GM-CSF for Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS

Study Overview
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Brief Summary
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The GRACE-2 study is a prospective, multi-center, double-blind, randomized controlled trial of the drug GM-CSF vs placebo in children with sepsis-induced multiple organ dysfunction syndrome (MODS) who have immunoparalysis with mild to moderate inflammation.

Detailed Description
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The GRACE-2 study is a is a prospective, multi-center, double-blind, randomized controlled trial of the drug GM-CSF vs placebo in children with sepsis-induced multiple organ dysfunction syndrome (MODS) who have immunoparalysis with mild to moderate inflammation. Eligible subjects will undergo centralized immunophenotyping on MODS Day 2. Those who are found to have immunoparalysis (a whole blood LPS-induced TNF-alpha production capacity < 200 pg/ml) with mild to moderate inflammation (serum ferritin level < 2000 ng/ml) will be randomized to receive intravenous (IV) GM-CSF at a dose of 125 mcg/m2/day x 7 days or placebo. The primary outcome variable is the cumulative 28-day Pediatric Logistic Organ Dysfunction (PELOD)-2 score. Secondary outcomes include measures of health-related quality of life and function status at 3 months from randomization.

Official Title
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GM-CSF for Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS

Conditions
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Pediatric Sepsis-induced Multiple Organ Dysfunction Syndrome

Intervention / Treatment
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* Drug: GM-CSF
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 40 weeks corrected gestational age to < 18 years; AND Admission to the PICU or CICU; AND Onset of ≥ 2 new organ dysfunctions within the last 3 calendar days (compared to pre-sepsis baseline) as measured by the modified Proulx criteria; AND Documented or suspected infection as the MODS inciting event. Exclusion Criteria: Weight <3kg; OR Limitation of care order at the time of screening; OR Patients at high likelihood of progression to brain death in opinion of the clinical team; OR Moribund condition in which the patient is unlikely to survive the next 48 hours in opinion of the clinical team; OR History of myeloid leukemia, myelodysplasia, or autoimmune thrombocytopenia; OR Current or prior diagnosis of hemophagocytic lymphohistiocytosis or macrophage activation syndrome; OR Peripheral white blood cell count < 1,000 cells/mm3 as the result of myeloablative therapy OR receipt of myeloablative therapy within the previous 14 days; OR Known allergy to GM-CSF; OR Known pregnancy; OR Lactating females; OR Receipt of anakinra or GM-CSF within the previous 28 days; OR Resolution of MODS by MODS Day 2; OR Previous enrollment in the GRACE-2 study.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, double-blind, placebo-controlled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GM-CSF<br>Intravenous GM-CSF 125 mcg/m2/day x 7 days | Drug: GM-CSF<br>* same as arm/group description<br>|
| Placebo Comparator: Placebo<br>Intravenous placebo x 7 days | Other: Placebo<br>* same as arm/group description<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative 28-day Pediatric Logistic Organ Dysfunction (PELOD)-2 score | Cumulative Pediatric Logistic Organ Dysfunction (PELOD)-2 score through 28 days post-randomization. The range of PELOD-2 score for a given day is 0 - 33 with a higher number being worse. | 28 days from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-month health-related quality of life | Change in Pediatric Quality of Life inventory (PedsQL) score from baseline to 3 months post-randomization. The range of PedsQL scores is from 0 - 100, with higher values corresponding to better quality of life. | 3 months post-randomization | 
| 3-month functional status | Change in Functional Status Score from baseline to 3 months post-randomization. The range of possible FSS score for a given subject is 6 - 30 with a higher score indicating worse function. | 3 months post-randomization |