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Termination of funding from sponsor.
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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)].
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Alternative Treatment | Experimental | Half of the participants will be randomized to blinded individualized lot selection for ITI. |
|
| Standard Treatment | Other | The other half of the participants will receive random lot selection for ITI. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Wilate | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | completion of immune tolerance induction, up to 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Achieve Partial and Complete Success | Secondary endpoints include time to achieve partial and complete success as defined according to the following criteria:
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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, Davis | Sacramento | California | 95817 | United States | ||
| Rady Children's Hospital San Diego |
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Only 1 participant enrolled, but did not complete study due to early study termination.
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| ID | Title | Description |
|---|---|---|
| FG000 | Alternative Treatment | Half of the participants will be randomized to blinded individualized lot selection for ITI. 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. |
| FG001 | Standard Treatment | The other half of the participants will receive random lot selection for ITI. 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Only 1 participant enrolled (standard treatment arm), and did not complete study due to loss of funding.
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| ID | Title | Description |
|---|---|---|
| BG000 | Alternative Treatment | Half of the participants will be randomized to blinded individualized lot selection for ITI. 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Study terminated, and no participants completed study. No outcome measure data to report. | Posted | completion of immune tolerance induction, up to 18 months |
|
6 months
Only 1 participant enrolled in study (Standard treatment arm) due to loss of funding.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Alternative Treatment | Half of the participants will be randomized to blinded individualized lot selection for ITI. 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sepsis | Infections and infestations | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fever | Infections and infestations | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jonathan Ducore | UC Davis | 916-734-3461 | jmducore@ucdavis.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 31, 2018 | May 14, 2020 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 28, 2018 | May 14, 2020 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D006467 | Hemophilia A |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| D014841 | von Willebrand Factor |
| ID | Term |
|---|---|
| D001779 | Blood Coagulation Factors |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
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|
| completion of immune tolerance induction, up to 18 months |
| 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 | measured with the Haemo-QOL questionnaire | 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 | 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 | 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 | screening/baseline |
| San Diego |
| California |
| 92123 |
| United States |
| Tulane University | New Orleans | Louisiana | 70112 | United States |
| BG001 | Standard Treatment | The other half of the participants will receive random lot selection for ITI. 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 |
| Standard Treatment |
The other half of the participants will receive random lot selection for ITI. 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. |
|
| Secondary | Time to Achieve Partial and Complete Success | Secondary endpoints include time to achieve partial and complete success as defined according to the following criteria:
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. | Study terminated, and no participants completed study. No outcome measure data to report. | Posted | completion of immune tolerance induction, up to 18 months |
|
|
| Secondary | Absence of Relapse, up to 12 Months After Achievement of Complete or Partial ITI Success | Study terminated, and no participants completed study. No outcome measure data to report. | Posted | one year after completion of immune tolerance induction, up to 30 months |
|
|
| Secondary | The Number of Break-through Bleeding Events During the Course of ITI-treatment· | Study terminated, and no participants completed study. No outcome measure data to report. | Posted | completion of immune tolerance induction, up to 18 months |
|
|
| Secondary | Cost of ITI - Including Bleeding Control Using Bypassing Agents Prior to Start and During ITI | Study terminated, and no participants completed study. No outcome measure data to report. | Posted | completion of immune tolerance induction, up to 18 months |
|
|
| Secondary | Subject Quality of Life | measured with the Haemo-QOL questionnaire | Study terminated, and no participants completed study. No outcome measure data to report. | Posted | completion of immune tolerance induction, up to 18 months |
|
|
| Secondary | Subject Compliance With ITI Treatment Regimen | We will be looking at drug accountability reports/ logs which will reflect each subject's usage of Wilate | Study terminated, and no participants completed study. No outcome measure data to report. | Posted | completion of immune tolerance induction, up to 18 months |
|
|
| Secondary | The Impact of Inhibitor Titer at Start of ITI and During the Course of ITI, Including the Peak Titer of the Inhibitor | Study terminated, and no participants completed study. No outcome measure data to report. | Posted | completion of immune tolerance induction, up to 18 months |
|
|
| Secondary | 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 | Study terminated, and no participants completed study. No outcome measure data to report. | Posted | screening/baseline |
|
|
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| EG001 | Standard Treatment | The other half of the participants will receive random lot selection for ITI. 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. | 0 | 1 | 1 | 1 | 1 | 1 |
| Headache | General disorders | Non-systematic Assessment |
|
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| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D001685 |
| Biological Factors |