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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

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.


Condition or disease Intervention/treatment Phase
Pediatric Sepsis-induced MODS Drug: GM-CSF Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
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
Official Title: GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS (GRACE)
Actual Study Start Date : December 5, 2018
Estimated Primary Completion Date : December 5, 2021
Estimated Study Completion Date : December 5, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis

Arm Intervention/treatment
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.
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

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.
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

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.
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

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.
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




Primary Outcome Measures :
  1. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03769844


Contacts
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Contact: Mark W Hall, MD 614-722-3438 mark.hall@nationwidechildrens.org

Locations
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United States, California
UCLA Mattel Children's Hospital Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Anil Sapru, MD    310-206-4730    asapru@mednet.ucla.edu   
Benioff Children's Hospital/UCSF Recruiting
San Francisco, California, United States, 94158
Contact: Patrick McQuillen, MD    415-476-9000    McQuillP@ucsf.edu   
United States, Colorado
Children's Hospital of Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Peter Mourani, MD    720-777-1234      
United States, District of Columbia
Children's National Medical Center Not yet recruiting
Washington, District of Columbia, United States, 20010
Contact: Murray Pollack, MD    202-476-5000      
United States, Michigan
Children's Hospital of Michigan Recruiting
Detroit, Michigan, United States, 48201
Contact: Kathleen Meert, MD    313-745-5437      
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Mark W Hall, MD    614-722-3438    Mark.Hall@NationwideChildrens.org   
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Athena Zuppa, MD    800-879-2467      
Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Joseph A Carcillo, MD    412-692-5325      
Sponsors and Collaborators
Nationwide Children's Hospital
Investigators
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Principal Investigator: Mark W Hall, MD Nationwide Children's Hospital

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Responsible Party: Mark Hall, Associate Professor, Department of Pediatrics, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT03769844     History of Changes
Other Study ID Numbers: GRACE
First Posted: December 10, 2018    Key Record Dates
Last Update Posted: July 22, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
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)
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mark Hall, Nationwide Children's Hospital:
sepsis
MODS
pediatric
immunoparalysis
GM-CSF
Additional relevant MeSH terms:
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Sepsis
Toxemia
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Sargramostim
Immunologic Factors
Physiological Effects of Drugs