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d9f3bd2a-5ce1-4192-93fa-fd4b066573c1 | PeRsonalizEd immunomodulation in pediatriC
sepsIS-inducEd MODS (PRECISE)
Study Protocol
GM-CSF for Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS (GRACE-2)
Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS (TRIPS)
Collaborative Pediatric Critical Care Research Network
Protocol Version 1.07
Version Date: June 16, 2023 | protocol.txt |
d45c83ea-5e7c-4a3e-9fc2-7c239d0ffe71 | Printing Date: June 16, 2023Copyright © 2021–2022. University of Utah School of Medicine on behalf of the Principal
Investigator, Mark W. Hall, Athena F. Zuppa and Peter Mourani and the Collaborative Pediatric
Critical Care Research Network (CPCCRN). All rights reserved.
This protocol is CPCCRN Protocol Number 90, and has been authored by Mark W. Hall, | protocol.txt |
620d5f32-8e7d-40ec-a0f7-146f7d0af4d1 | Athena F. Zuppa and Peter Mourani, Nationwide Children’s Hospital (Hall), Children’s Hospital
of Philadelphia (Zuppa) and Arkansas Children’s Hospital (Mourani), for implementation
with the CPCCRN investigators. This study is supported by PL1-HD105462 awarded to the
University of Utah (PI: J. Michael Dean) by the Eunice Kennedy Shriver National Institute for | protocol.txt |
37209fed-f19f-4763-a7a9-475b36f89571 | Child Health and Human Development (NICHD) and the associated RL-1 grants awarded to the
CPCCRN Clinical Centers. The CPCCRN Clinical Centers and their affiliated centers are listed
below.
CPCCRN Clinical Centers
CPCCRN Affiliated Centers
• Children’s Hospital of Colorado
• Children’s Hospital of Los Angeles
• Children’s Hospital of Michigan
• Children’s Hospital of Philadelphia | protocol.txt |
227180db-3e85-4b07-b4b1-3d9f00862e86 | • Children’s National Medical Center
• Duke University Medical Center
• Nationwide Children’s Hospital
• Texas Children’s Hospital
• UCSF Benioff
• University of Michigan
• University of Minnesota Masonic
• University of Pittsburgh Medical Center
• Arkansas Children’s Hospital
• Children’s Hospital of Orange County
• Primary Children’s Hospital
• Penn State University - Hershey | protocol.txt |
a4d510e0-56df-4789-ad57-29e0f6bb87b6 | • VCU Children’s Hospital of Richmond
• Medical University of South Carolina
• Rainbow Babies / Case Western
• Children’s Hospital of San Antonio
• UC Davis
• Medical College of Wisconsin
• Children’s Minnesota
• Children’s Mercy Kansas City
This document was prepared by the CPCCRN Data Coordinating Center located at the | protocol.txt |
bb62fa75-6893-4678-b2e4-a2a67a7211b4 | University of Utah School of Medicine, Salt Lake City, Utah. The CPCCRN Data Coordinating
Center at the University of Utah is supported by PL1-HD105462 . The document was written
and typeset using L A T E X 2ε.Protocol 90 (Hall, Zuppa and Mourani) Page 3 of 76
PROTOCOL TITLE:
PeRsonalizEd immunomodulation in pediatriC sepsIS-inducEd MODS
Short Title: PRECISE
CPCCRN Protocol Number: 90 | protocol.txt |
354d14fa-54a3-4eaf-86d4-89b3fe09636c | Lead Investigators and Authors:
Mark W. Hall, Athena F. Zuppa and Peter Mourani
Nationwide Children’s Hospital (Hall), Children’s Hospital of Philadelphia (Zuppa) and
Arkansas Children’s Hospital (Mourani)
Protocol Version: 1.07
Version Date: June 16, 2023
I confirm that I have read this protocol, I understand it, and I will conduct the study according | protocol.txt |
2b529f83-e4ba-4f48-a7b2-1f3b2b599a78 | to the protocol. I will also work consistently with the ethical principles that have their origin in
the Declaration of Helsinki and will adhere to the Ethical and Regulatory Considerations as
stated. I confirm that if I or any of my staff are members of the Institutional Review Board, we
will abstain from voting on this protocol, its future renewals, and its future amendments. | protocol.txt |
106cffe2-80fe-40fb-b841-24639f480608 | Principal Investigator Name:
Principal Investigator Signature:
Date:
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023
The Collaborative Pediatric Critical Care Research NetworkPage 4 of 76 Protocol 90 (Hall, Zuppa and Mourani)
THIS PAGE IS INTENTIONALLY BLANK.
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023 | protocol.txt |
f76a6307-c51d-4766-8612-22008d9b6f64 | The Collaborative Pediatric Critical Care Research NetworkContents
Contents 5
List of Tables 8
List of Figures 8
1 Rationale and Background 10
1.1 1.2 Immunologic Phenotypes in Sepsis-induced MODS . . . . . . . . . . . . . . . 10
GM-CSF for Immunosuppression (GRACE-2 Trial) . . . . . . . . . . . . . . . 11
1.2.1 Sepsis, MODS and Innate Immune Suppression . . . . . . . . . . . . . 11 | protocol.txt |
75e44666-cfa1-48b6-9271-8ecb21d5a91e | 1.2.2 Whole Blood ex vivo LPS-induced TNFαProduction Capacity . . . . . 12
1.2.3 Reversibility of Immunoparalysis Using GM-CSF Therapy . . . . . . . 12
1.2.4 Immunoparalysis and MAS/HLH . . . . . . . . . . . . . . . . . . . . . 14
1.3 Targeted Reversal of Inflammation (TRIPS Trial) . . . . . . . . . . . . . . . . 15
1.3.1 Heterogeneity of the Immune Response to Sepsis . . . . . . . . . . . . 15 | protocol.txt |
3cdc076f-5681-43fe-92f4-582dff0325e8 | 1.3.2 Immunoparalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
1.3.3 Inflammatory Biomarker Selection . . . . . . . . . . . . . . . . . . . . 17
1.3.4 Timing of Immunophenotyping . . . . . . . . . . . . . . . . . . . . . . 17
1.3.5 Rationale for Anakinra . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2 Study Summary 22 | protocol.txt |
6d21be20-9f14-4e4b-a08f-bbadb7178988 | 2.1 2.3 2.4 2.5 GRACE-2 Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.2 TRIPS Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Observational Cohorts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Longitudinal Immune Phenotyping . . . . . . . . . . . . . . . . . . . . . . . . 24 | protocol.txt |
110ec6fe-5791-491b-add6-abe3ca5f178b | Study Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3 Subject Eligibility, Accrual and Study Duration 26
3.1 3.2 Eligibility criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Subject Accrual and Study Duration . . . . . . . . . . . . . . . . . . . . . . . 27
4 Study Procedures 27 | protocol.txt |
23485fc0-f7b2-41d6-a7c5-49beb7f66f98 | 4.1 4.2 4.3 Screening and Enrollment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Immune Phenotyping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
GRACE-2 Study Drug Administration . . . . . . . . . . . . . . . . . . . . . . 29
4.3.1 Eligibility to Receive Study Drug Doses . . . . . . . . . . . . . . . . . 29 | protocol.txt |
32d27a22-8281-48e6-9f83-14bf0d3294f2 | 4.3.2 Intravenous Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5Page 6 of 76 Protocol 90 (Hall, Zuppa and Mourani)
4.3.3 Pharmacy Function and Monitoring . . . . . . . . . . . . . . . . . . . 30
4.4 TRIPS Study Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . 30
4.4.1 Intravenous Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 | protocol.txt |
2be5cc6e-d444-4f10-bae7-0b7a999a1977 | 4.4.2 Justification for IV Route of Administration . . . . . . . . . . . . . . . 31
4.4.3 Justification for Anakinra Dosing Strategy . . . . . . . . . . . . . . . . 31
4.4.4 Dose Adjustment for Severe Renal Dysfunction . . . . . . . . . . . . . 33
4.4.5 Pharmacy Function and Monitoring . . . . . . . . . . . . . . . . . . . 33 | protocol.txt |
1ea9bdc5-9107-43f2-a1d2-9934f00560c9 | 4.5 4.6 4.7 4.8 Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Blinding Study Arms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Biorepository Sample Collection and Processing . . . . . . . . . . . . . . . . . 34
Discontinuation of Study Drug . . . . . . . . . . . . . . . . . . . . . . . . . . 35 | protocol.txt |
2b88ac9d-9a12-4e84-8adf-e4e59d287077 | 4.9 Withdrawal from Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
4.10 PK Sample Collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
5 Data Collection 36
5.1 Demographic Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
5.2 Eligibility Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 | protocol.txt |
212c1c27-892b-4850-8848-bf7b14e1c0e2 | 5.3 Consent Procedure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.4 Baseline Review of Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.5 Baseline Admission Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.6 PICU/WARD Daily Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 | protocol.txt |
6ebbdf6d-a704-423b-9c2e-fe1ab2407d56 | 5.7 PELOD-2 Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.8 Immunophenotyping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.9 Randomization Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
5.10 Drug Administration Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 | protocol.txt |
38986423-0d16-4c1f-9ff5-c775a51e84d3 | 5.11 Biorepository Sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
5.12 Quality of Life Instruments . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
5.13 Data Logs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
5.14 Discontinuation or Withdrawal from Study . . . . . . . . . . . . . . . . . . . . 38
6 Statistical Summary 40 | protocol.txt |
e0fad42c-cde7-4090-8eee-4580d3af317a | 6.1 6.3 GRACE-2 Randomization and Power Estimation . . . . . . . . . . . . . . . . 40
6.2 TRIPS Randomization and Power Estimation . . . . . . . . . . . . . . . . . . 40
Data Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
6.3.1 Primary Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 | protocol.txt |
a1414573-3944-4586-8f52-901a7814e752 | 6.3.2 Secondary Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
6.3.3 Exploratory Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . 43
6.3.4 Safety Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023 | protocol.txt |
e808cf00-2ca2-4895-9944-83366cfdfe94 | The Collaborative Pediatric Critical Care Research NetworkProtocol 90 (Hall, Zuppa and Mourani) Page 7 of 76
6.3.5 6.3.6 Subgroup Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Handling of Missing Data . . . . . . . . . . . . . . . . . . . . . . . . 44
7 Data Management 45
7.1 7.2 Clinical Site Data Management . . . . . . . . . . . . . . . . . . . . . . . . . . 45 | protocol.txt |
3e127aad-9eb4-49e4-be10-6f3181f9550b | Data Coordinating Center . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
7.2.1 Data Center Description . . . . . . . . . . . . . . . . . . . . . . . . . 45
7.2.2 Facility, Hardware, Storage, Data Backup and System Availability . . . 46
7.2.3 Security, Support, Encryption, and Confidentiality . . . . . . . . . . . . 46 | protocol.txt |
25b861cb-eefa-4976-99b8-d32fb4f320b0 | 7.3 Electronic Data Capture System . . . . . . . . . . . . . . . . . . . . . . . . . 47
8 Study Site Monitoring 47
8.1 8.2 8.3 8.4 8.5 Site Monitoring Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Clinical Site Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Remote Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 | protocol.txt |
b6b5a7f6-dae0-4f07-93d2-5bc3a9fd5067 | Pharmacy Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Record Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
9 Protection of Human Subjects 49
9.1 Risks to Human Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
9.1.1 Human Subjects Involvement and Characteristics . . . . . . . . . . . . 49 | protocol.txt |
6d788fb2-1308-4409-90d5-8da68de1db38 | 9.1.2 Study Procedures and Materials . . . . . . . . . . . . . . . . . . . . . 50
9.1.3 Potential Risks of Study Participation . . . . . . . . . . . . . . . . . . 51
9.1.4 Alternatives to Study Participation . . . . . . . . . . . . . . . . . . . . 52
9.2 Adequacy of Protection Against Risks . . . . . . . . . . . . . . . . . . . . . . 52 | protocol.txt |
b159f263-0fea-43da-8a36-132e58e39d6c | 9.2.1 Parental Permission, Informed Consent and Assent . . . . . . . . . . . 52
9.2.2 Institutional Review Board and Human Research Protection . . . . . . 54
9.2.3 Protections Against Risk . . . . . . . . . . . . . . . . . . . . . . . . . 55
9.2.4 Vulnerable Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 | protocol.txt |
bb894255-c345-409d-b20c-68c0ff973ad8 | 9.3 9.4 Potential Benefits of Proposed Research . . . . . . . . . . . . . . . . . . . . . 56
Importance of the Knowledge to be Gained . . . . . . . . . . . . . . . . . . . 57
10 Data and Safety Monitoring Plan 57
10.1 Data Safety Monitoring Board (DSMB) . . . . . . . . . . . . . . . . . . . . . 57
10.2 Adverse Event Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 | protocol.txt |
7aef00e5-ab34-4c69-a2df-7d7047dd4baa | 10.2.1 Definition of Adverse Event and Serious Adverse Event . . . . . . . . . 58
10.2.2 Classification of Adverse Events (Relatedness and Expectedness) . . . . 58
10.2.3 Time Period for Adverse Events . . . . . . . . . . . . . . . . . . . . . 60
10.2.4 Data Collection Procedures for Adverse Events . . . . . . . . . . . . . 60
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023 | protocol.txt |
729d6b52-a02e-4089-b195-aec74b2c6b8b | The Collaborative Pediatric Critical Care Research Network10.2.5 Unanticipated Problems (UP) . . . . . . . . . . . . . . . . . . . . . . . 61
10.2.6 Monitoring Serious Adverse Events . . . . . . . . . . . . . . . . . . . 61
10.2.7 Individual Subject Stopping Rules for TRIPS Trial . . . . . . . . . . . 62
10.2.8 Follow-up of Serious, Unexpected and Related Adverse Events . . . . . 63 | protocol.txt |
fede888c-ea16-4bc6-bfb7-d3356253a80f | 10.2.9 Reporting to the Food and Drug Administration . . . . . . . . . . . . . 63
11 Study Training 63
12 Regulatory Considerations 64
12.1 Food and Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 64
12.2 Health Insurance Portability and Accountability Act . . . . . . . . . . . . . . . 64 | protocol.txt |
8ba524eb-3de0-4711-bfe3-db2dc4a0d920 | 12.3 Inclusion of Women and Minorities . . . . . . . . . . . . . . . . . . . . . . . . 64
12.4 Clinical Trial Registration Requirements . . . . . . . . . . . . . . . . . . . . . 64
12.5 Retention of Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
12.6 Public Use Data Set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
13 References 65
14 Bibliography 65 | protocol.txt |
bcee1149-8bc1-4da2-a41b-28766f5bc135 | List of Tables
1 Previous publications of immunomodulation with GM-CSF. . . . . . . . . . . . 13
2 Study Schedule of Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
List of Figures
1 Laboratory immune phenotyping to identify subject study eligibility. . . . . . . 11
2 Effects of GM-CSF on immune function in children. . . . . . . . . . . . . . . . 15 | protocol.txt |
02ddf950-e881-4ae6-b0cb-1ae9fc86f756 | 3 Immune response to pediatric sepsis includes SIRS and CARS. . . . . . . . . . 16
4 Reversal of immunoparalysis after anakinra. . . . . . . . . . . . . . . . . . . . 21
5 Distribution assumptions for GRACE-2 trial. . . . . . . . . . . . . . . . . . . . 41
8Protocol 90 (Hall, Zuppa and Mourani) Page 9 of 76
Abstract | protocol.txt |
43fb6691-0f89-45b2-aaf8-5bfd6b3a8d08 | In 2005, the Eunice Kennedy Shriver National Institute of Child Health and Human Devel-
opment (NICHD) established the Collaborative Pediatric Critical Care Research Network
(CPCCRN) to support multi-institutional randomized controlled trials (RCTs) and obser-
vational studies in critically ill children. The network will conduct a highly innovative | protocol.txt |
9af73250-c353-4207-b8d3-12a1739f9eb3 | large-scale multi-center study of personalized, targeted immune modulation in children
with sepsis-induced multiple organ dysfunction syndrome (MODS). This study is entitled
the “PeRsonalizEd immunomodulation in pediatriC sepsIS-inducEd MODS (PRECISE)”,
and includes two concurrent, immunophenotype-driven placebo controlled RCTs that will | protocol.txt |
93c3cc2e-f478-4120-b58b-a316742fecae | address the central hypothesis that individualized, pathophysiology-specific immunomodu-
lation will improve outcomes from sepsis-induced MODS in children. This study builds
on R01-funded CPCCRN studies that have demonstrated the existence of specific immune
phenotypes among children with sepsis-induced MODS (R01GM108618 PI: Carcillo) | protocol.txt |
99222531-b87f-4d38-aaaf-92c217022c91 | and successful reversal of immunosuppression by administration of the immunostimulant
granulocyte macrophage-colony stimulating factor (GM-CSF) (R01GM094203 PI: Hall). It
also complements the ongoing NICHD R01-funded study investigating the risk factors for
immunoparalysis in pediatric MODS (R01HD095976 MPI: Hall, Zuppa). | protocol.txt |
ee5e49a8-164b-4986-8cd5-19d13dcffa7a | Following informed consent, critically ill children with MODS will be immunopheno-
typed into one of four groups:
1. 2. Immunoparalysis with mild to moderate inflammation;
No immunoparalysis with mild inflammation;
3. No immunoparalysis with moderate to severe inflammation, OR immunoparalysis
with severe inflammation;
4. Very severe inflammation, probably macrophage activation syndrome (MAS) or | protocol.txt |
1c2aeebd-fcb5-4a82-b590-41d5fb8fcf65 | hemophagocytic lymphohistiocytosis (HLH).
Subjects in the first group will be enrolled in the GM-CSF for Reversal of Immunoparal-
ysis in Pediatric Sepsis-induced MODS (GRACE-2) trial, comparing GM-CSF versus
placebo. Subjects in the second group will be an observational cohort with no intervention,
because this group has very low mortality and morbidity. Subjects in the third group will | protocol.txt |
c01387b0-a96c-460e-be5d-d220e28cdfef | be enrolled in the Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS
(TRIPS) trial, comparing anakinra and placebo. The fourth group, with very severe inflam-
mation, will be an observational cohort because clinical management of the inflammation
is standard of care, and there is no equipoise about enrolling these children in a placebo | protocol.txt |
d853c884-8827-4993-a994-615d0de999d1 | controlled trial. The primary outcome of both trials will be duration and severity of organ
dysfunction using the cumulative PELOD-2 score, and secondary outcomes will assess
health related quality of life and family functioning at 3 and 12 months. A comprehensive
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023 | protocol.txt |
598950a5-ce92-4598-9f4f-80d874c9f361 | The Collaborative Pediatric Critical Care Research NetworkPage 10 of 76 Protocol 90 (Hall, Zuppa and Mourani)
biorepository will store specimens from all consented subjects, including those in the
observational cohorts.
The PeRsonalizEd immunomodulation in pediatriC sepsIS-inducEd MODS (PRECISE)
study represents a paradigm shift in the management of pediatric sepsis, finally moving | protocol.txt |
3e255a4f-4a94-4ca5-9b4a-cf048e79d1c1 | beyond simple supportive care. We are uniquely positioned to successfully execute this
approach to personalized, real-time, pathophysiology-directed sepsis treatment, leveraging
the strengths of a diverse and highly accomplished group of investigators to deliver high-
impact science to the benefit of our patients and our field.
1 Rationale and Background | protocol.txt |
a0e3c0cc-e1f5-4f3d-ac5b-201dc2192565 | 1.1 Immunologic Phenotypes in Sepsis-induced MODS
Current pediatric sepsis management is largely focused on antibiotics and supportive care
including fluid resuscitation and the use of vasoactive drugs. Except for titration of vasoactive
support based on hemodynamics, there are no recommended treatment approaches that are per- | protocol.txt |
b7e2d7dc-65ba-487a-89cd-8f9dc93e5341 | sonalized to the individual septic child’s pathophysiology in the 2020 pediatric Surviving Sepsis
guidelines, our field’s leading resource for evidence-based pediatric sepsis care.82 Our network
has systematically collected data from hundreds of septic children across multiple pediatric
centers clearly showing that children with sepsis-induced MODS have distinct pathophysiologic | protocol.txt |
b16af007-3bad-4a16-8b17-4f4f37d6720b | immune phenotypes that we hypothesize could benefit from personalized care.
The host’s immune response to a pathogen is the key driver of organ dysfunction in sepsis.
In the 1980s and 1990s, numerous studies in septic adults targeted the blockade or removal
of specific pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin | protocol.txt |
e07dd2d0-89f6-4eb4-8a8f-da04763d32fc | (IL)-1β, and others, but phase III clinical trials were not successful in reducing sepsis mortal-
ity.1, 2, 15, 20, 23, 63 Anti-cytokine therapies and other forms of immunomodulation in sepsis were
largely abandoned thereafter until we began to have a clearer understanding of the heterogeneity
of the immune response. Immunophenotyping studies, many conducted by CPCCRN mem- | protocol.txt |
5280d757-82bc-4456-a6de-bbae555699e7 | ber investigators,8, 9, 31, 32, 56 have shown that children with sepsis-induced MODS often have
markedly hypoactive circulating leukocytes and could potentially benefit from an immunos-
timulatory approach rather than an anti-inflammatory one, whereas others have evidence of
severe hyperinflammation that may benefit from anti-cytokine therapies. The prior generation of | protocol.txt |
95cc7628-267d-4843-8424-fb19259683a8 | clinical trials failed to account for these inter-individual variations in immune response, leading
many subjects to be treated with what may have been the wrong immunomodulator.
We have developed the laboratory infrastructure to rapidly diagnose these phenotypes,
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023 | protocol.txt |
976220b1-bbb0-410c-8681-d7ff075610da | The Collaborative Pediatric Critical Care Research NetworkProtocol 90 (Hall, Zuppa and Mourani) Page 11 of 76
allowing, for the first time, the creation of interventional protocols that are personalized to an
individual septic child’s immune state. Children for whom parents provide informed consent
will be phenotyped as indicated in Figure 1. | protocol.txt |
1335a014-61b9-4ec6-bd6a-528c865f5b3b | Figure 1: Laboratory immune phenotyping to identify subject study eligibility.
1.2 GM-CSF for Immunosuppression (GRACE-2 Trial)
1.2.1 Sepsis, MODS and Innate Immune Suppression
Severe sepsis/septic shock remain a major source of pediatric morbidity and mortality worldwide,
with the highest rates of adverse outcomes seen in children who develop failure of two or | protocol.txt |
48c3ccf6-be24-4573-951c-adb238ad11c0 | more organs. Children with sepsis-induced multiple organ dysfunction syndrome (MODS)
represent a heterogeneous group of patients who have been shown to have several distinct
phenotypes of underlying pathophysiology.8 The most common phenotype, immunoparalysis,
is the result of an exaggerated compensatory anti-inflammatory response. Impairment of the | protocol.txt |
54f15044-7e54-4231-ae85-f14487dbcabf | innate immune system is common and measurable in pediatric sepsis. Innate immune cells such
as monocytes and neutrophils serve critical functions including migration to sites of infection,
phagocytosis of pathogens, promotion of microbial killing, antigen presentation, and production
of immunomodulatory cytokines. We have repeatedly shown that severe reduction in the ability | protocol.txt |
5b8a5164-112e-4f6e-84f3-f4e63cb673c1 | PRECISE Protocol Version 1.07
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of a child’s circulating leukocytes to produce pro-inflammatory cytokines occurs commonly
in pediatric critical illness, and is strongly associated with increased risks of prolonged organ | protocol.txt |
a5299ff6-4107-48b7-99eb-835c6b97199f | dysfunction, nosocomial infection, and death.8, 31, 32, 55, 56, 62, 78
1.2.2 Whole Blood ex vivo LPS-induced TNFαProduction Capacity
Stimulation of whole blood with lipopolysaccharide (LPS) allows for quantification of the innate
immune system’s responsiveness to a new challenge. LPS stimulation should result in rapid and | protocol.txt |
7b3f43a0-efa0-405e-9ede-2f7385cb0a52 | robust production of the proinflammatory cytokine tumor necrosis factor (TNFα). Severe reduc-
tions in the TNFαresponse have been associated with adverse outcomes including increased
risks for prolonged organ dysfunction, nosocomial infection, and death in children with life-
threatening infection.8, 31, 32, 50, 56, 62 We have consistently shown that a TNFαresponse <200 | protocol.txt |
e7dcb3ba-018a-49b6-88c4-5bab76dc967d | pg/ml in our assay identifies the population of patients at highest risk for these adverse outcomes.
The Immune Surveillance Laboratory at The Abigail Wexner Research Institute at Nation-
wide Children’s Hospital, under the direction of Dr. Hall, has been conducting single- and
multi-center immune monitoring and modulation studies using the TNF-αresponse assay since | protocol.txt |
55b87762-d9ca-48e6-8adc-2f6de9ac5e1c | 2007. We use a consistent LPS type with rigorous quality control procedures, small blood
volumes appropriate for pediatric studies, a four-hour incubation period (suitable for same-day
processing), and TNF-αquantitation on a highly automated, Good Laboratory Practices instru-
ment. The Immulite 1000 (Siemens, Deerfield, IL) is an automated chemiluminometer that is | protocol.txt |
5121abd1-b089-4e4c-ab53-08ba41af3b74 | used to measure hormones and other analytes in the clinical laboratory. We perform quantitation
of TNF-αusing this instrument under a Research Use Agreement, though these test kits are
used clinically in Europe for patient management. The intra-assay coefficient of variation for the
TNF-αassay on the Immulite is less than 10%. By using the Immulite 1000 we avoid the need | protocol.txt |
ced322b0-0d8d-436f-8415-fb7b97775f17 | to perform highly operator-dependent assays such as enzyme-linked immunosorbent assays
(ELISAs).
1.2.3 Reversibility of Immunoparalysis Using GM-CSF Therapy
GM-CSF is an endogenous, immunostimulating cytokine produced primarily by TH1 lympho-
cytes. It is available in recombinant human form (sargramostim, Leukine; Partner Therapeutics, | protocol.txt |
fd109800-b64a-45ff-ae84-ee47833a15cf | Lexington, MA) and has been FDA-approved for bone marrow reconstitution following bone
marrow transplantation (BMT) since 1991. It has a long track record of safe use in acutely and
critically ill patients, including children, with a very low incidence of adverse events, the bulk
of which are rate-of-infusion related when given by the IV route.57–59 Rapid IV administration | protocol.txt |
bebb045c-54a7-4901-9aa0-e6de84a416fa | of GM-CSF (over less than 2 hours) has been associated with respiratory distress, peripheral
edema (11% incidence with GM-CSF vs 7% incidence with placebo) and pericardial effusion
(4% vs 1%), but these side effects have not been observed with IV infusion durations of >2
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023 | protocol.txt |
1ce09726-280e-4543-a947-423ec02fee41 | The Collaborative Pediatric Critical Care Research NetworkProtocol 90 (Hall, Zuppa and Mourani) Page 13 of 76
hours or via the subcutaneous (SQ) route.36
Table 1: Published evidence for use of GM-CSF for immunomodulation in critically ill adults
and children.
Monocyte hyporesponsiveness has been shown to be reversible in vitro through co-culture | protocol.txt |
926defb3-1f04-426c-ae02-301973e26f22 | with GM-CSF.5, 6, 25, 46, 68 GM-CSF has been used in several small published studies of im-
munomodulation in critically ill adults and children, summarized in Table 1. The doses used
were substantially lower than the FDA-approved dose that is used for bone marrow reconstitution
(250 g/m2/day). In all studies, immune recovery was prompt (within 3 days of initiation of | protocol.txt |
ee4c697b-2c16-4ad7-ae60-6bcffaa4f05e | GM-CSF therapy) though they were largely underpowered to detect effects on clinical outcomes.
There were no serious adverse events ascribed to GM-CSF in any of the studies. GM-CSF
therapy did not result in increased systemic inflammation as measured by plasma levels of the
pro-inflammatory cytokines IL-6 or IL-8. | protocol.txt |
10326d1e-c5d8-4c53-9ed2-e34eccbdb1d6 | The CPCCRN network has conducted two pilot, open-label, dose-finding trials of IV GM-
CSF over the last five years, also covered under IND#112277. The recently completed “GM-CSF
for Immunomodulation Following Trauma (GIFT)” study is a dose-escalation study for reversal
of critical trauma-induced immune suppression in children. We found that GM-CSF doses < | protocol.txt |
cb90ad89-488b-4ea1-bc11-c5ab256c541b | 125 mcg/m2/day were ineffective at normalizing innate immune function in the first week after
injury while a dose of 125 mcg/m2/day was associated with improvement in innate immune
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1d4a790e-d2e0-4a1d-a36b-23037c8c7187 | function. Further, we found that relapse of immune suppression was common when a short
duration of treatment was used (3 days), and treatment through the end of the first post-injury
week was required for lasting effect. Lastly, we found that IV GM-CSF, when administered at a
dose of 125 mcg/m2/day with each dose infusing over at least 6 hours, was not associated with | protocol.txt |
31fc5135-c219-4dbe-815c-9f8a4424e709 | drug-attributable adverse events.
Our group has also studied the effect of IV GM-CSF on immune function in critically
ill children with sepsis-induced MODS. In 2011 we reported the results of a single-center,
open-label, RCT of IV GM-CSF at a dose of 125 mcg/m2/day for 7 days vs standard care in a
14-subject cohort of immunoparalyzed children with MODS, most of whom had sepsis as the | protocol.txt |
41861aae-a919-493b-8ee5-ce61ab96f960 | MODS-inciting event. GM-CSF treatment was associated with significantly faster resolution of
immunoparalysis (Figure 2 on the facing page, A). No subjects in the GM-CSF-treated group
went on to develop nosocomial infection, while all of the subjects in the standard therapy group
did.32 The CPCCRN network recently replicated this approach on its multi-center platform by | protocol.txt |
57971888-e4e7-49a7-92aa-75d261b82ac6 | conducting the “GM-CSF for Reversal of immunopAralysis in pediatriC sEpsis-induced MODS
(GRACE) – 1” study. This is a multi-center, open-label, dose- and route-of-administration study
that is being carried out in 7 centers across the United States. Thus far, the GRACE–1 study has
shown that a GM-CSF dose of 125 mcg/m2/day given by the IV route for 7 days, with each dose | protocol.txt |
71ad8d7c-b5cb-4fe1-b7e6-5948651d5ea2 | being infused over a minimum of 6 hours, is associated with the safe reversal of immunoparalysis
in children with sepsis-induced MODS (Figure 2, B). Subcutaneous administration of GM-CSF
is still being evaluated in the GRACE–1 study. The restoration of a normal TNFαresponse
was not associated with the development of systemic inflammation. Rather, plasma biomarkers | protocol.txt |
b6cf9281-d2bf-4a64-b70f-5389e0f3eab6 | of inflammation including interleukin (IL)-6, IL-8, and ferritin decreased over time as TNFα
response normalized (Figure 2, C).
1.2.4 Immunoparalysis and MAS/HLH
Immunoparalysis is not the only pathophysiologic phenotype that is seen in children with sepsis-
induced MODS.8 Another phenotype in pediatric sepsis-induced MODS is one biochemically | protocol.txt |
de3e2f6c-3475-4bdc-97d6-ec2ef0f41b89 | similar to macrophage activation syndrome (MAS) or secondary hemophagocytic lymphohis-
tiocytosis (HLH). This is characterized by very high serum ferritin levels (typically ≥ 2,000
ng/ml), and children with this phenotype may benefit from targeted anti-inflammatory treatment
rather than immunostimulation. We will therefore screen for and exclude children with serum | protocol.txt |
4fe33c0b-2a7f-4b29-8b28-61b93f7173a2 | ferritin levels ≥ 2,000 ng/ml from receiving GM-CSF. This will also ensure that children with
primary HLH, who typically have serum ferritin levels >10,000 ng/ml and to whom treatment
with GM-CSF could potentially be harmful, are prevented from receiving GM-CSF.
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023 | protocol.txt |
6ec7ca2b-39f7-46e3-b835-2a19caa206cb | The Collaborative Pediatric Critical Care Research NetworkProtocol 90 (Hall, Zuppa and Mourani) Page 15 of 76
Figure 2: GM-CSF therapy is associated with restoration of innate immune function and
reduction of systemic inflammation in immunoparalyzed children with MODS. In a 14-subject
RCT, GM-CSF was associated with rapid normalization of the TNFαresponse (A). Dashed | protocol.txt |
d11292b5-6cca-4dac-a22a-0917a6057f62 | line represents immunoparalysis threshold. In the GRACE-1 study, the same regimen of GM-
CSF was associated with prompt resolution of immunoparalysis (N=10) (B) with reduction
in systemic inflammation (C). Shaded area represents immunoparalysis threshold. Error bars
represent interquartile range.
1.3 Targeted Reversal of Inflammation (TRIPS Trial) | protocol.txt |
d15d6719-0e92-483d-b137-c1375ac85d9d | 1.3.1 Heterogeneity of the Immune Response to Sepsis
The host’s immune response to a pathogen is the key driver of organ dysfunction in sepsis. Im-
mune cells and injured or stressed tissues produce cytokines and chemokines that make the local
environment favorable for fighting infection through vasodilation, increased capillary permeabil- | protocol.txt |
b783d89d-1346-42b6-ba6c-f7ed0eee5301 | ity, and recruitment of additional leukocytes. This response is beneficial when limited to the site
of infection, but is pathologic when it becomes systemic, resulting in fever, hypovolemia due to
capillary leak, tissue edema, malperfusion, and organ dysfunction. Numerous investigators have
identified mediators involved in the Systemic Inflammatory Response Syndrome (SIRS) that can | protocol.txt |
7c70eaba-88d9-49b6-a337-a12be5800604 | serve as biomarkers of the pro–inflammatory response including IL-1β, IL-6, TNFα, and others,
with high serum levels predicting adverse outcomes (Figure 3 on the next page).22, 28, 39, 72, 83
1.3.2 Immunoparalysis
Immunophenotyping studies, many of which were conducted by CPCCRN member investigators,
have shown that while some children with sepsis-induced MODS have severe hyperinflamma- | protocol.txt |
7ad372d7-5026-4c6e-a184-cdb104611fe5 | tion that may benefit from anti-cytokine therapies, others have markedly hypoactive circulating
leukocytes and could potentially benefit from an immunostimulatory approach rather than an
anti-inflammatory one.8, 9, 31, 32, 56 Innate immune suppression in children with sepsis-induced
MODS is a manifestation of the compensatory anti-inflammatory response syndrome (CARS) | protocol.txt |
4b9bcc98-58d9-42ee-9322-52ecefd4460f | (Figure 3 on the following page) and, when severe, is termed immunoparalysis. This can be
PRECISE Protocol Version 1.07
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Figure 3: Immune response to pediatric sepsis includes systemic inflammation (SIRS), compen- | protocol.txt |
1732e5fe-aef8-4681-8997-e49a9b1a2ac6 | satory anti-inflammatory response syndrome (CARS), or both. When severe, both are associated
with adverse outcomes.
diagnosed in our research laboratory through the measurement of the ability of a subject’s
whole blood to make the pro-inflammatory cytokine TNFαupon ex vivo stimulation with a
highly standardized lipopolysaccharide (LPS) solution. A low TNFαresponse is characteristic | protocol.txt |
c64c9f84-3a7f-48e6-9f77-9653da25fd61 | of immune suppression, and a TNFαresponse <200 pg/ml is diagnostic of immunoparalysis
in our hands. Immunoparalysis, as defined by our assay, has been validated in independent
cohorts to be associated with adverse outcomes in critically infected children including those
with MODS (mortality: RR 5.8 (2.1-16)32), influenza (mortality: AUC: 0.97, p<0.0001;31 mor- | protocol.txt |
ac84e014-7ded-4254-87d1-57f350a01a37 | tality: 9.3% vs 0%, p=0.00762), and severe sepsis/septic shock (mortality: RR: 1.98 (1.08-3.61),
p<0.05;8 prolonged organ dysfunction: AUC:0.71, RR: 1.25 (1.1-1.4), p=0.000556). In sum,
immunoparalysis is occult, is measurable in the research laboratory, and is associated with pro-
longed organ dysfunction and death in children with sepsis.8, 9, 31, 32, 56 Unless immunoparalysis | protocol.txt |
03809009-43cb-4967-937c-8ae761d9c8a7 | occurs in the setting of very high levels of systemic inflammation, data from our group and others
suggest that this population of patients will benefit from treatment with immunostimulatory
drugs (e.g. granulocyte macrophage-colony stimulating factor [GM-CSF]).32, 49, 69 Accordingly,
we will use prospective immune function testing to exclude children with immunoparalysis who | protocol.txt |
3fa9513d-7ed7-44a0-88f9-491c84f85426 | have mild to moderate inflammation (i.e. a serum ferritin level <2,000 ng/ml) from the TRIPS
trial. Those subjects will be instead entered into a completely distinct clinical trial of immune
stimulation with GM-CSF (GRACE-2) that is covered by a separate IND (#112277).
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023 | protocol.txt |
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1.3.3 Inflammatory Biomarker Selection
Assays for pro-inflammatory cytokines are not readily available in most clinical laboratories,
rendering them difficult to use for treatment decision-making. Our group has extensive experi- | protocol.txt |
0c682762-6c9e-48c1-84bf-be9279cf0379 | ence using serum ferritin and C-reactive protein (CRP), both of which are easily measured in
clinical laboratories around the world, as indicators of the magnitude of the pro-inflammatory
response to sepsis. We, in the 401-subject PHENOMS study,8 found that systemic elevations in
ferritin and CRP are common in septic children, with 96% of the cohort having a serum CRP | protocol.txt |
8afd6d9d-2313-4d7b-9814-281826107003 | level >4 mg/dl or a ferritin level >500 ng/ml. The greatest mortality risk (40%) occurred in
those with marked elevations in both biomarkers.
Ferritin is an iron-binding protein that, in sepsis, is released by activated macrophages
and other innate immune cells. Systemic ferritin levels are therefore a reflection of the pro- | protocol.txt |
98e85c5d-1f0f-460a-9814-7d12939c23c1 | inflammatory innate immune phenotype. While very severe elevations in serum ferritin levels
(>10,000 ng/ml) are characteristic of disorders like systemic juvenile idiopathic arthritis (sJIA)-
induced macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis
(HLH),3 more moderate hyperferritinemia (e.g. levels 500 – 10,000 ng/ml) is frequently seen in | protocol.txt |
bcd67ea7-aa19-49c6-ae07-24a792067076 | children with sepsis-induced MODS.10
CRP is an acute phase reactant that is produced by the liver in response to IL-6. CRP has
long been used as a marker of systemic inflammation and is increasingly used as a measure of
response to therapy for inflammatory conditions.16, 18, 61, 87 Together, ferritin and CRP represent | protocol.txt |
f5eee25a-776a-45b6-af73-13ddb516575c | a parsimonious and immediately clinically translatable panel of biomarkers that identify children
with severe systemic inflammation. Despite this, neither ferritin nor CRP is currently used as
part of an evidence-based, personalized approach to pediatric sepsis care.
1.3.4 Timing of Immunophenotyping | protocol.txt |
e2f2aa1e-1f70-44a1-9bd2-ce1cf8f96f56 | Morbidity and mortality from severe sepsis in children is bimodal. It is the minority of pediatric
sepsis deaths in the U.S. (a third or fewer) that occur in the setting of refractory shock within the
first 2-3 days of illness.7, 81 The majority of pediatric sepsis deaths occur over the ensuing days | protocol.txt |
639cabb2-de71-44dc-8257-11de7450abe2 | to weeks in the setting of unresolving organ dysfunction.8, 81 It is this population with persistent
sepsis-induced MODS that we are targeting with the TRIPS trial, which targets septic children
with MODS on day 2-3 who we believe will benefit from targeted anti-inflammatory therapy.
It is the next critical step in this line of research to show that an individualized approach to | protocol.txt |
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