Hemophilia A With InhibitorPhase 4INITIATENCT03204539
INdividualized ITI Based on Fviii(ATE) Protection by VWF
A Phase 4 study testing Wilate in people with Hemophilia A With Inhibitor and Hemophilia A, run by University of California, Davis at 3 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Any age, men only
- Conditions the study is for
- Hemophilia A With Inhibitor, Hemophilia A
- What is being tested?
- Wilate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 3 sitesUnited States
- Study dates
- 1 Jun 2017to 19 Jul 2019
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- Men only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Tulane University
New Orleans, Louisiana, 70112
University of California, Davis
Sacramento, California, 95817
Rady Children's Hospital San Diego
San Diego, California, 92123
About this study
Official title: INdividualized ITI Based on Fviii(ATE) Protection by VWF (INITIATE)
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)].
Read the 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.
- Conditions
- Hemophilia A With Inhibitor, Hemophilia A
- Being tested
- Wilate
- Keywords
- inhibitor, Factor VIII inhibitor
- Medical subject headings
- Hemophilia A
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
WilateDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Alternative Treatment | Experimental | Half of the participants will be randomized to blinded individualized lot selection for ITI. Receives: Drug: Wilate |
| Standard Treatment | Other | The other half of the participants will receive random lot selection for ITI. Receives: Drug: Wilate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to Negative Inhibitor
This endpoint was chosen because a shorter time to negative inhibitor should decrease monthly break-through bleeding frequency in the early phase of ITI
Measured: completion of immune tolerance induction, up to 18 months
Secondary outcomes (8)
Time to Achieve Partial and Complete Success
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.
Measured: completion of immune tolerance induction, up to 18 months
Absence of Relapse, up to 12 Months After Achievement of Complete or Partial ITI Success
Measured: 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·
Measured: completion of immune tolerance induction, up to 18 months
Cost of ITI - Including Bleeding Control Using Bypassing Agents Prior to Start and During ITI
Measured: completion of immune tolerance induction, up to 18 months
Subject Quality of Life
measured with the Haemo-QOL questionnaire
Measured: completion of immune tolerance induction, up to 18 months
Subject Compliance With ITI Treatment Regimen
We will be looking at drug accountability reports/ logs which will reflect each subject's usage of Wilate
Measured: completion of immune tolerance induction, up to 18 months
The Impact of Inhibitor Titer at Start of ITI and During the Course of ITI, Including the Peak Titer of the Inhibitor
Measured: completion of immune tolerance induction, up to 18 months
Understand Other Factors Related to ITI Success Using Additional Biologic Assays
If subject consents, the following assays will be performed:
epitope mapping immunogenotyping/HLA genotyping FVIII genetic testing
Measured: screening/baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jul 2017
- Study start1 Jun 2017
- Primary completion19 Jul 2019
- Study completion19 Jul 2019
Why it stopped: Termination of funding from sponsor.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Hemophilia A With InhibitorStudies of the same condition, open and under way.
- More trials run by University of California, DavisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, Davis
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03204539
- Sponsor's protocol ID
- 988465
- Acronym
- INITIATE
- Status last verified
- May 2020
- First submitted
- 13 Jun 2017
- Last updated
- 29 May 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- INdividualized ITI Based on Fviii(ATE) Protection by VWF (INITIATE)
- ClinicalTrials.gov ID
- NCT03204539
- Acronym / sponsor ID
- INITIATE / 988465
- Conditions
- Hemophilia A With Inhibitor, Hemophilia A
- Keywords
- inhibitor, Factor VIII inhibitor
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Termination of funding from sponsor.
- Enrolment
- 1 participants (actual)
- Lead sponsor
- University of California, DavisUniversity, hospital or other
- Study start
- 1 Jun 2017 (actual)
- Primary completion
- 19 Jul 2019 (actual)
- Study completion
- 19 Jul 2019 (actual)
- First posted
- 2 Jul 2017 (actual)
- Results
- Posted 29 May 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Alternative Treatment | Experimental | Drug: WilateHalf of the participants will be randomized to blinded individualized lot selection for ITI. |
| Standard Treatment | Other | Drug: WilateThe other half of the participants will receive random lot selection for ITI. |
Who may qualify
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| WilateWilate® 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. | Drug | Alternative Treatment, Standard Treatment |
Primary outcome
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
8 secondary outcomes
Time to Achieve Partial and Complete Success
Time frame: completion of immune tolerance induction, up to 18 months
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
The Number of Break-through Bleeding Events During the Course of ITI-treatment·
Time frame: completion of immune tolerance induction, up to 18 months
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
Subject Quality of Life
Time frame: completion of immune tolerance induction, up to 18 months
Subject Compliance With ITI Treatment Regimen
Time frame: completion of immune tolerance induction, up to 18 months
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
Understand Other Factors Related to ITI Success Using Additional Biologic Assays
Time frame: screening/baseline
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 May 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Wilate in people with Hemophilia A With Inhibitor and Hemophilia A, run by University of California, Davis at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 29 May 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 May 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to Negative Inhibitor (time frame: completion of immune tolerance induction, up to 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2020.