Pediatric Sepsis-induced MODS
Conditions
Keywords
sepsis, MODS, pediatric, immunoparalysis, GM-CSF
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.
Interventions
DRUGGM-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.
Sponsors
Nationwide Children's Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Restoration of the 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 |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMark W Hall, MD
Nationwide Children's Hospital
Participant flow
Recruitment details
All patients admitted to the pediatric or cardiac ICU at CPCCRN sites will be evaluated for study eligibility. Patients who meet inclusion criteria will be entered into the data capture system and exclusion criteria will be recorded in that system. If the patient is eligible (no exclusion criteria are present) then the legal guardian(s) will be approached and offered the opportunity for their child to participate in the GRACE study.
Pre-assignment details
After enrollment, subjects undergo measurement of the TNF response, with ONLY those having immunoparalysis (TNF response \<200pg/ml) going on to get study drug. Many subjects who are consented for immune phenotyping do NOT have immunoparalysis, so the number of subjects assigned to an interventional cohort will be fewer than the number consented. Since an adequate immune response was achieved with the 125 mcg/m2/dose strategy, no subjects were enrolled in the 250 mcg/m2/dose arms.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 2.85 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Initial TNF response | 126 pg/ml |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 |
| other Total, other adverse events | 9 / 10 | 8 / 9 |
| serious Total, serious adverse events | 1 / 10 | 1 / 9 |
Outcome results
None listed