PALETTE - Adaptive platform trial for personalisation of sepsis treatment in children and adults: a multi-national, treatable traits-guided, adaptive, exploratory, bayesian basket trial

The primary objective is to provide exploratory estimates of the effect of study treatments on all-cause mortality and persistent life-supportive therapies at 28 days after randomization for each pairwise comparison with the usual care arm in patients with sepsis. This exploratory evaluation aims to generate hypotheses to be further confirmed in separate confirmatory studies, addressing the critical clinical need for personalized treatment approaches in sepsis management across pediatric and adult populations.

Secondary objectives include:

• Exploratory evaluation of the efficacy of treatable-traits guided interventions on sepsis-related complications in the short-term (28 days), mid-term (90 days), and long-term (1 and 3 years)

• Evaluation of experimental interventions safety profile

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes **male and female patients** across a broad age spectrum, encompassing **children** (aged greater than 37 weeks corrected gestational age), **adolescents**, and **adults**. Participants are individuals diagnosed with **sepsis**, defined according to the Sepsis-3 criteria for adults aged 18 years and older, and the PHOENIX sepsis criteria for children under 18 years of age. Key inclusion criteria require documented or suspected **infection** and a **Sequential Organ Failure Assessment (SOFA) score** of 2 or higher for adults, or a PHOENIX sepsis score of 2 or higher for children. The trial population was selected based on these clinical diagnostic parameters. This study involves a **vulnerable population**. No specific lifestyle considerations such as diet, physical activity, or habits were reported by the sponsor.

This clinical trial is designed as an adaptive platform trial investigating personalized treatment approaches for **sepsis** in both pediatric and adult populations. The study employs a multi-national, treatable traits-guided, adaptive, exploratory, **Bayesian basket trial** design. The trial is classified as **Phase IV** and is categorized as a Phase II/III study. The primary objective is to provide exploratory estimates of the effect of various study treatments compared to usual care on **all-cause mortality** and persistent life-supportive therapies at 28 days after randomization through pairwise comparisons. The trial aims to generate hypotheses that will be further confirmed in subsequent confirmatory studies. The estimated recruitment start date is January 1, 2026, with an anticipated trial completion date of December 31, 2030.

The trial investigates multiple investigational medicinal products administered through various routes. These include **hydrocortisone** (powder for solution for infusion, intravenous administration, maximum daily dose 200 mg, maximum treatment period 7 days), **anakinra** (subcutaneous injection, maximum daily dose 100 mg, maximum treatment period 10 days), **tocilizumab** (solution for intravenous infusion, maximum daily dose 800 mg, maximum treatment period 1 day), **human plasma protein** (OCTAPLASLG solution for infusion, intravenous infusion, maximum daily dose 12 milliliters/kilogram, maximum treatment period 5 days), **interferon gamma** (subcutaneous administration, maximum daily dose 50 micrograms/square meter, maximum treatment period 15 days), **baricitinib** (film-coated tablet via enteral feeding tube, maximum daily doses of 2 mg or 4 mg depending on dosing regimen, maximum treatment period 7 days), **heparin** (intravenous infusion, maximum treatment period 6 days), **dalteparin sodium** (subcutaneous use, maximum daily dose 18,000 IU, maximum treatment period 6 days), **fludrocortisone acetate** (oral, nasogastric tube, or percutaneous endoscopic gastrostomy tube use, maximum daily dose 50 micrograms, maximum treatment period 7 days), and **filgrastim** (subcutaneous administration, maximum daily dose 5 micrograms/kilogram, maximum treatment period 5 days).

Eligible participants include patients of all genders aged greater than 37 weeks corrected gestational age for children. Adults (≥18 years) must meet the **Sepsis-3 definition**, while children (<18 years) must meet the **PHOENIX sepsis criteria**. All participants must have documented or suspected infection and either a **Sequential Organ Failure Assessment (SOFA) score** ≥2 for adults or a PHOENIX sepsis score ≥2 for children. Health insurance is required for participation.

The trial employs dual primary endpoints: 28-day all-cause mortality and the number of days alive without life-supportive therapies at day 28 after randomization. Life-supportive therapies include 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), and renal support (intermittent or continuous **renal replacement therapy**). Secondary endpoints include a composite and hierarchized assessment of the two primary outcomes using **Generalized Pairwise Comparison (GPC)** for prioritized outcomes, survival rates at 90 days, 1 year, and 3 years, hospital-free days at 1 and 3 years, time to recover walking without aid, time to resume previous social and professional activities, and quality of life assessments. Quality of life will be measured using **SF-36** and **5-level EQ-5D version (EQ-5D-5L)** in adults, and the **Functional Status Scale (FSS)** and **PedsQL** in children at 90 days, 1 year, and 3 years.

The expected duration of participant involvement extends up to 3 years for long-term follow-up assessments, with the primary evaluation period occurring at 28 days post-randomization. The trial incorporates an adaptive design that allows for modifications based on accumulating data throughout the study period. Conditions that may lead to early termination from the study are not explicitly detailed in the available protocol information.

**Hydrocortisone** is administered as a **powder for solution for infusion** containing hydrocortisone as the active substance. The maximum daily dose is 200 mg, with a maximum total dose of 1400 mg administered over a treatment period of up to 7 days. The route of administration is **intravenous administration**. Hydrocortisone functions as a glucocorticoid in this trial.

**Anakinra** is administered via **subcutaneous injection**. The maximum daily dose is 100 mg, with a maximum total dose of 1000 mg over a treatment period of up to 10 days. Anakinra is a protein-derived substance classified under ATC code L04AC03.

**Tocilizumab** is administered as a **solution for intravenous infusion**. The maximum daily dose is 800 mg, with a maximum total dose of 800 mg administered over a treatment period of 1 day. Tocilizumab is a protein-derived substance classified under ATC code L04AC07.

**Octaplaslg** is a solution for infusion containing **human plasma protein** as the active substance, derived from blood. The pharmaceutical form is solution for infusion administered via **intravenous infusion**. The maximum daily dose is 12 milliliters per kilogram, with a maximum total dose of 60 milliliters per kilogram over a treatment period of up to 5 days. This product is classified under ATC code B05AA as a blood substitute and plasma protein fraction.

**Interferon gamma** is administered via **subcutaneous** route. The maximum daily dose is 50 micrograms per square meter, with a maximum total dose of 750 micrograms per square meter over a treatment period of up to 15 days. This substance is classified under ATC code L03AB03.

**Baricitinib** is administered as a **film-coated tablet** via **enteral feeding tube**. Two dosing regimens are utilized in this trial. The first regimen involves a maximum daily dose of 2 mg with a maximum total dose of 14 mg over 7 days. The second regimen involves a maximum daily dose of 4 mg with a maximum total dose of 28 mg over 7 days. Baricitinib is a chemical substance.

**Heparin** is administered via **intravenous infusion**. The dosing is expressed in international units per milliliter. The maximum treatment period is up to 6 days. Heparin is a polymer-derived substance classified under ATC code B01AB01.

**Dalteparin sodium** is administered via **subcutaneous use**. The maximum daily dose is 18000 international units, with a maximum total dose of 108000 international units over a treatment period of up to 6 days. Dalteparin is a polymer-derived substance classified under ATC code B01AB04.

**Fludrocortisone acetate** is administered orally, via **nasogastric tube or percutaneous endoscopic gastrostomy tube**. The maximum daily dose is 50 micrograms, with a maximum total dose of 350 micrograms over a treatment period of up to 7 days. Fludrocortisone acetate is a chemical substance functioning as a mineralocorticoid, classified under ATC code H02AA02.

**Filgrastim** is administered via **subcutaneous** route. The maximum daily dose is 5 micrograms per kilogram, with a maximum total dose of 25 micrograms per kilogram over a treatment period of up to 5 days. Filgrastim is a protein-derived substance classified under ATC code L03AA02.

Efficacy will be assessed using dual primary endpoints. The first primary endpoint is 28-day all-cause mortality. The second primary endpoint is the number of days alive without life-supportive therapies at day 28 after randomization. Life-supportive therapies are defined as respiratory support (including high flow oxygen, non-invasive or invasive mechanical ventilation, extracorporeal membrane oxygenation or CO2 removal), cardiovascular support (including continuous infusion of any dose of vasopressor or inotrope, or mechanical circulatory assistance), and renal support (including intermittent or continuous renal replacement therapy).

Secondary efficacy endpoints include a composite and hierarchised measure of the two dual primary outcomes using a Generalized Pairwise Comparison for Prioritized Outcomes. Long-term survival will be evaluated at 90 days, 1 year, and 3 years. Hospital-free days will be assessed at 1 year and 3 years. Time to recover walking without aid and time to resume previous social and professional activities will be measured. Quality of life will be evaluated at 90 days, 1 year, and 3 years using validated instruments. In adults, the SF-36 and the 5-level EQ-5D version (EQ-5D-5L) will be used. In children, the Functional Status Scale and the PedsQL will be employed.