication Trials: Bleeding events including hematoma, joint, central nervous system, other [ Time Frame: Up to 48 weeks ]
    Number of bleeding events

  2. Prevention & Eradication Trials: Factor VIII trough activity by chromogenic assay [ Time Frame: Up to 48 weeks ]
    FVIII activity

  3. Prevention & Eradication Trials: HLA type and factor VIII genotype [ Time Frame: Up to 48 weeks ]
    HLA haplotype and FVIII mutation


Other Outcome Measures:
  1. Prevention & Eradication Trials: T Cell Elispot Assay [ Time Frame: Up to 48 weeks ]
    T cell reactivity to FVIII


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   4 Months to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02196207


Locations
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United States, Pennsylvania
Hemophilia Center of Western Pennsylvania
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
Margaret Ragni
Investigators
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Principal Investigator: Margaret V Ragni, MD, MPH University of Pittsburgh
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Margaret Ragni, Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02196207    
Other Study ID Numbers: PRO14020038
First Posted: July 21, 2014    Key Record Dates
Last Update Posted: August 20, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: A biologic specimen and data repository for this trial will be available, pending NHLBI approval, at BioLINCC https://biolincc.nhlbi.nih.gov, to any research or investigator who makes formal application request and is formally approved by NHLBI.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Within one year of trial completion.
Access Criteria: Access will be determined by NHLBI.

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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
Keywords provided by Margaret Ragni, University of Pittsburgh:
Severe Hemophilia A
Hemophilia Inhibitor Formation
Eloctate
 Emicizumab
Inhibitor Prevention
Inhibitor Eradication
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
 Hemorrhagic Disorders
Genetic Diseases, Inborn
Antibodies, Bispecific
Immunologic Factors
Physiological Effects of Drugs