LONDON – In the first major breakthrough in therapeutics for COVID-19 infection, dexamethasone has been shown to have a statistically significant impact on mortality in the most seriously ill patients.

There was a one-third reduction in deaths in patients on ventilators, while in patients receiving oxygen therapy there was a 15% reduction in 28-day mortality, in the U.K. Recovery trial. No benefit was seen in patients who were sick enough to be in the hospital but did not need help breathing.

The steroid was delivered either orally or intravenously at a dose of 6 mg per day. In total, 2,104 patients were randomized to the active arm and 4,321 to standard of care. There were no serious treatment-related adverse events.

Peter Horby, professor of emerging infectious diseases at Oxford University, and one of the chief investigators for the trial, said, “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.”

In addition to being readily available and cheap, dexamethasone is a well-understood drug that has shown some benefits in treating lung infections. However, use of the drug in treating patients in the earlier SARS-CoV-1 epidemic did not deliver clear-cut results.

Horby noted that 13 national and international clinical care guidelines he has consulted specifically advise against the use of dexamethasone in treating COVID-19 infections. “There’s huge clinical uncertainty and that’s why it’s included in the trial,” he said. In the light of the results, “all guidelines will need to be updated,” Horby said, promising the full results will be published as soon as possible.

Of all COVID-19 patients admitted to the hospital in the U.K., 40% of those requiring ventilation have died, as have 25% of those requiring oxygen therapy and 13% of patients who did not require assistance with breathing.

Overall, dexamethasone reduced the 28-day mortality rate by 17% (p=0.0007). For patients on ventilators, the risk of death reduced from 40% to 28% (p=0.0003), which chief investigator Martin Landray, professor of medicine and epidemiology at Oxford University, said “is a completely compelling response.” Out of every eight patients, one will survive who would have died.

For patients needing oxygen, the mortality rate fell from 25% to 20% (p=0.0021). “The biggest benefits are in those at the highest risk,” said Landray.

If dexamethasone had been known to have those benefits at the start of the pandemic, in the U.K. alone, 4,000 to 5,000 fewer people would have died. “The epidemic is international; this is a result of instant global impact,” Landray said.

“This is a major breakthrough. Dexamethasone is the first and only drug that has made a significant difference to patient mortality for COVID-19. Potentially preventing one death in every eight ventilated patients would be remarkable,” said Nick Cammack, who is lead for the COVID-19 Therapeutics Accelerator at the U.K. research charity Wellcome Trust. “While this study suggests dexamethasone only benefits severe cases, countless lives will be saved globally,” Cammack said.

In the U.K., a complete course of dexamethasone costs £5.40 (US$6.80); in India, the cost is around $1. “Dexamethasone will save lives, and will do so at a very low cost,” said Landray.

Currently, there are about 400 COVID-19 patients on ventilators in the U.K. Landray said advice is going to all hospitals recommending they are all treated with dexamethasone.

The only other drug to have turned in positive results in COVID-19 is Gilead Sciences Inc.’s remdesivir. The antiviral has been shown to reduce duration of symptoms from 15 days to 11 days, but there are no data, as yet, indicating there is an effect on mortality.

Horby said it is possible that remdesivir and dexamethasone would work in synergy. “There’s no theoretical reason to think the two drugs would interact; one tackles the virus, the other inflammation,” he said.

Since it started on April 3, the Recovery trial has recruited 11,575 patients in 176 hospitals. With the positive results in dexamethasone, that arm of the trial is now closed. On June 5, Recovery data showed there are no benefits from using the malaria drug hydroxychloroquine, and that arm of the study also has been stopped.

The remaining treatments under test in the Recovery trial are the HIV combination therapy lopinavir/ritonavir, the antibiotic azithromycin, convalescent plasma and the rheumatoid arthritis treatment Actemra (tocilizumab).

“Dexamethasone now becomes the standard of care, but the trial continues because we still need more treatments. Essentially, [each arm] becomes a combination treatment because all patients get dexamethasone. We want to see if any drugs provide additional benefits,” said Landray. “On a scientific basis, to show [dexamethasone] reduces mortality opens up the possibility of other drugs [doing so],” he said.

Coming on top of the hydroxychloroquine findings, the dexamethasone results underline the importance of large-scale, randomized trials to detect effects in what is a very complex disease. The data “highlight the tremendous power of the Recovery trial to confidently assign benefit, or lack thereof, to the numerous therapies postulated to help treated SARS-CoV-2-infected patients,” said Stephen Griffin, associate professor of medicine at Leeds University, who is not involved in the study.

No Comments