<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02196207</url>
  </required_header>
  <id_info>
    <org_study_id>PRO14020038</org_study_id>
    <nct_id>NCT02196207</nct_id>
  </id_info>
  <brief_title>Hemophilia Inhibitor Clinical Trials (INHIBIT) Platform</brief_title>
  <acronym>INHIBIT</acronym>
  <official_title>Phase III INHIBIT Platform: Prevention Trial, Eloctate vs Emicizumab to Prevent Inhibitors; Eradication Trial: Eloctate Immune Tolerance (ITI) Plus Emicizumab vs vs Eloctate ITI Alone to Eradicate Inhibitors in Severe Hemophilia A</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Margaret Ragni</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will evaluate if Eloctate is superior to Emicizumab in reducing inhibitors in&#xD;
      children with severe hemophilia when given before the first bleed (preemptive) and continued&#xD;
      weekly to prevent bleeds (prophylaxis); and whether Eloctate immune tolerance induction (ITI)&#xD;
      plus emicizumab is superior to Eloctate ITI alone in eradicating inhibitor formation in&#xD;
      children and adults with severe hemophilia A.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multi-center, randomized Phase III Clinical Trials Platform (INHIBIT) in which&#xD;
      hemostatic agents will be compared using adaptive design to prevent and eradicate inhibitors&#xD;
      in patients with severe hemophilia A. This adaptive design is necessary as randomized trials&#xD;
      in rare diseases are otherwise not possible. The INHIBIT Trial Platform includes one&#xD;
      Inhibitor Prevention Trial and one Inhibitor Eradication Trial that will be conducted at up&#xD;
      to 41 U.S. hemophilia treatment centers (HTCs) affiliated with universities. The Inhibitor&#xD;
      Prevention Trial is a 48-week randomized phase III trial in which 66 previously untreated&#xD;
      patients (PUPs) (children &lt; 6 yr) with severe hemophilia A will be enrolled and randomized to&#xD;
      preemptive weekly Eloctate vs. Emicizumab to prevent inhibitor formation, defined as&#xD;
      anti-FVIII &gt; 5.0 BU. The Inhibitor Eradication Trial is a 48-week randomized phase III trial&#xD;
      in which 90 previously-treated patients (PTPs) with severe hemophilia A and high-responding&#xD;
      inhibitors (anti-VIII &gt;5.0 B.U.), including subjects developing inhibitors during the&#xD;
      Prevention Trials and adults or children of any age at the same HTCs refractory to or never&#xD;
      previously tolerated, will be enrolled and randomized to Eloctate ITI god plus weekly&#xD;
      Emicizumab vs. Eloctate ITI alone to eradicate inhibitor formation, defined as anti-FVIII&lt;0.6&#xD;
      B.U. Blood draws will be minimized to 6 timepoints, pre, 4, 12, 24, 36, and 48 weeks, and&#xD;
      validated for small volumes, 3.8 cc (¾ tsp) each. The Inhibit Trials Platform is considered&#xD;
      greater than minimal risk as study drug is given before the first bleed and special inhibitor&#xD;
      studies are obtained.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    The trial was revised to be two protocols, one Prevention, one Eradication Trials.&#xD;
  </why_stopped>
  <start_date type="Anticipated">August 2020</start_date>
  <completion_date type="Anticipated">July 2027</completion_date>
  <primary_completion_date type="Anticipated">July 2027</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Two phase III randomized trials, each with two arms, including one inhibitor prevention trial and one inhibitor eradication trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Prevention Trial: Time to inhibitor formation</measure>
    <time_frame>Up to 48 weeks</time_frame>
    <description>Inhibitor formation is defined as anti-FVIII &gt; / = 5.0 B.U. by chromogenic Nijmegen-modified Bethesda assay, performed on plasma, repeated for confirmation.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Eradication Trial: Time to inhibitor eradication</measure>
    <time_frame>Up to 48 weeks</time_frame>
    <description>Inhibitor eradication is defined as anti-FVIII &lt; 0.6 B.U. by chromogenic Nijmegen Bethesda assay, performed on plasma, repeated for confirmation.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Prevention &amp; Eradication Trials: Bleeding events including hematoma, joint, central nervous system, other</measure>
    <time_frame>Up to 48 weeks</time_frame>
    <description>Number of bleeding events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevention &amp; Eradication Trials: Factor VIII trough activity by chromogenic assay</measure>
    <time_frame>Up to 48 weeks</time_frame>
    <description>FVIII activity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevention &amp; Eradication Trials: HLA type and factor VIII genotype</measure>
    <time_frame>Up to 48 weeks</time_frame>
    <description>HLA haplotype and FVIII mutation</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Prevention &amp; Eradication Trials: T Cell Elispot Assay</measure>
    <time_frame>Up to 48 weeks</time_frame>
    <description>T cell reactivity to FVIII</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Severe Hemophilia A</condition>
  <arm_group>
    <arm_group_label>Eloctate Prophylaxis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Prevention Trial, Arm A: rFVIIIFc (Eloctate) 65 IU/kg weekly will be administered by intravenous infusion in previously untreated children with severe hemophilia A beginning before the first bleed and continued for up to 48 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Emicizumab Prophylaxis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Prevention Trial, Arm B: Emicizumab 1.5 mg/kg weekly (following 4-wk induction at 3 mg/kg weekly) will be administered by subcutaneous injection in previously untreated children with severe hemophilia A beginning before the first bleed and continued for up to 48 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Eloctate ITI plus Emicizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eradication Trial, Arm A: Eloctate 100 IU/kg every other day will be administered by intravenous infusion as immune tolerance plus Emicizumab 1.5 mg/kg weekly by subcutaneous injection in previously treated children and adults with severe hemophilia A and high-titer inhibitors and continued for up to 48 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Eloctate ITI Alone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Eradication Trial, Arm B: Eloctate 100 IU/kg every other day will be administered by intravenous infusion as immune tolerance alone in previously treated children and adults with severe hemophilia A and high-titer inhibitors and continued for up to 48 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eloctate Prophylaxis</intervention_name>
    <description>Prevention Trial, Arm A: Eloctate (65 IU/kg) will be administered weekly by intravenous infusion for up to 48 weeks in previously untreated children with severe hemophilia A beginning before the first bleed.</description>
    <arm_group_label>Eloctate Prophylaxis</arm_group_label>
    <other_name>rFVIIIFc Prophylaxis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Emicizumab Prophylaxis</intervention_name>
    <description>Prevention Trial, Arm B: Emicizumab (1.5 mg/kg) will be administered weekly by subcutaneous injection for up to 48 weeks in previously untreated children with severe hemophilia A.</description>
    <arm_group_label>Emicizumab Prophylaxis</arm_group_label>
    <other_name>Hemlibra Prophylaxis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eloctate ITI plus Emicizumab</intervention_name>
    <description>Eradication Trial, Arm A: Eloctate (100 IU/kg) ITI every other day by intravenous infusion plus Emicizumab (1.5 mg/kg) weekly by subcutaneous injection will be administered for up to 48 weeks as immune tolerance in children and adults with severe hemophilia A and high-titer inhibitors.</description>
    <arm_group_label>Eloctate ITI plus Emicizumab</arm_group_label>
    <other_name>rFVIIIFc ITI plus Hemlibra</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eloctate ITI</intervention_name>
    <description>Eradication Trial, Arm A: Eloctate (100 IU/kg) ITI every other day by intravenous infusion will be administered for up to 48 weeks as immune tolerance in children and adults with severe hemophilia A and high-titer inhibitors.</description>
    <arm_group_label>Eloctate ITI Alone</arm_group_label>
    <other_name>rFVIIIFc ITI</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Prevention Trial, Inclusion Criteria:&#xD;
&#xD;
          -  Male children &gt;/= 4 months of age.&#xD;
&#xD;
          -  Severe hemophilia A (FVIII &lt; 0.01 U/ml)&#xD;
&#xD;
          -  No previous bleed or surgery requiring treatment (except circumcision)&#xD;
&#xD;
          -  No previous factor VIII product (except for circumcision)&#xD;
&#xD;
          -  Willingness to comply with weekly prophylaxis for 48 weeks&#xD;
&#xD;
          -  Willingness of parent/caregiver to keep a personal diary of bleeding frequency and&#xD;
             factor treatment.&#xD;
&#xD;
          -  Willingness to make monthly visits and coagulation testing at weeks 4, 12, 24, 36, and&#xD;
             48 (end of study)&#xD;
&#xD;
        Prevention Trial, Exclusion Criteria:&#xD;
&#xD;
          -  Acquired hemophilia.&#xD;
&#xD;
          -  Any bleeding disorder other than hemophilia A.&#xD;
&#xD;
          -  Treatment with clotting factor previously, other than circumcision.&#xD;
&#xD;
          -  Presence of an inhibitor to factor VIII.&#xD;
&#xD;
          -  Use of an experimental drug(s).&#xD;
&#xD;
          -  Surgery anticipated in the next 48 weeks.&#xD;
&#xD;
          -  Life expectancy less than 5 years.&#xD;
&#xD;
          -  Inability to comply with study requirements.&#xD;
&#xD;
        Eradication Trial, Inclusion Criteria:&#xD;
&#xD;
          -  Male adults or children with no age limitation.&#xD;
&#xD;
          -  Severe hemophilia A (FVIII &lt;0.01 U/ml).&#xD;
&#xD;
          -  Presence of an inhibitor to FVIII (anti-FVIII &gt; 5.0 B.U.)&#xD;
&#xD;
          -  Willingness to comply with study drugs for up to 48 weeks.&#xD;
&#xD;
          -  Willingness to keep a personal diary of bleed frequency and drug treatment.&#xD;
&#xD;
          -  Willingness to make monthly visits and coagulation testing at weeks 4, 12, 24, 36, and&#xD;
             48 (end of study).&#xD;
&#xD;
        Eradication Trial, Exclusion Criteria:&#xD;
&#xD;
          -  Acquired hemophilia.&#xD;
&#xD;
          -  Any bleeding disorder other than hemophilia A.&#xD;
&#xD;
          -  Current use of Emicizumab, or if used, &gt; 8 weeks since last treatment.&#xD;
&#xD;
          -  Use of an experimental drug(s).&#xD;
&#xD;
          -  Surgery anticipated in the next 48 weeks.&#xD;
&#xD;
          -  Life expectancy less than 5 years.&#xD;
&#xD;
          -  Inability to copy with study requirements.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>4 Months</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Margaret V Ragni, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hemophilia Center of Western Pennsylvania</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>July 17, 2014</study_first_submitted>
  <study_first_submitted_qc>July 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 21, 2014</study_first_posted>
  <last_update_submitted>August 16, 2019</last_update_submitted>
  <last_update_submitted_qc>August 16, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 20, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Margaret Ragni</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Severe Hemophilia A</keyword>
  <keyword>Hemophilia Inhibitor Formation</keyword>
  <keyword>Eloctate</keyword>
  <keyword>Emicizumab</keyword>
  <keyword>Inhibitor Prevention</keyword>
  <keyword>Inhibitor Eradication</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemophilia A</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Antibodies, Bispecific</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>A biologic specimen and data repository for this trial will be available, pending NHLBI approval, at BioLINCC https://biolincc.nhlbi.nih.gov, to any research or investigator who makes formal application request and is formally approved by NHLBI.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>Within one year of trial completion.</ipd_time_frame>
    <ipd_access_criteria>Access will be determined by NHLBI.</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02196207
org study id: PRO14020038
nct id: NCT02196207
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This study will evaluate if Eloctate is superior to Emicizumab in reducing inhibitors in
      children with severe hemophilia when given before the first bleed (preemptive) and continued
      weekly to prevent bleeds (prophylaxis); and whether Eloctate immune tolerance induction (ITI)
      plus emicizumab is superior to Eloctate ITI alone in eradicating inhibitor formation in
      children and adults with severe hemophilia A.
This is a multi-center, randomized Phase III Clinical Trials Platform (INHIBIT) in which
      hemostatic agents will be compared using adaptive design to prevent and eradicate inhibitors
      in patients with severe hemophilia A. This adaptive design is necessary as randomized trials
      in rare diseases are otherwise not possible. The INHIBIT Trial Platform includes one
      Inhibitor Prevention Trial and one Inhibitor Eradication Trial that will be conducted at up
      to 41 U.S. hemophilia treatment centers (HTCs) affiliated with universities. The Inhibitor
      Prevention Trial is a 48-week randomized phase III trial in which 66 previously untreated
      patients (PUPs) (children < 6 yr) with severe hemophilia A will be enrolled and randomized to
      preemptive weekly Eloctate vs. Emicizumab to prevent inhibitor formation, defined as
      anti-FVIII > 5.0 BU. The Inhibitor Eradication Trial is a 48-week randomized phase III trial
      in which 90 previously-treated patients (PTPs) with severe hemophilia A and high-responding
      inhibitors (anti-VIII >5.0 B.U.), including subjects developing inhibitors during the
      Prevention Trials and adults or children of any age at the same HTCs refractory to or never
      previously tolerated, will be enrolled and randomized to Eloctate ITI god plus weekly
      Emicizumab vs. Eloctate ITI alone to eradicate inhibitor formation, defined as anti-FVIII<0.6
      B.U. Blood draws will be minimized to 6 timepoints, pre, 4, 12, 24, 36, and 48 weeks, and
      validated for small volumes, 3.8 cc (¾ tsp) each. The Inhibit Trials Platform is considered
      greater than minimal risk as study drug is given before the first bleed and special inhibitor
      studies are obtained.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Two phase III randomized trials, each with two arms, including one inhibitor prevention trial and one inhibitor eradication trial.
primary purpose: Treatment
masking: None (Open Label)
measure: Prevention Trial: Time to inhibitor formation
time frame: Up to 48 weeks
description: Inhibitor formation is defined as anti-FVIII > / = 5.0 B.U. by chromogenic Nijmegen-modified Bethesda assay, performed on plasma, repeated for confirmation.
measure: Eradication Trial: Time to inhibitor eradication
time frame: Up to 48 weeks
description: Inhibitor eradication is defined as anti-FVIII < 0.6 B.U. by chromogenic Nijmegen Bethesda assay, performed on plasma, repeated for confirmation.
measure: Prevention & Eradication Trials: Bleeding events including hematoma, joint, central nervous system, other
time frame: Up to 48 weeks
description: Number of bleeding events
measure: Prevention & Eradication Trials: Factor VIII trough activity by chromogenic assay
time frame: Up to 48 weeks
description: FVIII activity
measure: Prevention & Eradication Trials: HLA type and factor VIII genotype
time frame: Up to 48 weeks
description: HLA haplotype and FVIII mutation
measure: Prevention & Eradication Trials: T Cell Elispot Assay
time frame: Up to 48 weeks
description: T cell reactivity to FVIII
arm group label: Eloctate Prophylaxis
arm group type: Experimental
description: Prevention Trial, Arm A: rFVIIIFc (Eloctate) 65 IU/kg weekly will be administered by intravenous infusion in previously untreated children with severe hemophilia A beginning before the first bleed and continued for up to 48 weeks.
arm group label: Emicizumab Prophylaxis
arm group type: Experimental
description: Prevention Trial, Arm B: Emicizumab 1.5 mg/kg weekly (following 4-wk induction at 3 mg/kg weekly) will be administered by subcutaneous injection in previously untreated children with severe hemophilia A beginning before the first bleed and continued for up to 48 weeks.
arm group label: Eloctate ITI plus Emicizumab
arm group type: Experimental
description: Eradication Trial, Arm A: Eloctate 100 IU/kg every other day will be administered by intravenous infusion as immune tolerance plus Emicizumab 1.5 mg/kg weekly by subcutaneous injection in previously treated children and adults with severe hemophilia A and high-titer inhibitors and continued for up to 48 weeks.
arm group label: Eloctate ITI Alone
arm group type: Active Comparator
description: Eradication Trial, Arm B: Eloctate 100 IU/kg every other day will be administered by intravenous infusion as immune tolerance alone in previously treated children and adults with severe hemophilia A and high-titer inhibitors and continued for up to 48 weeks.
intervention type: Drug
intervention name: Eloctate Prophylaxis
description: Prevention Trial, Arm A: Eloctate (65 IU/kg) will be administered weekly by intravenous infusion for up to 48 weeks in previously untreated children with severe hemophilia A beginning before the first bleed.
arm group label: Eloctate Prophylaxis
other name: rFVIIIFc Prophylaxis
intervention type: Drug
intervention name: Emicizumab Prophylaxis
description: Prevention Trial, Arm B: Emicizumab (1.5 mg/kg) will be administered weekly by subcutaneous injection for up to 48 weeks in previously untreated children with severe hemophilia A.
arm group label: Emicizumab Prophylaxis
other name: Hemlibra Prophylaxis
intervention type: Drug
intervention name: Eloctate ITI plus Emicizumab
description: Eradication Trial, Arm A: Eloctate (100 IU/kg) ITI every other day by intravenous infusion plus Emicizumab (1.5 mg/kg) weekly by subcutaneous injection will be administered for up to 48 weeks as immune tolerance in children and adults with severe hemophilia A and high-titer inhibitors.
arm group label: Eloctate ITI plus Emicizumab
other name: rFVIIIFc ITI plus Hemlibra
intervention type: Drug
intervention name: Eloctate ITI
description: Eradication Trial, Arm A: Eloctate (100 IU/kg) ITI every other day by intravenous infusion will be administered for up to 48 weeks as immune tolerance in children and adults with severe hemophilia A and high-titer inhibitors.
arm group label: Eloctate ITI Alone
other name: rFVIIIFc ITI
criteria: 
gender: Male
minimum age: 4 Months
maximum age: 99 Years
healthy volunteers: No
last name: Margaret V Ragni, MD, MPH
role: Principal Investigator
affiliation: University of Pittsburgh
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Margaret Ragni
investigator title: Professor of Medicine
mesh term: Hemophilia A
mesh term: Antibodies, Bispecific
sharing ipd: Yes
ipd description: A biologic specimen and data repository for this trial will be available, pending NHLBI approval, at BioLINCC https://biolincc.nhlbi.nih.gov, to any research or investigator who makes formal application request and is formally approved by NHLBI.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: Within one year of trial completion.
ipd access criteria: Access will be determined by NHLBI.