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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Recruitment Status : Withdrawn (The trial was revised to be two protocols, one Prevention, one Eradication Trials.)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

Tracking Information
First Submitted Date  ICMJE July 17, 2014
First Posted Date  ICMJE July 21, 2014
Last Update Posted Date August 20, 2019
Estimated Study Start Date  ICMJE August 2020
Estimated Primary Completion Date July 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 19, 2019)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 18, 2014)
Development of an inhibitor [ Time Frame: Up to 48 weeks ]
Inhibitor development is defined as anti-F.VIII > / = 5 B.U. (Bethesda units) repeated for confirmation by Nijmegen-modified Bethesda assay performed on plasma.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2019)
  • Prevention & Eradication Trials: Bleeding events including hematoma, joint, central nervous system, other [ Time Frame: Up to 48 weeks ]
    Number of bleeding events
  • Prevention & Eradication Trials: Factor VIII trough activity by chromogenic assay [ Time Frame: Up to 48 weeks ]
    FVIII activity
  • Prevention & Eradication Trials: HLA type and factor VIII genotype [ Time Frame: Up to 48 weeks ]
    HLA haplotype and FVIII mutation
Original Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2014)
  • Bleeding events including joint, central nervous system, other [ Time Frame: Up to 48 weeks ]
  • Factor VIII trough activity [ Time Frame: Up to 48 weeks ]
  • HLA type and factor VIII genotype [ Time Frame: Up to 48 weeks ]
Current Other Pre-specified Outcome Measures
 (submitted: April 19, 2019)
Prevention & Eradication Trials: T Cell Elispot Assay [ Time Frame: Up to 48 weeks ]
T cell reactivity to FVIII
Original Other Pre-specified Outcome Measures
 (submitted: July 18, 2014)
T Cell ELISPOT Assay [ Time Frame: Up to 48 weeks ]
 
Descriptive Information
Brief Title  ICMJE Hemophilia Inhibitor Clinical Trials (INHIBIT) Platform
Official Title  ICMJE 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
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE Severe Hemophilia A
Intervention  ICMJE
  • 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
  • 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
  • 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
  • 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
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Eloctate 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.
    Intervention: Drug: Emicizumab 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.
    Intervention: Drug: Eloctate ITI plus Emicizumab
  • 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.
    Intervention: Drug: Eloctate ITI
Publications * Ragni MV. The effect of emicizumab regimen on haemophilia outcomes. Lancet Haematol. 2019 Jun;6(6):e286-e287. doi: 10.1016/S2352-3026(19)30070-5. Epub 2019 Apr 16.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: August 16, 2019)
0
Original Estimated Enrollment  ICMJE
 (submitted: July 18, 2014)
45
Estimated Study Completion Date  ICMJE July 2027
Estimated Primary Completion Date July 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 4 Months to 99 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02196207
Other Study ID Numbers  ICMJE PRO14020038
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Within one year of trial completion.
Access Criteria: Access will be determined by NHLBI.
Responsible Party Margaret Ragni, University of Pittsburgh
Study Sponsor  ICMJE Margaret Ragni
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Margaret V Ragni, MD, MPH University of Pittsburgh
PRS Account University of Pittsburgh
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP