Efficacy and Mechanism Evaluation (Jul 2025)
Building an international precision medicine platform trial for the acute respiratory distress syndrome (ARDS): an expert consensus project report
- Kiran Reddy,
- Neil Aggarwal,
- Narges Alipanah-Lechner,
- Djillali Annane,
- David B Antcliffe,
- Daphne Babalis,
- J Kenneth Baillie,
- Abigail Beane,
- Lieuwe DJ Bos,
- Aidan Burrell,
- Carolyn S Calfee,
- Kiki Cano-Gamez,
- Victoria R Cornelius,
- Mary Cross,
- Emma Davenport,
- Lorenzo del Sorbo,
- Laura Esserman,
- Eddy Fan,
- Vito Fanelli,
- Niall D Ferguson,
- D Clark Files,
- Christoph Fisser,
- Shigeki Fujitani,
- Ewan C Goligher,
- Anthony C Gordon,
- Giacomo Grasselli,
- Fergus Hamilton,
- Rashan Haniffa,
- Andrea Haren,
- Daniel JR Harvey,
- Leanne M Hays,
- Anna Heath,
- Nicholas Heming,
- Susanne Herold,
- Tim Hicks,
- Nao Ichihara,
- Vinod Jaiswal,
- Jun Kataoka,
- Julian C Knight,
- Patrick R Lawler,
- Kathleen Liu,
- John C Marshall,
- David M Maslove,
- Michael A Matthay,
- Daniel F McAuley,
- Nuala J Meyer,
- Jonathan A Millar,
- Holger Müller-Redetzky,
- Alistair Nichol,
- John Norrie,
- Marlies Ostermann,
- Andrew Owen,
- Cecilia M O’Kane,
- Dhruv Parekh,
- Rachel Phillips,
- Duncan Richards,
- Bram Rochwerg,
- Anthony J Rostron,
- Hiroki Saito,
- Romit J Samanta,
- Vittorio Scaravilli,
- Wesley Self,
- Manu Shankar-Hari,
- A John Simpson,
- Pratik Sinha,
- Marry R Smit,
- Jonathan Stewart,
- B Taylor Thompson,
- István Vadász,
- Ed Waddingham,
- Steve Webb,
- Graham Wheeler,
- D Martin Witzenrath,
- Mark M Wurfel,
- Thomas R Martin
Affiliations
- Kiran Reddy
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
- Neil Aggarwal
- Division of Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado, Aurora, CO, USA
- Narges Alipanah-Lechner
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Djillali Annane
- INSERM U1173, Université de Versailles SQY-Université Paris Saclay, Garches, France
- David B Antcliffe
- Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London, UK
- Daphne Babalis
- School of Public Health, Faculty of Medicine, Imperial College London, London, UK
- J Kenneth Baillie
- Centre for Inflammation Research, Deanery of Clinical Sciences, University of Edinburgh, Midlothian, UK
- Abigail Beane
- Centre for Inflammation Research, Deanery of Clinical Sciences, University of Edinburgh, Midlothian, UK
- Lieuwe DJ Bos
- Department of Intensive Care and Laboratory of Experimental Intensive Care and Anaesthesiology, Amsterdam UMC, Amsterdam, The Netherlands
- Aidan Burrell
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
- Carolyn S Calfee
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Kiki Cano-Gamez
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
- Victoria R Cornelius
- School of Public Health, Faculty of Medicine, Imperial College London, London, UK
- Mary Cross
- School of Public Health, Faculty of Medicine, Imperial College London, London, UK
- Emma Davenport
- Wellcome Sanger Institute, Cambridgeshire, UK
- Lorenzo del Sorbo
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Li Ka Shing Knowledge Institute, Toronto, Canada
- Laura Esserman
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
- Eddy Fan
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Li Ka Shing Knowledge Institute, Toronto, Canada
- Vito Fanelli
- Anesthesiology and Intensive Care Division, Surgical Sciences Department, Città della Salute e della Scienza, University of Turin, Turin, Italy
- Niall D Ferguson
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Li Ka Shing Knowledge Institute, Toronto, Canada
- D Clark Files
- Section of Pulmonary, Critical Care, Allergy, and Immunology, School of Medicine, Wake Forest University, Winston-Salem, NC, USA
- Christoph Fisser
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
- Shigeki Fujitani
- Department of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
- Ewan C Goligher
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Li Ka Shing Knowledge Institute, Toronto, Canada
- Anthony C Gordon
- Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London, UK
- Giacomo Grasselli
- Department of Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Fergus Hamilton
- Department of Population Health Sciences, University of Bristol, Bristol, UK
- Rashan Haniffa
- Centre for Inflammation Research, Deanery of Clinical Sciences, University of Edinburgh, Midlothian, UK
- Andrea Haren
- Department of Anaesthesiology and Intensive Care, St. Vincent’s University Hospital, Dublin, Ireland
- Daniel JR Harvey
- Division of Anaesthesia and Intensive Care, School of Medicine, The University of Nottingham, Nottingham, UK
- Leanne M Hays
- University College Dublin Clinical Research Centre, St. Vincent’s University Hospital, Dublin, Ireland
- Anna Heath
- Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
- Nicholas Heming
- INSERM U1173, Université de Versailles SQY-Université Paris Saclay, Garches, France
- Susanne Herold
- Department of Internal Medicine V, University of Giessen and Marburg Lung Center, Giessen, Germany
- Tim Hicks
- NIHR Newcastle In Vitro Diagnostics Co-operative, Newcastle University, Newcastle upon Tyne, UK
- Nao Ichihara
- Osaka University, Osaka, Japan
- Vinod Jaiswal
- Department of Intensive Care, Mediclinic City Hospital, Dubai, United Arab Emirates
- Jun Kataoka
- Department of Pulmonary and Critical Care Medicine, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Japan
- Julian C Knight
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Patrick R Lawler
- Cardiology Division, McGill University Health Centre, McGill University, Montreal, Canada
- Kathleen Liu
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- John C Marshall
- Department of Surgery, University of Toronto, Toronto, Canada
- David M Maslove
- Department of Critical Care Medicine, School of Medicine, Queen’s University, Kingston, Canada
- Michael A Matthay
- Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
- Daniel F McAuley
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
- Nuala J Meyer
- Pulmonary, Allergy, and Critical Care Division, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Jonathan A Millar
- Centre for Inflammation Research, Deanery of Clinical Sciences, University of Edinburgh, Midlothian, UK
- Holger Müller-Redetzky
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Alistair Nichol
- Department of Critical Care Medicine, School of Medicine, University College Dublin, Health Sciences Centre, Dublin, Ireland
- John Norrie
- Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, UK
- Marlies Ostermann
- Department of Critical Care Medicine, King’s College London, Guy’s & St Thomas Hospital, London, UK
- Andrew Owen
- Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
- Cecilia M O’Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
- Dhruv Parekh
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- Rachel Phillips
- School of Public Health, Faculty of Medicine, Imperial College London, London, UK
- Duncan Richards
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Disorders, University of Oxford, Oxford, UK
- Bram Rochwerg
- Faculty of Health Sciences, McMaster University, Hamilton, Canada
- Anthony J Rostron
- Translation and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Hiroki Saito
- Department of Emergency and Critical Care Medicine, St. Marianna University Yokohama Seibu Hospital, Yokohama, Japan
- Romit J Samanta
- Department of Medicine, School of Clinical Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
- Vittorio Scaravilli
- Department of Biomedical, Surgical, and Dental Sciences, University of Milano, Milan, Italy
- Wesley Self
- Department of Emergency Medicine, School of Medicine, Vanderbilt University, Nashville, TN, USA
- Manu Shankar-Hari
- Centre for Inflammation Research, Deanery of Clinical Sciences, University of Edinburgh, Midlothian, UK
- A John Simpson
- Faculty of Health Sciences, McMaster University, Hamilton, Canada
- Pratik Sinha
- Department of Anesthesiology, Washington University in St. Louis, St. Louis, WA, USA
- Marry R Smit
- Department of Intensive Care and Laboratory of Experimental Intensive Care and Anaesthesiology, Amsterdam UMC, Amsterdam, The Netherlands
- Jonathan Stewart
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
- B Taylor Thompson
- Division of Pulmonary and Critical Care, Department of Medicine, Harvard University, Boston, MA, USA
- István Vadász
- Department of Internal Medicine V, University of Giessen and Marburg Lung Center, Giessen, Germany
- Ed Waddingham
- School of Public Health, Faculty of Medicine, Imperial College London, London, UK
- Steve Webb
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
- Graham Wheeler
- School of Public Health, Faculty of Medicine, Imperial College London, London, UK
- D Martin Witzenrath
- Pulmonary, Allergy, and Critical Care Division, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Mark M Wurfel
- Division of Pulmonary and Critical Care, Department of Medicine, University of Washington, Seattle, WA, USA
- Thomas R Martin
- Division of Pulmonary and Critical Care, Department of Medicine, University of Washington, Seattle, WA, USA
Abstract
Background Almost all large-scale trials of disease-modifying therapeutic agents in critical care have failed to show benefit for patients, which may be explained in part by the clinical and biological heterogeneity inherent in virtually all critical illness syndromes. Enrichment strategies have been developed to separate responders from non-responders and better target treatments. In patients with the acute respiratory distress syndrome, a critical illness syndrome involving severe lung inflammation, latent class analysis and other clustering approaches have led to the discovery of subgroups (phenotypes) that appear to respond differently to treatment based on retrospective analyses of published clinical trials and observational cohorts. The next step is to test these phenotypes in a prospective trial. Rapid, point-of-care analytical methods have now made such a trial possible. There is a need to advance treatment for patients with acute respiratory distress syndrome and other critical illness syndromes by incorporating a phenotype-based approach into prospective trial design. The hyperinflammatory and hypoinflammatory phenotypes, that have been identified in acute respiratory distress syndrome, will be the first to be included in such a trial, with scope for further phenotypes to be studied over time. Future work This Efficacy and Mechanism Evaluation report, through expert consensus, describes a new Phase II, multiarm, adaptive platform randomised controlled trial design that tests multiple pharmacological therapies in a population of patients with acute respiratory distress syndrome stratified by baseline inflammatory phenotype. This report also reviews issues to be considered in developing precision medicine trials in critical care, which are designed with newly developed clinical phenotypes in mind. This work has been used to develop the Precision medicine Adaptive Network platform Trial in Hypoxaemic acutE respiratory failuRe precision medicine trial in acute respiratory distress syndrome, which has been funded and will begin recruitment in June 2025. Limitations This report is the result of expert consensus review, rather than utilising strict review methodologies (e.g. Delphi consensus process). However, expert consensus has been found to generate similar results to consensus processes when a high degree of agreement is reached and > 70% agreement was reached for all included recommendations. Funding This article presents independent research funded by the (NIHR) Efficacy and Mechanism Evaluation programme as award number NIHR154493. Plain language summary Almost all attempts to find new medicines that can help patients in intensive care have not worked. One explanation could be that groups of intensive care patients whom we think are similar are actually different from each other in their underlying biology. A treatment that we use in a clinical trial might work for some patients with a critical illness syndrome but may not work for others with the same syndrome, or worse, cause harm. We need better ways to identify groups of patients for whom a new treatment will work. This is a problem for patients with the acute respiratory distress syndrome, which is a syndrome of lung failure and inflammation in intensive care. Many patients with acute respiratory distress syndrome do not survive, and many of those who do survive have prolonged health problems and disability. Based on information from previous clinical trials, researchers have discovered the ‘hyperinflammatory’ and ‘hypoinflammatory’ subgroups (phenotypes) of acute respiratory distress syndrome, which may respond differently to new treatments. New advances have made it possible to quickly determine whether an individual patient has the hyperinflammatory or hypoinflammatory phenotype. This means that we can design large clinical trials to determine whether new medicines work better for one subgroup than the other. This Efficacy and Mechanism Evaluation report reviews new designs for clinical trials based on recent learnings from the coronavirus disease discovered in 2019 pandemic, new approaches to defining intensive care syndromes and new research about the biology of acute respiratory distress syndrome. This report describes a new clinical trial designed by a group of international researchers that will determine whether some medicines work differently for acute respiratory distress syndrome patients with the hyperinflammatory or the hypoinflammatory phenotypes, and it provides the blueprints for how the clinical trial might be adapted to test medicines in other phenotypes as we learn more. This new approach will be important for developing individualised, ‘precision medicine’ for patients in intensive care units.
Keywords
- acute respiratory distress syndrome
- platform trials
- precision medicine
- biomarker-guided trials
- intensive care
- critical care
- airway extubation
- algorithms
- biological specimen banks
- biological variation
- population
- biomarkers
- covid-19
- clinical trials
- phase ii as topic
- cluster analysis
- critical illness
- cytokines
- intensive care units
- intubation
- intratracheal
- logistic models
- noninvasive ventilation
- outcome assessment
- health care
- pandemics
- phenotype
- pneumonia
- randomized controlled trials as topic
- reproducibility of results
- respiration
- artificial
- respiratory distress syndrome
- respiratory insufficiency
- sepsis
- simvastatin
