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

Study Overview
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Brief Summary
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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.

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

Conditions
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Pediatric Sepsis-induced MODS

Intervention / Treatment
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* Drug: GM-CSF


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV GM-CSF 125 mcg/m2/dose<br>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<br>* 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.<br>* Other names: Leukine;|
| Experimental: SQ GM-CSF 125 mcg/m2/dose<br>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<br>* 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.<br>* Other names: Leukine;|
| Experimental: IV GM-CSF 250 mcg/m2/dose<br>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<br>* 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.<br>* Other names: Leukine;|
| Experimental: SQ GM-CSF 250 mcg/m2/dose<br>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<br>* 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.<br>* Other names: Leukine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TNF-alpha response | 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 | Subjects will be screened for immunoparalysis throughout their first three weeks of sepsis-induced MODS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunoparalysis, sepsis, MODS, pediatric, GM-CSF