Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS

Study Overview
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Brief Summary
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The TRIPS study is a prospective, multi-center, double-blind, adaptively randomized, placebo-controlled clinical trial of the drug anakinra for reversal of moderate to severe hyperinflammation in children with sepsis-induced multiple organ dysfunction syndrome (MODS).

Detailed Description
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The TRIPS study is a prospective, multi-center, double-blind, adaptively randomized, placebo-controlled clinical trial of the drug anakinra for reversal of moderate to severe hyperinflammation in children with sepsis-induced multiple organ dysfunction syndrome (MODS). Eligible subjects will undergo centralized immunophenotyping on day 2 of MODS. Subjects without immunoparalysis (a whole blood ex vivo LPS-induced TNF-alpha production capacity < 200 pg/ml) and a serum ferritin level of 500 - 2,000 ng/ml or a serum C-reactive protein (CRP) ≥ 4 mg/dl will be eligible for randomization, along with subjects with a serum ferritin level of 2,000 - 10,000 ng/ml regardless of their TNF-alpha response. Eligible subjects will receive intravenous (IV) anakinra at a dose of 4, 8, 12, or 16 mg/kg/day or placebo for 7 days.

Official Title
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Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS (TRIPS)

Conditions
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Pediatric Sepsis-induced Multiple Organ Dysfunction Syndrome (MODS)

Intervention / Treatment
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* Drug: Anakinra
* Drug: 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 therapyOR receipt of myeloablative therapy within the previous 14 days; OR Known allergy to anakinra, or E. coli-derived products; 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 TRIPS 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, adaptively-randomized, double-blind, placebo controlled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Anakinra 4 mg/kg/day<br>IV Anakinra 4mg/kg/day x 7 days | Drug: Anakinra<br>* See information in arm/group descriptions<br>|
| Active Comparator: Anakinra 8 mg/kg/day<br>IV Anakinra 8 mg/kg/day x 7 days | Drug: Anakinra<br>* See information in arm/group descriptions<br>|
| Active Comparator: Anakinra 12 mg/kg/day<br>IV Anakinra 12 mg/kg/day x 7 days | Drug: Anakinra<br>* See information in arm/group descriptions<br>|
| Active Comparator: Anakinra 16 mg/kg/day<br>IV Anakinra 16 mg/kg/day x 7 days | Drug: Anakinra<br>* See information in arm/group descriptions<br>|
| Placebo Comparator: Placebo<br>IV placebo x 7 days | Drug: Placebo<br>* See information in arm/group descriptions<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 | The cumulative Pediatric Logistic Organ Dysfunction (PELOD)-2 score over 28 days from randomization. The range of daily PELOD-2 scores is from 0 - 33, with higher scores representing worse organ function. | 28 days from randomization | 

Secondary Outcome Measures

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