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INdividualized ITI Based on Fviii(ATE) Protection by VWF (INITIATE)

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ClinicalTrials.gov Identifier: NCT03204539
Recruitment Status : Recruiting
First Posted : July 2, 2017
Last Update Posted : May 1, 2019
Sponsor:
Information provided by (Responsible Party):
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)].

Condition or disease Intervention/treatment Phase
Hemophilia A With Inhibitor Hemophilia A Drug: Wilate Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: INdividualized ITI Based on Fviii(ATE) Protection by VWF (INITIATE)
Actual Study Start Date : June 1, 2017
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : December 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: Alternative Treatment
Half of the participants will be randomized to blinded individualized lot selection for ITI.
Drug: Wilate
Wilate® is a high-purity (i.e. 100 IU FVIII/mg total protein) pdVWF/FVIII complex concentrate.Wilate® possesses all the important features asked for in ITI, namely high purity, a very high pathogen safety profile, and an excellent protection of its FVIII by VWF - all achieved through unique, novel, and innovative techniques.

Standard Treatment
The other half of the participants will receive random lot selection for ITI.
Drug: Wilate
Wilate® is a high-purity (i.e. 100 IU FVIII/mg total protein) pdVWF/FVIII complex concentrate.Wilate® possesses all the important features asked for in ITI, namely high purity, a very high pathogen safety profile, and an excellent protection of its FVIII by VWF - all achieved through unique, novel, and innovative techniques.




Primary Outcome Measures :
  1. Time to negative inhibitor [ Time Frame: 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 :
  1. Time to achieve partial and complete success [ Time Frame: 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.


  2. Absence of relapse, up to 12 months after achievement of complete or partial ITI success [ Time Frame: one year after completion of immune tolerance induction, up to 30 months ]
  3. The number of break-through bleeding events during the course of ITI-treatment· [ Time Frame: completion of immune tolerance induction, up to 18 months ]
  4. Cost of ITI - including bleeding control using bypassing agents prior to start and during ITI [ Time Frame: completion of immune tolerance induction, up to 18 months ]
  5. Subject quality of life [ Time Frame: completion of immune tolerance induction, up to 18 months ]
    measured with the Haemo-QOL questionnaire

  6. Subject compliance with ITI treatment regimen [ Time Frame: 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

  7. The impact of inhibitor titer at start of ITI and during the course of ITI, including the peak titer of the inhibitor [ Time Frame: completion of immune tolerance induction, up to 18 months ]
  8. Understand other factors related to ITI success using additional biologic assays [ Time Frame: screening/baseline ]

    If subject consents, the following assays will be performed:

    epitope mapping immunogenotyping/HLA genotyping FVIII genetic testing




Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Diagnosis of congenital Hemophilia A and baseline FVIII ≤2%.
  2. Weight ≥ 5 kg
  3. History of FVIII inhibitor titer ≥5 BU
  4. Current FVIII inhibitor titer ≥5 BU or ≥0.6 BU and failed ITI defined by FVIII recovery <66% normal and half-life <6 hours
  5. Adequate venous access for daily concentrate infusions
  6. 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.
  7. Ability to comply with study related treatments, evaluations, and follow-up.

Exclusion Criteria:

  1. Acquired hemophilia
  2. Congenital or acquired bleeding disorder in addition to Hemophilia A
  3. 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
  4. HIV positive with viral load ≥200 particles/μL or ≥400,000 copies/mL
  5. Rituximab within the past 3 months
  6. IVIG within the past 1 month
  7. Treatment with other immunosuppressive drugs within the past 1 month (excluding intermittent steroid use for asthma)
  8. Concomitant experimental treatment
  9. History of hypersensitivity to plasma-derived VWF- or FVIII-containing concentrates
  10. Elective surgery planned in the next 6 months (excluding vascular access procedure)
  11. Any condition or chronic illness, which in the opinion of the investigator makes participation ill-advised
  12. Inability or unwillingness to complete required screening, follow-up, and exit studies

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03204539


Contacts
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Contact: Katrina Wheeler 916-703-9197 krimson@ucdavis.edu
Contact: April Cuellar 916-703-9195 ammedina@ucdavis.edu

Locations
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United States, California
University of California, Davis Recruiting
Sacramento, California, United States, 95817
Contact: Jenny Fong    916-734-3469    jeafong@ucdavis.edu   
Principal Investigator: Jonathan Ducore, MD, MPH         
Sub-Investigator: Adam Giermasz, MD         
Sub-Investigator: Anjali Pawar, MD         
Rady Children's Hospital San Diego Not yet recruiting
San Diego, California, United States, 92123
Contact: Jacqueline Limjoco    858-966-1700 ext 7376    jlimjoco1@rchsd.org   
Principal Investigator: Courtney Thornburg, MD, MS         
United States, Louisiana
Tulane University Recruiting
New Orleans, Louisiana, United States, 70112
Contact: Melody Benton, MPH,MAS,CCRP    504-988-3596    mbenton@tulane.edu   
Principal Investigator: Tammuella Singleton, MD         
Sub-Investigator: Maissaa Janbain         
Sponsors and Collaborators
University of California, Davis

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Responsible Party: University of California, Davis
ClinicalTrials.gov Identifier: NCT03204539     History of Changes
Other Study ID Numbers: 988465
First Posted: July 2, 2017    Key Record Dates
Last Update Posted: May 1, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of California, Davis:
inhibitor
Factor VIII inhibitor
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants