<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/NCT03769844</url>
  </required_header>
  <id_info>
    <org_study_id>GRACE</org_study_id>
    <nct_id>NCT03769844</nct_id>
  </id_info>
  <brief_title>GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS Study</brief_title>
  <acronym>GRACE</acronym>
  <official_title>GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS (GRACE)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nationwide Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Nationwide Children's Hospital</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is an open-label, multi-center, interventional trial in which children with&#xD;
      sepsis-induced MODS undergo surveillance immune function testing beginning on Day 2 of MODS.&#xD;
      Those children who demonstrate immunoparalysis (TNF-alpha response &lt;200 pg/ml) will receive a&#xD;
      7-day course of GM-CSF at a dose of 125 or 250 mcg/m2/day by either the intravenous (IV) or&#xD;
      subcutaneous (SQ) route.&#xD;
&#xD;
      The goal of the study is to establish the dose and route of delivery that results in&#xD;
      resolution of immunoparalysis (TNF-alpha response &gt;=200 pg/ml) by the morning after the 3rd&#xD;
      scheduled dose with persistent resolution of immunoparalysis on the morning after the 7th&#xD;
      scheduled dose. Resolution of immunoparalysis in 8 out of the first 10 subjects in a study&#xD;
      treatment arm represents a successful dose and route. The goal of this study will be achieved&#xD;
      through the following Specific Aims:&#xD;
&#xD;
      Specific Aim 1. Establish the immunologic efficacy of GM-CSF administered by the IV and SQ&#xD;
      routes in children with immunoparalysis in the setting of sepsis-induced MODS.&#xD;
&#xD;
      Specific Aim 2. Estimate the pharmacokinetic parameters by the IV and SQ GM-CSF administered&#xD;
      in pediatric sepsis-induced MODS.&#xD;
&#xD;
      Specific Aim 3. Demonstrate the feasibility of screening, enrollment, drug delivery, and&#xD;
      sample collection for a multi-center immunostimulation trial in children with sepsis-induced&#xD;
      MODS.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 5, 2018</start_date>
  <completion_date type="Anticipated">December 5, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 5, 2023</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>This is an open-label, sequential, dose- and route of administration-finding study that will be conducted in sequential cohorts of children with sepsis-induced MODS</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>TNF-alpha response</measure>
    <time_frame>Subjects will be screened for immunoparalysis throughout their first three weeks of sepsis-induced MODS</time_frame>
    <description>Success in a cohort is defined as improvement in the whole blood ex vivo LPS-induced TNF-alpha production capacity (TNF response) to &gt;= 200 pg/ml by the morning after the 3rd dose and persisting to the morning after the 7th dose in at least 8 out of 10 treated subjects within a cohort</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Pediatric Sepsis-induced MODS</condition>
  <arm_group>
    <arm_group_label>IV GM-CSF 125 mcg/m2/dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects in this arm who demonstrate immunoparalysis will receive GM-CSF by the intravenous (IV) route at a dose of 125 mcg/m2/day for 7 consecutive days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SQ GM-CSF 125 mcg/m2/dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects in this arm who demonstrate immunoparalysis will receive GM-CSF by the subcutaneous (SQ) route at a dose of 125 mcg/m2/day for 7 consecutive days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>IV GM-CSF 250 mcg/m2/dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>If the IV 125 mcg/m2/dose arm is not successful in the first cohort of subjects, we will transition to 250 mcg/m2/day via the IV route for 7 consecutive days in a subsequent cohort.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SQ GM-CSF 250 mcg/m2/dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>If the SQ 125 mcg/m2/dose arm is not successful in a cohort of subjects (or if the IV dose had to be escalated to 250 mcg/m2/dose), we will transition to 250 mcg/m2/day via the SQ route for 7 consecutive days in a subsequent cohort.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GM-CSF</intervention_name>
    <description>Subjects demonstrating immunoparalysis (defined by a whole blood ex vivo LP-induced TNF-alpha production capacity &lt; 200 pg/ml) will receive 7 days of GM-CSF treatment by either the IV or SQ route at a dose of either 125 or 250 mcg/m2/day for 7 days.</description>
    <arm_group_label>IV GM-CSF 125 mcg/m2/dose</arm_group_label>
    <arm_group_label>IV GM-CSF 250 mcg/m2/dose</arm_group_label>
    <arm_group_label>SQ GM-CSF 125 mcg/m2/dose</arm_group_label>
    <arm_group_label>SQ GM-CSF 250 mcg/m2/dose</arm_group_label>
    <other_name>granulocyte macrophage colony-stimulating factor</other_name>
    <other_name>Leukine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  &gt;= 40 weeks gestational age to &lt;18 years; AND&#xD;
&#xD;
          -  Onset of &gt;=2 new organ dysfunctions (compared to pre-sepsis baseline) as measured by&#xD;
             the Proulx criteria; AND&#xD;
&#xD;
          -  Documented or suspected infection as the MODS inciting event.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unable to collect a cumulative total of 20.5 mL of blood for this study due to&#xD;
             research blood draw limits; OR&#xD;
&#xD;
          -  Limitation of care order at the time of screening; OR&#xD;
&#xD;
          -  Patients at high risk for brain death; OR&#xD;
&#xD;
          -  Active (or planned within 7 days) immunosuppressive treatment for oncologic,&#xD;
             transplant, or rheumatologic disease; OR&#xD;
&#xD;
          -  Known primary immunodeficiency disorder; OR&#xD;
&#xD;
          -  Diagnosis of myeloid leukemia, myelodysplasia, or autoimmune thrombocytopenia;OR&#xD;
&#xD;
          -  Known allergy to GM-CSF; OR&#xD;
&#xD;
          -  Documented hyperferritinemia (serum ferritin &gt;= 500 ng/ml) during current sepsis&#xD;
             event; OR&#xD;
&#xD;
          -  Contraindication to SQ injection (ECMO); OR&#xD;
&#xD;
          -  Burns where &gt;5% of the total body surface area is affected; OR&#xD;
&#xD;
          -  Renal replacement therapy at the time of screening; OR&#xD;
&#xD;
          -  On ECMO or anticipated to require ECMO; OR&#xD;
&#xD;
          -  Known pregnancy; OR&#xD;
&#xD;
          -  Inability to collect and ship sample for immune testing on MODS Day 2; OR&#xD;
&#xD;
          -  Previous enrollment in the GRACE study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark W Hall, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Nationwide Children's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UCLA Mattel Children's Hospital</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Benioff Children's Hospital/UCSF</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's National Medical Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Michigan</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nationwide Children's Hospital</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>December 6, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 10, 2018</study_first_posted>
  <last_update_submitted>February 7, 2023</last_update_submitted>
  <last_update_submitted_qc>February 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Nationwide Children's Hospital</investigator_affiliation>
    <investigator_full_name>Mark Hall</investigator_full_name>
    <investigator_title>Professor, Department of Pediatrics</investigator_title>
  </responsible_party>
  <keyword>sepsis</keyword>
  <keyword>MODS</keyword>
  <keyword>pediatric</keyword>
  <keyword>immunoparalysis</keyword>
  <keyword>GM-CSF</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sepsis</mesh_term>
    <mesh_term>Toxemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Molgramostim</mesh_term>
    <mesh_term>Sargramostim</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>After subject enrollment and follow up have been completed, the DCC will prepare a final study database for analysis. A releasable database will be produced and completely de-identified in accordance with the definitions provided in the Health insurance Portability and Accountability Act (HIPAA). Namely, all identifiers specified in HIPAA will be recoded in a manner that will make it impossible to deduce or impute the specific identity of any patient. The database will not contain any institutional identifiers.</ipd_description>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>After subject enrollment and follow up have been completed. Data will be available indefinitely.</ipd_time_frame>
    <ipd_access_criteria>The public use dataset will be available through the CPCCRN website</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/NCT03769844
org study id: GRACE
nct id: NCT03769844
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study is an open-label, multi-center, interventional trial in which children with
      sepsis-induced MODS undergo surveillance immune function testing beginning on Day 2 of MODS.
      Those children who demonstrate immunoparalysis (TNF-alpha response <200 pg/ml) will receive a
      7-day course of GM-CSF at a dose of 125 or 250 mcg/m2/day by either the intravenous (IV) or
      subcutaneous (SQ) route.

      The goal of the study is to establish the dose and route of delivery that results in
      resolution of immunoparalysis (TNF-alpha response >=200 pg/ml) by the morning after the 3rd
      scheduled dose with persistent resolution of immunoparalysis on the morning after the 7th
      scheduled dose. Resolution of immunoparalysis in 8 out of the first 10 subjects in a study
      treatment arm represents a successful dose and route. The goal of this study will be achieved
      through the following Specific Aims:

      Specific Aim 1. Establish the immunologic efficacy of GM-CSF administered by the IV and SQ
      routes in children with immunoparalysis in the setting of sepsis-induced MODS.

      Specific Aim 2. Estimate the pharmacokinetic parameters by the IV and SQ GM-CSF administered
      in pediatric sepsis-induced MODS.

      Specific Aim 3. Demonstrate the feasibility of screening, enrollment, drug delivery, and
      sample collection for a multi-center immunostimulation trial in children with sepsis-induced
      MODS.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: This is an open-label, sequential, dose- and route of administration-finding study that will be conducted in sequential cohorts of children with sepsis-induced MODS
primary purpose: Treatment
masking: None (Open Label)
measure: TNF-alpha response
time frame: Subjects will be screened for immunoparalysis throughout their first three weeks of sepsis-induced MODS
description: Success in a cohort is defined as improvement in the whole blood ex vivo LPS-induced TNF-alpha production capacity (TNF response) to >= 200 pg/ml by the morning after the 3rd dose and persisting to the morning after the 7th dose in at least 8 out of 10 treated subjects within a cohort
arm group label: IV GM-CSF 125 mcg/m2/dose
arm group type: Experimental
description: Subjects in this arm who demonstrate immunoparalysis will receive GM-CSF by the intravenous (IV) route at a dose of 125 mcg/m2/day for 7 consecutive days.
arm group label: SQ GM-CSF 125 mcg/m2/dose
arm group type: Experimental
description: Subjects in this arm who demonstrate immunoparalysis will receive GM-CSF by the subcutaneous (SQ) route at a dose of 125 mcg/m2/day for 7 consecutive days.
arm group label: IV GM-CSF 250 mcg/m2/dose
arm group type: Experimental
description: If the IV 125 mcg/m2/dose arm is not successful in the first cohort of subjects, we will transition to 250 mcg/m2/day via the IV route for 7 consecutive days in a subsequent cohort.
arm group label: SQ GM-CSF 250 mcg/m2/dose
arm group type: Experimental
description: If the SQ 125 mcg/m2/dose arm is not successful in a cohort of subjects (or if the IV dose had to be escalated to 250 mcg/m2/dose), we will transition to 250 mcg/m2/day via the SQ route for 7 consecutive days in a subsequent cohort.
intervention type: Drug
intervention name: GM-CSF
description: Subjects demonstrating immunoparalysis (defined by a whole blood ex vivo LP-induced TNF-alpha production capacity < 200 pg/ml) will receive 7 days of GM-CSF treatment by either the IV or SQ route at a dose of either 125 or 250 mcg/m2/day for 7 days.
arm group label: IV GM-CSF 125 mcg/m2/dose
arm group label: IV GM-CSF 250 mcg/m2/dose
arm group label: SQ GM-CSF 125 mcg/m2/dose
arm group label: SQ GM-CSF 250 mcg/m2/dose
other name: granulocyte macrophage colony-stimulating factor
other name: Leukine
criteria: 
gender: All
minimum age: N/A
maximum age: 17 Years
healthy volunteers: No
last name: Mark W Hall, MD
role: Principal Investigator
affiliation: Nationwide Children's Hospital
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Nationwide Children's Hospital
investigator full name: Mark Hall
investigator title: Professor, Department of Pediatrics
mesh term: Sepsis
mesh term: Toxemia
mesh term: Molgramostim
mesh term: Sargramostim
sharing ipd: Yes
ipd description: After subject enrollment and follow up have been completed, the DCC will prepare a final study database for analysis. A releasable database will be produced and completely de-identified in accordance with the definitions provided in the Health insurance Portability and Accountability Act (HIPAA). Namely, all identifiers specified in HIPAA will be recoded in a manner that will make it impossible to deduce or impute the specific identity of any patient. The database will not contain any institutional identifiers.
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: After subject enrollment and follow up have been completed. Data will be available indefinitely.
ipd access criteria: The public use dataset will be available through the CPCCRN website