Platform trials long predate the emergence of COVID-19. But the pandemic amply demonstrated the potential of the format. The investigators for the RECOVERY trial have so far identified four therapies that reduce mortality in patients hospitalised with COVID-19, and have shown that another six therapies are ineffective. The discovery that dexamethasone decreased deaths in severely ill patients by a third was particularly notable. It came in June, 2020, within 3 months of the start of the trial, and meant that clinicians had an inexpensive and widely available drug to prescribe to patients with COVID-19. RECOVERY now has sites in countries in Asia and Africa and has broadened its remit to include therapies for influenza.
The Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) was established in 2014 with a pandemic in mind. The Chief Investigator in the UK is Anthony Gordon, Chair in Anaesthesia and Critical Care at Imperial College London, London, UK. “We thought that if we had the platform up and running, we could introduce new drugs as soon as we were hit by a major outbreak of respiratory disease”, he explained. REMAP-CAP has shown the benefits of IL-6 antagonists, tocilizumab and sarilumab, and the anticoagulant, heparin, in patients with COVID-19.
The key features of platform trials are their scope and adaptability. They are designed to evaluate multiple therapies. “Rather than test drugs one at a time, you test them all at the same time; you get the results much more quickly and you can look for combinations of therapies, which is especially useful, because that is how we treat people in the intensive care unit”, said Gordon. REMAP-CAP is examining a wide range of drugs, including antibiotics, corticosteroids, antivirals, and antiplatelet therapies. It has around 200 sites in 15 European countries. The aim is to provide an evidence base for the 20–30 treatments that patients with community-acquired pneumonia might be prescribed in the intensive case unit.
Platform trials are set up to study diseases, rather than specific interventions. As such, they can continue indefinitely, adding new arms to test new therapies, discontinuing existing ones as soon as it becomes clear the drug is ineffective or harmful, and substituting the control arm for a new standard-of-care, if the evidence favours such a move. As data accumulate, it informs the trial so that the investigators can accelerate their decisions and select for treatments that work. The randomisation process can be amended so that new participants are more likely to receive the better performing therapies.
Gisli Jenkins is the Margaret Turner Warwick Chair of Thoracic Medicine at Imperial College London and principal investigator for a planned global platform trial for interstitial lung disease (ILD), REMAP-ILD. “Life expectancy for patients with idiopathic pulmonary fibrosis [IPF] is around 3–5 years”, he said. “Under the current system, it takes 15 years to bring a drug through clinical trials. That is way too long. Patients who are around for phase 1 have died by the end of phase 3.” Jenkins added that conventional clinical trials are expensive and wasteful, with the infrastructure for each study dismantled at completion. The pharmaceutical companies who run the big trials have little incentive to study interventions from which they cannot profit, such as off-patent drugs like dexamethasone.
“The purpose of a standard trial is to demonstrate efficacy”, said Jenkins. “To optimise the chances of success, the investigators assign inclusion criteria which typically excludes the vast majority of patients, at least in respiratory medicine. So even if the drug gets to the clinic, there is a lack of generalisability. With platform trials, you can easily add an arm to look at how a given drug works in a specific patient subgroup. You have a seamless transition from phase to phase, retaining and accumulating data, so you avoid the massively inefficient situation in which phase 2 and phase 3 are separate entities.” Platform trials might also be a more enticing prospect for patients than studies in which they have a 50% chance of receiving the placebo.
Nonetheless, building the global infrastructure to run the trial is a huge undertaking. It requires a protocol that can be delivered in low, medium, and high-income settings. “I was glad that REMAP-CAP was not the first clinical trial I was overseeing”, said Gordon.
ILD is highly complicated. None of the currently available treatments improve long-term survival. “We are talking about a chronic progressive condition. We are not expecting to see lots of new therapies approved through platform trials in the next 10 years, but identifying a few effective therapies and disregarding non-effective therapies over this timeframe would be hugely valuable”, Jenkins told The Lancet Respiratory Medicine.
Jenkins is encouraged by the finding that meaningful changes in forced vital capacity for patients with ILD can be detected at 3 months. “We are now in a position to use 3-month data to assess the trajectory of disease, which means we can shorten the study”, he said. “We can learn from what has been done in motor neurone disease, where they have successfully delivered an adaptive platform trial. I am optimistic. The COVID-19 pandemic has shown the amazing things that can come out of a truly pragmatic clinical trial.”
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