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The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design.
Ann Am Thorac Soc. 2020 07; 17(7):879-891.AA

Abstract

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Authors+Show Affiliations

The Clinical Research Investigation and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.Berry Consultants, LLC, Austin, Texas.Berry Consultants, LLC, Austin, Texas. Department of Emergency Medicine, Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, California. Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.Division of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare National Health Service Trust, London, United Kingdom.Intensive Care Department, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia.Julius Center for Health Sciences and Primary Care.Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.Julius Center for Health Sciences and Primary Care. Department of Medical Microbiology, and.Berry Consultants, LLC, Austin, Texas.Center for Clinical Studies and Center for Sepsis Control and Care, Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, Victoria, Australia. Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.Medical Intensive Care Unit, Hôpital Cochin, Paris Descartes University, Paris, France.Department of Medical Microbiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.Berry Consultants, LLC, Austin, Texas.Department of Microbiology, Antwerp University Hospital, Antwerp, Belgium.Division of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare National Health Service Trust, London, United Kingdom.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.Julius Center for Health Sciences and Primary Care.Intensive Care Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia.Université de Sherbrooke, Sherbrooke, Quebec, Canada.School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. Interdepartmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada.Berry Consultants, LLC, Austin, Texas.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. Cardiothoracic and Vascular Intensive Care Unit and. Medical Research Institute of New Zealand, Wellington, New Zealand.Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, United Kingdom.University of British Columbia School of Medicine, Vancouver, British Columbia, Canada.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. Department of Anesthesia and Intensive Care, St Vincent's University Hospital, Dublin, Ireland. School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.Cardiothoracic and Vascular Intensive Care Unit and. Medical Research Institute of New Zealand, Wellington, New Zealand. School of Nursing, University of Auckland, Auckland, New Zealand.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.Department of Respiratory Medicine, University Hospital Frankfurt, Frankfurt, Germany. CAPNETZ Foundation, Hannover, Germany.Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, United Kingdom.Medical Research Institute of New Zealand, Wellington, New Zealand.Medical Research Institute of New Zealand, Wellington, New Zealand. Intensive Care Unit, Wellington Hospital, Wellington, New Zealand; and.Julius Center for Health Sciences and Primary Care. Intensive Care Center, University Medical Center Utrecht, Utrecht, the Netherlands.Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand. Medical Research Institute of New Zealand, Wellington, New Zealand.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia. St. John of God Hospital, Subiaco, Western Australia, Australia.

Pub Type(s)

Adaptive Clinical Trial
Clinical Trial Protocol
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

32267771

Citation

Angus, Derek C., et al. "The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design." Annals of the American Thoracic Society, vol. 17, no. 7, 2020, pp. 879-891.
Angus DC, Berry S, Lewis RJ, et al. The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design. Ann Am Thorac Soc. 2020;17(7):879-891.
Angus, D. C., Berry, S., Lewis, R. J., Al-Beidh, F., Arabi, Y., van Bentum-Puijk, W., Bhimani, Z., Bonten, M., Broglio, K., Brunkhorst, F., Cheng, A. C., Chiche, J. D., De Jong, M., Detry, M., Goossens, H., Gordon, A., Green, C., Higgins, A. M., Hullegie, S. J., ... Webb, S. A. (2020). The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design. Annals of the American Thoracic Society, 17(7), 879-891. https://doi.org/10.1513/AnnalsATS.202003-192SD
Angus DC, et al. The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design. Ann Am Thorac Soc. 2020;17(7):879-891. PubMed PMID: 32267771.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design. AU - Angus,Derek C, AU - Berry,Scott, AU - Lewis,Roger J, AU - Al-Beidh,Farah, AU - Arabi,Yaseen, AU - van Bentum-Puijk,Wilma, AU - Bhimani,Zahra, AU - Bonten,Marc, AU - Broglio,Kristine, AU - Brunkhorst,Frank, AU - Cheng,Allen C, AU - Chiche,Jean-Daniel, AU - De Jong,Menno, AU - Detry,Michelle, AU - Goossens,Herman, AU - Gordon,Anthony, AU - Green,Cameron, AU - Higgins,Alisa M, AU - Hullegie,Sebastiaan J, AU - Kruger,Peter, AU - Lamontagne,Francois, AU - Litton,Edward, AU - Marshall,John, AU - McGlothlin,Anna, AU - McGuinness,Shay, AU - Mouncey,Paul, AU - Murthy,Srinivas, AU - Nichol,Alistair, AU - O'Neill,Genevieve K, AU - Parke,Rachael, AU - Parker,Jane, AU - Rohde,Gernot, AU - Rowan,Kathryn, AU - Turner,Anne, AU - Young,Paul, AU - Derde,Lennie, AU - McArthur,Colin, AU - Webb,Steven A, PY - 2020/4/9/pubmed PY - 2020/9/12/medline PY - 2020/4/9/entrez KW - Bayesian adaptive KW - community-acquired pneumonia KW - coronavirus disease 2019 KW - master protocol KW - platform trial KW - randomized clinical trial SP - 879 EP - 891 JF - Annals of the American Thoracic Society JO - Ann Am Thorac Soc VL - 17 IS - 7 N2 - There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707). SN - 2325-6621 UR - https://www.unboundmedicine.com/medline/citation/32267771/full_citation L2 - https://www.atsjournals.org/doi/10.1513/AnnalsATS.202003-192SD?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -