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How will ‘mega-trials’ identify the most effective treatments for COVID-19, and when will they report?

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In response to COVID-19, very large international trials of potential treatments have been set up with unprecedented speed. For example, the RECOVERY trial is the fastest growing trial in medical history, enrolling 1,000 patients at 132 hospitals within its first 15 days. Why are these trials needed, and how will they work?

There are currently no treatments proven to work against COVID-19. Large randomised controlled trials are using innovative designs to evaluate the most promising treatments at speed – but are unlikely to find a ‘magic bullet’.

What treatments are being tested?

Treatments are urgently needed that are known to be safe and can be made rapidly available at scale.[1] For this reason, most trials are focusing on treatments already used for other diseases. These include lopinavir/ritonavir (used to treat HIV), hydroxychloroquine (an anti-malarial drug), remdesivir (developed to treat Ebola), azithromycin (an antibiotic), and drugs that reduce inflammation such as steroids and beta-interferons (used to treat multiple sclerosis).[2]

Large trials have been set up to test these treatments for a range of purposes. For example the international COP-COV study aims to prevent infection among healthcare workers, the PRINCIPLE study in the UK aims to reduce hospital admissions through primary care treatments and there are several trials in hospital patients including the World Health Organization’s global SOLIDARITY trial, the DISCOVERY trial in Europe, and the RECOVERY trial in the UK. The REMAP-CAP study aims to identify the best combination of treatments in critical care.

Why do we need big trials?

Small studies can be nimble – the first trial of COVID-19 treatment started only a week after the virus had been identified.[3] However, small trials can only detect large improvements in outcomes. With few patients, it is difficult to detect even moderate differences in outcome between treated and untreated patient groups and these differences cannot easily be distinguished from chance. Small trials have not found evidence of large effects of treatment, suggesting that any benefits are likely to be modest.

Large trials follow more patients and so can detect smaller differences in outcomes between treatment and control groups. Small improvements in outcomes can still make a big difference in pandemics. When large numbers of people are infected, even a small increase in survival translates into a large number of survivors. If a treatment reduced mortality among people with severe COVID-19 infection from 25% to 20%, then given to a hundred thousand severely unwell patients it could save 5,000 lives. High-profile ‘flagship’ trials also encourage other researchers to adopt common standards, so that trials generate results which can be meaningfully compared.[4]

How are studies being designed to be efficient and adapt to emerging evidence?

The World Health Organization’s SOLIDARITY trial is deliberately simple. Launched in 13 countries and run like a franchise, each country will follow the same protocol. When a patient is recruited, the clinical details are entered into the WHO website and this allocates the patient to a particular treatment or to ‘standard of care’ at random, depending on what drugs are locally available. Although drug trials are often ‘blinded’, meaning that scientists conceal from patients and doctors which treatment has been assigned, SOLIDARITY is not blinded, making it easier to give the drugs. The only measurements taken after recruitment are whether the patient died, whether the hospital stay was shortened, and whether the patient required oxygen or ventilation. This minimal approach improves the speed of recruitment, limits the extra demand on healthcare workers’ time, reduces the costs of the trial and ensures that hospitalised patients in low and middle-income countries can also participate in the study.

Both the World Health Organization’s SOLIDARITY trial and the RECOVERY trial in the UK are initially comparing four different treatment groups against one control group, to study not only whether a treatment works, but which treatment works best. Compared to separate studies, each with its own control group, these trials give patients a higher chance of receiving one of the new treatments rather than standard care. This also reduces the number of patients needed to test all four drugs, and more participants benefit immediately if the treatments are effective.

Randomisation is the cornerstone of clinical trials which means the outcome can only be attributed to the trial drug not to the characteristics of the patients receiving it. For efficiency, one trial can be used to compare different complementary interventions in the same study, each involving its own randomisation. In REMAP-CAP, an international study of treatment in critical care, each patient is randomised to receive lopinavir/ritonavir or control treatment and then is randomised three more times to receive, or not receive, a steroid regime, prolonged antibiotics, and an immune modulator such as beta-interferon. This approach also means that the trial can evaluate interactions between interventions in different domains (see Figure).[5]

How will ‘mega-trials’ identify the most effective treatments for COVID-19, and when will they report?
Figure: structure of the REMAP-CAP trial

Research into COVID-19 is constantly evolving. Several trials are using ‘adaptive designs’ to increase the probability of finding an effective treatment.[6] Trial results will be monitored on an ongoing basis, and treatments which are clearly ineffective will be discontinued promptly. Trials may also add in a new treatment if other evidence suggests promise. REMAP-CAP uses adaptive randomisation, in which results from patients already taking part in the study are used to guide randomisation of new patients, so that if any particular treatment arm is proving effective, a higher proportion of patients will receive that intervention. Adaptive approaches assign patients progressively to more effective treatments, increasing the probability of finding a successful treatment rapidly, and ensuring trial participants are increasingly receiving the drugs that appear most effective to date.

When can we expect to hear results?

New drug development, safety testing and randomised controlled trials normally take 10–15 years to complete. However, by testing existing safe medications rather than designing new ones, and through shrewd study design and multi-centre recruitment, several large COVID-19 trials will report as soon as early summer 2020.

In the meantime, large-scale recruitment to international trials means that more patients who are unwell now have the opportunity to try these treatments, while also building knowledge to help others who are unwell in the future.

Declaration of interest

The UK Research and Innovation (UKRI) funds trials of treatment for COVID-19, including the RECOVERY and PRINCIPLE trials.

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References

  1. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Apr. DOI: 10.1001/jama.2020.6019.

  2. Mahase E. Covid-19: what treatments are being investigated? BMJ. 2020 Mar;368:m1252. DOI: 10.1136/bmj.m1252.

  3. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. The New England Journal of Medicine. 2020 Mar. DOI: 10.1056/NEJMoa2001282.

  4. Mullard A. Flooded by the torrent: the COVID-19 drug pipeline. Lancet (London, England). 2020 Apr;395(10232):1245-1246. DOI: 10.1016/s0140-6736(20)30894-1.

  5. What is an adaptive clinical trial?. REMAP-CAP. Accessed: 2020 Apr 24.

  6. Chow SC, Chang M. Adaptive design methods in clinical trials - a review. Orphanet Journal of Rare Diseases. 2008 May;3:11. DOI: 10.1186/1750-1172-3-11.

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