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

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ClinicalTrials.gov Identifier: NCT03769844
Recruitment Status : Recruiting
First Posted : December 10, 2018
Last Update Posted : July 22, 2019
Sponsor:
Information provided by (Responsible Party):
Mark Hall, Nationwide Children's Hospital

Tracking Information
First Submitted Date  ICMJE December 6, 2018
First Posted Date  ICMJE December 10, 2018
Last Update Posted Date July 22, 2019
Actual Study Start Date  ICMJE December 5, 2018
Estimated Primary Completion Date December 5, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 6, 2018)
TNF-alpha response [ Time Frame: 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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03769844 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS Study
Official Title  ICMJE GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS (GRACE)
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE 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
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pediatric Sepsis-induced MODS
Intervention  ICMJE 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
Study Arms  ICMJE
  • 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.
    Intervention: Drug: GM-CSF
  • 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.
    Intervention: Drug: GM-CSF
  • 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.
    Intervention: Drug: GM-CSF
  • 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.
    Intervention: Drug: GM-CSF
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 6, 2018)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 5, 2021
Estimated Primary Completion Date December 5, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mark W Hall, MD 614-722-3438 mark.hall@nationwidechildrens.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03769844
Other Study ID Numbers  ICMJE GRACE
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan 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.
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: After subject enrollment and follow up have been completed. Data will be available indefinitely.
Access Criteria: The public use dataset will be available through the CPCCRN website
Responsible Party Mark Hall, Nationwide Children's Hospital
Study Sponsor  ICMJE Nationwide Children's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mark W Hall, MD Nationwide Children's Hospital
PRS Account Nationwide Children's Hospital
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP