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Ann Am Thorac Soc ; 17(7): 879-891, 2020 07.
Article in English | MEDLINE | ID: covidwho-679536


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 (NCT02735707).

Community-Acquired Infections/therapy , Coronavirus Infections/therapy , Influenza, Human/therapy , Pneumonia, Viral/therapy , Pneumonia/therapy , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , COVID-19 , Evidence-Based Medicine , Humans , Pandemics , Point-of-Care Systems , SARS-CoV-2
J Paediatr Child Health ; 57(4): 474-476, 2021 04.
Article in English | MEDLINE | ID: covidwho-1115061


The COVID-19 pandemic provides a pertinent reminder of the imperative to generate timely reliable clinical evidence. Delivery of optimal paediatric care is predicated on the availability of comprehensive, high quality, clinical evidence in a relevant population. However, over 80% of current clinical guidelines and bedside decisions are not based on direct high-level evidence. Integration of research activities into routine clinical care is paramount to address this shortfall. Active engagement of patients, families and hospital administrations is required to reframe integrated clinical trials as a tenet of quality health-care delivery. Current research funding in health care is 1-2 orders of magnitude below that of other industries. At an institutional level, investment in research should be prioritised with enhanced funding and supportive policies. Thoughtful integration of trials into routine bedside care will enable pragmatic research outcomes, tangible returns on financial investments and improved decision-making for patients in the medium- to long-term.

COVID-19 , Clinical Trials as Topic , Delivery of Health Care , Evidence-Based Medicine , Humans , Pediatrics
Wellcome Open Res ; 6: 14, 2021.
Article in English | MEDLINE | ID: covidwho-1090165


The Randomized Embedded Multifactorial Adaptive Platform (REMAP-CAP) adapted for COVID-19) trial is a global adaptive platform trial of hospitalised patients with COVID-19. We describe implementation in three countries under the umbrella of the Wellcome supported Low and Middle Income Country (LMIC) critical  care network: Collaboration for Research, Implementation and Training in Asia (CCA). The collaboration sought to overcome known barriers to multi centre-clinical trials in resource-limited settings. Methods described focused on six aspects of implementation: i, Strengthening an existing community of practice; ii, Remote study site recruitment, training and support; iii, Harmonising the REMAP CAP- COVID trial with existing care processes; iv, Embedding REMAP CAP- COVID case report form into the existing CCA registry platform, v, Context specific adaptation and data management; vi, Alignment with existing pandemic and critical care research in the CCA. Methods described here may enable other LMIC sites to participate as equal partners in international critical care trials of urgent public health importance, both during this pandemic and beyond.