Preventing Inhibitor Recurrence Indefinitely

Brief Title

Preventing Inhibitor Recurrence Indefinitely

Official Title

A Multi-center, Prospective Study Evaluating the Rate of Inhibitor Recurrence Following Successful ITI in Patients Receiving Ongoing Once Per Weekly Factor VIII Therapy Along With Emicizumab and in Patients Who Discontinue FVIII Therapy and Are on Emicizumab for Prophylaxis

Brief Summary

      This study will enroll children who have hemophilia A with inhibitors who successfully
      completed immune tolerance induction per the ISTH criteria (negative inhibitor titer,
      recovery >66% of expected, and half-life of >6 hours with their current FVIII concentrate).
      Previous to emicizumab, there was only one option for these patients which was to continue
      FVIII therapy in a prophylaxis mode to prevent bleeding. There was a sense that the ongoing
      FVIII served to maintain tolerance however no evidence for this notion exists and in fact
      what limited data is available suggests that continuing FVIII may not be necessary simply to
      maintain tolerance.

      To figure out this question, this will be a randomized, controlled 2 arm study which will
      randomize patients post-successful ITI to emicizumab plus weekly FVIII (for maintenance of
      tolerance) versus emicizumab alone. Patients will be followed for up to 2 years. We aim to
      enroll 52 subjects. The FVIII weekly arm can use any factor VIII concentrate and emicizumab
      is standard of care for inhibitor and non-inhibitor patients.

Detailed Description

      Background & rationale: Hemophilia A is a serious life-long genetic bleeding disorder
      resulting from a mutation in the Factor VIII (FVIII) gene leading to abnormally low levels of
      FVIII. Treatment consists of replacing the missing FVIII with FVIII clotting factor
      concentrates (CFC). While FVIII CFC are very effective at preventing joint bleeding, they are
      immunogenic such that ~30% of patients develop anti-drug antibodies which neutralize the
      effect of the medications and are thus called inhibitors. Patients with inhibitors have worse
      morbidity and mortality as a result of increased and more difficult to treat bleeding
      episodes. Therefore, the major goal of therapy for patients who develop these antibodies is
      eradication of the inhibitor. The only approach that has been shown to be effective is called
      immune tolerance induction (ITI), and as its name implies, the purpose is to induce the
      patient's immune system to no longer make the inhibitors. Immune tolerance induction involves
      administering FVIII CFC on a regular and often intensive (daily) schedule for many months if
      not years. It can be effective, however, with successful ITI ranging from 40-90% in numerous
      previous studies. there exists a sizable minority of patients (~20-25% of all hemophilia A
      patients) who are ITI successes. For these patients, ongoing FVIII therapy has been the
      standard of treatment although once tolerization has been achieved, the treatment modality
      reverts to prophylaxis, however the continued regular exposure to prophylaxis is felt to also
      serve the purpose of maintaining tolerance.there is little to no data on whether ongoing
      FVIII exposure is required to maintain tolerance, and it is entirely possible that patients
      can discontinue routine factor therapy and not have a recurrence of their inhibitor. Only one
      study has even addressed this issue, and it found that inhibitor recurrence rates were the
      same among a group of tolerized patients who were subsequently adherent to a prophylaxis
      regimen and another group who were not adherent and therefore not receiving regular FVIII
      exposure.

      While historically, this was a moot issue since the only appropriate therapy for severe
      hemophilia patients following successful ITI was to be prescribed FVIII prophylaxis, the
      recent licensure of a new medication has now made this question and knowledge gap very
      important. Emicizumab (Hemlibra, Roche, Basel, Switzerland) is a novel, bispecific,
      monoclonal antibody which can substitute for the function of activated FVIII by bringing
      activated factor IX and factor X into proper alignment and induce the formation of activated
      factor X.

      Despite the high degree of efficacy of emicizumab for bleed prevention in inhibitor patients,
      the hemophilia community has still largely taken the stance that inhibitor eradication is a
      vital goal for any child who develops an inhibitor. The issue that the advent of emicizumab
      has raised, however, is what to do following successful ITI. As stated, traditionally,
      patients would continue FVIII therapy in the form of prophylaxis and the question of loss of
      tolerance and inhibitor recurrence was moot, however given the advantages of emicizumab, it
      is likely that many patients/parents will not accept continuing with the need for repeated
      intravenous infusions (and central venous catheters in many children) when an alternative
      agent with excellent efficacy and a much lower treatment burden exists. Thus, objective of
      this study is to determine whether ongoing factor VIII therapy is required for maintenance of
      tolerance.

      Study population: patients who have undergone successful ITI and are currently on emicizumab
      or willing to be on emicizumab.

      Study methodology: This will be a prospective, randomized trial of weekly FVIII CFC therapy
      versus no routine FVIII therapy for patients who have undergone successful ITI and are
      currently on emicizumab or willing to be on emicizumab.

      Description of study arms: Group 1 will receive ongoing once per weekly factor VIII therapy
      along with emicizumab after completion of a successful ITI. Group 2 will discontinue FVIII
      therapy and are on emicizumab for prophylaxis after completion of a successful ITI.

      Study endpoints: Study endpoints are to find out the number of subjects that maintained
      immune tolerance with/without FVIII exposure, understand the need for FVIII exposure for
      maintaining immune tolerance and to estimate the treatment burden and the cost effectivity
      for ongoing FVIII exposure after a successful ITI.

      Follow-up: Patients will be seen every month for inhibitor recurrence until 4th month of the
      study, and every two months until the first year of the study, at 18th month and at the end
      of the study. If there is a bleeding episode or an inhibitor, then there will be an
      unscheduled visit.

      Statistics: Patients will be categorized as either having a recurrence of an inhibitor or
      not. Thus, a 2x2 Chi-square contingency table will be able to group the subjects into those
      who received ongoing factor VIII and those who did not and those who did versus those who did
      not have an inhibitor recurrence. Fisher's exact test will be used to calculate the
      difference in proportion between the groups (inhibitor-positive and inhibitor-negative).

      Plans for analysis: Our goal is to complete the project including a submission for an
      abstract and publication within 24 months from the start of patient accrual.

Study Phase

Phase 4

Study Type

Interventional

Primary Outcome

Inhibitor recurrence

Condition

Hemophilia A

Intervention

FVIII

Study Arms / Comparison Groups

 Emicizumab + FVIII weekly

Description:  In addition to emicizumab prophylaxis,participants will receive non-prophylactic exposure to FVIII concentrates through weekly 50 IU/kg ±10% doses - the choice of FVIII concentrate is at the discretion of the PI.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status

Drug

Estimated Enrollment

Start Date

September 21, 2020

Completion Date

April 20, 2025

Primary Completion Date

September 20, 2024

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≤12 years at the time of signing the informed consent

          2. Male patients with severe (<1%) or moderate (<2%) hemophilia A

          3. History of a high titer (>5 BU) inhibitor

          4. Within 1 year of successful ITI, according to ISTH definitions (inhibitor titer <0.6
             BU, recovery more than 60% of expected, and half-life of >6 hours). Successful ITI has
             been achieved with any FVIII concentrate.

          5. Currently on emicizumab or willing to alter their prophylaxis treatment to emicizumab
             per study protocol.

        Exclusion Criteria:

          1. Age >12 years at the time of signing the informed consent

          2. Partial tolerance (not meeting criteria for complete tolerance per ISTH)

          3. History of anti-drug antibodies to emicizumab

          4. Unwilling to receive exposure to intravenous FVIII concentrates.

          5. History per the investigator's discretion of non-compliance to prior therapy.

Gender

Male

Ages

N/A - 12 Years

Accepts Healthy Volunteers

No

Contacts

Guy Young, MD, ,

Location Countries

United States

Location Countries

United States

Administrative Informations

NCT ID

NCT04621916

Organization ID

CHLA-20-00189

Responsible Party

Principal Investigator

Study Sponsor

Children's Hospital Los Angeles

Collaborators

 Grifols Biologicals, LLC

Study Sponsor

Guy Young, MD, Principal Investigator, Professor of Pediatrics, Director of Hemostasis and Thrombosis Center

Verification Date

February 2023