Precision Medicine Adaptive Network Platform Trial in Hypoxemic Acute Respiratory Failure

The goal of this trial is to accelerate the development of pharmacological therapies for critical illness by identifying biological sub phenotypes in patients with acute respiratory distress syndrome (ARDS). The trial will stratify participants by biological markers into different sub phenotypes, then randomized 1:1:1 to active treatment 1, active treatment 2, or usual care. Initial stratification will be into hyperinflammatory and hypoinflammatory sub phenotypes in ARDS based on plasma biomarker profiles. Regular adaptive analyses will enable efficient identification of treatment effects within each sub phenotype, stopping interventions where there is evidence of efficacy or futility, and bringing in new interventions and potentially new sub phenotypes.

Inclusion Criteria: Critically ill patients in hospital and at least 1 of the following: 1. Acute respiratory distress syndrome (ARDS). ARDS as defined by: 1. a known acute clinical insult or new or worsening respiratory dysfunction 2. receiving respiratory support via invasive mechanical ventilation or non- invasive mechanical ventilation including continuous positive airway pressure, or high flow nasal oxygen greater than or equal to 30L/min 3. within the same 24-hour time period: i. bilateral opacities on chest imaging not fully explained by effusion, lobar/lung collapse/atelectasis, or nodules ii. respiratory failure not fully explained by cardiac failure, fluid overload, pulmonary embolism, acute airway disease iii. Pa02/Fi02 ration \8 times the upper limit of the normal range 4. Absolute neutrophil count less than 0.5x10 9/L 5. Currently receiving ongoing immunosuppressants (high dose corticosteroids, B and T cell targeted therapies, interferon, or JAK inhibitors) 6. Severe renal impairment (eGFR \< 15mL/min) or receiving renal replacement therapy 7. Known active tuberculosis infection or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines. 8. Contraindication to enteral drug administration, e.g., patients with mechanical bowel obstruction. Patients with high gastric aspirates due to an ileus are not excluded. 9. Known hypersensitivity to baricitinib