In the piece “Are We Any Nearer to a COVID-19 Cure?” (click here to read) the UK Recovery Trial was cited as the largest drug trial in the world.
It has recruited 11,500 patients from 175 different hospitals and is studying five different drugs:
Lopinavir-Ritonavir (as in the Solidarity Trial)
Low-dose Dexamethasone (a type of steroid which is used to reduce inflammation and swelling)
Hydroxychloroquine (see update of 5 June, now withdrawn from trial)
Azithromycin (A commonly used antibiotic. Although antibiotics do not kill viruses, only bacteria, azithromycin is unusual because it also modifies the body's immune reaction and has been shown to have some action against viruses through this effect)
Tocilizumab (an anti-inflammatory treatment given by injection that can also modify the body's immune reaction) (1)
On 5 June 2020, it was announced that hydroxychloroquine had been withdrawn from its trial. Just over 1,500 patients had received it and researchers found it had no effect on the virus. (2)
Further results from the trial were not expected until early July but it was announced on 16 June 2020 that the dexamethasone arm of the trial had shown a clear survival benefit in seriously ill COVID-19 patients.
Professor Peter Horby, the lead researcher at the University of Oxford, UK, 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.” (3)
For patients on ventilators, it cut the risk of death from 40% to 28%. For patients needing oxygen, it cut the risk of death from 25% to 20%. It had no effect on patients who did not need oxygen or ventilation but it is important to remember that these patients are the most likely to recover and had not developed the complications dexamethasone is most likely treating (see below for more details). (4)
As always with any kind of breakthrough there has already been scepticism. US and Brazillian doctors in particular have been quick to criticise aspects of the study, with some US doctors even taking to Twitter to voice their dissent. (5) (6) (7)
However, their views are not representative of the vast majority of doctors and researchers across the world.
Most studies to date on possible treatments for COVID-19 have been retrospective. They have looked back in time and tried to work out which, if any, treatment has worked. Retrospective studies are scientifically not as robust as prospective studies which go forward in time and have tighter controls. (8)
A simple analogy would be a trial that wants to know if substance A, B or C caused water to turn red. A retrospective study would look back on cases of water turning red and try to see if A, B or C were present. It can take a long time to gather enough cases and you cannot know for sure if something else entirely, which you are not even looking for, was the cause of the water turning red. The time involved to do such a study and the errors of margin are both large.
A prospective study would start in the present by taking substances A, B and C and adding them to water individually. Not only can you see which substance changes the water red, you know it has to be that substance because you are controlling the experiment and are certain there are no other factors turning the water red. A control arm, where you add nothing to the water, can be run at the same time allowing you to be certain the water does not turn red anyway if left alone.
The Oxford University trial on dexamethasone is a prospective study and that is what makes it significant. It was carried out in 175 NHS hospitals and no single institution or company gains monetarily from the findings. This is very different to studies done elsewhere in the world by private companies with a vested interest in a positive result that will allow them to market their product to the highest bidder. (9)
Doctors on the frontline realised that the seriously ill COVID-19 patients experienced an inflammatory reaction to the virus greater than that seen with other viral pneumonias. This reaction is known as a cytokine storm and damages every organ of the body. (10) (11)
As a potent anti-inflammatory drug several small, retrospective studies around the world had tried to establish if dexamethasone could help in COVID-19, including one in China based on anecdotal reports of it helping some patients. (12)
Trials like The Recovery Trial are needed because national treatment guidelines cannot be made on the basis of results from a few, small retrospective studies. Guidelines should only be based on rigorous, prospective trials. The Recovery Trial meets this criteria and, in the same way it was able to show that hydroxychloroquine had no role to play in the treatment of COVID-19, it has been able to demonstrate that dexamethasone has.
