INdividualized ITI Based on Fviii(ATE) Protection by VWF

Phase 4

Terminated

Conditions: Hemophilia A With Inhibitor
Hemophilia A

Interventions: Drug: Wilate

Registration Number: NCT03204539

Lead Sponsor: University of California, Davis

Brief Summary: The primary goal of the INITIATE trial is to compare the clinical outcome of individualized lot selection to random lot selection utilizing one plasma-derived von Willebrand factor (VWF)/coagulation factor (FVIII) complex concentrate for immune tolerance induction (ITI) in subjects with congenital Hemophilia A, FVIII activity ≤2%, and a historical high-titer inhibitor \[≥5 Bethesda Unit (BU)\].

Detailed Description: Participants will be randomized on a one-to-one basis between one of two study arms, individualized lot selection (alternative treatment arm) and random lot selection (standard treatment arm, current US clinical practice in ITI). Study sites, participants, and investigators will be blinded to the treatment status assigned.

Alternative treatment arm:

Half of the participants will be randomized to blinded individualized lot selection for ITI. The target initial dose of FVIII for ITI is \~200 IU/kg/day intravenously. The suggested maximum dose is 20,000 IU/day. Investigators may adjust the dose to a minimum dose of 150 units/kg if infusion volume is not feasible in patients without central venous access or in patients with von Willebrand factor levels \>250%. Splitting dose into two infusions per day must be approved by the Steering Committee, and if approved, will be considered a protocol deviation. Wilate® will be the VWF/FVIII complex concentrate (Octapharma USA, Inc., U.S. License No. 1646) prescribed for ITI.

Individualized lot selection will be performed according to a modified Oxford method in a central laboratory, by testing subject's plasma against 4-6 lots of Wilate® and selecting the one with the highest residual FVIII (lowest Oxford titer) activity remaining after incubation. The same lot will be used throughout the entire ITI course for each subject. If the selected lot is depleted prior to the completion of ITI, a second individualized lot selection will be performed using the original plasma sample provided at baseline.

Each Wilate® batch includes 1.6-1.8 million IU and is expected to last for about 3-57 months depending on the weight of the subject and prescribed dose.

Standard treatment arm:

The other half of the participants will receive random lot selection for ITI. The dose and concentrate used will be the same. Concentrate will be randomly selected from available Wilate® lots. The same lot will be used throughout the entire ITI course for each subject. If the random lot is depleted prior to the completion of ITI, a second lot will be randomly selected. In both cases the random lot will be tested against subject's plasma to measure the residual FVIII activity left after incubation but this result will not affect lot selection.

The primary hypothesis is that the time to negative inhibitor (\<0.6 BU) will be shorter with individualized lot selection compared to random lot selection and that this will impact monthly break-through bleeding and reduce costs.

Recruitment & Eligibility

Status: TERMINATED

Sex: Male

Target Recruitment: 1

Inclusion Criteria

Diagnosis of congenital Hemophilia A and baseline FVIII ≤2%.
Weight ≥ 5 kg
History of FVIII inhibitor titer ≥5 BU
Current FVIII inhibitor titer ≥5 BU or ≥0.6 BU and failed ITI defined by FVIII recovery <66% normal and half-life <6 hours
Adequate venous access for daily concentrate infusions
For participants <18 years, a parent or guardian willing and able to provide informed consent with verbal or written assent from the child if require by the local institution. For participants ≥18 years, a willingness and ability to provide informed consent from the subject.
Ability to comply with study related treatments, evaluations, and follow-up.

Exclusion Criteria

Acquired hemophilia
Congenital or acquired bleeding disorder in addition to Hemophilia A
ITI factor replacement regimen within the past one month unless there is clear evidence of ITI failure with no reduction in inhibitor titer over the past two months
HIV positive with viral load ≥200 particles/μL or ≥400,000 copies/mL
Rituximab within the past 3 months
IVIG within the past 1 month
Treatment with other immunosuppressive drugs within the past 1 month (excluding intermittent steroid use for asthma)
Concomitant experimental treatment
History of hypersensitivity to plasma-derived VWF- or FVIII-containing concentrates
Elective surgery planned in the next 6 months (excluding vascular access procedure)
Any condition or chronic illness, which in the opinion of the investigator makes participation ill-advised
Inability or unwillingness to complete required screening, follow-up, and exit studies

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Alternative Treatment	Wilate	Half of the participants will be randomized to blinded individualized lot selection for ITI.
Standard Treatment	Wilate	The other half of the participants will receive random lot selection for ITI.

Primary Outcome Measures

Name	Time	Method
Time to Negative Inhibitor	completion of immune tolerance induction, up to 18 months	This endpoint was chosen because a shorter time to negative inhibitor should decrease monthly break-through bleeding frequency in the early phase of ITI

Secondary Outcome Measures

Name	Time	Method
Time to Achieve Partial and Complete Success	completion of immune tolerance induction, up to 18 months	Secondary endpoints include time to achieve partial and complete success as defined according to the following criteria: * Inhibitor titer \<0.6 BU. * Incremental in vivo FVIII recovery in the normal range \[≥66% of normal (1.5% per IU/kg), equal to 0.99%per IU/kg\] with samples taken prior to and 15 or 30 minutes after concentrate treatment. The recovery assessment should be done without any wash-out period. * Half-life of FVIII \>6 hours. The half-life assessment should be done in a non-bleeding status without any wash-out period. Complete Success (CS) of ITI: All three criteria above met. Partial Success (PS) of ITI: The first two of the three criteria above met. Partial Response (PR) of ITI: One of the three criteria above met. Partial Failure (PF) of ITI: Inhibitor still present, but titer is decreased to \<5 BU in contrast to ≥5 BU before start. Complete Failure (CF) of ITI: None of the above mentioned criteria met, and the inhibitor titer is still ≥5 BU.
Absence of Relapse, up to 12 Months After Achievement of Complete or Partial ITI Success	one year after completion of immune tolerance induction, up to 30 months
The Number of Break-through Bleeding Events During the Course of ITI-treatment·	completion of immune tolerance induction, up to 18 months
Cost of ITI - Including Bleeding Control Using Bypassing Agents Prior to Start and During ITI	completion of immune tolerance induction, up to 18 months
Subject Quality of Life	completion of immune tolerance induction, up to 18 months	measured with the Haemo-QOL questionnaire
Subject Compliance With ITI Treatment Regimen	completion of immune tolerance induction, up to 18 months	We will be looking at drug accountability reports/ logs which will reflect each subject's usage of Wilate
The Impact of Inhibitor Titer at Start of ITI and During the Course of ITI, Including the Peak Titer of the Inhibitor	completion of immune tolerance induction, up to 18 months
Understand Other Factors Related to ITI Success Using Additional Biologic Assays	screening/baseline	If subject consents, the following assays will be performed: epitope mapping immunogenotyping/HLA genotyping FVIII genetic testing

Trial Locations

Locations (3): Tulane University
🇺🇸
New Orleans, Louisiana, United States
University of California, Davis
🇺🇸
Sacramento, California, United States
Rady Children's Hospital San Diego
🇺🇸
San Diego, California, United States