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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IV GM-CSF 125 mcg/m2/dose | Experimental | 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. |
|
| SQ GM-CSF 125 mcg/m2/dose | Experimental | 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. |
|
| IV GM-CSF 250 mcg/m2/dose | Experimental | 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. |
|
| SQ GM-CSF 250 mcg/m2/dose | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GM-CSF | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Subjects With Restoration of the 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 | Subjects will be screened for immunoparalysis throughout their first three weeks of sepsis-induced MODS |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mark W Hall, MD | Nationwide Children's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCLA Mattel Children's Hospital | Los Angeles | California | 90095 | United States | ||
| Benioff Children's Hospital/UCSF |
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.
After subject enrollment and follow up have been completed. Data will be available indefinitely.
The public use dataset will be available through the CPCCRN website
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | IV GM-CSF 125 mcg/m2/Dose | Subjects in this arm who demonstrate immunoparalysis (a TNF response < 200 pg/ml) will receive GM-CSF by the intravenous (IV) route at a dose of 125 mcg/m2/day for 7 consecutive days. |
| BG001 | SQ GM-CSF 125 mcg/m2/Dose |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Subjects With Restoration of the 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 | Posted | Count of Participants | Participants | Subjects will be screened for immunoparalysis throughout their first three weeks of sepsis-induced MODS |
|
From first dose of study drug through the following 21 days (or until hospital discharge, whichever occurred first)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | IV GM-CSF 125 mcg/m2/Dose | Subjects in this arm who demonstrate immunoparalysis (a TNF response < 200 pg/ml) will receive GM-CSF by the intravenous (IV) route at a dose of 125 mcg/m2/day for 7 consecutive days. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Wound infection | Infections and infestations | Systematic Assessment | Not related |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mark W. Hall, MD | Nationwide Children's Hospital | 6147223438 | mark.hall@nationwidechildrens.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 29, 2019 | Jun 18, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D018805 | Sepsis |
| D009102 | Multiple Organ Failure |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D016178 | Granulocyte-Macrophage Colony-Stimulating Factor |
| D003115 | Colony-Stimulating Factors |
| C081222 | sargramostim |
| ID | Term |
|---|---|
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D016298 | Hematopoietic Cell Growth Factors |
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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
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|
| San Francisco |
| California |
| 94158 |
| United States |
| Children's Hospital of Colorado | Aurora | Colorado | 80045 | United States |
| Children's National Medical Center | Washington D.C. | District of Columbia | 20010 | United States |
| Children's Hospital of Michigan | Detroit | Michigan | 48201 | United States |
| Nationwide Children's Hospital | Columbus | Ohio | 43205 | United States |
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
| Children's Hospital of Pittsburgh | Pittsburgh | Pennsylvania | 15224 | United States |
Subjects in this arm who demonstrate immunoparalysis (a TNF response < 200 pg/ml) will receive GM-CSF by the subcutaneous (SQ) route at a dose of 125 mcg/m2/day for 7 consecutive days. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Initial TNF response | This value represents the subject's pre-treatment TNF response, with < 200 pg/ml being diagnostic of immunoparalysis | Median | Inter-Quartile Range | pg/ml |
|
Subjects in this arm who demonstrate immunoparalysis (a TNF response < 200 pg/ml) will receive GM-CSF by the subcutaneous (SQ) route at a dose of 125 mcg/m2/day for 7 consecutive days. |
|
|
| 0 |
| 10 |
| 1 |
| 10 |
| 9 |
| 10 |
| EG001 | SQ GM-CSF 125 mcg/m2/Dose | Subjects in this arm who demonstrate immunoparalysis (a TNF response < 200 pg/ml) will receive GM-CSF by the subcutaneous (SQ) route at a dose of 125 mcg/m2/day for 7 consecutive days. | 0 | 9 | 1 | 9 | 8 | 9 |
| Bacteremia | Infections and infestations | Systematic Assessment | Not related |
|
| Bacterial infection | Infections and infestations | Systematic Assessment | Not related |
|
| Wound dehiscence | Skin and subcutaneous tissue disorders | Systematic Assessment | Not related |
|
| Intra-abdominal abscess | Infections and infestations | Systematic Assessment | Possibly related |
|
| Acidosis | Metabolism and nutrition disorders | Systematic Assessment |
|
| Agitation | Psychiatric disorders | Systematic Assessment |
|
| Alkalosis | Metabolism and nutrition disorders | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Increased aPTT | Blood and lymphatic system disorders | Systematic Assessment |
|
| Atelectasis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Elevated bilirubin | Hepatobiliary disorders | Systematic Assessment |
|
| Bradycardia | Cardiac disorders | Systematic Assessment |
|
| Low BUN | Renal and urinary disorders | Systematic Assessment |
|
| BUN increased | Renal and urinary disorders | Systematic Assessment |
|
| Cellulitis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Elevated CRP | Immune system disorders | Systematic Assessment |
|
| Delirium | Psychiatric disorders | Systematic Assessment |
|
| Diaphragm paralysis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Emesis | Gastrointestinal disorders | Systematic Assessment |
|
| Facial paralysis | Nervous system disorders | Systematic Assessment |
|
| Fever | General disorders | Systematic Assessment |
|
| Elevated D-dimer | Blood and lymphatic system disorders | Systematic Assessment |
|
| Head injury | Nervous system disorders | Systematic Assessment |
|
| Hepatic infarction | Hepatobiliary disorders | Systematic Assessment |
|
| Hepatomegaly | Hepatobiliary disorders | Systematic Assessment |
|
| Hypercalcemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypernatremia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperphosphatemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypertension | Cardiac disorders | Systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypomagnesemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypophosphatemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypotension | Cardiac disorders | Systematic Assessment |
|
| Hypoxemia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Thrombosis - IVC | Blood and lymphatic system disorders | Systematic Assessment |
|
| Leukocytosis | Blood and lymphatic system disorders | Systematic Assessment |
|
| Increased lipase | Gastrointestinal disorders | Systematic Assessment |
|
| Confusion | Nervous system disorders | Systematic Assessment |
|
| Metabolic alkalosis | Metabolism and nutrition disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Opiate withdrawal | Nervous system disorders | Systematic Assessment |
|
| Decreased oxygen saturation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pain | Nervous system disorders | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pruritis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Pyelonephritis | Infections and infestations | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Red-man syndrome | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Respiratory failure - recurrent | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Septic embolism | Infections and infestations | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | Systematic Assessment |
|
| Tachypnea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Thrombocytosis | Blood and lymphatic system disorders | Systematic Assessment |
|
| Thrombosis - dural sinus | Nervous system disorders | Systematic Assessment |
|
| Urinary retention | Renal and urinary disorders | Systematic Assessment |
|
| Subdural hygroma | Nervous system disorders | Systematic Assessment |
|
| Tricuspid regurgitation | Cardiac disorders | Systematic Assessment |
|
| Bladder distention | Renal and urinary disorders | Systematic Assessment |
|
| Hypertriglyceridemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Central line infection | Infections and infestations | Systematic Assessment |
|
| Delayed wound closure | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Gram positive infection | Infections and infestations | Systematic Assessment |
|
| Elevated GGT | Hepatobiliary disorders | Systematic Assessment |
|
| Increased nasogastric output | Gastrointestinal disorders | Systematic Assessment |
|
| Poor feeding | Metabolism and nutrition disorders | Systematic Assessment |
|
| Pseudomeningocele | Nervous system disorders | Systematic Assessment |
|
| Intra-abdominal abscess | Infections and infestations | Systematic Assessment |
|
| Weakness - unilateral | Nervous system disorders | Systematic Assessment |
|
| Elevated procalcitonin | Infections and infestations | Systematic Assessment |
|
| Elevated BNP | Cardiac disorders | Systematic Assessment |
|
| Streptococcus viridans infection | Infections and infestations | Systematic Assessment |
|
| Increased airway secretions | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pressure injury | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Buttock injury | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Intra-abdominal fluid collection | Gastrointestinal disorders | Systematic Assessment |
|
| Hemorrhage | Blood and lymphatic system disorders | Systematic Assessment |
|
| Lung opacity | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
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| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
| D016207 |
| Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |