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ture. The backup repositories are encrypted-at-rest using AES-256. The storage area networking
applications, clusters, and switch-to-switch links are highly redundant. Incremental backups of
data occur Monday through Friday. A full data backup occurs weekly. Full backups are sent
off-site on a weekly basis to a secure secondary location. The data center currently manages
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over 125 terabytes of data.
Information systems are available 24/7/365 unless a scheduled maintenance period or
mitigation of an unexpected event is required. Critical systems availability has exceeded 99.9%
for the past 5 years.
7.2.3 Security, Support, Encryption, and Confidentiality
The data center coordinates the network infrastructure and security with University Information
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Technology (UIT) at the University of Utah. This provides us with robust firewall hardware,
automatic network intrusion detection, and the expertise of dedicated security experts working
at the University. Centralized authentication and communication over public networks are
encrypted using transport layer security (TLS) and/or virtual private network (VPN) technolo-
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gies. Direct access to data center machines is only available while on premise or via a VPN client.
All network traffic is monitored for intrusion attempts. Security scans are regularly run
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against data center servers and IT staff are notified of intrusion alerts. Security is maintained
with Windows user/group domain-level security. Users are required to change their passwords
every 90 days. All files are protected at user/group levels and database security is handled in a
similar manner with group-level access to databases, tables, and views. Finally, all laptops used
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by faculty and staff in the DCC are whole-disk encrypted.
The data center uses monitoring tools to continuously monitor applications and servers. En-
vironmental and network systems are also monitored to ensure up-time. System Administrators
are on-call 24/7/365 to respond to urgent events.
All personnel involved with the DCC have signed confidentiality agreements concerning data
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encountered in the course of their daily work. All personnel (including administrative staff) have
received Human Subjects Protection and Health Information Portability and Accountability Act
education. We require all users to sign specific agreements concerning security, confidentiality,
and use of our information systems before access is provided.
7.3 Electronic Data Capture System
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The Data Coordinating Center (DCC) will develop an electronic data capture system for this
study. Data will be entered by each clinical site, and data quality will be monitored at the DCC.
The DCC will use an electronic discrepancy management system to notify sites of inconsistent or
erroneous data entry, which will be corrected by the clinical site. The discrepancy management
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system maintains an audit trail of all discrepancy resolution.
8 Study Site Monitoring
The investigators recognize the importance of ensuring data of excellent quality. Study moni-
toring is critical to this process. Monitoring has been a very effective tool for maintaining data
quality in previous Collaborative Pediatric Critical Care Research Network studies, and we will
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utilize this process to ensure excellent quality data in the proposed study. The DCC utilizes
risk-based methodology to identify and correct problems that may arise at sites. The risk-based
approach to monitoring focuses on oversight activities and preventing or mitigating key risks to
data quality, as well as to processes critical to human subject protection and integrity of the trial
or study.
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Study monitors must be provided with appropriate access to study materials and the medical
records for study subjects. If the medical records are in electronic form, the clinical investigator
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or an authorized individual must provide any assistance necessary to facilitate the study monitor’s
review of data in the electronic medical record.
8.1 Site Monitoring Plan
A supplemental study-specific risk-based monitoring plan, separate from the protocol, will be
completed which outlines specific criteria for monitoring. This plan may include the number of
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planned site visits, criteria for focused visits, additional visits or remote monitoring, a plan for
chart review and a follow up plan for non-compliant sites. The monitoring plan also describes
the type of monitoring that will take place (e.g., sample of all subjects within a site; key data or
all data), the schedule of visits, how they are reported and a time frame to resolve any issues
found.
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8.2 Clinical Site Monitoring
Site monitoring visits will be performed by a trained site monitor during the study period
to ensure regulatory compliance, patient safety, and to monitor the quality of data collected.
Essential document binders, regulatory documents and data collection forms may be reviewed.
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Interim visits will take place depending on grant budget, site enrollment, and compliance issues
identified. The site monitor will provide each site with a written report, and sites will be required
to follow up on any deficiencies. It is anticipated that the study monitoring visits for this protocol
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will consist of an in-person or virtual site initiation visit (prior to patient enrollment), interim
visits, and a close out visit. The site initiation may take place as group training made up of site
investigators and research assistants.
8.3 Remote Monitoring
The DCC may supplement on-site monitoring with remote monitoring activities. Remote moni-
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toring involves detailed review of the data entered by the enrolling site and consultations with
the enrolling site investigator and/or research coordinator to review safety and data quality. This
may require uploading copies of medical records, patient study files, regulatory documentation,
or other source documents for the monitor to review. Alternatively, other methods, such as
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remotely viewing source documentation, may be utilized. This helps assure protocol compliance
and accurate data collection. The DCC may conduct more remote monitoring activities early in
the trial to assure protocol compliance and identify any training issues that may exist. Remote
monitoring documents will be retained in accordance with federal requirements. Safety of
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subjects will be monitored and ensured in accordance with the Data and Safety Monitoring
Board (DSMB) plan.
8.4 Pharmacy Monitoring
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This trial will use the investigational pharmacy at Nationwide Children’s Hospital as a central
pharmacy. Each clinical site pharmacy must maintain adequate records of all dispensed study
drug. Each pharmacy will be monitored and may be requested to send copies of these documents
to the DCC and/or the investigational pharmacy at Nationwide Children’s Hospital which will
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conduct remote audits at regular intervals.
8.5 Record Access
The medical record and study files (including informed consent, permission, and assent docu-
ments) must be made available to authorized representatives of the Data Coordinating Center,
upon request, for source verification of study documentation. In addition, medical information
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and data generated by this study must be available for inspection upon request by representatives
(when applicable) of the Food and Drug Administration (FDA), NIH, other Federal funders or
study sponsors, and the Institutional Review Board (IRB) for each study site.
9 Protection of Human Subjects
9.1 Risks to Human Subjects
9.1.1 Human Subjects Involvement and Characteristics
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Subject Population to be Studied Participating sites will enroll infants, children and adoles-
cent patients who are admitted to a Pediatric or Cardiac Intensive Care Unit with sepsis-induced
multiple organ dysfunction syndrome (MODS). The goal is to determine if personalized im-
munomodulation is an effective strategy to reduce mortality and morbidity from sepsis-induced
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MODS. All subjects in this study will be less than 18 years of age and ≥ 40 weeks corrected
gestational age. The inclusion and exclusion criteria are listed in Section 3 on page 26.
Subjects enrolled in sepsis-induced MODS trials face significant mortality and morbidity
from the sepsis-induced MODS, and the study drugs (GM-CSF, anakinra) are associated with
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known risks. These risks will be specified in the parental / guardian permission forms and will
be explained thoroughly when permission is obtained by the site investigator or designee.
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Collaborating Sites Performing the Research All of the collaborating sites are tertiary or
quaternary pediatric intensive care units in large academic health centers or children’s hospitals.
The patients who are eligible for participation in the trials are critically ill with sepsis-induced
multiple organ dysfunction syndrome (MODS), and require 24 hour care by pediatric critical
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care physicians, nurses, respiratory therapists, and other clinical staff specialized in pediatric
critical care.
9.1.2 Study Procedures and Materials
Study Procedures Patients will be screened by site research staff, and if eligible, their
parents/guardians will be approached for permission to participate in the study. Patients whose
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parents or legal representative give permission will have 1 - 3 ml of blood (adjusted for body
weight) drawn on MODS Day 2 for measurement of whole blood LPS-induced TNFαproduction
capacity and inflammatory biomarkers, including serum ferritin levels and CRP. Blood samples
will be stimulated on-site within one hour of sample collection using highly standardized
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LPS stimulation kits provided by the Immune Surveillance Laboratory at the Abigail Wexner
Research Institute at Nationwide Children’s Hospital. The incubation period is 4 hours. After
stimulation, samples will immediately centrifuged and all supernatants will be overnight-shipped
on dry ice to Nationwide, where TNFαwill be quantitated in the LPS-stimulated supernatants
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along with serum ferritin levels and CRP the next morning. The results will be double checked
to assure correct immunophenotype assignment, assigning the subject to GRACE-2, TRIPS, or
to observational cohorts without study interventions.
Study Materials Sources of research material will include data collected specifically for
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the study, as well as data that are normally found in the subject’s medical record. These data
will be collected during the acute hospitalization during which the subject is enrolled, at three
months, and at 12 months following randomization. Data may be recorded on worksheets at
each clinical site, and then entered into a computerized data system maintained by the DCC.
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The final analysis data sets will be de-identified by the DCC.
Study Resource Sharing Biological samples will be obtained for storage in the study biorepos-
itory that will be located at Nationwide Children’s Hospital. These will include plasma, serum,
DNA, RNA, and tracheal aspirates. These samples will be analyzed to better understand sepsis-
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induced MODS and to understand the results of the trial. Specific consent for additional use
of these samples will be included in the parental permission document. A separate consent
document will also be used for subjects that turn 18 years old prior to the 12 month follow up
visit. We will use a layered consent to enable a parent or adult subject to restrict the additional
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purposes for which these samples may be used in subsequent studies.
Parental permission forms and the separate consent form, if needed, will include language
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explaining that de-identified study data will be made available for other research, and that
residual biological samples will be stored at a biorepository after research in this study is
completed.
9.1.3 Potential Risks of Study Participation
GM-CSF. GM-CSF is FDA-approved for the reconstitution of bone marrow following
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chemotherapy and bone marrow transplantation for certain malignancies and has a long track
record of safe use in adults and children. The incidence of adverse events such as fever, chills,
bone pain, dyspnea, tachycardia, and hemodynamic instability was no different between GM-
CSF and placebo-treated groups in controlled adult BMT studies. Rapid IV administration of
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GM-CSF (over ≤ 2 hours) has been associated with peripheral edema (11% incidence with
GM-CSF vs 7% incidence with placebo) and pericardial effusion (4% vs 1%), but this appears
to be related to the rate of infusion. Out of an abundance of caution, we infuse GM-CSF over at
least 6 hours. We are unaware of these side effects being reported with slow IV infusion. Also,
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the GRACE-2 trial will use a daily dose that is 1/2 of the FDA-approved dose, based on our
pilot work. Among the published small randomized controlled trials in critically ill adults and
neonates, there were no GM-CSF related adverse events reported and no evidence that GM-CSF
treatment resulted in increased systemic inflammation. In the original dose-finding GRACE
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study and the GIFT study, GM-CSF administration has not been associated with increased
systemic inflammation nor other significant adverse events. A risk of hypersensitivity/allergic
reaction exists with any drug.
Anakinra. Anakinra is FDA-approved for the treatment of rheumatoid arthritis (RA) and
cryopyrin-associated pediatric syndromes (PDA). Since anakinra will be given by the IV route
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in the TRIPS trial, we will not have the risk of injection sites reactions which occur in up to 71%
of subcutaneous injection recipients. Anakinra has been associated with an increased incidence
of serious infections (2%) vs. placebo (<1%) in clinical trials of long-term use in RA. The
other most serious adverse reaction with prolonged use in RA was neutropenia, particularly
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when used in combination with TNF blocking agents. We do not expect to see these adverse
events in this study given the short duration of treatment (7 days). Hypersensitivity reactions,
including anaphylactic reactions and angioedema, have been reported rarely.
Biological Sampling. Another potential risk to enrolled subjects in this study is a low red
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blood cell count or anemia. Any blood sampling can contribute to anemia. While many children
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with critical illness go on to require a blood transfusion, we will keep the total blood drawn for
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research purposes to <5.0 ml/kg on MODS Day 2, and 9.5 ml/kg over the entire study period.
This volume of blood loss should not significantly increase the risk of an enrolled subject to
require a blood transfusion.
Some children enrolled in this study may need to undergo additional venipuncture and/or
capillary sticks for the purposes of study sample collection, particularly for later time points
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when central catheters may have been removed. We will try to coordinate blood sampling
with previously ordered phlebotomy but if we are unable to do this we may have to perform
venipuncture. While venipuncture and capillary sticks can cause pain, bruising, bleeding, and
rarely, infection, these risks are generally viewed as modest. Guidance will be provided to
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sites for truncation of sampling or reduction of blood sample volume such that infants may
participate in the immunomodulation study without exceeding the 9.5 ml/kg total blood draw
limit. Venipuncture and/or capillary sticks will not be performed for blood sampling of subjects
in the observational cohort studies after discharge from the ICU.
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Tracheal aspirates for the biorepository will be obtained in intubated patients at the time of
suctioning that is clinically indicated.
Loss of Confidentiality. this study.
There is a minimal risk of loss of confidentiality for data collected in
9.1.4 Alternatives to Study Participation
Study participation is not required for patients to receive state-of-the-art critical care for sepsis-
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induced multiple organ dysfunction syndrome. Parents may elect to discontinue study interven-
tions at any time, which will be considered discontinuation of study drug. Data collection and
blood sampling will continue unless parents wish to discontinue all study participation. Data
that have been collected up to that point will be retained in the study, and only safety data will
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be collected through Study Day 28 or ICU discharge, whichever occurs first.
9.2 Adequacy of Protection Against Risks
9.2.1 Parental Permission, Informed Consent and Assent
Waiver of Consent For Screening Data Collection Waiver of consent is requested for collec-
tion of demographic data, eligibility data, and details of the consent procedures. Our justification
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for waiver of consent for these observational data is based on the following factors:
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1. The scientific validity of the study is dependent on non-biased enrollment of eligible
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patients, and these data are required to properly create the trial CONSORT diagram, as
well as to ensure that eligible patients were not excluded based on race, ethnicity, or
gender.
2. Collection of these screening data will not require additional patient or parent contact.
3. The minimal risk of loss of privacy is mitigated by secure data management at the DCC,
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and analysis datasets will be de-identified.
Parental Permission Subjects who are eligible for this study are under 18 years of age, and
written permission will be required for participation. After determining that a subject is eligible,
the site investigator or designee will approach the parent or legal guardian to offer participation
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for their child in the study. Single parent permission is permitted under 45 CFR §46.405. The
parent or legal guardian will be informed about the objectives of the study and the potential
risks and benefits of their child’s participation. If the parent or legal guardian refuses permission
for their child to participate, then all clinical management will continue to be provided by the
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clinical ICU staff in accordance with institutional practice and judgment.
Child Assent Subjects who are eligible for this study will be critically ill, and child assent is
typically not possible at the time of study enrollment. However, during follow up after discharge
from the ICU, issues about assent become applicable. Children who are capable of giving assent
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and who are alert and competent, may be asked, following an age-appropriate discussion of
risks and benefits, to give assent to the study for collection of follow up information at 3 and
12 months. Assent will be waived if the child is too young, has a severely reduced mental age,
decreased level of consciousness, psychological problems, or other legitimate reasons as judged
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by the single IRB and the institution’s specific Human Research Protection program policies.
Subject Consent If a subject attains the age of 18 years during the study intervention period
while critically ill, it will not be possible to obtain informed consent from the subject. During
the follow up, after discharge from the ICU, reasonable efforts will be made to obtain informed
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consent from 18-year-old subjects who are alert, competent, and capable of giving consent.
Subject consent will be waived if the subject has a severely reduced mental age, decreased level
of consciousness, psychological problems, or other legitimate reasons as judged by the single
IRB and the institution’s specific Human Research Protection program policies.
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Permission for Additional Analyses of Biorepository Specimens and DNA Sequencing
Data. Permission will be obtained from the adult subject, parents, or other legally empowered
guardians to conduct research using biorepository specimens, to potentially include DNA se-
quencing data, that is beyond the original scope of the PRECISE study. We will use a layered
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consent with opt-in and opt-out choices that include:
• Permission for the use of all retained samples in future studies that are unrelated to the
PRECISE study;
• Permission for the use of retained samples other than DNA in future studies that are
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unrelated to the PRECISE study;
• No permission to use any of the retained samples in future studies that are unrelated to
the PRECISE study.
The level of consent will be recorded in the Data Coordinating Center and retained at
the clinical site. The level of consent will be stored in conjunction with the samples in the
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biorepository to maintain restrictions placed on usage during the consent process.
Upon completion and final closure of the study, the Data Coordinating Center will assign
new study numbers for all study subjects. The Data Coordinating Center will then instruct the
repository to strip all samples of their original study identifiers and re-label them with the new
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study subject numbers. This will prevent investigators from using the original study identifiers
to identify individual subjects in the future.
Should an adult subject, parent, or legal guardian revoke their permission for additional
biorepository or DNA analyses prior to the use or deidentification of specimens, the clinical site
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will notify the Data Coordinating Center. The Data Coordinating Center will then contact the
repository and request that all samples collected for that patient (identified by the original study
number) be labeled with the restrictions. Restricting use of samples is only possible prior to
their use and/or the final closure of the study; after that, there will be no way to identify samples
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since they will have been anonymized.
For subjects who attain the age of 18 years prior to the 12 month follow up visit, the clinical
site will contact the subjects to obtain informed consent for additional biorepository analyses,
including DNA sequencing data. The informed consent will be layered in a similar manner
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to the original permission. If after a good faith effort, we are unable to contact the subject to
obtain consent, the biorepository samples will continue to be used as allowed by the parental
permission form.
9.2.2 Institutional Review Board and Human Research Protection
The Institutional Review Board (IRB) at the University of Utah will serve as the single IRB.
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The Utah IRB has extensive experience with single IRB implementation due to our participation
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in the NCATS funded Trial Innovation Center, which has implemented over 35 sIRB studies.
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No human subjects research activities will be conducted at any CPCCRN site prior to sIRB
approval at the University of Utah.
In addition to sIRB activities, each institution has Human Research Protection activities that
will be completed prior to site activation. These include conflict of interest, assuring competence
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of investigators, impact on hospital services, etc., and are individualized to each site.
9.2.3 Protections Against Risk
Study Drug Risk All patients in this study have sepsis-induced MODS and will be receiving
antibiotic therapy to treat the underlying infection. They will be in critical care units and closely
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monitored for changes in infection status or laboratory abnormalities, which will be recorded as
adverse events (see Section 10.2 on page 57).
GM-CSF will be given at a low dose (1/2 of the FDA-approved dose), for a short duration
(7 days), and with a conservative infusion rate (over 6 hours). Accordingly, we do not expect
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56c1a060-bbe6-470d-9a5e-27c815946ae6
|
to see rate-of-infusion-related adverse events nor do we expect to generate severe leukocytosis
(white blood count >50,000 cells/mm2) or exacerbate systemic inflammation. We have not
seen serum ferritin levels increase above 2,000 ng/ml during treatment with GM-CSF in our
prior dose-finding work and we have consistently seen a reduction in systemic pro-inflammatory
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7ea6920f-e3d5-43be-947e-ea7e8f3248a6
|
cytokine levels in the setting of GM-CSF-induced reversal of immunoparalysis.
Anakinra is highly specific for a single cytokine signaling pathway (IL-1β), leaving other
signaling pathways for ongoing host defense. While increased infection risk is possible with
prolonged use of anakinra, we are using it for a very short period of time (7 days) and are
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3a7d87a7-c4c1-414a-97ea-bd2dc753bd44
|
restricting its use to subjects with documented hyperinflammation. We are also excluding chil-
dren with severely impaired innate immune function (immunoparalysis) in the setting of mild
to moderate inflammation, as well as those who have severe leukopenia due to myeloablative
therapy. We will not be starting study drug until at least 3 days following the onset of sepsis,
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4c70f8ad-a006-43bd-88e6-093454d3dca2
|
during which subjects will have been receiving antimicrobial therapy. It is therefore highly
unlikely that we will be giving anakinra to children with uncontrolled infection. Increased
nosocomial infection risk has not been seen in adult studies of sepsis, stroke, TBI, or COVID-19
in which the cumulative dose of anakinra was up to three times higher than the highest dose to
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489e66be-a24b-48a9-861d-91124af422c7
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be used in the TRIPS trial.
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023
The Collaborative Pediatric Critical Care Research NetworkPage 56 of 76 Protocol 90 (Hall, Zuppa and Mourani)
Phlebotomy Risks The risk of anemia is minimized by minimizing the volume of blood
samples taken and by reducing the sampling volume for infants. The risk of phlebotomy is
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3a883bd1-3e45-475f-a224-a0fb6cf58fac
|
minimized by making use of indwelling catheters when present and by timing sampling with
previously scheduled venipuncture if able.
Loss of Confidentiality The minimal risk of loss of privacy is mitigated by the substantial
data management resources and security described in Section 7.2.3 on page 46.
9.2.4 Vulnerable Subjects
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5152cc1e-b7c7-4b9b-b7d2-d216bf9f0ad5
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All subjects enrolled in this study will be children <18 years of age and this is a vulnerable
population. The study will be carried out in pediatric intensive care units staffed by board-
certified or board-eligible pediatric critical care physicians, and a pediatric clinical team that is
specifically trained and expert in the clinical management of critically ill infants, children and
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fd61a86d-091e-4318-b52c-0600a1ca90ea
|
adolescents. All clinical sites in CPCCRN are pediatric intensive care units that normally admit
patients within the age group eligible for this study.
Research in children involves special protections under 45 CFR §46 Subpart D “Additional
DHHS protections for children involved as subjects in research” and 21 CFR §50 and §56. The
study in this protocol is permissible under these regulations as:
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7bcbb7a4-e99e-46f6-8fd1-00bb8bc4eb1a
|
• Research involving greater than minimal risk but presenting the prospect of direct benefit
to the individual subjects (45 CFR §46.405).
9.3 Potential Benefits of Proposed Research
The goal of this study is to improve outcomes from pediatric sepsis-induced MODS through nor-
malization of immune function with resulting enhancement of infection clearance, improvement
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5e46ff3c-59f7-4364-852a-4e9eddc8fc34
|
in surveillance for new infection, and promotion of tissue healing, all of which we hypothesize
will speed resolution of organ failure. For research participants who are allocated to GRACE-2,
it is not known if GM-CSF will be effective in reducing organ dysfunction or mortality. For
research participants who are allocated to TRIPS, it is not known if anakinra will be effective
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aa52aad6-2993-498a-8ee0-aa1bc439d3b3
|
in reducing organ dysfunction or mortality. If effective, there is potential for direct benefit to
participants in terms of both morbidity and mortality. Knowledge gained from this study may
help other children in the future.
For research participants who are not allocated to GRACE-2 or TRIPS, (but are included
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6fe8cbc8-8396-4724-8f85-8236e18200da
|
as an observational cohort with longitudinal phenotyping), their screening sample will provide
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023
The Collaborative Pediatric Critical Care Research NetworkProtocol 90 (Hall, Zuppa and Mourani) Page 57 of 76
them and their clinical team with protocolized information about their immune function and
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edc5b0dd-478f-4840-83fa-cfd593c78195
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inflammatory state. In the case of children with severe hyperferritinemia (≥10,000 ng/ml) this
information would likely prompt the treatment team to pursue alternate diagnoses and treatments
that may benefit the subject. Knowledge gained from their participation in the study may help
other children in the future.
9.4 Importance of the Knowledge to be Gained
|
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|
3b657166-3725-45eb-ba35-dfd5c227761d
|
Multiple organ dysfunction syndrome (MODS) increases mortality from sepsis by over 10-fold
and is a leading cause of death and morbidity in critically ill children. Current treatment of
sepsis and MODS is largely supportive in nature. The overall hypothesis of this proposal is that
using immune phenotyping to personalize immune care for each patient will reduce mortality
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3a80602d-c95b-4437-8f91-83c2455fc7de
|
and morbidity from sepsis-induced MODS. This transformative study will provide highly unique
information about whether this personalized approach is beneficial, potentially improving the
outcomes of critically ill infants, children and adolescents in the future.
10 Data and Safety Monitoring Plan
10.1 Data Safety Monitoring Board (DSMB)
|
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|
2d105b9c-87f9-4610-b43f-1dac8f73b261
|
The study will have a Data Safety Monitoring Board (DSMB) including members who have
expertise in pediatric sepsis, pediatric critical care medicine, immunology, biostatistics and/or
bioethics. The DSMB will have a charter, will approve the protocol prior to implementation,
and will review interim data as applicable. The purpose of the DSMB is to advise the Principal
|
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|
c2b2db9a-cf87-4e1b-9aff-c2a5d8150ae5
|
Investigator(s) regarding the continuing safety of study subjects and the continuing validity and
scientific merit of the study. The DSMB is responsible for monitoring accrual of study subjects,
adherence to the study protocol, assessments of data quality, performance of individual Clinical
Center, review of adverse events, and other subject safety issues.
10.2 Adverse Event Reporting
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a76506c0-2ff9-4cb1-995a-9cf2f27ef4fe
|
The site investigator is responsible for evaluating all adverse events at their Clinical Center and
ensuring that they are properly reported. Adverse events that occur during this study will be
recorded. The nature of each experience, date and time (where appropriate) of onset, outcome,
course, and relationship to treatment will be documented. For subjects who are not in either
|
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|
71f6872e-5d5f-4780-bcdc-d53eb0795f9c
|
interventional trial and are in the observation cohorts, adverse events will not be separately
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023
The Collaborative Pediatric Critical Care Research NetworkPage 58 of 76 Protocol 90 (Hall, Zuppa and Mourani)
recorded or reported, because such events are related to underlying critical illness. Events of
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1af2a19a-0eed-4573-92e4-d4964c130708
|
scientific interest are already recorded in the study database.
10.2.1 Definition of Adverse Event and Serious Adverse Event
Adverse Event (AE). An adverse event means any untoward medical occurrence associated
with the use of an intervention in humans, whether or not considered intervention-related (21
|
protocol.txt
|
fd354ed7-9371-4e9b-ae87-6e94a38bcb3d
|
CFR 312.32 (a)). An event constitutes a disease, a set of related signs or symptoms, or a single
sign or symptom.
Serious Adverse Event (SAE). A serious adverse event (SAE) for this population is an
adverse event that:
• results in death; or
• is life-threatening (immediate danger of death from the event as it occurred); or
|
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|
2b219df4-750e-4ffc-8ae9-abf117f01211
|
• requires new inpatient hospitalization or prolongs an existing hospitalization; or
• results in persistent or significant disability or incapacity; or
• results in congenital anomaly/birth defect; or
• any other event that, based upon appropriate medical judgment, may jeopardize the
subject’s health and may require medical or surgical intervention to prevent one of the
|
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|
a2c28964-a46c-4fde-9e07-e4b22f04029f
|
other outcomes listed in this definition.
10.2.2 Classification of Adverse Events (Relatedness and Expectedness)
Clinical judgment is required for properly classifying relatedness and expectedness for adverse
events. It is not appropriate to classify an event as possibly related if, in the opinion of the
|
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|
ed522a22-6586-48cc-a317-4b5fc5d0835d
|
clinical investigator, it is clinically unlikely that the event is related. It is impossible to prove a
negative, and the FDA expects clinical judgment to be used in assessing relatedness. Similarly,
it is not appropriate to classify an event as unexpected because the patient was not anticipated to
suffer the event at the time of enrollment into the study, if the event is a known sequelae of the
|
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|
6a75f217-61fe-4d25-b2c8-11d32ec8ad4e
|
underlying disease process (sepsis-induced MODS) or has been previously noted with study
interventions as determined from the package insert or investigator brochure of the study drug.
Relatedness: The suspected relationship between study interventions and any adverse event
will be determined by the site investigator using the criteria below. Relatedness must be assessed
|
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|
8ca7b800-6b85-47c4-a890-066ba9291f29
|
by an investigator and may not be assessed by a research coordinator.
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023
The Collaborative Pediatric Critical Care Research NetworkProtocol 90 (Hall, Zuppa and Mourani) Page 59 of 76
Not Related: The event is believed to be related to other factors, such as the subject’s clinical
|
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|
3d16c326-3b49-419a-bb8d-b20382b231e7
|
state, therapeutic interventions, or concomitant drugs administered to the subject.
Possibly Related: The event follows a clinically compatible temporal sequence from the time
of beginning the assigned study intervention, but could have been produced by other
factors such as the subject’s clinical state, therapeutic interventions, or concomitant drugs
administered to the subject.
|
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|
3e077445-816e-4a23-8f52-4e91aed8b228
|
Probably Related: The event follows a reasonable temporal sequence from the time of be-
ginning the assigned study intervention, and cannot be reasonably explained by other
factors such as the subject’s clinical state, therapeutic interventions, or concomitant drugs
administered to the subject.
Expectedness of the Event: All adverse events, including serious adverse events, will be
|
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|
d3889555-8be7-4d2b-b4de-7b166b5b717b
|
evaluated as to whether their occurrence was expected or unexpected. An AE will be considered
unexpected if the nature, severity, or frequency of the event is not consistent with complications
of sepsis-induced MODS and critical illness, nor consistent with adverse events noted in the
drug investigator brochures.
|
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|
f7954454-0b2f-4445-8318-561d43d9ae20
|
Expected: An event is considered expected if it is known to be associated with the underlying
condition or is related to the study intervention and is mentioned in the protocol, informed
consent, or other study documents. An event may be expected despite the study subject’s
clinical state immediately prior to the event.
|
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|
923037e1-a38c-4feb-8cea-862082112445
|
Unexpected: An event is considered unexpected if there are no prior data linking this event with
either the condition or intervention under study or an event that occurred unexpectedly in
the course of treatment.
Treatment or Action Taken: an intervention was required:
For each adverse event, the site investigator will record whether
• Medical or surgical procedure
|
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|
1592d58b-467d-4585-9423-50cbc5bb9517
|
• Concomitant medication: started, changed, or discontinued
• Other, specify
• No action taken
PRECISE Protocol Version 1.07
Protocol Version Date: June 16, 2023
The Collaborative Pediatric Critical Care Research NetworkPage 60 of 76 Protocol 90 (Hall, Zuppa and Mourani)
Outcome of Event: adverse event as follows:
Finally, the site investigator will record the clinical outcome of each
• Death
|
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|
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