Case study: REMAP-CAP tests treatments for COVID-19
A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia
Community-acquired pneumonia (CAP) is a syndrome where people develop an acute infection of the lungs before being admitted to hospital. Bacterial and viral infections – like COVID-19 - are responsible for the vast majority of CAP. If severe enough, this condition will require admission to an Intensive Care Unit (ICU) and may present a substantial risk of death.
REMAP-CAP is part of a suite of nationally-prioritised COVID-19 studies supported by the NIHR. The trial, which uses an adaptive platform design, aims to provide answers about the best treatment options for those patients who develop severe CAP.
When caring for a patient with CAP, doctors may choose from a number of different treatments. However, doctors don’t always know which treatment option will work best because individuals, or groups of individuals, may respond differently. REMAP-CAP aims to help doctors understand which treatments, or combinations of treatments, are most likely to be effective in treating both the COVID-19 infection and its effects on the body.
Patients who are eligible to participate in REMAP-CAP are randomised to receive one intervention in each of one or more categories of treatment (also called domains), these are: antibiotics, antivirals and steroids.
Keith Hugill is a Research Coordinator in the critical care unit at James Cook University Hospital in Middlesbrough. His role is to screen, identify, consent, and randomise participants to the study domains. He also supports the doctors and nurses to deliver the study in the challenging ICU setting: The clinical teams have worked incredibly hard to ensure that these interventions are delivered in an extremely difficult environment”, explains Keith.
"I sincerely hope that the results of this research will allow the NHS to identify the causative factors that make this virus so deadly for some, and that the effective treatments identified will allow as many patients as possible to make a quick, full recovery from this terrible disease.
REMAP-CAP was specifically designed to respond rapidly to a pandemic. Its adaptive platform design enables evaluation of multiple treatment options simultaneously and new treatments - like the convalescent plasma transfusion - can be added to the study quickly and efficiently. Similarly, where the study data shows that a treatment is less effective, that part (or arm) of the study can be halted. Consequently, the adaptive approach is able to determine and continuously update the optimal set of treatments for CAP patients.
Professor Anthony Gordon, Professor of Anaesthesia and Critical Care and NIHR Research Professor at Imperial College London, and the Chief Investigator for REMAP-CAP, explains more:
"New treatments can be added as we learn more. The sample size isn’t fixed and it keeps recruiting until it finds that a treatment is better, worse, or the same as another.
The study “learns” from that data so that patients are more likely to receive those interventions that are performing best and equally important we can stop using ineffective treatments.
“These adaptive design features are key in a pandemic when we are learning more about the disease all the time. Traditional studies require everything to be fixed before the study begins and this is done to ensure high quality results. An adaptive study will fix all the study rules (to ensure high quality results) but it allows flexibility to modify certain things within those fixed rules.
“Another critical factor in a pandemic, when clinical services are being stretched, is having the ability to recruit patients easily and quickly. The bedside clinician can enroll a patient to REMAP-CAP in minutes. And the fact that we can study several different types of treatments at the same time helps us to understand how different treatments work in combination, as well enabling us to get more answers quicker; we hope to get answers within months rather than years.”
Results from REMAP-CAP’s corticosteroids treatment arm show a high probability that a seven-day course of hydrocortisone - a steroid similar to dexamethasone - improved outcomes such as survival and more rapid recovery compared with no hydrocortisone treatment among critically ill patients with COVID-19.
The results were published in the Journal of the American Medical Association (JAMA) in August 2020, alongside three other papers on the use of corticosteroids to treat COVID-19. The papers reinforce evidence that outcomes for severely affected patients can be significantly improved by using these inexpensive and widely available drugs.
Another of the papers, co-ordinated by the World Health Organisation (WHO) and led by researchers at the University of Bristol and the NIHR’s Bristol Biomedical Research Centre, provides a meta-analysis (evidence summary) of global steroid use across seven randomly controlled trials (RCTs) in 12 countries spanning five continents. It also included data drawn from REMAP-CAP and the NIHR-funded RECOVERY study, which has already shown that the steroid dexamethasone can be successfully used in treatment of moderate to severe COVID-19. It concludes that corticosteroids can reduce the risk of death in the most ill patients by up to 20%.
The remaining two papers are on research by teams working in France and Brazil which also support the use of steroids in critically ill patients with COVID-19.
Professor Jonathan Van-Tam, Deputy Chief Medical Officer said:
"These findings offer further evidence that corticosteroids can be an important part of COVID-19 treatment for severe patients.
Both the REMAP-CAP and the Bristol University papers show the important work that has been done here in the UK by researchers in making further major contributions towards the international evidence. It is impressive to see so many UK participants willing to take part in studies, and able to volunteer due to the rapid recruitment response of the NIHR’s Clinical Research Network. Research such as this will make the difference in controlling this virus.
The trial has also shown that treating critically ill COVID-19 patients with drugs, tocilizumab and sarilumab – both types of immune modulators called IL-6 receptor antagonists and typically used for arthritis - may significantly improve survival, reducing mortality by 8.5%.
Professor Gordon said: “Previous trials using IL-6 receptor agonists have showed no clear benefit on either disease progression or survival in COVID-19 patients, but those studies included less severely ill patients and started treatment at different stages in the disease course.
“A crucial difference may be that in our study, critically ill patients were enrolled within 24 hours of starting organ support. This highlights a potential early window for treatment where the sickest patients may gain the most benefit from immune modulation treatment.”
In April last year, the REMAP-CAP study team began investigating whether convalescent plasma transfusions improve the speed of recovery and chances of survival for patients with COVID-19 with CAP. Convalescent plasma is the antibody-rich plasma of someone who has recovered from a virus and may contain antibodies that their immune system has produced which can then be transfused into infected patients.
In January 2021, preliminary results from this treatment domain show that convalescent plasma infusions did not improve outcomes among patients needingICU support. The trial is continuing to analyse data in case there is evidence of benefit in a subgroup, and to see whether patients who haven’t already started making their own antibodies may still benefit from being given convalescent plasma.
Planning for REMAP-CAP began in 2011, following the H1N1 (swine flu) pandemic. It is supported by multiple government grants around the world. For the past several years, REMAP-CAP has been recruiting patients with severe community acquired pneumonia (CAP) in three continents. It opened in the UK in May 2019.
Responding to the COVID-19 crisis, REMAP-CAP is now being carried out at more than 290 sites across 15 countries, including 142* hospitals in the UK. Across the globe a total of 5250 patients have been randomised into the study and 4475 of those participants are COVID-19 patients.
The UK has recruited an impressive 75% (3399) (as of January 2021) of the total number of COVID-19 participants. Professor Anthony Gordon, describes why the UK has been able to make such a huge contribution to this international trial:
“The UK has been able to deliver so well in this study because of the joined up research processes that we have in this country. The NIHR provides infrastructure support to ensure research can be delivered efficiently throughout the whole NHS. This system is the envy of our international colleagues.
“But also the Health Research Authority (HRA), ethics committees and Medicines and Healthcare products Regulatory Agency (MHRA) have all provided rapid review and approvals for COVID-19 research. This supportive environment, along with an engaged UK critical care community, has allowed us to deliver clinical research to improve patient care, even during the busiest of times .”
Professor Paul Dark is an expert in critical care. His roles include National Specialty Lead for Critical Care for the NIHR Clinical Network and Honorary NHS Consultant in Critical Care Medicine at Salford Royal NHS Foundation Trust - one of the sites delivering REMAP-CAP. He agrees that the NIHR research infrastructure has been a key factor of the success of REMAP-CAP in the UK, along with the enthusiasm of NHS staff and patients:
"NIHR's National Specialty Group in Critical Care, in partnership with NIHR Clinical Research Network, has an established history of working with and supporting international clinical trials of the greatest importance to NHS patients. Endorsing and supporting REMAP-CAP planning prior to COVID-19 has been crucial for rapid expansion of the trial across critical care in all four nations during the pandemic. We thank our patients and carers across the UK for study participation which will deliver important results to improve care in the NHS and globally."
- Watch a short film of REMAP-CAP - as featured in a new research category on the Royal College of Physicians iplayer, tells us more about the trial
- Read results for the corticosteroids arm of the trial published in JAMA
- Read results on arthritis drug treatments published in the BMJ
- Learn more about how the NIHR supports complex and innovative trials design and delivery.
* figures correct at 15 January 2021