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b58a719d-f880-4b97-9d13-39c59b0edf21 | immunomodulation will improve outcomes in children with sepsis-induced MODS.
The performance of next-day immunophenotyping will allow us to exclude children with
immunoparalysis who only have mild to moderate inflammation from being randomized into the
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92b68bc8-ac0e-4bc8-97ad-bd7b09b5e9e5 | The Collaborative Pediatric Critical Care Research NetworkPage 18 of 76 Protocol 90 (Hall, Zuppa and Mourani)
TRIPS trial, enhancing its safety profile. Children with immunoparalysis who have serum ferritin
levels >2,000 ng/ml will be randomized into the TRIPS trial, since GM-CSF is contraindicated
in those patients and hyperinflammation may be contributory to their immunoparalysis. | protocol.txt |
abf9c682-897a-48e9-a9fe-4bf78232e9aa | 1.3.5 Rationale for Anakinra
Potential for Direct Benefit. Anakinra is a recombinant version of the endogenous counter-
regulatory cytokine IL-1 receptor antagonist (IL-1ra) which has been FDA-approved since 2001
for the treatment of rheumatoid arthritis and Cryopyrin-Associated Periodic Syndromes (CAPS)
including neonatal-onset multisystem inflammatory disease (NOMID) at doses ranging from | protocol.txt |
94edc23b-4261-40e4-94b0-4fbed6134c1c | 1 to 8 mg/ kg/day. Anakinra was, however, initially developed as a sepsis therapeutic, and
was evaluated in multiple phase II and III clinical trials in septic adults in the 1990s.23, 24, 63
Those clinical trials failed to meet their therapeutic goals (mortality reduction) in the cohorts
as a whole, though it is likely that the drug effects were diluted by subjects with relatively | protocol.txt |
fd7f418b-adee-47d9-9e71-87f97262c980 | low severity of illness and/or low levels of inflammation. Secondary analyses of both phase
III trials showed strong survival benefits for anakinra in the subset of subjects with ≥1 organ
dysfunction (p=0.002),23, 24 those with higher a priori risk of death (p<0.005),42 those with
higher-pretreatment cytokine levels (aRR: -0.12 [-0.23 – -0.01]),51 and those with hepatobiliary | protocol.txt |
ae9df13e-ee1f-415d-a7ee-4da26c220aff | dysfunction and disseminated intravascular coagulation suggesting an MAS-like phenotype
(HR:0.28 [0.11– 0.71], p=0.007).71 It is noteworthy that both phase III sepsis trials used anakinra
by the intravenous route and with a dose well in excess of the FDA-approved dose (48 mg/kg/
day) with no increase in nosocomial infection risk or other drug-related adverse events. | protocol.txt |
202d4dfc-331b-4bf2-bc58-54f96c37d9f6 | The TRIPS study will only enroll children with sepsis-induced MODS (the highest severity
of illness within the septic population) and we will restrict the use of anakinra to those with
high levels of systemic inflammation (serum ferritin 500 –10,000 ng/ml or CRP ≥4 mg/dL).
This enhances the likelihood that children enrolled in the TRIPS trial will derive direct benefit | protocol.txt |
cf769318-057b-4e18-ae75-543b1673389d | from targeted anti-inflammatory therapy with anakinra. Further, we will exclude children with
immunoparalysis in the setting of mild to moderate inflammation, a population in whom anti-
inflammatory therapies may be harmful.
The COVID-19 pandemic has afforded another opportunity to evaluate the use of anakinra | protocol.txt |
7c5d0295-770e-45c6-a4b7-1d6bc62191f6 | in the setting of active infection. While prospective randomized controlled trials are ongoing,
multiple non-randomized cohort studies have suggested direct benefit of anakinra when used
in hospitalized adults with inflammation due to COVID-19. Three meta-analyses of the use of
anakinra in COVID-19 have been done to date and they all demonstrated a reduced mortality | protocol.txt |
b36d7956-eb40-43f5-b8fa-6bca95b3a5ce | risk in anakinra-treated subjects (aOR: 0.32, 95% CI: 0.23 – 0.45, P<0.00001;4); (aOR: 0.34,
95% confidence interval [CI], 0.21 – 0.54, P<0.00001;76); (aOR: 0.26, 95% CI 0.14 – 0.48,
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0858d37b-789b-4ddb-9bc8-45bb062a8202 | P<0.0001;64). There were no differences in the risk of adverse events in these meta-analyses,
including liver dysfunction or nosocomial infection. There are currently at least 15 active studies
of anakinra for the treatment of COVID-19-related pneumonia and/or cytokine storm in adults
or children listed on www.ClinicalTrials.gov. | protocol.txt |
69950bd5-b073-4eb3-9d39-22fba5bf29d4 | Anakinra is increasingly used as part of a chemotherapy-sparing approach for the treatment
of hyperinflammation due to HLH/MAS in adults and children, including an ongoing clini-
cal trial of anakinra (10 mg/kg/day) in children with MAS (NCT02780583). The literature
supports anakinra’s safe use as an anti-inflammatory treatment in children with MAS, with | protocol.txt |
a5307ae1-bc86-4954-af44-155d9f3ab7b8 | doses ranging from 1 – 48 mg/kg/day being associated with resolution of organ dysfunction
and/or improvement in disease activity.14, 41, 65, 67 Recent clinical trials of anakinra in chil-
dren with MAS and sJIA include NCT02780583 and NCT03265132. We reported the use of
anakinra (5 – 10 mg/kg/day) in a series of children with critical illness due to secondary HLH | protocol.txt |
94d8fc32-297f-4448-a08d-85a6da12a68b | and showed a 67% reduction in CRP levels and a 64% reduction in ferritin levels over a week
of anakinra treatment, with survival in 7/8 subjects with no occurrence of nosocomial infection.67
Together, these data strongly support the potential for direct benefit of anakinra in critically
ill, hyper-inflamed children with sepsis-induced MODS. | protocol.txt |
caf76fbb-eef1-4b1f-bbc2-516c58dd3ee5 | Safety of Anakinra. Anakinra has a long history of safe use in acutely and critically ill chil-
dren and adults. While its long-term use in adults with rheumatoid arthritis has been associated
with an increased incidence of severe infections (2% vs <1%), particularly in patients who
were receiving concurrent therapy with TNFαblocking drugs, this risk has not been seen with | protocol.txt |
810f16b4-3a12-49ac-be02-16e10f096cc6 | short-term use. In placebo-controlled studies of long-term treatment of adults with anakinra,
8% of patients receiving anakinra had decreases in total white blood counts of at least one
WHO toxicity grade, compared with 2% of placebo patients, though statistically significant
reductions in white blood cell counts have not been seen with short-term use. There were no | protocol.txt |
d3cf0cb8-76ad-4c92-9a66-03f079486936 | drug-attributable adverse events (including nosocomial infection and leukopenia) reported in the
1994 and 1997 phase II and III clinical trials that enrolled over 1,600 septic adults, despite using
a dose of 48 mg/kg/day (six times higher than the upper FDA-approved dose, and three times
higher than the highest dose to be evaluated in the TRIPS trial). Anakinra use was not associated | protocol.txt |
12211c54-3366-4ba6-9102-7f1e2c683d46 | with increased risk for adverse events (including nosocomial infection and leukopenia) in any
of the three meta-analysis of its use in adults with acute COVID-19 disease to date.4, 64, 76 In
another example of the safe use of extremely high-dose anakinra, no increased risk for adverse
events was noted in reports of anakinra use in adults with acute brain injury due to stroke19 or | protocol.txt |
d17ce4e6-ba78-46de-b6ff-30d0b0c7e04d | traumatic injury34 despite using doses as high as 48 mg/kg/day.
Anakinra was similarly well-tolerated in non-controlled reports of its use for pediatric
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20108664-5471-48f4-a3ea-db6f42468840 | HLH/MAS at doses ranging from 1 – 20 mg/kg/day.14, 41, 65, 67 Among a total of 31 reported
anakinra-treated subjects, there was one instance of reversible transaminase elevation, and four
instances of low white blood cell counts (three of which were associated with concurrent corti-
costeroid use, and none of which resulted in secondary infections). Anakinra has a strong record | protocol.txt |
1deb5629-3355-459f-9894-bb3e00b25c39 | of safety in the treatment of neonatal-onset multisystem inflammatory disease (NOMID) for
which it is FDA-approved (including in infants) at a dose of 8 mg/kg/day, with no dose-limiting
toxicities reported.29, 60, 73
We hypothesize that short-duration treatment with anakinra has the potential to safely restore | protocol.txt |
edaba426-ec80-41c0-8c64-e730a384a02e | immunologic homeostasis in hyper-inflamed children with sepsis-induced MODS. This includes
children with hyperferritinemia without immunoparalysis and those with immunoparalysis in the
setting of marked hyperferritinemia, both of whom stand to benefit from targeted reduction in
systemic inflammation. In contrast to prior adult studies of anti-cytokine therapy, anakinra will | protocol.txt |
0024b026-5d17-48d9-8830-187ea7efca5e | not be given to subjects with immunoparalysis in the setting of mild to moderate inflammation.
We expect that this will enhance both the safety and efficacy of our personalized approach to
immunomodulation in sepsis-induced MODS.
Biological Rationale for Anakinra Use. Hyperferritinemic sepsis is increasingly recognized | protocol.txt |
4d1a6212-6184-42e8-a4aa-fdc72373ce46 | as a clinically important entity whose pathophysiology includes (but is not limited to) overac-
tivation of the macrophage’s IL-1β-producing “inflammasome” pathway, but likely does not
require the degree of immunosuppressive treatment (e.g. etoposide, high-dose glucocorticoids)
that is typical for primary HLH.10 Patients with HLH and MAS often have serum ferritin levels | protocol.txt |
c38f990c-f2d0-4900-bcf5-83ac043f5434 | >10,000 ng/ml while patients with hyperferritinemic sepsis typically have ferritin levels below
10,000 ng/ml.8 Hyperferritinemic sepsis can result in liver injury, disseminated intravascular
coagulation, and lymphopenia.
Anakinra can reverse this pathology by reducing inflammation through the induction of
a Type 1 interferon response to facilitate resolution of infection. Anakinra has been FDA | protocol.txt |
106443ac-3ced-48d8-af48-e75518024479 | approved since 2001 for the treatment of rheumatoid arthritis and Cryopyrin-Associated Peri-
odic Syndromes (CAPS) and is increasingly used as part of a chemotherapy-sparing approach
for the treatment in HLH/MAS in adults and children, including an ongoing clinical trial of
anakinra (10 mg/kg/day) in children with MAS (NCT02780583). The literature already supports | protocol.txt |
f405db5e-7fc1-4787-bfc5-a4fe6609b05a | anakinra’s use as an anti-inflammatory treatment in patients with MAS70 and sJIA,77 with recent
clinical trials for these indications including NCT02780583 and NCT03265132. Anakinra is
also being used in patients with infection-related hyper-inflammation including a recent trial in
hyperferritinemic septic adults (8-10 mg/kg/day) (NCT03332225). There are currently at least | protocol.txt |
7a41333c-cdec-40ff-96fe-3e8ee0559ffa | 15 active studies of anakinra for the treatment of COVID-19-related pneumonia and/or cytokine
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storm in adults or children listed on www.ClinicalTrials.gov. | protocol.txt |
775b4d05-e1fb-4c0d-a8dc-20ea05f540eb | We reported the use of anakinra in a series of children with hyperferritinemic sepsis-induced
MODS and showed a 67% reduction in CRP levels and a 64% reduction in ferritin levels over
a week of anakinra treatment, with survival in 7/8 subjects with no occurrence of nosocomial
infection.67 In post hoc analysis of an adult septic shock trial we found that, compared to | protocol.txt |
beb976aa-4968-41a3-895a-a0f4672178c2 | placebo, anakinra improved mortality associated with hyperferritinemia, hepatobiliary dys-
function, and disseminated intravascular coagulation.71 Exome analysis of adult subjects with
hyperferritinemic sepsis frequently found monogenic disorders amenable to anakinra therapy.40
Use of anakinra in this population can reduce inflammation, increase viral immunity, reverse | protocol.txt |
ae67ccdd-f9e6-4d01-91bd-e6ce54c36bcb | lymphopenia, and resolve immunoparalysis. Figure 4 shows the effect of anakinra on one of
our patients, a child with serum ferritin >2,000 ng/ml and immunoparalysis in the setting of
adenovirus infection. Once the cycle of hyper-inflammation was broken with anakinra, there
was prompt recovery of the TNFαresponse and clearance of the virus, providing rationale for | protocol.txt |
14b06c69-1883-4ae3-b0ed-9bbfc3115eeb | including immunoparalyzed children with ferritin levels of 2,000 – 10,000 ng/ml in the TRIPS
trial. Anakinra has also been shown to improve the TNFαresponse in adults with stroke-induced
immune suppression74 without impairing other aspects of host defense.48
Figure 4: Anakinra was associated with reversal of immunoparalysis and survival in a child | protocol.txt |
7b71441f-dd1a-47e2-8ecf-92756d938198 | with hyperferritinemic MODS. Lower dashed line represents threshold for immunoparalysis;
shaded area represents healthy control values.
Anakinra has been shown to reduce systemic inflammation in the absence of hyperferritine-
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7788b7bd-f8db-4a50-8f85-4c2d32e809ff | The Collaborative Pediatric Critical Care Research NetworkPage 22 of 76 Protocol 90 (Hall, Zuppa and Mourani)
mia in conditions including adult heart failure,79 myocardial infarction,54 ischemic stroke,19, 75
subarachnoid hemorrhage,27 chronic renal failure37 , traumatic brain injury34 , and Kawasaki
Disease.43 The majority of studies of anakinra for the treatment of COVID-19-related pneumo- | protocol.txt |
ce9b0b02-423e-40b3-bd56-492b9ae3616f | nia and/or cytokine storm that are currently listed on www.ClinicalTrials.gov require either no
specific inflammatory biomarker elevation for inclusion or accept elevations of either ferritin or
CRP as evidence of hyperinflammation. Anakinra is also part of the recommended treatment
algorithm for hyperinflamed children with severe Multi-system Inflammatory Syndrome in | protocol.txt |
15f75a85-918e-4077-8f9c-e6b7cdc174a2 | Children (MISC) in consensus guidelines in the US,35 the UK,33 and Latin America.21
We will quantify plasma levels of IL-1βin all samples from all subjects so that we may, in
post hoc analyses, 1) understand if there is a differential treatment effect of anakinra based upon
pre-treatment cytokine levels, and 2) identify thresholds and trajectories of IL-1βthat predict | protocol.txt |
9a04cd5d-053b-424f-a991-2091f443c591 | differential treatment effects, if present.
2 Study Summary
2.1 GRACE-2 Trial
The “GM-CSF for the Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS (GRACE)-
2” study is a prospective, double-blind, randomized controlled trial of the drug GM-CSF vs
placebo in children with a TNFαresponse <200 pg/ml and a serum ferritin level <2,000 ng/ml | protocol.txt |
c8549261-8437-45f5-98f6-8f8caabddaf2 | in the setting of sepsis-induced MODS. This allows us to use GM-CSF only in subjects who
have immunoparalysis and will minimize the risk of inadvertently giving GM-CSF to a child
who has HLH/MAS. The GRACE-2 study will use adaptive sample size determination to use
the smallest sample size possible.
Subjects with immunoparalysis and a serum ferritin level <2,000 ng/ml (an expected 40% of | protocol.txt |
38cb60d5-1e7a-4b95-8472-c36068eb8c6f | the total cohort) will be assigned to the GRACE-2 trial in which subjects will be randomized to
receive GM-CSF at a dose of 125 mcg/m2/day intravenously x 7 days or placebo. A maximum
ferritin level of 2,000 ng/ml to limit inclusion in the GRACE-2 trial was chosen in a conservative
effort to avoid giving GM-CSF to subjects who may have MAS/HLH. An adaptive interim look | protocol.txt |
8b570328-a0c4-493a-9d1c-83f24d50bb66 | approach will be used to ensure the smallest possible sample size.85
2.2 TRIPS Trial
The “Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS (TRIPS)” study
is a prospective, double-blind, adaptively randomized, placebo-controlled trial of anakinra in
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2c65cab4-8278-4733-9349-25fdb99cce35 | The Collaborative Pediatric Critical Care Research NetworkProtocol 90 (Hall, Zuppa and Mourani) Page 23 of 76
children with sepsis-induced MODS and moderate to severe hyperinflammation. The primary
objective of the trial is to demonstrate reduced duration/severity of organ dysfunction and mortal-
ity in children with sepsis-induced MODS and moderate to severe hyper-inflammation through | protocol.txt |
7677ba5c-a9ed-4774-8737-a2c6f9f50c54 | the use of targeted anti-inflammatory therapy with anakinra. Secondary objectives include
understanding the impact of anakinra treatment in this population on short-term health-related
quality of life and functional status. Exploratory objectives include understanding the impact of
anakinra treatment in this population on longer-term health-related quality of life and discrete | protocol.txt |
1f12c72d-7c28-4d2f-b330-d14f8a09f222 | effects on mortality and organ dysfunction.
Populations that are allocated to the TRIPS study include children with moderate to se-
vere systemic inflammation (serum ferritin level ≥500 ng/ml or CRP ≥ 4 mg/dl) without
immunoparalysis, and children with immunoparalysis whose ferritin level is too high to receive
GM-CSF (>2,000 ng/ml). This approach allows us to avoid use of anti-inflammatory drugs | protocol.txt |
c3709df6-54e3-43b4-9353-97ae46bb6c6a | in children whose immune function is critically impaired except for those in whom severe
hyperinflammation may be driving their immune suppression.
Subjects with evidence of moderate to severe inflammation (serum CRP level ≥ 4 mg/dl or
ferritin level 500 – 10,000 ng/ml) without immunoparalysis and subjects with immunoparalysis | protocol.txt |
0151db1f-03db-48e9-a1da-6803c9a58e2c | and a ferritin level ≥ 2,000 ng/ml are, together, expected to represent 50% of the total cohort
that is immunophenotyped. These subjects will be adaptively randomized into the TRIPS trial
to receive placebo or anakinra (4, 8, 12, or 16 mg/kg/day X 7 days), as justified in Section 4.4.3
on page 31.
After undergoing immunophenotyping, the following subjects will be randomized into the
TRIPS trial: | protocol.txt |
39015907-50bd-4263-bd9a-897c7b5b0bfc | • Subjects who have moderate to severe systemic inflammation (serum ferritin 500 – 10,000
ng/ml or CRP >4 mg/dl) without immunoparalysis;
• Subjects with immunoparalysis (TNFαresponse <200 pg/ml) whose serum ferritin is
between 2,000 and 10,000 ng/ml
The following subjects will not be randomized into the TRIPS trial: | protocol.txt |
153b6ca0-e56e-407d-ba31-61c053ebaab2 | • Subjects with immunoparalysis (TNFαresponse <200 pg/ml) and a serum ferritin level
<2,000 ng/ml;
• Subjects without immunoparalysis whose serum ferritin level is <500 ng/ml and whose
CRP is <4 mg/dl;
• Subjects whose serum ferritin level is >10,000 ng/ml.
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These criteria were chosen in order to exclude subjects from the TRIPS trial who may
benefit from immunostimulation rather than an anti-inflammatory approach (immunoparalysis
with mild to moderate inflammation); those who likely do not require immunomodulation (no | protocol.txt |
18897f8f-4517-459c-acca-c8646c305f12 | immunoparalysis with mild inflammation); and those with MAS/HLH who may be harmed by
placebo.
Subjects randomized into the TRIPS trial will receive standard-of-care therapy for sepsis-
induced MODS, in addition to study drug, at the discretion of their clinical teams.
2.3 Observational Cohorts
Subjects without either immunoparalysis or severe systemic inflammation (an estimated 5% of | protocol.txt |
083bc21d-ee73-47f8-8d92-b8fce336ece3 | the total cohort) are expected to have a good outcome and will receive no immunomodulatory
therapy. Subjects whose serum ferritin level is >10,000 ng/ml (expected to be <5% of the total
cohort) have a high likelihood of having a diagnosis of HLH/MAS.3 These subjects will undergo
evaluation and immunomodulatory management at the discretion of their clinical teams. These | protocol.txt |
cae19f0d-7498-44ca-8db0-6034d650c038 | subjects will form two observational cohorts, with full data collection, longitudinal immune
phenotyping, and biorepository sampling.
2.4 Longitudinal Immune Phenotyping
All subjects receiving study drug will undergo serial immune phenotyping including quantitation
of inflammatory biomarkers and immune function twice weekly for two weeks. This follow- | protocol.txt |
b98dbb25-6b69-454d-ad3b-f83e60967b79 | up sampling allows us to 1) quantitate the effects of the study drugs on inflammation and
immune function; 2) detect the presence of immunologic relapse in the week after study
drug discontinuation; and 3) understand the trajectory of immune function and inflammation,
including identification of further immune subphenotypes, over time in all subjects. Subjects in | protocol.txt |
8af86480-24a9-4d92-af8c-24add14ed19b | the observational cohorts will be sampled for through day 17 ± 1 day or until ICU discharge,
whichever occurs first.
2.5 Study Outcomes
Primary Outcome
The primary outcome of the study will be a composite of duration/severity of organ dysfunction
and mortality as measured by the cumulative Pediatric Logistic Organ Dysfunction (PELOD)-2 | protocol.txt |
a38476bc-6bf1-42df-8d8c-617a99298486 | score47 over 28 days after randomization, with non-survivors being assigned the highest possible
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PELOD-2 score. On any given day, the minimum score is 0 and maximum score is 33, with | protocol.txt |
eb1271c4-bc64-4f24-8bd5-49c268e32a00 | lower values indicating less organ dysfunction. This corresponds to a maximum possible 28-day
sum of 924. Mortality is incorporated into this analysis, with children who die within 28 days of
randomization assigned the worst possible score in a rank-based analysis. Rank based analyses
will be performed to account for mortality as well as the fact that for surviving children, a | protocol.txt |
053c1982-bb1e-4f51-b6a3-50e8b4a1b879 | difference in the cumulative PELOD-2 of a specified magnitude may reflect different clinical
consequences.
Secondary Outcomes
The two formal secondary efficacy outcomes are:
• Change from baseline status to 3 months after randomization in the Pediatric Quality of
Life Inventory (PedsQL) Generic Core or Infant Scales; | protocol.txt |
fb4c8be5-cb38-43cc-8d40-bd05ab6353b0 | • Change from baseline status to 3 months after randomization in the Functional Status
Scale (FSS).
In both analyses, children deceased at the 3-month timepoint will be treated as having the worst
possible change in outcome at 3 months.
Exploratory Outcomes
Exploratory outcomes include:
• Hospital and 28-day mortality;
• MODS-free days in 28 days following randomization; | protocol.txt |
750b9e59-c24e-4294-b3e6-7b5415fa13a5 | • Days free of any organ dysfunction in 28 days following randomization;
• Incidence of nosocomial infection (by CDC criteria) from the time of enrollment through
28 days following randomization;
• Change from baseline to 12-month PedsQL Generic Core or Infant Scales;
• Change from baseline to 12-month FSS score;
• Change from baseline to 3-month and 12-month PedsQL Family Impact Module 2.0 | protocol.txt |
dd12d99d-a685-4800-8a86-72d19f3af11a | score;
• Change from baseline to 3-month and 12-month Pediatric Evaluation of Disability Inven-
tory – Computer Adaptive Test score;
• Hospital readmissions occurring by 3 and 12 months after randomization.
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Safety Outcomes | protocol.txt |
7b7d5af9-7dbe-4248-9387-0ed26095d706 | In the GRACE-2 trial, hyperinflammation will be monitored by measuring systemic (plasma or
serum) levels of IL-6, ferritin, and CRP twice weekly during throughout the immune monitoring
period (through study day 17 ± 1 or hospital discharge, whichever is earlier). In the TRIPS
trial, the rate of nosocomial infections will be monitored through 28 days after randomization | protocol.txt |
c867e0fa-ac6e-4926-b6e6-ce009fc513db | (already an exploratory outcome).
Though not a formal safety outcome, the development of neutropenia is a potential non-
infectious treatment-emergent adverse event, though transient neutropenia can occur in the
setting of sepsis-induced MODS regardless of study arm assignment. In the event that a subject
is found to have a new reduction in absolute neutrophil count (ANC) to <1,000 cells/mm3 for | protocol.txt |
e329f047-a9ce-4a78-ad4b-0d99a84244ff | two consecutive days while receiving study drug, the drug will be discontinued.
Adverse events will be monitored as described in Section 10.2.6 on page 61. The medical
monitor has the authority to suspend enrollment in the event of an unexpected, study-related
serious adverse event that is judged to change the risk/benefit of subject participation. | protocol.txt |
dd93a8ac-2301-4d9b-b5c1-35a552d4fdb3 | 3 Subject Eligibility, Accrual and Study Duration
3.1 Eligibility criteria.
Eligible participants will be identified by on-site study staff. Inclusion criteria are:
• ≥ 40 weeks corrected gestational age∗∗ to <18 years; AND
• Admission to the PICU or CICU; AND
• Onset of ≥ 2 new organ dysfunctions within the last 3 calendar days (compared to | protocol.txt |
cd56594e-d05b-4237-801f-bfe426ae6f42 | pre-sepsis baseline) as measured by the modified Proulx criteria; AND
• Documented or suspected infection as the MODS inciting event.
∗∗ Corrected gestational age will be used in infants ≤ 4 months of age with a history of prematu-
rity. It will be calculated as the current chronological age in weeks + estimated gestational age | protocol.txt |
0e58a52f-23d4-41e9-a09b-d844b01fe980 | at birth (as reported by the parent/guardian and/or medical record review).
Exclusion criteria are:
• Weight <3kg; OR
• Limitation of care order at the time of screening; OR
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f0355cba-e847-41fe-b33f-bc3e6cba583a | • Patients at high likelihood of progression to brain death in opinion of the clinical team;
OR
• Moribund condition in which the patient is unlikely to survive the next 48 hours in opinion
of the clinical team; OR
• History of myeloid leukemia, myelodysplasia, or autoimmune thrombocytopenia; OR
• Current or prior diagnosis of hemophagocytic lymphohistiocytosis or macrophage activa- | protocol.txt |
1fb6f0c7-c9d3-4a0a-b976-be4103cbc1e5 | tion syndrome; OR
• Peripheral white blood cell count < 1,000 cells/mm3 as the result of myeloablative
therapyOR receipt of myeloablative therapy within the previous 14 days; OR
• Known allergy to GM-CSF, anakinra, or E. coli-derived products; OR
• Dependence on maintenance of strict ketosis; OR
• Known pregnancy; OR
• Lactating females; OR | protocol.txt |
e8f09d62-2fe0-4a10-bc36-63f082d01a55 | • Receipt of anakinra or GM-CSF within the previous 28 days; OR
• Resolution of MODS by MODS Day 2; OR
• Previous enrollment in the PRECISE study.
If all organ failure is resolved on Study Day 1 (the day following immune phenotyping), or
if the subject has developed an exclusion criterion since immune phenotyping, the subject’s
participation in the study will end. | protocol.txt |
2d1beaec-7d30-4e97-8240-dde0eb0742e5 | 3.2 Subject Accrual and Study Duration
Up to 1095 subjects will be phenotyped and have at least single organ failure on Study Day
1 over a four year period. We estimate that 40% will have immunoparalysis, 50% will have
moderate to severe hyperinflammation, 5% will have neither, and 5% will have very severe
hyperinflammation (likely MAS or HLH). We anticipate enrolling 400 subjects into the GRACE- | protocol.txt |
c712d65d-7aab-4d3c-91cb-cb5de1612548 | 2 trial. We anticipate enrolling 500 subjects into the TRIPS trial.
4 Study Procedures
4.1 Screening and Enrollment
All patients admitted to the pediatric or cardiac ICU at CPCCRN sites will be evaluated for
eligibility for our overall immune phenotyping and immunomodulation study that will feed
subjects into the TRIPS or GRACE-2 trials depending on their immune phenotyping results, | protocol.txt |
97b30200-7ccd-4255-8b7a-7a499f07c690 | which will not be known at the time of enrollment. Patients who meet inclusion criteria will be
entered into the data capture system and exclusion criteria (if present) will be recorded in that
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4396a133-0af0-46d4-ab6d-8131a9127f54 | 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 overall immune
phenotyping and immunomodulation study, as well as the interventional trial based on the
phenotyping results. Randomization into the interventional trial will only occur after immune | protocol.txt |
a198af3c-98b4-44a2-807d-ec633ffef3d1 | phenotyping data are known.
4.2 Immune Phenotyping
We have developed a highly feasible, highly standardized, next-day approach to multi-center
immunophenotyping in critically ill children. This includes the measurement of systemic
levels of serum ferritin levels and CRP on a clinical-grade instrument (the Immulite 1000 | protocol.txt |
fe9ef4c9-a90f-4a23-b65a-79aaadd3ec57 | automated chemiluminometer [Siemens Healthcare Diagnostics]) using commercially available,
FDA-approved test kits. We also use this instrument to quantitate TNFαlevels in the stimulated
supernatants using commercially available kits that are used clinically in Europe but are available
to us under a Research Use Only agreement. | protocol.txt |
a4411b62-0ec9-4775-ad5d-b8e5ea0ac4c0 | We will evaluate subjects for blood sampling on the second day after the onset of sepsis-
induced MODS (MODS Day 2). If MODS has resolved on what would have been MODS Day
2, we will not perform immune testing and subject’s participation in the study will be complete.
If MODS persists on MODS Day 2, the subject will undergo immune function screening. The | protocol.txt |
5ef53427-ad74-4f6c-a183-8da1d1d35159 | subject will undergo an approximately 2 ml blood draw for measurement of whole blood LPS-
induced TNFαproduction capacity (TNFαresponse) 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 LPS stimulation kits provided by the Immune | protocol.txt |
a11bed1e-6b9f-472d-b69b-412bb112f3ca | Surveillance Laboratory (ISL) at the Research Institute at Nationwide Children’s Hospital.
Briefly, aliquots of 50 µL of heparinized whole blood will be stimulated in duplicate, using
tubes containing 500 pg/ml of LPS (phenol-extracted from Salmonella abortus equi, Alexis
Biochemicals). Stimulation tubes will be incubated at 37◦ C for four hours after which the | protocol.txt |
4cf5d101-210d-465e-94ab-309bbfe1ca22 | samples will be immediately centrifuged. LPS-stimulated supernatants, along with unstimulated
serum, will be overnight-shipped on dry ice to the ISL where TNFαproduction capacity and
serum ferritin levels and CRP will be measured as early as possible the next day (Study Day 1).
If a subject’s TNFαproduction capacity is <200 pg/ml and the serum ferritin is <2,000 | protocol.txt |
f043948d-9bdf-424a-b766-bc9fc17d289f | ng/ml, the subject will be considered to have immunoparalysis with a very low likelihood of
MAS/HLH, and will therefore be eligible to be randomized to receive GM-CSF or placebo.
Subjects who have improved to single-organ dysfunction on the day of randomization will con-
tinue to receive study drug per-protocol. While the Nationwide Children’s site is able to assess | protocol.txt |
8d6aa1dc-8041-4ff2-9fd4-e4c63a374994 | subject eligibility on the same day as LPS stimulation (MODS Day 2), GM-CSF administration
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will be delayed until the next morning (Study Day 1) in order to remain consistent with the
dosing schedule at other CPCCRN sites. | protocol.txt |
74bfe79f-4496-43c7-8054-e4da3c629178 | Subjects with evidence of moderate to severe inflammation (serum CRP level ≥ 4 mg/dl or
ferritin level 500 – 10,000 ng/ml) without immunoparalysis and subjects with immunoparalysis
and a ferritin level ≥ 2,000 ng/ml are, together, expected to represent 50% of the total cohort
that is immunophenotyped. These subjects will be adaptively randomized into the TRIPS trial | protocol.txt |
2b774eec-c182-48b2-8662-7e12d7e7576f | to receive anakinra or placebo.
In addition to phenotyping on MODS Day 2, subjects will undergo follow-up immune
function testing including measurement of the TNFαresponse and systemic biomarkers on the
day after the third dose of study drug, the day after the seventh dose of study drug, and on
study days 12±1, and 17±1. These follow-up samples will be processed locally, frozen at -70◦ | protocol.txt |
039bf59a-ec0c-4091-823f-1e287ed126a5 | C, and batch-shipped to the ISL at the conclusion of the subject’s study participation. These
samples will not be used to drive additional study drug delivery but will instead be used to
understand the relationships between immunologic response to study drug and clinical outcomes.
4.3 GRACE-2 Study Drug Administration
4.3.1 Eligibility to Receive Study Drug Doses | protocol.txt |
e2a9ffb2-52ca-4b1d-96a1-4c627281fcd7 | In order to minimize the risk of leukostasis, study drug will not be administered if the subject’s
total while blood cell (WBC) count is >50,000 cells/mm3. If not already ordered by the clinical
team, subjects will undergo measurement of a complete blood count (CBC) prior to receiving
their first dose of study drug and prior to receiving their fourth dose of study drug. If, on either | protocol.txt |
daaf7525-5961-44a7-acda-d485ef168647 | other of these assessments (or on any clinically-obtained CBC during the study drug treatment
period), the subject’s total peripheral WBC count is >50,000 cells/mm3, the study drug will be
held and the CBC will be assessed the following day. Study drug will be resumed if/when the
total WBC count drops to ≤ 50,000 cells/mm3 with the total treatment duration not to exceed 7 | protocol.txt |
aeb7b031-4c0a-4be2-acbd-7c028c4863a4 | days from the day of randomization. A peripheral WBC count of >50,000 cells/mm3 was not
seen in any subjects in the GIFT or GRACE-1 studies to date.
4.3.2 Intravenous Infusion
The study drug will be infused over a minimum of 6 hours on the day after the qualifying
immune testing sample (Study Day 1). The infusion may be interrupted if needed, but must | protocol.txt |
dfa38e55-d2b9-411f-a37b-5236ec2ed2b4 | run over a total of no more than 12 hours. Study drug may be given via a peripheral or central
IV catheter. The first administered dose of study drug will be initiated as soon as possible
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8c11a631-c15a-4a9d-b4a0-ad25242cb9ce | after randomization. All subsequent IV doses will be initiated between 4 AM and noon. If the
window is missed, study drug should still be started as soon as possible.
If logistical problems with sample shipping result in up to a 1 calendar day delay in receiving
the immune phenotyping sample at the Immune Surveillance Laboratory, the sample is able to | protocol.txt |
61e218e0-5df9-4ff1-939b-99c6d0ac65a8 | be analyzed, and at least single organ dysfunction persists, randomization will be performed
on Study Day 2, administration of GM-CSF may be started on Study Day 2, and continued
for a total treatment duration not to exceed 7 days after randomization. In addition, if the
investigational pharmacy is unavailable to dispense study drug on Study Day 1, randomization | protocol.txt |
4ae491c7-6265-4e4d-bd70-73436f4a0f39 | should not be performed on Study Day 1. On Study Day 2, if the subject still has single organ
dysfunction, randomization and study drug administration may be performed. In no instances
should randomization or study drug be initiated later than Study Day 2.
4.3.3 Pharmacy Function and Monitoring
The investigational pharmacy at Nationwide Children’s Hospital will serve as the central phar- | protocol.txt |
ec70d1fa-0cff-4cb1-835c-8192dde61c3a | macy for the GRACE-2 study. They will intake GM-CSF from the manufacturer (Partner
Therapeutics), document lot number and expiration information, facilitate blinding, and ship
study drug to clinical sites’ investigational pharmacies. They will also develop source documen-
tation, pharmacy training materials, operating manuals, and study-specific pharmacy procedures | protocol.txt |
6fc6e274-6fc1-4d60-934c-1245bfe2330d | as needed. Clinical sites’ investigational pharmacies will be responsible for preparing placebo
doses, all of which will consist of normal saline infusions of equivalent volume to GM-CSF.
The 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 Data | protocol.txt |
89d8becb-3614-42f8-a6ee-7cfb66463fda | Coordinating Center and/or the investigational pharmacy at Nationwide Children’s Hospital
which will conduct remote audits at regular intervals.
4.4 TRIPS Study Drug Administration
4.4.1 Intravenous Infusion
Anakinra may be given via a peripheral or central IV catheter. The first administered dose of
study drug will be initiated as soon as possible after randomization. All subsequent IV doses | protocol.txt |
b3b19047-2d26-4ca9-b388-a93d50f0a585 | will be initiated every 12 hours (+/-2 hours from the previous dose) thereafter for a total of 14
doses (unless renal function-related dose reduction is required.)
If logistical problems with sample shipping result in up to a 1 calendar day delay in receiving
the immune phenotyping sample at the Immune Surveillance Laboratory, the sample will be | protocol.txt |
c627e846-b344-49a7-836c-ed8ffe77803d | analyzed. If at least single organ dysfunction persists, and the subject qualifies for study drug by
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laboratory analysis, randomization will be performed on Study Day 2 (instead of Study Day | protocol.txt |
2867f5fb-63b5-447c-860d-bf066397a84e | 1). Administration of study drug would begin on Study Day 2 and continue for a total of 14
doses (7 days after randomization). Shipping delays of more than 1 calendar day would result
in the subject being withdrawn from the study. In addition, if the investigational pharmacy is
unavailable to dispense study drug on Study Day 1, randomization should not be performed on | protocol.txt |
021b9554-452d-487b-9f95-390ef3fa0682 | Study Day 1. On Study Day 2, if the subject still has single organ dysfunction, randomization
and study drug administration may be performed. In no instances should randomization or study
drug be initiated later than Study Day 2.
4.4.2 Justification for IV Route of Administration
Anakinra is currently approved for administration by the subcutaneous (SQ) route, though it | protocol.txt |
742bc55d-d9a7-4758-88be-cf9fb122705a | can also be given by the intravenous (IV) route. All studies of anakinra for the treatment of
sepsis to date have been done using the IV route. This is because sepsis and sepsis-induced
MODS are characterized by abnormalities in tissue perfusion and edema, both of which dra-
matically affect drug absorption when given by the SQ route. Pediatric sepsis, in particular, is | protocol.txt |
200a5200-913e-4ef3-ba2c-993af1bf3cfb | frequently accompanied by peripheral vasoconstriction that would significantly decrease SQ
drug absorption.13 For the purposes of ensuring similar bioavailability across all study subjects,
it will be essential to deliver anakinra via the IV route in the TRIPS trial. Further, patients
with sepsis-induced MODS may have coagulopathy that would predispose them to bleeding | protocol.txt |
78416b39-bf3f-4fb2-9fa8-a404a5c4ba98 | with SQ injections. Intravenous administration will eliminate these risks, along with risk of SQ
injection site reactions which have been commonly reported in adults and children. In addition
to the adult sepsis trials, anakinra has been reported to be safely administered by the IV route in
children with HLH/MAS,14, 65, 67 adults with HLH/MAS,,38, 52 adults with acute stroke,19 adults | protocol.txt |
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