Tackling COVID-19 from the intensive care bed

In a bid to outsmart respiratory pandemics such as COVID-19, global human trials of a suite of flu and pneumonia drugs are being undertaken with critically ill patients from intensive care units.

The trial, in which Monash University is playing a leading role, involves researchers from Australia, the United Kingdom, the Netherlands, Germany, the United States, Canada, Saudi Arabia, Singapore, Belgium, Ireland, and New Zealand. It’s called REMAP-CAP – with “CAP” meaning “community-acquired pneumonia”. Two Monash experts are primary investigators – Associate Professor Alistair Nichol and Professor Steve Webb, both intensive care clinicians, and both with the University’s School of Public health and Preventive Medicine.

The team also includes intensive care clinicians and researchers Dr Colin McArthur, from New Zealand, and Dr Lennie Derde, from the Netherlands. Monash infectious diseases specialist Professor Allen Cheng is a senior investigator on the project.

So far COVID-19 has killed more than 34,000 people worldwide.

The study is taking place at more than 50 health facilities in 13 countries, Australia included. So far, 43 patients with suspected or proven COVID-19 have been randomised – meaning placed in a trial. The number is growing every day. “Unfortunately,” says Associate Professor Nicoll, “it will increase exponentially.”

Targeting severe pneumonia

The study is specifically trialling interventions for patients with severe pneumonia, a lung infection close in structure to COVID-19. Consenting patients may receive a combination of multiple treatments to try and help doctors figure out which are safest and most effective. The study is unique in that it allows information gleaned from patients already enrolled in it to be trialled on newer patients.

The aim is to find out the impact on 90-day mortality of a range of antibacterial drugs, immunomodulatory drugs (which modify the body’s immune response), steroids, and antiviral drugs.

The project began in response to the 2009 swine flu (H1N1) pandemic, which reached 74 countries and killed an estimated 20,000 people. So far COVID-19 has killed more than 34,000 people worldwide. Swine flu was the second H1N1 pandemic, the first being Spanish flu in 1918, still the deadliest pandemic in history. COVID-19 is a novel (new) strain of coronavirus.

The REMAP-CAP team learned from H1N1 in 2009 that it would be necessary to build research infrastructure ahead of the next pandemic – which happens to be now. It’s a form of future-proofing.

“It was too hard to get regulatory approvals,” says Associate Professor Nichol. “We put that knowledge and those feelings together and came up with the REMAP-CAP project.” The trial is funded by the European Commission, and medical science bodies in Canada, Australia, New Zealand and Ireland.

“We essentially set up the trial for use during peacetime,” he says. “We set up all of the infrastructure, contracts, ethics approvals, medicine approvals and all the rest of it so that we could randomise people with community-acquired pneumonia, which is how pandemic flu or pandemic coronavirus presents in ICU. So, we were able to go with some ready interventions when the pandemic broke out. We had an emergency trial steering group meeting in which we switched to pandemic mode, and we were able to begin.”

Embedded into practice

Associate Professor Nichol says several components of the trial are unique and effective: “It is randomised, so it’s not an observational study. It’s embedded in the trial to get results. It’s a complex trial, but it’s simple at the bedside. It’s embedded into clinical practice so the doctors and nurses looking after patients can enrol patients into the study in a way that is not complicated. It doesn’t need trial staff to do that, which is important during a pandemic when everyone is stretched.”

This manipulation of the usual trial protocols is called an adaptive clinical trial. REMAP stands for “Randomised, Embedded, Multifactorial, Adaptive Platform”. “Randomised” in this context means each patient receives one drug in one or more of the categories – antibiotics, antivirals and steroids. All can be tested simultaneously, and results can be acted on more quickly.

The trial is drawing on data from an extraordinary trial in China, beginning on January 18 in the pandemic’s ground zero of Wuhan, of patients with COVID-19.

"We were able to go with some ready interventions when the pandemic broke out. We had an emergency trial steering group meeting in which we switched to pandemic mode, and we were able to begin.”

The REMAP-CAP team say the Chinese trial was an “extraordinary achievement of launching and completing the trial in truly remarkable time”. However, they say it’s also important to continue trialling the HIV drug combination (sold as kaletra), because it was not tested in many critically ill patients, and the trial was relatively small.

Members of a separate taskforce – of which the REMAP-CAP team were a part – were able to establish in a paper published last year that most ICU patients (up to nearly 82 per cent) thought it was important to medically research patients during an pandemic, and that special rules should be applied to make it easier to conduct such research.

Meanwhile a US clinical trial of a potential coronavirus vaccine has begun in the Seattle area. It will take at least a year to know if the vaccine is safe and effective against the virus, according to top US health officials.

The virus was genetically sequenced only about two months ago.