Clinical trial NCT02196207: Hemophilia Inhibitor Clinical Trials (INHIBIT) Platform
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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Severe Hemophilia A
Keywords: Severe Hemophilia A
Hemophilia Inhibitor Formation
Eloctate
Emicizumab
Inhibitor Prevention
Inhibitor Eradication
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2014-07-21
Enrollment: 0
Sex: MALE
Minimum age (years): 4
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two phase III randomized trials, each with two arms, including one inhibitor prevention trial and one inhibitor eradication trial.
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Prevention Trial: Time to inhibitor formation
timeFrame: Up to 48 weeks
measure: Eradication Trial: Time to inhibitor eradication
timeFrame: Up to 48 weeks
Secondary outcomes:
measure: Prevention & Eradication Trials: Bleeding events including hematoma, joint, central nervous system, other
timeFrame: Up to 48 weeks
measure: Prevention & Eradication Trials: Factor VIII trough activity by chromogenic assay
timeFrame: Up to 48 weeks
measure: Prevention & Eradication Trials: HLA type and factor VIII genotype
timeFrame: Up to 48 weeks
Other outcomes:
measure: Prevention & Eradication Trials: T Cell Elispot Assay
timeFrame: Up to 48 weeks
Locations:
city: Pittsburgh
country: United States
facility: Hemophilia Center of Western Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Margaret V Ragni, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.