Findings so far reported from the adaptive platform trial REMAP-CAP have demonstrated that corticosteroids and interleukin-6 inhibitors tocilizumab and sarilumab improve clinical outcomes in critically ill COVID-19 patients; and that full dose anticoagulants improve outcomes in hospitalized, non-critically ill patients. Several other drugs (full dose anticoagulants in critically ill patients, convalescent plasma, interleukin-1 inhibitor anakinra and antiplatelet medications) did not improve outcomes, whereas lopinavir-ritonavir, hydroxychloroquine, or their combination may even worsen outcomes.

In previous virus outbreaks, the search for effective medication often only started when the epidemic was over. Partly thanks to the REMAP-CAP trial (for study design, click here), such investigations are now possible at a much earlier stage. REMAP-CAP is about how smart thinking after the Mexican flu in 2009 has made it possible to start testing medicines for COVID-19, beginning immediately after the start of the outbreak. With the current coronavirus outbreak, the fear of many came to life: a new infectious virus that affects people worldwide and for which no vaccine or treatment exists.

Quick results needed

“Why so late?” “Is it possible to speed up the process?” These are obvious questions. Then patients will benefit from it already during the epidemic and we will be better prepared for future outbreaks. “Yes, identification of suitable drugs can be done quicker” says intensivist Lennie Derde of UMC Utrecht. Together with physician-microbiologist Marc Bonten, she coordinates the REMAP-CAP study in Europe. Since July 2021, Lennie also chairs the International Trial Steering Committee of REMAP-CAP. “This study was originally designed as an ongoing international study for patients hospitalized with community-acquired pneumonia in intensive care units (ICU). Community-acquired pneumonia, or CAP, is pneumonia contracted outside the hospital. Annually, around 3 million people worldwide die from CAP and an estimated one quarter of all hospitalized pneumonia patients end up in the ICU.”

Adaptive platform

One goal of the REMAP-CAP study is to test different types of interventions for effectiveness against pneumonia. The different treatment options are selected on the basis of an estimate of how serious the disease is and what the possible pathogens are. REMAP-CAP is a so-called Adaptive Platform Trial (REMAP stands for Randomized, Embedded, Multifactorial, Adaptive Platform), a clinical study with an innovative design that allows to test multiple medicines concurrently. Lennie: “This is a randomized trial with a control group, but smarter and more flexible. In a traditional clinical study, patients receive one treatment from a short list of alternatives - usually one or two. In REMAP-CAP we can test several groups of medicines in parallel. We also have faster results: in a regular study, one works for years towards the end point at which the results become clear and one cannot look “under the hood” in the meantime. An adaptive platform trial is specifically designed to perform frequent adaptive analyses, making sure we get to a conclusion about the effectiveness of an intervention as soon as we can, and allowing more people to be randomized to the more promising options during the trial. If a particular drug shows better results, a larger percentage of new patients will be allocated to that drug. Hence fewer people are exposed to less promising medicines. As a result, patients are more likely to benefit from the knowledge that is gradually yielded by this type of study.”

Five years of preparation

The idea for REMAP-CAP was conceived after the Mexican flu epidemic in 2009 and preparations for the trial started in 2014: a preparation time of no less than four years until 2018 when the study started and eventually ran in ICUs (including the Netherlands) in Europe, Australia, New Zealand and Canada. The first patients were enrolled in 2018 at UMC Utrecht. It took four years of preparation during which all kinds of obstacles in design, regulatory aspects and contracting had to be resolved to enable this unique international cooperation. Lennie: “If there is an outbreak and the patients come in, participating hospitals must be ready to start the investigation immediately. They should then be able to start assigning patients to different treatment options right away to get valid results as soon as possible.”

COVID-19 outcomes

In addition to long-term pneumonia research, REMAP-CAP was also designed to be immediately adaptable in the event of a pandemic. "Most pandemics stem from viruses that cause patients to develop pneumonia," says Lennie. “Thanks to the design and international collaboration of ICUs, REMAP-CAP offers the large-scale infrastructure to be able to conduct scientific research into potentially effective medicines immediately after the start of the outbreak. In the case of COVID-19, we were able to start testing treatments from early March 2020.” So far, REMAP-CAP has randomized more than 8.000 patients (of which more than 7.000 diagnosed with suspected or proven COVID-19), investigating 48 (ongoing or completed) interventions, and, in addition to the regions mentioned above, is now also active in the United States, India, Nepal, Pakistan, Colombia and Japan.

Lennie Derde and Marc Bonten on REMAP-CAP outcomes in critically ill COVID-19 patients (in Dutch)

COVID-19 patients often also suffer from pneumonia and the most serious cases are admitted to the ICU. Lennie: “For COVID-19, the possibility of testing multiple medicines in parallel as with REMAP-CAP means that we investigate for example which antivirals, which anticoagulants and which immune-modulators work best. We currently test six different groups of treatments for COVID-19. In the meantime, REMAP-CAP has provided several urgently needed answers with immediate impact on the treatment of hospitalized COVID-19 patients. Findings so far (cut-off date August 9, 2021) reported from the REMAP-CAP trial can be found in the bullets below.

Hospitalized critically ill COVID-19 patient:

• Corticosteroids (JAMA, September 2020) and interleukin-6 inhibitors tocilizumab and sarilumab (New England Journal of Medicine, February 2021, Preprint on medXriv, June 2021) improved outcomes;
• Therapeutic (full-dose) anticoagulants, interferon beta 1a, interleukine-1 inhibitor anakinra (New England Journal of Medicine, August 2021), convalescent plasma (JAMA, October 2021), antiplatelet therapy (JAMA, March 2022) did not improve outcomes;
• Lopinavir-ritonavir (Intensive Care Medicine, July 2021), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (JAMA, April 2023) likely worsened outcomes;
• Hydroxychloroquine worsened outcomes (Intensive Care Medicine, July 2021)

Hospitalized moderately ill COVID-19 patients:

• Therapeutic (full-dose) anticoagulants improved outcomes (New England Journal of Medicine, August 2021)

For detailed information about the REMAP-CAP study, go to www.remapcap.org or www.remapcap.eu.