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

Assistance Publique - Hôpitaux de Paris

Status and phase: Begins enrollment in 11 months; Phase 3

Conditions: Sepsis

Treatments: Drug: Low molecular weight heparin; Drug: Sivelestat; Drug: Anakinra; Drug: Hydrocortisone and fludrocortisone; Drug: Heparin; Other: Usual care; Drug: Tocilizumab; Biological: Fresh frozen plasma; Drug: Recombinant humanThrombomodulin( rhTM); Drug: Baricitinib; Drug: Hydrocortisone

Study type: Interventional

Funder types: Other

Identifiers

NCT06381661

APHP240385

Details and patient eligibility

About

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.

Enrollment: 2,000 estimated patients

Sex: All

Ages: 37 weeks to 100 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• All genders patients aged >37 weeks corrected gestational age with sepsis as per Sepsis-3 definition for adults, and as per the PHOENIX sepsis for children
• documented or suspected infection
• a Sequential Organ Failure Assessment (SOFA) score ≥2 for adults, and PHOENIX sepsis score of ≥2 for children.

Domain specific additional inclusion criteria :

1. Hyper or hypo inflammation based

   • For adults on, respectively: beta, delta and gamma sub-phenotypes, and/or circulating levels of IL-6 > 100pg/mL, and lymphocytes counts < 1.0 × 109/L and/or HLA-DR <5,000 HLA-DR receptors/monocytes
   • For children on: the PODIUM (+specific criteria for children)

2. Corticosteroids domain Corticosteroids responses based on the combination of Glucocorticoid-induced 1 GLCCI1) AA and nuclear factor (NF)-KB1 DI genotypes.

3. Coagulation domain

   • Hypercoagulation state defined as a SIC score ≥4 points and neutrophils side fluorescence light (NEUT-SFL) >66 Arbitrary Units (patients with disseminated intravascular coagulopathy, DIC) or NEUT-SFL ≤66 AU (septic coagulopathy)
   • Hypofibrinolytic state defined as SIC score ≥4 points and decreased plasminogen level <1.2 nM.

Exclusion criteria

• refused to consent participating in the study
• pregnancy
• any condition for which patient's primary physician will consider inappropriate enrolling patient in the study
• previous enrollment in the study.
• additional domain specific exclusion criteria relevant to specific interventions, i.e. tocilizumab, baricitinib, anakinra, hydrocortisone, fludrocortisone, unfractioned heparin, tinzaparin, human recombinant thrombomodulin, sivelestat, fresh frozen plasma, according to the "base de données publiques des medicaments"

Patients can be included in multiple domains.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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2,000 participants in 11 patient groups

Immuno-modulation : Tocilizumab

Experimental group

Treatment:

Drug: Tocilizumab

Immuno-modulation Baricitinib

Experimental group

Treatment:

Drug: Baricitinib

Immuno-modulation Anakinra

Experimental group

Treatment:

Drug: Anakinra

Cortico-steroids : Hydrocortisone

Experimental group

Treatment:

Drug: Hydrocortisone

Cortico-steroids :Hydrocortisone and fludrocotisone

Experimental group

Treatment:

Drug: Hydrocortisone and fludrocortisone

Coagulation : Heparin

Experimental group

Treatment:

Drug: Heparin

Coagulation : Low molecular weight heparin

Experimental group

Treatment:

Drug: Low molecular weight heparin

Coagulation : Recombinant humanThrombomodulin( rhTM)

Experimental group

Treatment:

Drug: Recombinant humanThrombomodulin( rhTM)

Coagulation : Sivelestat

Experimental group

Treatment:

Drug: Sivelestat

Coagulation : Fresh Frozen Plasma

Experimental group

Treatment:

Biological: Fresh frozen plasma

Control

Active Comparator group

Treatment:

Other: Usual care