Remdesivir, one of the big treatment hopes for Covid-19, has very little effect on preventing deaths, according to a large and comprehensive trial run by the World Health Organization.
The drug, made by the US biotech firm Gilead, has been talked up as a potential cure and was taken by Donald Trump. A trial in the US had previously showed it reduced the length of stay in hospital. But the gold-standard Solidarity WHO trial, which was based on a far larger sample – 3,000 people on the drug, compared with as many who were not – showed remdesivir had little effect on deaths over 28 days.
Gilead was told about the results on 23 September, 10 days before publication, and was given a first draft of the study on 28 September. The WHO said the company was told the outcome in advance as part of an agreement to provide the drug for free.
On 8 October, Gilead signed a contract for 500,000 doses of the drug with the European commission – which did not know the results – at a cost of €850m (£733m).
The agreement to disclose the results to the company before publication was made at the beginning of the trial, said Dr Soumya Swaminathan, chief scientist at the WHO. “It is an agreement in good faith,” she said, adding that it allowed Gilead to check whether any errors had been made, but did not allow the company to change the analysis or conclusions.
Many countries have already put remdesivir on their treatment list for Covid-19 patients, based on the much smaller US study that found the drug shortened hospital stays.
The WHO’s guideline committee will look at the data from its trial and others and decide what recommendations to make about the drug.
Three other drugs were trialled in the Solidarity study, which has recruited more than 12,000 patients across 30 countries, and none had very much effect on mortality. They were hydroxychloroquine, which had already been found to have no benefit by the University of Oxford’s Recovery trial, lopinavir, an antiretroviral used in HIV treatment, and interferon, given as an injection under the skin.
“Interferon was disappointing,” said Oxford’s Prof Sir Richard Peto, who was the chief statistician in the trial. “This regime didn’t do much for survival.”
However, it is still possible that interferon given in other ways or in different formulations may have an effect.
The remdesivir results constitute the bulk of the evidence for the drugs being used, Peto said. “It is more than three times as big as all the other evidence in the world put together.”
The Solidarity trial had to be taken seriously, he continued. “The quality of this trial is excellent. This is real world evidence. The phrase has been hijacked by people – a lot of wrong answers have come out from people trying to play games by avoiding randomisation.
With remdesivir, there were 300 deaths among people randomly assigned to the drug and 300 among others not on the drug. “It doesn’t guarantee there is exactly no effect, but it does very much constrain what it is possible to claim,” he said.
Martin Landray, a professor of medicine and epidemiology at Oxford and one of the leads on the Recovery trial, said the results of the Solidarity trial were important but sobering.
“Four different drugs were studied in over 11,000 patients at 405 hospitals in 30 countries. The trial is beautiful in its simplicity and clarity of purpose – large, randomised and focused on the ultimate clinical outcome of survival. None of the four treatments studied – hydroxychloroquine, lopinavir, interferon, remdesivir – showed worthwhile benefits.”
Hydroxychloroquine, also known by its brand name, Plaquenil, is a drug used to treat malaria. It is a less toxic version of chloroquine, another malaria drug, which itself is related to quinine, an ingredient in tonic water.
A widely publicized study in France where 40 coronavirus patients were given hydroxychloroquine, with more than half experiencing the clearing of their airways within three to six days has led to it being touted in some quarters as a potential cure for Covid-19. This apparent improvement is important as it would curtail the timeframe in which infected people could spread Covid-19 to others.
However, experts have warned that the study is small and lacks sufficient rigour to be classed as evidence of a potential treatment. The French study followed work by Chinese researchers which suggested that hydroxychloroquine can slow infections by blocking the virus behind Covid-19 from entering cells in the body. But more recent, albeit small-scale, research from China has shown that patients who were treated with the drugs fought off coronavirus no more quickly than those who didn’t get it. Indeed, one patient given hydroxychloroquine severely worsened in condition while four patients on the medicine developed signs of liver damage and experienced diarrhoea. US president Donald Trump has claimed he takes hydroxychloroquine despite FDA warnings.
Here is a guide to the scientific studies into hydroxychloroquine and coronavirus carried out so far.
Regardless of these findings, any drug being used for a certain purpose before full clinical trials are completed is, by definition, untested and unproven. It’s too early to say if hydroxychloroquine can have a major benefit or not. The European Medicines Agency, an agency of the EU, has said hydroxychloroquine should not be taken by coronavirus patients except for clinical trials or emergency use programs.
Remdesivir has received plenty of attention over the past few months and was one of a number of treatments given to Trump. It is now recommended in some clinical guidelines. But there have been significant concerns about supply, cost, and access. The cost varies around the world but is about $2,000 (£1,450) a treatment course, which involves the drug being administered by intravenous infusion for five to 10 days.
“The WHO Solidarity trial found that remdesivir had no meaningful effect on mortality,” Landray said. “Covid affects millions of people and their families around the world. It is not a rare disease. We need scalable, affordable, and equitable treatments.
“The WHO Solidarity trial has done the world a huge favour by producing clear, independent and robust results, showing once more the value of large randomised trials in providing the knowledge we need to tackle the worst consequences of this pandemic.”
In a statement to the Guardian, Gilead said it did not have the full data from the trials when it signed the deal with the European Commission for 500,000 doses.
“WHO provided an initial, heavily redacted manuscript in late September. As of today, Gilead has still not received the underlying datasets or statistical analysis plan necessary to validate the results. We received the full manuscript, which included materially different information than what was included in the initial draft, only hours before it was published yesterday,” it said.
“The joint procurement agreement with the European Commission (EC) does not obligate the EC or any participating countries to purchase Veklury (Remdesivir). The agreement enables the purchase of up to 500,000 treatment courses, but countries control the quantities they choose to purchase.”
