Hemophilia Inhibitor Clinical Trials (INHIBIT) Platform (INHIBIT)

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Severe Hemophilia A
• Intervention / Treatment: Drug: Eloctate Prophylaxis; Drug: Emicizumab Prophylaxis; Drug: Eloctate ITI plus Emicizumab; Drug: Eloctate ITI

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: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Hemophilia Center of Western Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 99 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: rFVIIIFc ITI

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevention & Eradication Trials: T Cell Elispot Assay	T cell reactivity to FVIII	Up to 48 weeks

Collaborators and Investigators

• Sponsor: Margaret Ragni

Publications and helpful links

General 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. No abstract available.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): August 1, 2020
• Primary Completion (ANTICIPATED): July 1, 2027
• Study Completion (ANTICIPATED): July 1, 2027

Study Registration Dates

• First Submitted: July 17, 2014
• First Submitted That Met QC Criteria: July 18, 2014
• First Posted (ESTIMATE): July 21, 2014

Study Record Updates

• Last Update Posted (ACTUAL): August 20, 2019
• Last Update Submitted That Met QC Criteria: August 16, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Emicizumab; Eloctate; Severe Hemophilia A; Hemophilia Inhibitor Formation; Inhibitor Prevention; Inhibitor Eradication
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Bispecific
• Other Study ID Numbers: PRO14020038

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Time Frame: Within one year of trial completion.
• IPD Sharing Access Criteria: Access will be determined by NHLBI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• 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