Sepsis
Conditions
Keywords
Sepsis, Platform trial, Precision Medicine
Brief summary
PALETTE is a perpetual adaptive platform to efficiently study sepsis interventions within 'treatable traits' in all-ages patients enabling prompt evaluation of pandemic treatments. Treatable traits, therapeutic targets identified by phenotypes or endotypes (defined by biological mechanism or by treatment response) through validated biomarkers (measurable characteristic reflecting normal or pathogenic processes, or treatment responses), may include multi-omics, cellular, immune, metabolic, endocrine features, or intelligent algorithms. PALETTE Bayesian adaptive design enables parallel investigations of multiple interventions for sepsis, and quick inclusion of pandemic pathogens. PALETTE's new conceptual model will respond to the challenges of standard approaches, i.e. series of sepsis trials, each investigating one or two interventions, expensive, time consuming, and inappropriate in pandemic context.
Interventions
DRUGPlasminogen
2,2 mg/kg/day (intravenous infusion) during 3 days.
DRUGTocilizumab
8 mg per kilogram of body weight enterally (oral or via a gastric tube) once daily for 14 days (or hospital discharge pending which will occur first) (same for adults and children)
DRUGBaricitinib
4mg, enterally (oral or via a gastric tube) once daily for 14 days (or hospital discharge pending which will occur first) (same for adults and children)
DRUGAnakinra
100 mg subcutaneously once daily for 10 days (or hospital discharge pending which will occur first) (same for adults and children)
DRUGHydrocortisone
50mg (in children: 1-2 mg/kg) IV Q6 for 7 days
DRUGHydrocortisone and fludrocortisone
Hydrocortisone 50mg IV Q6 for 7 days + Fludrocortisone 50mg orally or via gastric tube once a day for 7 days.
DRUGHeparin
Therapeutic unfractionated heparin (UFH) starting at 400 (in children: 20 IU/kg/h) IU/kg/24h (target between 0.3 and 0.5 IU/ml), adapted to the therapeutic Partial Thromboplastin Time targeting values in the range of 60 to 100 seconds, with lower intensity dosing in the range of 60 to 80 seconds, for 7 days (or ICU discharge, pending which will occur first).
DRUGLow molecular weight heparin
Therapeutic low weight molecular heparin (LMWH) tinzaparin, considering its contraindications, recommended dose ranges and monitoring if applicable, as follows: 175 (in children 100 U/kg) IU/kg/24h, for 7 days (or hospital discharge pending which will occur first).
DRUGRecombinant humanThrombomodulin( rhTM)
Recombinant human thrombomodulin (rhTM) 0.06 mg/kg/j IV, for 7 days (or ICU discharge, pending which will occur first).
DRUGSivelestat
0.2 mg/kg/h for 7 days (or ICU discharge, pending which will occur first)
OTHERUsual care
Usual care
OTHERblood purification with MTx.100 Plasma Adsorption Column
up to 4 hours a day, up to four days in a row
DRUGG-CSF filgrastim
0.5 MIU (5μg)/kg/day subcutaneously for 5 consecutive days (or up to ICU discharge pending which occurs first) - same for adults and children .
DRUGInterferon gamma-1b
rhIFNg subcutaneously at 50 µg/m2 if body surface \>0,5 m2, or 1.5µg/kg if body surface of 0,5 m2or less, every other day for 15 days (or up to ICU discharge pending which occurs first)
DRUGFludrocortisone
50µg orally (or via the gastric tube) once a day for 7 days (or ICU discharge pending which will occur first) (same for adults and children)
DRUGProphylactic unfractionated heparin (UFH)
100 IU/kg/24h for 6 days
DRUGOctaplas LG
12 mL/kg on day 1; repeated daily from day 2 to day 5, provided that PT/INR remains ≥ 1.40 (This intervention will be opened for randomisation once a supply circuit is in place)
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomization will concern 6 specific treatable traits (hyperinflammation, hypoinflammation, Macrophage Activation Like Syndrome, Corticoid response, hypercoagulation, Hypofibrinolysis). In each treatable trait, patients will be randomly allocated between control (usual care) and 1 to 4 experimental treatments using parallell arms.
Eligibility
Sex/Gender
ALL
Age
37 Weeks to No maximum
Healthy volunteers
No
Inclusion criteria
Platform inclusion criteria will be: * All genders patients * Aged \>37 weeks corrected gestational age * Sepsis as per Sepsis-3 definition for adults, and as per the PHOENIX sepsis for children Briefly, all following criteria will be required: 1. Documented or suspected infection, 2. Sequential Organ Failure Assessment (SOFA) score ≥2 for adults, and PHOENIX sepsis score of ≥2 for children. * Health insurance Platform
Exclusion criteria
Any of the following: * Refusal to consent for participating in the study, * Pregnancy measured by beta-HCG blood levels * Breast feeding * Acute coronary disease in the past 3 months * Stroke episode in the past 3 months * Any condition for which patient's primary physician will consider inappropriate enrolling patient in the study Treatable trait inclusion criteria : * Hyperinflammation : Subphenotypes Beta, Delta, Gamma for adults; Subphenotypes PedSep-B, C, D for children * Hypoinflammation : lymphocytes count \< 1.0 × 10\^9/L * Macrophage Activation Like Syndrome : Ferritin \>4,420 ng/mL for adults, Ferritin \>500 ng/mL for children * Corticosteroids: Positive for i-RECORDS algorithm signature * Hypercoagulation (adults) : Prothrombin time (PT)/INR ≥ 1.40 AND Platelet count \< 150 000/mm3 or greater than 30% decrease in platelets in 24 hours * Hypofibrinolysis (adults): Plasminogen deficit \< 0.5 µmol/L There are also inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause mortality | At day 28 | Dual primary endpoint |
| Number of days alive without persistent life-supportive therapies | At day 28 | Dual primary endpoint Respiratory support: high flow oxygen, non-invasive or invasive mechanical ventilation, extracorporeal membrane oxygenation or CO2 removal; cardiovascular support: continuous infusion of any dose of vasopressor or inotrope, or mechanical circulatory assistance; renal support: intermittent or continuous renal replacement therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Net benefit probability of intervention vs. control, assessed with a Generalized Pairwise Comparison (mortality prioritized over life-support-free days) | At day 28 | The Generalized Pairwise Comparison (GPC) method will be used to derive a single composite outcome. Each patient in the intervention group will be compared to each patient in the control group. For each pair, a score of +1, -1, or 0 will be assigned according to prioritized outcomes: (1) all-cause mortality at day 28, and (2) number of days alive without life-supportive therapies at day 28 if both patients have the same mortality status. The net benefit will be calculated as the sum of all pairwise scores divided by the total number of pairs, corresponding to the probability that a randomly chosen patient has a better outcome in one group than in the other. |
| Overall Survival | At day 90 | — |
| Number of hospital free days | At 1 year | — |
| Time to recover walking | At day 90 | — |
| Time to resume previous social and professional activities | At 1 year | — |
| Quality of life score for adults assessed by SF-36 | At day 90 | The Short Form (36) (SF-36) Health Survey is a 36-item measure if health status. The score obtained varies between 0 and 100. The higher the score the less disability. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Med Care 1992;30:473-83. |
| Quality of life score for adults assessed by EQ-5D-5L | At day 90 | EQ-5D-5L : It evaluates five dimensions : mobility, self-care, usual activities, pain/discomfort and anxiety/depression and each dimension has five levels : no problems, slight problems, moderate problems, severe problems and extreme problems. Answers are given on a 5-point scale by domain, the higher the score, the poorer the quality of life. |
| Pediatric Quality of Life Inventory (PedsQL) | At day 90 | Standardized tool used to measure health-related quality of life (HRQoL) in children and adolescents (ages 2-18) It is a 23-item score divided in four domains : Phtsical functioning, Emotional functioning, Social functioning, School functioning The total score vary from 0 to 100. The higher the score the hiher the quality of life. |
| Quality of life score for children assessed by FSS | At day 90 | Functional Status Scale (FFS) : It examines 6 domains of functioning, and each domain receives a score of 1 (normal), 2 (mild dysfunction), 3 (moderate dysfunction), 4 (severe dysfunction), or 5 (very severe dysfunction). Final scores range from 6 to 30. |
| Number of adverse events | Up to 3 years | Tolerance of interventions considering any grade of 3 serious adverse events. |
| Incidence of new sepsis episodes | At day 90 | — |
| Incidence of new unscheduled hospitalizations | At day 90 | — |
| Incidence of sequels in neurocognitive, neuromuscular; cardiovascular, respiratory, renal, metabolic, and immune systems | At 3 years | — |
| Number of grade 3 serious adverse events | At day 28 | — |
Contacts
CONTACTDjillali Annane, Pr
CONTACTJérôme Lambert
Outcome results
None listed