GRACE: GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS Study

Sponsor
Nationwide Children's Hospital (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03769844
Collaborator
(none)
120
8
4
48
15
0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 4

Study Design

Study Type:
Interventional
Anticipated Enrollment :
120 participants
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 MODSThis 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
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS (GRACE)
Actual Study Start Date :
Dec 5, 2018
Anticipated Primary Completion Date :
Dec 5, 2022
Anticipated Study Completion Date :
Dec 5, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: IV GM-CSF 125 mcg/m2/dose

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.

Drug: GM-CSF
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.
Other Names:
  • granulocyte macrophage colony-stimulating factor
  • Leukine
  • Experimental: SQ GM-CSF 125 mcg/m2/dose

    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.

    Drug: GM-CSF
    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.
    Other Names:
  • granulocyte macrophage colony-stimulating factor
  • Leukine
  • Experimental: IV GM-CSF 250 mcg/m2/dose

    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.

    Drug: GM-CSF
    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.
    Other Names:
  • granulocyte macrophage colony-stimulating factor
  • Leukine
  • Experimental: SQ GM-CSF 250 mcg/m2/dose

    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.

    Drug: GM-CSF
    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.
    Other Names:
  • granulocyte macrophage colony-stimulating factor
  • Leukine
  • Outcome Measures

    Primary Outcome Measures

    1. TNF-alpha response [Subjects will be screened for immunoparalysis throughout their first three weeks of sepsis-induced MODS]

      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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 17 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • = 40 weeks gestational age to <18 years; AND

    • Onset of >=2 new organ dysfunctions (compared to pre-sepsis baseline) as measured by the Proulx criteria; AND

    • Documented or suspected infection as the MODS inciting event.

    Exclusion Criteria:
    • Unable to collect a cumulative total of 20.5 mL of blood for this study due to research blood draw limits; OR

    • Limitation of care order at the time of screening; OR

    • Patients at high risk for brain death; OR

    • Active (or planned within 7 days) immunosuppressive treatment for oncologic, transplant, or rheumatologic disease; OR

    • Known primary immunodeficiency disorder; OR

    • Diagnosis of myeloid leukemia, myelodysplasia, or autoimmune thrombocytopenia;OR

    • Known allergy to GM-CSF; OR

    • Documented hyperferritinemia (serum ferritin >= 500 ng/ml) during current sepsis event; OR

    • Contraindication to SQ injection (ECMO); OR

    • Burns where >5% of the total body surface area is affected; OR

    • Renal replacement therapy at the time of screening; OR

    • On ECMO or anticipated to require ECMO; OR

    • Known pregnancy; OR

    • Inability to collect and ship sample for immune testing on MODS Day 2; OR

    • Previous enrollment in the GRACE study

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UCLA Mattel Children's Hospital Los Angeles California United States 90095
    2 Benioff Children's Hospital/UCSF San Francisco California United States 94158
    3 Children's Hospital of Colorado Aurora Colorado United States 80045
    4 Children's National Medical Center Washington District of Columbia United States 20010
    5 Children's Hospital of Michigan Detroit Michigan United States 48201
    6 Nationwide Children's Hospital Columbus Ohio United States 43205
    7 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    8 Children's Hospital of Pittsburgh Pittsburgh Pennsylvania United States 15224

    Sponsors and Collaborators

    • Nationwide Children's Hospital

    Investigators

    • Principal Investigator: Mark W Hall, MD, Nationwide Children's Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Mark Hall, Professor, Department of Pediatrics, Nationwide Children's Hospital
    ClinicalTrials.gov Identifier:
    NCT03769844
    Other Study ID Numbers:
    • GRACE
    First Posted:
    Dec 10, 2018
    Last Update Posted:
    Feb 25, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Mark Hall, Professor, Department of Pediatrics, Nationwide Children's Hospital
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Feb 25, 2022