GM-CSF for Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS (GRACE-2)

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.

Study Overview

• Status: Completed
• Conditions: Pediatric Sepsis-induced Multiple Organ Dysfunction Syndrome
• Intervention / Treatment: Drug: GM-CSF; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles
    • Oakland, California, United States, 64609
      • Benioff Children's Hospital - Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Sacramento, California, United States, 95618
      • University of California - Davis
    • San Francisco, California, United States, 94143
      • Benioff Children's Hospital - Mission Bay
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • CS Mott Children's Hospital
    • Detroit, Michigan, United States, 48202
      • Children's Hospital of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospital of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Mercy Children's Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Pennsylvania State University
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15260
      • Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • San Antonio, Texas, United States, 78207
      • Children's Hospital of San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84158
      • Primary Children's Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53233
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Nationwide Children's Hospital
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• VanBuren JM, Hall M, Zuppa AF, Mourani PM, Carcillo J, Dean JM, Watt K, Holubkov R. The Design of Nested Adaptive Clinical Trials of Multiple Organ Dysfunction Syndrome Children in a Single Study. Pediatr Crit Care Med. 2023 Dec 1;24(12):e635-e646. doi: 10.1097/PCC.0000000000003332. Epub 2023 Jul 27.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2022
• Primary Completion (Actual): September 10, 2025
• Study Completion (Actual): September 10, 2025

Study Registration Dates

• First Submitted: February 23, 2022
• First Submitted That Met QC Criteria: March 2, 2022
• First Posted (Actual): March 4, 2022

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Toxemia; Multiple Organ Failure; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Carbohydrates; Intercellular Signaling Peptides and Proteins; Glycoproteins; Glycoconjugates; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Granulocyte-Macrophage Colony-Stimulating Factor
• Other Study ID Numbers: GRACE-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No