New Steroid Studies Are a Missed Opportunity for Concrete Answers About Covid-19 Treatment

While the data suggests a benefit from the drugs, the research was cut short

A member of staff at a pharmacy in London holds a packet of anti-inflammatory drug dexamethasone. Credit: Yui Mok — PA Images / Getty Images

In June, scientists in England trumpeted good news about Covid-19: A simple steroid called dexamethasone reduced the death rate by 36% in people with severe cases of Covid-19 who were hospitalized and on ventilation. A month later, a paper published in the New England Journal of Medicine provided the data to back up the claim.

Three new studies out of Brazil, France, and the United States, published today in the Journal of the American Medical Association (JAMA), attempted to expand upon this research and strengthen the evidence. However, all of the studies were deliberately cut short in June upon the issuance of the British press release. As a result of being ended prematurely, the clinical trials testing dexamethasone and another steroid, hydrocortisone, in severely ill Covid-19 patients show positive but statistically nonsignificant findings because they didn’t have enough people enrolled to conduct adequate comparisons.

Fortunately, a meta-analysis, also published today in JAMA, run by the World Health Organization, that looked at seven clinical trials of corticosteroids for Covid-19 — the four studies listed above and three others yet to be published — provided more concrete support for the treatment. By pooling 1,703 Covid-19 patients across the seven trials — 678 who received a steroid and 1,025 who had the usual standard of care — the analysis was able to show that people who received the drugs were 34% less likely to die over 28 days, a rate consistent with the initial British trial. The WHO now formally recommends steroids be used to treat people who are critically ill with Covid-19, but not those who have a mild form of the disease.

An editorial that accompanied the four articles took a positive tone, stating, “These trials and the meta-analysis have strengthened confidence, further defined the benefit, and shifted usual care of Covid-19-related [acute respiratory distress syndrome] to include corticosteroids.”

Stopping clinical trials early in light of information from another study is not unheard of. The rationale is that if the treatment is shown to be unquestionably effective in the first study, it becomes unethical to deprive patients of it who are in the control arm of subsequent trials. The consequence is that, from a statistical point of view, the truncated clinical trials have too few people enrolled to find a significant benefit of the treatment.

In an email to Elemental, Todd Rice, MD, an associate professor of medicine at Vanderbilt University who co-authored the editorial but was not involved in any of the research, supported the three studies’ decision to stop early. “Continuing to enroll participants into a placebo arm would have been exposing them to unnecessary risk,” he says. “Overall, I am not concerned about the findings — I think the findings are incredibly important and consistent with the [British] results — and the group of trials all together just really confirm the benefit of treatment with steroids in critically ill patients with Covid-19.”

By stopping the studies short, several questions — such as the proper dose to give, which steroid is most effective, and which patients benefit the most — remain unanswered. Steroids are anti-inflammatory drugs, and they are thought to rein in the overactive immune system that can become lethal in Covid-19. There is a concern that if the drugs are given too early they can dampen the immune response too much, hindering the body’s defense against the virus. Also, the evidence from the first clinical trial suggests that the drugs don’t work for everybody and are only effective in the sickest patients. The three studies published today might have been able to provide more insight into some of these issues. Hopefully, future studies will provide more concrete answers.

Health and science writer • PhD in 🧠 • Words in Scientific American, STAT, The Atlantic, The Guardian • Award-winning Covid-19 coverage for Elemental

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