The remap-cap (Randomized embedded multifactorial adaptive platform for community-acquired pneumonia) Study rationale and design: Rationale and Design
Angus, Derek C; Berry, Scott; Lewis, Roger J; Al-Beidh, Farah; Arabi, Yaseen; van Bentum-Puijk, Wilma; Bhimani, Zahra; Bonten, Marc; Broglio, Kristine; Brunkhorst, Frank; Cheng, Allen C; Chiche, Jean-Daniel; De Jong, Menno; Detry, Michelle; Goossens, Herman; Gordon, Anthony; Green, Cameron; Higgins, Alisa M; Hullegie, Sebastiaan J; Kruger, Peter; Lamontagne, Francois; Litton, Edward; Marshall, John; McGlothlin, Anna; McGuinness, Shay; Mouncey, Paul; Murthy, Srinivas; Nichol, Alistair; O'Neill, Genevieve K; Parke, Rachael; Parker, Jane; Rohde, Gernot; Rowan, Kathryn; Turner, Anne; Young, Paul; Derde, Lennie; McArthur, Colin; Webb, Steven A
(2020) Annals of the American Thoracic Society, volume 17, issue 7, pp. 879 - 891
(Article)
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
... read more
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).
show less
Download/Full Text
Keywords: Bayesian adaptive platform trial, Community-acquired pneumonia, Coronavirus disease 2019, Master protocol, Randomized clinical trial, Pandemics, Humans, Community-Acquired Infections/therapy, Pneumonia/therapy, Evidence-Based Medicine, COVID-19, SARS-CoV-2, Point-of-Care Systems, Antiviral Agents/therapeutic use, Betacoronavirus, Pneumonia, Viral/therapy, Influenza, Human/therapy, Anti-Bacterial Agents/therapeutic use, Coronavirus Infections/therapy, master protocol, randomized clinical trial, community-acquired pneumonia, coronavirus disease 2019, Pulmonary and Respiratory Medicine, Journal Article, Randomized Controlled Trial
ISSN: 2329-6933
Publisher: American Thoracic Society
Note: Funding Information: Supported by the European Union, FP7-HEALTH-2013-INNOVATION-1 grant 602525 to the PREPARE (Platform for European Preparedness Against [Re-] emerging Epidemics) Consortium, Australian National Health and Medical Research Council grant APP1101719, New Zealand Health Research Council grant 16/631, and Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant 158584; the original design was supported by a development grant from the British Embassy. Funding Information: Table 1 summarizes key trial features. REMAP-CAP is a global program intended to enroll critically ill patients with CAP worldwide (clinical trials registration no. NCT02735707; universal trial no. U1111-1189-1653). The trial was launched in Europe under the PREPARE (Platform for European Preparedness against (Re-) emerging Epidemics) consortium (https:// www.prepare-europe.eu/about-us/ workpackages/workpackage-5) with funding from the European Union. REMAP-CAP has also launched in Australia and New Zealand, supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group and in Canada supported by the Canadian Critical Care Clinical Trials Group, with funding from the respective national governments. Together, these programs fund the first 4,000 patients, and are anticipated to recruit in 50 sites in Europe, 35 sites in Australia and New Zealand, and 15 sites in Canada. Other regions of the world will join as funding becomes available. Over 500 patients were enrolled as of March 2020. The trial is overseen by an international trial steering committee. An overview of trial structure is provided in Figure 2B. Publisher Copyright: Copyright © 2020 by the American Thoracic Society Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
(Peer reviewed)