Randomized, Embedded, Multifactorial, Adaptive Platform trial for Community-Acquired Pneumonia
Funder: European Commission
Sponsor: University Medical Centre Utrecht (Netherlands)
CI: Prof Anthony Gordon
Approval Date: 27 March 2020
The aim of this trial is to determine the best range of treatments for patients who become severely ill due to COVID-19. Patients admitted to the Intensive Care Unit (ICU) with severe illnesses normally receive a combination of many different treatments to help them recover. For example, there are a number of different possible drugs to fight the coronavirus but patients also require treatment to help their breathing, circulation and kidneys. REMAP-CAP has many recruiting sites around the world and aims to enrol thousands of patients in more than 100 ICUs in the UK. The trial is designed to flexible and adaptive. Each hospital will choose which treatments to make available to patients from those available within the trial. Currently the trial is evaluating different anti-viral drugs (Lopinavir-Ritonavir and hydroxychloroquine), steroids to reduce inflammation and treatments which act on the immune system, often used to treat other conditions such as rheumatoid arthritis, (interferon-ß1a, anakinra, tocilizumab and sarilumab). The trial will look at how these drugs work in combination. Additional treatments will be added over time. Information will be reviewed regularly and, dependent upon the results, the trial will allocate more patients to the treatments that seem to be the most effective. Information is available at https://www.remapcap.org/
REMAP-CAP is a trial designed by clinicians who cared for patients and conducted research during the 2009 H1N1 pandemic. Planning began in 2011. REMAP-CAP builds on the combined input of the world's leading ICU trial networks. These networks have enrolled tens of thousands of patients into trials. They have extensive experience designing, conducting, and reporting clinical trials that enroll patients who are severely ill. Our goal is to generate evidence that can be applied during the pandemic to reduce mortality or reduce the length of ICU admission in critically ill patients with COVID-19 infection. For the past several years, REMAP-CAP has been recruiting patients with severe CAP in the inter- pandemic period. We are currently recruiting in more than 50 ICUs in 13 countries on 3 continents. Another 50 ICUs are in start-up, and more countries and networks are being added. REMAP-CAP was designed to adapt to an acute pandemic need: that time has come. Changes necessary for the pandemic have been approved or submitted for approval. REMAP-CAP can be recruit without dedicated research staff. The treating clinician can enrol patients in as little as 5 minutes. The trial is a Bayesian Adaptive Platform Trial. It will generate answers to many questions, as rapidly as possible: The platform is multifactorial: each patient can be randomised to multiple different combinations of treatment at once. It uses frequent interim analyses - a question is concluded as soon as there is sufficient information to support a conclusion. Analyses can occur every week. It detects superiority, inferiority, or equivalence of interventions within the platform Additional interventions are added, as required, based on availability and external evidence Current treatments REMAP-CAP will study, on an open-label basis: Antiviral therapy (no antiviral, lopinavir/ritonavir (Kaletra), hydroxychloroquine being added) Corticosteroid strategy (no steroid, fixed 7 days, only while in septic shock) Immune modulation (no modulator, interferon-beta, anakinra) Convalescent plasma Therapeutic anticoagulation (heparin versus standard local antithrombotic treatment). The platform can evaluate interactions, e.g. do steroids work only when an active antiviral is administered. In Australia, New Zealand, Canada, and in United States, the platform is coordinated with planned pre-ICU trials. The platform uses Response Adaptive Randomization. After each interim analysis, the weighting of randomization is modified so that patients are more likely to receive those interventions that are doing better. In addition to testing different treatment categories, the trial will also be 'adaptive'. In REMAP-CAP data will be reviewed regularly and dependent upon the results, the trial will allocate more patients to the treatments that seem to be the most beneficial. Each research site will also be able to choose which interventions to make available at that site, from among those available within the trial. REMAP-CAP will take place in 20 hospitals within the UK and aims to enrol 800 patients. The primary objective is to identify the most clinically effective treatments for adult ICU patients with severe CAP. The eligibility criteria for patients are applied at two levels. The first level is the patient eligibility to the overall trial. Once the patient meets these criteria, they can then be reviewed for eligibility to specific treatment categories. Patients will be followed up to 6 months after enrolment. This important and high quality trial will allow us to determine the best range of treatments for treating community acquired pneumonia on a global scale.
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