Precision medicine Adaptive Network platform Trial in Hypoxemic acutE respiratory failuRe (PANTHER)

Research question

In patients with ARDS with hyper and hypoinflammatory phenotypes, do pharmacological interventions in addition to usual care, compared to usual care alone, reduce the risk of death or the duration of organ support? Background

ARDS is a heterogeneous clinical syndrome characterised by acute, inflammatory lung injury resulting in hypoxaemic respiratory failure. There are currently no pharmacological treatments for ARDS. Distinct hyper and hypoinflammatory phenotypes of ARDS can be identified which are distinguishable largely based on plasma biomarker profiles, suggesting that patients with a specific phenotype have a more homogeneous host biological response.

ARDS phenotypes demonstrate differential responses to specific interventions in secondary analyses of completed clinical trials.

Overall aim: To accelerate the development of pharmacological therapies for ARDS by establishing an international phase 2 precision medicine adaptive platform trial. Initial objectives

1) To test in patients with ARDS with hyperinflammatory and hypoinflammatory phenotypes the efficacy of simvastatin and baricitinib to improve 28-day organ-support free days. 2) To develop an infrastructure for testing additional phenotypes and therapies in a platform trial.

Methods: We will use a Bayesian Adaptive Multi-Arm Trial design with pre-defined triggers for efficacy and futility (compared to usual care). Regular adaptive analyses will enable us to identify differential treatment responses across phenotypes by examining treatment effect in phenotype strata and stopping arms where there is evidence of futility or efficacy.

Precision Medicine factors

Inflammatory phenotype will be determined with a validated automated quantitative plasma immunoassay for IL-6 and sTNFR1. The IL-6 and sTNFr-1 values will be used with bicarbonate measured in an arterial blood gas to determine phenotype using a validated algorithm. Setting: At least 70 hospitals in the UK and internationally.

Population: Adult patients with ARDS. Exclusion criteria Platform level:

a) >48 hours from ARDS diagnosis, b) Planned treatment withdrawal within 24 hours, c) Previous enrolment in the trial, d) Declined consent, e) Domiciliary mechanical ventilation. Additional intervention-specific exclusion criteria will be included. Interventions being assessed: We will start the platform with 3 arms:

Simvastatin 80mg enterally once daily for 28 days Baricitinib 4mg enterally once daily for 10 days. Usual care. Primary Outcome 28-day organ support-free days, incorporating mortality. Secondary Outcomes

(1) Progression to invasive mechanical ventilation, extracorporeal membrane oxygenation or death, (2) vasopressor-free days, (3) respiratory support–free days, (4) receiving new renal replacement therapy, (5) ICU and (6) hospital length of stay, (7) mortality at 28 and 90 days, (8) health-related quality of life at 90 days (EQ-5D-5L), and (9) serious adverse events.

Sample size: Projected maximum sample size of 1956.

Timeline: Months 1-12 study set up, months 13-60 trial recruitment. Data cleaning/lock, analysis, write up, dissemination will be ongoing during the study.

Anticipated impact and dissemination: This project will deliver a precision medicine adaptive platform trial designed to accelerate identification of pharmacological treatments for patients with ARDS to improve patient care. With the support of our PPI members, we will disseminate our findings widely to ensure global reach.