Adaptive Platform Trial for Personnalisation of Sepsis Treatment in Children and Adults: a Multi-national, Treatable Traits-guided, Adaptive, Exploratory, Bayesian Basket Trial

Official title

PALETTE- Adaptive Platform Trial for Personnalisation of Sepsis Treatment in Children and Adults: a Multi-national, Treatable Traits-guided, Adaptive, Exploratory, Bayesian Basket Trial

Overview

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

• Drug Tocilizumab
  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)
• Drug Baricitinib
  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)
• Drug Anakinra
  100 mg subcutaneously once daily for 10 days (or hospital discharge pending which will occur first) (same for adults and children)
• Drug Hydrocortisone
  50mg (in children: 1-2 mg/kg) IV Q6 for 7 days
• Drug Hydrocortisone and fludrocortisone
  Hydrocortisone 50mg IV Q6 for 7 days + Fludrocortisone 50mg orally or via gastric tube once a day for 7 days.
• Drug Heparin
  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).
• Drug Low 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).
• Drug Recombinant humanThrombomodulin( rhTM)
  Recombinant human thrombomodulin (rhTM) 0.06 mg/kg/j IV, for 7 days (or ICU discharge, pending which will occur first).
• Drug Sivelestat
  0.2 mg/kg/h for 7 days (or ICU discharge, pending which will occur first)
• Other Usual care
  Usual care

Primary outcome measures

• All-cause mortality [Time frame: At day 28]
• Number of days alive without persistent life-supportive therapies [Time frame: At day 28]

Secondary outcome measures (12)

• Net benefit probability of intervention vs. control, assessed with a Generalized Pairwise Comparison (mortality prioritized over life-support-free days) [Time frame: At day 28]
• Overall Survival [Time frame: At day 90]
• Overall Survival [Time frame: At 1 year]
• Overall Survival [Time frame: At 3 years]
• Number of hospital free days [Time frame: At 1 year]
• Number of hospital free days [Time frame: At 3 years]
• Time to recover walking [Time frame: At day 90]
• Time to resume previous social and professional activities [Time frame: At 1 year]
• Quality of life score for adults assessed by SF-36 [Time frame: At day 90]
• Quality of life score for adults assessed by EQ-5D-5L [Time frame: At day 90]
• Pediatric Quality of Life Inventory (PedsQL) [Time frame: At day 90]
• Quality of life score for children assessed by FSS [Time frame: At day 90]

Eligibility 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:

• Documented or suspected infection,
• 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 exclusion criteria related to treatable traits and interventions.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06381661 · APHP240385

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗