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The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design.

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).

SUBMITTER: Angus DC

PROVIDER: S-EPMC7328186 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Vaccine effectiveness is usually determined in randomized controlled trials (RCT) and if effective, additional information, e.g. on cost-effectiveness, is required to allow evidence-based decision making. A prerequisite for proper health economic modelling is the availability of good quality data on health care resources use, health outcomes and quality-of-life (QoL) data. The "Collecting health outcomes and economic data on hospitalized Community Acquired Pneumonia (CHO-CAP)--a prospective cohort study" is executed alongside the Community Acquired Pneumonia Immunization Trial with Adults (CAPiTA trial) to capture health outcomes and economic data of elderly hospitalized with CAP and matched controls without CAP.CAPiTA is a placebo-controlled double-blind RCT evaluating the effectiveness of a 13-valent conjugated pneumococcal vaccine in preventing vaccine-type pneumococcal CAP in 84,496 elderly in the Netherlands. Participants of CAPiTA, who consented and provided information on health status (EQ-5D) and socio-demographic background at the time of vaccination, constitute the source population of CHO-CAP and are eligible for the nested matched cohort study. CHO-CAP patients hospitalized with CAP form the "diseased" cohort and the "non-diseased" cohort consists of unaffected persons (i.e. no CAP). Observations in the diseased cohort and in matched controls from the non-diseased cohort are used to determine excess costs and QoL changes attributable to CAP.Based on an estimated 2,000 CAPiTA participants being hospitalized with CAP and an assumed CHO-CAP participation rate of 30% of all CAPiTA participants (±25,000), 600 CAP episodes are expected among CHO-CAP participants (the "diseased" cohort). For each patient with CAP, two non-diseased CHO-CAP subjects will be selected from the CHO-CAP cohort, with matching for age, gender and EQ-5D baseline-score. Data on healthcare and non-healthcare resources use, quality-of-life (using EQ-5D and SF-36 questionnaires) and selected health outcomes will be collected at 0, 1, 6 and 12 months after hospitalization for CAP.The CHO-CAP study was approved by the Central Committee on Research involving Human Subjects in the Netherlands.With an expected 600 CAP episodes this study will be one of the biggest prospectively studied cohorts of hospitalized elderly with CAP with regard to resources use and Qol data. Strengths of this study further include collection of out-of-pocket costs of patients and productivity losses of both patients and their caregivers and the follow-up period of up to one year post-discharge. This study is therefore expected to add more in-depth knowledge on the short and longer term outcomes of pneumonia in elderly.ClinicalTrials.gov, NCT00812084.

Project description:ObjectiveTo improve the understanding of the determinants of prognosis and accurate risk stratification in community-acquired pneumonia (CAP).DesignMulticentre collaboration of prospective cohorts.Setting6 cohorts from the USA, Canada, Hong Kong and Spain.ParticipantsFrom a published meta-analysis of risk stratification studies in CAP, the authors identified and pooled individual patient-level data from six prospective cohort studies of CAP (three from the USA, one each from Canada, Hong Kong and Spain) to create the International CAP Collaboration Cohort. Initial essential inclusion criteria of meta-analysis were (1) prospective design, (2) in English language, (3) reported 30-day mortality and transfer to an intensive or high dependency care and (4) minimum 1000 participants. Common baseline patient characteristics included demographics, history and physical examination findings, comorbidities and laboratory and radiographic findings.Primary and secondary outcome measuresThis paper reports the rationale, hypotheses and analytical framework and also describes study cohorts and patients. The authors aim to (1) compare the prognostic accuracy of existing CAP risk stratification tools, (2) assess patient-level determinants of prognosis, (3) improve risk stratification by combined use of scoring systems and (4) understand prognostic factors for specific patient groups.ResultsThe six cohorts assembled from 1991 to 2007 included 13?784 patients (median age 71 years, 54% men). Aside from one randomised controlled study, the remaining five were cohort studies, but all had similar inclusion criteria. Overall, there was 0%-6% missing data. A total of 6159 (44%) had severe pneumonia by Pneumonia Severity Index class IV/V. Mortality at 30 days was 8% (1036). Admission to intensive care or high dependency unit was also 8% (1059).ConclusionsInternational CAP Collaboration Cohort provides a pooled multicentre data set of patients with CAP, which will help us to better understand the prognosis of CAP.

Project description:IntroductionAs the population ages, there is interest in strategies to promote resiliency, especially for frail patients at risk of its complications. The physiological stress of surgery in high-risk individuals has been proposed both as an important cause of accelerated age-related decline in health and as a model testing the effectiveness of strategies to improve resiliency to age-related health decline. We describe a randomised, embedded, multifactorial, adaptative platform (REMAP) trial to investigate multiple perioperative interventions, the first of which is metformin and selected for its anti-inflammatory and anti-ageing properties beyond its traditional blood glucose control features.Methods and analysisWithin a multihospital, single healthcare system, the Core Protocol for Strategies to Promote ResiliencY (SPRY) will be embedded within both the electronic health record (EHR) and the healthcare culture generating a continuously self-learning healthcare system. Embedding reduces the administrative burden of a traditional trial while accessing and rapidly analysing routine patient care EHR data. SPRY-Metformin is a placebo-controlled trial and is the first SPRY domain evaluating the effectiveness of three metformin dosages across three preoperative durations within a heterogeneous set of major surgical procedures. The primary outcome is 90-day hospital-free days. Bayesian posterior probabilities guide interim decision-making with predefined rules to determine stopping for futility or superior dosing selection. Using response adaptative randomisation, a maximum of 2500 patients allows 77%-92% power, detecting >15% primary outcome improvement. Secondary outcomes include mortality, readmission and postoperative complications. A subset of patients will be selected for substudies evaluating the microbiome, cognition, postoperative delirium and strength.Ethics and disseminationThe Core Protocol of SPRY REMAP and associated SPRY-Metformin Domain-Specific Appendix have been ethically approved by the Institutional Review Board and are publicly registered. Results will be publicly available to healthcare providers, patients and trial participants following achieving predetermined platform conclusions.Trial registration numberNCT03861767.

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The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design.

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