Which treatments will save lives in ICU?

NHMRC supported the development of REMAP-CAP with initial funding of $4.4 million  in 2015 (as OPTIMISE-CAP) and has provided additional COVID-19 related support of $25,000 via the Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE). 

Around the world, ICUs are being overwhelmed by critically ill patients with life-threatening pneumonia. “We need to identify interventions that can reduce mortality and reduce ICU length of stay,” says Professor Steve Webb, Chair of the International Trial Steering Committee and Chief Investigator in Australia of REMAP-CAP. “We are currently simultaneously testing seven areas of treatment (domains) for COVID-19 including antivirals, immune modulation, antibodies, anticoagulants, macrolides, corticosteroids and vitamin C.”

REMAP-CAP has been years in development, but it’s been expanded at breakneck speed in response to COVID-19. Recruitment of COVID-19 patients reached 471 in mid-May. The team anticipate reaching 1000 over the coming months. 

“In the ICU a clinician can enrol a patient in less than five minutes, and they can choose from a smorgasbord of treatment options customised for their intensive care unit,” says Webb. “The complexity is hidden ‘under the bonnet’, with Bayesian statistics driving the simultaneous trial of multiple interventions,” says Webb, who is both an ICU clinician at the Royal Perth Hospital and a Monash University researcher. 
 

The Chief Medical Officers of the United Kingdom have identified REMAP-CAP as one of three key national trials for COVID-19. In a public statement calling for enrolments they say, “As yet, there are no proven treatments for COVID-19. We need to gather reliable evidence through clinical trials … These trials are being run as simply as they can to reduce the burden on the NHS, with adaptive designs so further treatments can be added if new promising candidates are identified.” Their full statement is avilable for download here.

“The rapid rollout has only been possible because of years of pre-pandemic preparation by the research team, backed by the European Union, and the Australian, New Zealand, and Canadian governments,” says Professor Allen Cheng, a member of the International Trial Steering Committee and an investigator on the Australian arm of the study. 

It all started with a group of ICU clinician researchers who were trying to save lives during the swine flu pandemic. In 2009, Webb was working in an ICU with every ventilator in use. Then a seriously ill ‘flu patient was admitted to emergency.

Two major lessons came out of the ‘flu pandemic for Webb and his colleagues:

1. That lives could be saved in ICU if we had a better understanding of community acquired pneumonia and improved options for treating it;
2. That a new approach was needed to rapidly trial treatment options and improve patient outcomes during a pandemic. 

So, a small group started designing alternatives. 

Today, REMAP-CAP’s Australian investigators comprise Steve Webb, Allen Cheng and Alistair Nichol, all from Monash; Ed Litton (UWA); Jeff Presneill (University of Melbourne); and Peter Kruger (University of Queensland). They are working with leading clinicians and researchers from Canada, the US, Saudi Arabia, Germany, the Netherlands, France, Ireland and the UK. The members of the international trial steering committee are listed on the REMAP-CAP’s website. 

The European Union was the first major supporter followed by Australia’s National Health and Medical Research Council, the Health Research Council of New Zealand, the Canadian Institutes of Health Research, the Irish Health Research Board, and the UK National Institute for Health Research. The global expansion of REMAP-CAP, as well as preparedness in Australia, has also been generously supported by the Minderoo Foundation.

Recruitment started in 2018, looking at three areas of intervention for pneumonia. Participants reached 340 by the end of 2019. Then, COVID-19. “On 23 January we held our first meeting of collaborators, by middle of March we’d adapted the trial to include specific COVID-19 treatments, and our collaborators around the world started enrolling patients in the expanded study,” says Webb.

The seven domains of COVID-19 treatment being evaluated are: 

• Antiviral therapies
• Immune Modulation therapy
• Antibody therapy with convalescent plasma
• Therapeutic anticoagulation, evaluating forms of heparin
• High dose vitamin C

And two of the trial’s original domains that are appropriate for COVID-19:

• Prolonged macrolide antibiotic therapy to modulate immune function
• Corticosteroid strategies.

For further information visit www.remapcap.org.

For updates on the treatment domains visit the REMAP-CAP response to the COVID-19 pandemic webpage. 

To sign up your ICU to RECAP-MAP visit www.remapcap.org/contact-us for details for your country. Or contact Cameron Green info@remapcap.org, +61 3 9903 0247.

Supporting material from REMAP-CAP
REMAP-CAP is the Randomised, Embedded, Multifactorial, Adaptive, Platform Trial of Community Acquired Pneumonia. 
REMAP-CAP operates through APPRISE, the Australian Partnership for Preparedness Research on Infectious Disease Emergencies. APPRISE is a Centre of Research Excellence (CRE) funded by the National Health and Medical Research Council to improve Australia’s response to infectious disease emergencies. It includes 19 investigators and more than 50 collaborators from every state and territory in Australia who have worked across four pillars and four cross-cutting platforms since 2016.

What is REMAP-CAP?
REMAP-CAP is an existing multi-site international adaptive platform trial that was predesigned to adapt in the event of a pandemic. 

It is currently enrolling patients with severe community acquired pneumonia, the clinical syndrome that results from COVID-19 infection. 

The platform is multifactorial, allowing multiple simultaneous randomisation events in the same patient. A Bayesian statistical model is utilised to identify the independent treatment effect of each randomisation option. 

The REMAP-CAP COVID-19 domains
All participating sites can participate in seven domains (areas of treatment). These are:

• Evaluation of prolonged macrolide therapy, as a modulator of immune function;
• Evaluation of alternative corticosteroid strategies (no corticosteroids, hydrocortisone for 7 days, or hydrocortisone while the patient is in septic shock);
• Antiviral therapy: evaluating no antiviral therapy for COVID-19 (and no placebo), lopinavir/ritonavir (Kaletra), hydroxychloroquine, and the combination of hydroxychloroquine and lopinavir/ritonavir;
• Immune Modulation therapy: evaluating no immune-modulating therapy for COVID-19 (and no placebo), Interferon-beta-1a, interleukin-1 receptor antagonist (Anakinra), tocilizumab and sarilumab;
• Antibody therapy: evaluating the use of convalescent plasma for COVID-19;
• Therapeutic anticoagulation: evaluating the use of low molecular-weight heparin or unfractionated heparin compared to standard pharmacologic thromboprophylaxis;
• Vitamin C: evaluating the use of high-dose vitamin C for patients with severe CAP including CAP caused by COVID-19.

Additional interventions against COVID-19 are being considered and may be introduced into these domains. For the latest information visit the REMAP-CAP response to the COVID-19 pandemic webpage. 

What is an adaptive clinical trial?
REMAP-CAP uses a study design known as a REMAP, a Randomised, Embedded, Multifactorial, Adaptive Platform trial. The broad objective of this REMAP is, over time, to determine and continuously update the optimal set of treatments for community-acquired pneumonia.

In a traditional clinical trial, selected patients are allocated to receive one treatment from a short list of alternatives (typically one or two). Different questions are tested sequentially. 

Patients who are eligible for participation in REMAP-CAP will be randomised to receive one intervention in each of one or more categories of treatment (known as “domains”). These interventions can be tested simultaneously. 

Information from patients already participating can also be used to help guide the treatment of new patients joining the study. Most trials are not able to do this. 

In contrast to a conventional trial, the adaptive design of a REMAP has a number of benefits:

• Ambiguous results are avoided;
• Answers to a question can be concluded when sufficient data have accrued, rather than when a pre-specified sample size is reached;
• The effect of treatment options can be evaluated in pre-defined subgroups of patients (termed “strata”);
• Data that is already accrued is utilised to increase the likelihood that patients within the trial are randomised to treatments that are more likely to be beneficial;
• Multiple questions can be evaluated simultaneously;
• New questions can be substituted into the trial as initial questions are answered, meaning that the trial can be perpetual (or at least open-ended);
• Interactions between interventions in different domains can be evaluated.

Updated 24 November 2020