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

Primary Purpose

Pediatric Sepsis-induced MODS

Status
Active
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
GM-CSF
Sponsored by
Nationwide Children's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pediatric Sepsis-induced MODS focused on measuring sepsis, MODS, pediatric, immunoparalysis, GM-CSF

Eligibility Criteria

undefined - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • UCLA Mattel Children's Hospital
  • Benioff Children's Hospital/UCSF
  • Children's Hospital of Colorado
  • Children's National Medical Center
  • Children's Hospital of Michigan
  • Nationwide Children's Hospital
  • Children's Hospital of Philadelphia
  • Children's Hospital of Pittsburgh

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

IV GM-CSF 125 mcg/m2/dose

SQ GM-CSF 125 mcg/m2/dose

IV GM-CSF 250 mcg/m2/dose

SQ GM-CSF 250 mcg/m2/dose

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Full Information

First Posted
December 6, 2018
Last Updated
February 7, 2023
Sponsor
Nationwide Children's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03769844
Brief Title
GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS Study
Acronym
GRACE
Official Title
GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS (GRACE)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 5, 2018 (Actual)
Primary Completion Date
December 5, 2023 (Anticipated)
Study Completion Date
December 5, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Nationwide Children's Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pediatric Sepsis-induced MODS
Keywords
sepsis, MODS, pediatric, immunoparalysis, GM-CSF

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Sequential Assignment
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)
Allocation
Non-Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
IV GM-CSF 125 mcg/m2/dose
Arm Type
Experimental
Arm Description
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.
Arm Title
SQ GM-CSF 125 mcg/m2/dose
Arm Type
Experimental
Arm Description
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.
Arm Title
IV GM-CSF 250 mcg/m2/dose
Arm Type
Experimental
Arm Description
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.
Arm Title
SQ GM-CSF 250 mcg/m2/dose
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
GM-CSF
Other Intervention Name(s)
granulocyte macrophage colony-stimulating factor, Leukine
Intervention Description
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.
Primary Outcome Measure Information:
Title
TNF-alpha response
Description
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
Time Frame
Subjects will be screened for immunoparalysis throughout their first three weeks of sepsis-induced MODS

10. Eligibility

Sex
All
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark W Hall, MD
Organizational Affiliation
Nationwide Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
UCLA Mattel Children's Hospital
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Benioff Children's Hospital/UCSF
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Facility Name
Children's Hospital of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Children's Hospital of Michigan
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
IPD Sharing Time Frame
After subject enrollment and follow up have been completed. Data will be available indefinitely.
IPD Sharing Access Criteria
The public use dataset will be available through the CPCCRN website

Learn more about this trial

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

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