Dexamethasone, a cheap and widely-used steroid, has become the first drug shown to save COVID-19 lives, in what University of Oxford scientists said is a “major breakthrough”. Preliminary trials show dexamethasone reduced death rates by a third among seriously ill patients, with researchers recommending it should immediately become standard care for such cases.
Reuters Health reports that in March 2020, the RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was established as a randomised clinical trial to test a range of potential treatments for COVID-19, including low-dose dexamethasone (a steroid treatment). Over 11,500 patients have been enrolled from over 175 National Health Service (NHS) hospitals in the UK.
On 8 June, recruitment to the dexamethasone arm was halted since, in the view of the trial Steering Committee, sufficient patients had been enrolled to establish whether or not the drug had a meaningful benefit.
A total of 2104 patients were randomised to receive dexamethasone 6 mg once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomised to usual care alone. Among the patients who received usual care alone, 28-day mortality was highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%).
Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75; p=0.14).
Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.
Given the public health importance of these results, the researchers are now working to publish the full details as soon as possible.
Peter Horby, professor of emerging infectious diseases in the Nuffield department of medicine, University of Oxford, and one of the chief investigators for the trial, said: “Dexamethasone is the first drug to be shown to improve survival in COVID-19. This is an extremely welcome result. The survival benefit is clear and large in those patients who are sick enough to require oxygen treatment, so dexamethasone should now become standard of care in these patients. Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.”
Martin Landray, professor of medicine and epidemiology at the Nuffield department of population health, University of Oxford, one of the chief investigators, said: “Since the appearance of COVID-19 six months ago, the search has been on for treatments that can improve survival, particularly in the sickest patients. These preliminary results from the RECOVERY trial are very clear – dexamethasone reduces the risk of death among patients with severe respiratory complications. COVID-19 is a global disease – it is fantastic that the first treatment demonstrated to reduce mortality is one that is instantly available and affordable worldwide.”
The UK government’s chief scientific adviser, Sir Patrick Vallance, said: “This is tremendous news today from the Recovery trial showing that dexamethasone is the first drug to reduce mortality from COVID-19. It is particularly exciting as this is an inexpensive widely available medicine. This is a ground-breaking development in our fight against the disease, and the speed at which researchers have progressed finding an effective treatment is truly remarkable. It shows the importance of doing high quality clinical trials and basing decisions on the results of those trials.”
England’s chief medical officer, Chris Whitty, said in the Reuters Health report that the announcement was “the most important trial result for COVID-19 so far.” His deputy, Jonathan Van-Tam, said the results highlighted the importance of properly conducted clinical trials and robust data.
“We hope the data on which these results are based will be published as soon as possible so that doctors can confidently put the treatment into practice,” said Robin Ferner, honorary professor of clinical pharmacology at University of Birmingham.
Dr Thomas McGinn, deputy physician-in-chief at Northwell Health, New York’s largest healthcare system, is quoted in the report as saying that physicians at Northwell hospitals have been using steroids on a case-by-case basis because they can suppress patients’ immune systems and possibly make them susceptible to other infections.
He said that if the data is peer-reviewed and legitimised, it could spread the use of steroids in the sickest COVID-19 patients.
“Across the country now intensivists have been using it based on their judgement calls. If this is legitimate, you may find … instead of say five out of 10 intensive-care COVID patients getting it, maybe everybody would get it,” McGinn said.
The report says dexamethasone is on the US Food and Drug Administration’s list of drugs in shortage, but several manufacturers, including the largest supplier to the US, say it is available.
“It’s a startling result,” says Kenneth Baillie, an intensive-care physician at the University of Edinburgh, UK, who serves on the steering committee of the trial. “It will clearly have a massive global impact.” Nature reports that treatment guidelines from the World Health Organisation and many countries have cautioned against treating people with coronavirus with steroids, and some investigators were concerned about anecdotal reports of widespread steroid treatment. The drugs suppress the immune system, which could provide some relief from patients whose lungs are ravaged by an over-active immune response that sometimes manifests in severe cases of COVID-19. But such patients may still need a fully functioning immune system to fend off the virus itself.
The RECOVERY trial suggests that at the doses tested, the benefits of steroid treatment may outweigh the potential harm. The study found no outstanding adverse events from the treatment, investigators said. “This treatment can be given to pretty much anyone,” says Horby.
And the pattern of response – with a greater impact on severe COVID-19 and no effect on mild infections – matches the notion that a hyperactive immune response is more likely to be harmful in long-term, serious infections, Nature quotes Anthony Fauci, head of the US National Institute of Allergy and Infectious Disease as saying. “When you’re so far advanced that you’re on a ventilator, it’s usually that you have an aberrant or hyperactive inflammatory response that contributes as much to the morbidity and mortality as any direct viral effect.”
“Finding effective treatments like this will transform the impact of the COVID-19 pandemic on lives and economies across the world,” said Nick Cammack, head of the COVID-19 Therapeutics Accelerator at Wellcome, a UK biomedical research charity in London, in a statement. “While this study suggests dexamethasone only benefits severe cases, countless lives will be saved globally.”
Nature reports that so far, the only drug shown to benefit COVID-19 patients in a large, randomized, controlled clinical trial is the antiviral drug remdesivir. Although remdesivir1 was shown to shorten the amount of time that patients may need to spend in the hospital, it did not have a statistically significant effect on deaths.
Remdesivir is also in short supply. Although the drug’s maker – Gilead Sciences – has taken steps to ramp up production of remdesivir, it is currently available only to a limited number of hospitals around the world. And remdesivir is complex to administer: it must be given by injection over the course of several days.
Dexamethasone, by contrast, is a medical staple found on pharmaceutical shelves worldwide and is available as a pill – a particular benefit as coronavirus infections continue to rise in countries with limited access to healthcare.
The findings could also have implications for other severe respiratory illnesses, Baillie adds. For example, steroid treatments for a condition called acute respiratory distress syndrome are also controversial. “This really gives us a very good reason to look closely at that, because the mortality benefit is so extraordinarily large,” Baillie says. “I think this will affect patients well beyond COVID-19.”
Pharmaceutical giant Aspen produces dexamethasone injections in South Africa, and its CEO Stephen Saad confirmed to Business Insider SA that there should be sufficient supplies to meet local demand. “It all depends on where and when we get the surges. We should be fine for South Africa, (as) we make this in South Africa.”
The report says South Africa faced a shortage of dexamethasone, which is also used to treat leukaemia and terminal brain tumours as recently as in 2016, after Merck & Company discontinued production in the country.
Since then Aspen has started production, and other companies including Adcock Ingram and Sanofi are registered to distribute dexamethasone in South Africa.
The report says Aspen is also a major supplier of the medicine in other markets, including the UK.
The regulated price per dexamethasone injection is between R149 and R176 in South Africa.
South Africa’s Health Minister Dr Zweli Mkhize said he was "extremely excited" that there has been an important breakthrough in one of the therapeutic trials for COVID-19 management, News24 reports. "The RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial has published results on the therapeutic merits of low-dose dexamethasone, which are extremely promising and are easily implementable in our country," Mkhize said.
Mkhize said dexamethasone is a well-known and widely used steroid which has potent anti-inflammatory properties. "It is used in allergic reactions, asthma and other conditions where the inflammatory component of the disease needs to be controlled for better outcomes."
The Ministerial Advisory Committee (MAC) on COVID-19 issued an advisory pertaining to the clinical applications of these breaking study results. In terms of the advisory, the full publication of the RECOVERY trial is eagerly awaited. "There are important aspects of the results that will be needed to make a full assessment of the data," the MAC said. "Data on the absolute risk reduction and the numbers of events per patient group will also be needed to fully interpret the evidence provided."
[link url="https://uk.reuters.com/article/us-health-coronavirus-steroid/steroid-drug-hailed-as-breakthrough-in-covid-19-as-trial-shows-it-saves-lives-idUKKBN23N1VP"]Full Reuters Health report[/link]
[link url="http://www.ox.ac.uk/news/2020-06-16-dexamethasone-reduces-death-hospitalised-patients-severe-respiratory-complications"]University of Oxford material[/link]
[link url="https://www.nature.com/articles/d41586-020-01824-5"]Full Nature report[/link]
[link url="https://www.businessinsider.co.za/business/dexamethasone-made-in-south-africa-2020-6"]Full Business Insider report[/link]
[link url="https://www.news24.com/news24/southafrica/news/breakthrough-in-covid-19-treatment-is-extremely-promising-says-zweli-mkhize-20200617"]Full News24 report[/link]