Clinical trial NCT04303572: The Hemophilia Inhibitor Eradication Trial
Official title: Phase III Multi-Center, Randomized, Controlled Inhibitor Eradication Trial, Comparing Eloctate Immune Tolerance Induction (ITI) Plus Emicizumab vs. Eloctate ITI Alone to Eradicate Inhibitor Formation in Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Hemophilia A With Inhibitor
Keywords: hemophilia
inhibitor formation
Eloctate
Emicizumab
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Health Resources and Services Administration (HRSA)
First posted: 2020-03-11
Enrollment: 1
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a phase III open-label, randomized controlled trial comparing immune tolerance induction with one drug, with or without a second drug in the eradication of hemophilia inhibitors.
Primary purpose: TREATMENT

Brief summary: This is a multi-center randomized phase III clinical trial, the Inhibitor Eradication Trial, in which Eloctate ITI plus Emicizumab will be compared with Eloctate ITI alone to eradicate inhibitors in severe hemophilia A.

Detailed description: This is a multi-center randomized phase III clinical trial, the Inhibitor Eradication Trial, in which Eloctate ITI plus Emicizumab will be compared with Eloctate ITI alone to eradicate inhibitors in patients with severe hemophilia A This adaptive design is necessary as randomized trials in rare diseases are often not possible. The INHIBIT Clinical Trials Platform includes two linked trials, the Inhibitor Prevention Trial (Prevention Trial) and the Inhibitor Eradication Trial (Eradication Trial) that will be conducted at up to 41 U.S. hemophilia treatment centers (HTCs) affiliated with universities. 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 \> 0.6 B.U.), will be enrolled. Subjects will include individuals with severe hemophilia A who develop inhibitors during the linked Inhibitor Prevention Trial and adults or children at the same HTCs refractory to or never undergoing immune tolerance induction (ITI). Once enrolled, subjects who meet all the inclusion and none of the exclusion criteria, will be randomized to weekly Eloctate ITI plus weekly Emicizumab vs. weekly 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 Inhibitor Eradication Trial is considered greater than minimal risk as study drug is given before the first bleed and special inhibitor studies are obtained. (NB: The Inhibitor Eradication Trial (PRO19070080) is linked to the Inhibitor Prevention Trial (PRO19040140), as part of the INHIBIT Clinical Trials Platform, and both trials will be conducted efficiently in the same hemophilia treatment centers (HTCs), with the same MDs, coordinators, visit frequency, blood sampling, and assays.

Eligibility criteria: Inclusion Criteria:

1. Male adults or children \> 4 months of age.
2. Severe hemophilia A (FVIII \< 0.01 U/ml).
3. Current or past high-responding inhibitor, anti-FVIII \>= 5.0 B.U., ITI-refractory or ITI-naive.

Exclusion Criteria:

1. Acquired hemophilia or any bleeding disorder other than hemophilia A.
2. Current use of Emicizumab, or if used, \> 8 weeks since last treatment.
3. Use of an experimental drug(s).
4. Surgery anticipated in the next 48 weeks.
5. Life expectancy less than 5 years.
6. Patient/parent/caretaker unable or unwilling to keep a personal diary of bleeding frequency and study drug treatment, make monthly visits and blood draws at weeks 4, 8, 12, 24, 36, and 48.
7. Other illness, condition, or reason in the opinion of the investigator that would make the patient unsuitable for the trial.

Primary outcomes:
measure: Inhibitor Eradication
timeFrame: 48 weeks
Secondary outcomes:
measure: Number of Bleeding Events
timeFrame: 48 weeks
measure: FVIII Trough Level
timeFrame: 48 weeks
measure: Human Leukocyte Antigen (HLA) Haplotype
timeFrame: 48 weeks
measure: FVIII Mutation
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Hemophilia Center of Western PA
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh and Hemophilia Center Western PA
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Margaret V Ragni, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ragni MV, George LA; Members of Working Group 1, the NHLBI State of the Science Workshop on factor VIII inhibitors: Generating a national blueprint for future research. The national blueprint for future factor VIII inhibitor clinical trials: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors. Haemophilia. 2019 Jul;25(4):581-589. doi: 10.1111/hae.13717.
citation: Ebbert PT, Xavier F, Malec LM, Seaman CD, Ragni MV. Observational study of recombinant factor VIII-Fc, rFVIIIFc, in hemophilia A. Thromb Res. 2020 Nov;195:51-54. doi: 10.1016/j.thromres.2020.07.004. Epub 2020 Jul 5.
citation: Bertolet M, Brooks MM, Ragni MV. The design of a Bayesian platform trial to prevent and eradicate inhibitors in patients with hemophilia. Blood Adv. 2020 Nov 10;4(21):5433-5441. doi: 10.1182/bloodadvances.2020002789.