Data from a large randomized controlled trial in the United Kingdom showing a benefit from use of the steroid dexamethasone in hospitalized COVID-19 patients was released today in the New England Journal of Medicine (NEJM), while two more studies show no benefit for the malaria drug hydroxychloroquine.
The NEJM data, which were originally reported in a press release in mid-June by the chief investigators of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial after an interim analysis, show that in patients needing mechanical ventilation, dexamethasone reduced deaths by 36% compared with usual care. In patients receiving oxygen, the incidence of death was 18% lower for patients on dexamethasone.
"The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support," investigators with the RECOVERY Collaborative Group, which is led by scientists from the University of Oxford, wrote.
Prior to the trial, there had been debate over whether steroids such as dexamethasone could play a role in COVID-19 treatment. But, based on these results, guidelines from UK chief medical officers and the National Institutes of Health were quickly updated to recommend the cheap, widely available steroid for treatment of COVID-19 patients requiring ventilation or oxygen, and the drug is now in wide use.
Reduced mortality in dexamethasone patients
In the controlled, open-label trial, which is investigating several treatments in more than 11,000 hospitalized COVID-19 patients in the United Kingdom, 2,104 patients were assigned to receive oral or intravenous dexamethasone daily for up to 10 days, and 4,321 patients received usual care. The primary outcome was 28-day mortality.
The results showed, overall, that 28-day mortality was lower in the dexamethasone group than in the usual-care group, with 482 deaths (22.9%) in patients receiving dexamethasone and 1,110 deaths (25.7%) in patients receiving usual care (age-adjusted ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93). But the biggest reduction in deaths was observed in patients needing mechanical ventilation (29.3% in the dexamethasone arm vs 41.4% in the usual care arm; rate ratio 0.64; 95% CI, 0.51 to 0.81) and in those receiving oxygen (23.3% vs 26.2%; rate ratio 0.82; 95% CI, 0.72 to 0.94).
There was no mortality benefit from dexamethasone, however, among patients not needing respiratory support. In fact, deaths were higher among patients in the dexamethasone arm (17.8% vs 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55).
The results also showed a greater mortality benefit in patients with longer duration of symptoms, and that patients in the dexamethasone group spent less time in the hospital (median, 12 days vs 13 days) and had a greater probability of discharge from the hospital within 28 days (rate ratio, 1.10; 95% CI, 1.03 to 1.17).
The investigators suggested the benefits of dexamethasone, which is used in a wide range of conditions for its anti-inflammatory and immunosuppressant effects, are likely related to treating the inflammation and the immune response caused by COVID-19.
"The greater mortality benefit of dexamethasone in patients with COVID-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role," they wrote.
Writing in an accompanying editorial, H. Clifford Lane, MD, and Anthony Fauci, MD, of the National Institute of Allergy and Infectious Diseases, said the findings provide "clarity to an area of therapeutic controversy and probably will result in many lives saved."
Lane and Fauci also said that more trials like RECOVERY will be needed to improve outcomes in COVID-19 patients.
"Scientifically robust and ethically sound clinical research remains the quickest and most efficient pathway to effective treatment and prevention strategies for patients with COVID-19," they wrote.
More uninspiring hydroxychloroquine data
While the results from the RECOVERY trial indicate that dexamethasone can help some severely ill COVID-19 patients, two trials investigating the efficacy of hydroxychloroquine found it provided no benefit for patients with mild COVID-19.
In a study published yesterday in the Annals of Internal Medicine, researchers from the University of Minnesota, the University of Manitoba, and McGill University randomized 491 patients with laboratory-confirmed COVID-19 or probable COVID-19 and high-risk exposure to receive 5 days of oral hydroxychloroquine or placebo within 4 days of symptom onset. The aim of the study was to see whether starting hydroxychloroquine therapy within the first few days of symptoms could reduce symptom severity or duration and prevent hospitalization.
The researchers emailed surveys to participants on days 1, 3, 5, 10, and 14 to assess COVID-19 symptom severity, adverse effects, medication adherence, and hospitalization status. They assessed symptom severity on a 10-point scale, with 0 indicating no symptoms and 10 indicating severe symptoms.
The initial primary outcome was hospitalization status, intensive care unit stay, or death by day 14. But because interim analysis showed that the pooled event rate of hospitalization rate or death was substantially lower than expected, the primary end point was changed to overall symptom severity by day 14.
The results showed that, among the 423 participants who provided data, hydroxychloroquine failed to cause a statistically significant difference in symptom severity or prevalence over the 14-day period. The hydroxychloroquine patients had a mean reduction from baseline of 2.60 points in the 10-point symptom severity scale, compared with a 2.33-point reduction for the placebo group (difference in symptom severity: relative, 12%; absolute, –0.27 points; 95% CI, –0.61 to 0.07 points; P = 0.117). At day 14, 24% of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% of patients receiving placebo.
"Hydroxychloroquine did not substantially reduce symptom severity or prevalence over time in nonhospitalized persons with COVID-19," the authors of the study wrote.
Adverse effects occurred in 43% of patients taking hydroxychloroquine versus 22% of those receiving placebo. Hospitalizations occurred in 4 patients taking hydroxychloroquine, with 1 death, while 10 placebo patients were hospitalized (2 for non-COVID–related issues), and 1 died. The incidence of hospitalization or death did not differ between groups.
The authors note that the results are limited by the fact that only 58% of the participants received testing for SARS-CoV-2, the virus that causes COVID-19, because of testing shortages at the time of enrollment.
In the other study, a multicenter trial conducted in Spain, 293 non-hospitalized patients with confirmed SARS-CoV-2 infections were randomized to receive either hydroxychloroquine (the intervention arm) within 5 days of symptom onset or no antiviral treatment (the control arm). The primary outcomes were reduction of viral RNA load in nasopharyngeal swabs up to 7 days after treatment, patient disease progression, and time to complete resolution of symptoms.
The results of the trial showed no difference in the mean viral reduction load at day 7 ( –3.37 and –3.44 Log10 copies per milliliter in the control and intervention arm, respectively; difference, –0.07; 95% CI, –0.44 to 0.29). In addition, treatment with hydroxychloroquine did not significantly reduce the risk of hospitalization (7.1% for the control arm vs 5.9% for the intervention arm; risk ratio, 0.75; 95% CI, 0.32 to 1.77) or shorten the time to complete resolution of symptoms (12 days for the control arm vs 10 days for the intervention arm; P = 0.38).
"The results of this randomized controlled trial convincingly rule out any meaningful virological or clinical benefit of [hydroxychloroquine] in outpatients with mild COVID-19," the authors wrote in Clinical Infectious Diseases.
Time to move on from hydroxychloroquine
Jason Gallagher, PharmD, a clinical professor and specialist in infectious diseases at Temple University School of Pharmacy, says these trial results add to the growing body of evidence that hydroxychloroquine is not an effective treatment for COVID-19, either for hospitalized patients or those in the early stages of the infection.
"I wish that hydroxychloroquine had been successful, but it has been conclusively found to be ineffective," said Gallagher, who was not involved in either study. "All of the well-designed, randomized, controlled trials have found the same thing—it does not work."
Hope for hydroxychloroquine, which received an emergency use authorization from the US Food and Drug Administration in March, was based on the results of a small French study that found the drug reduced SARS-CoV-2 viral load when combined with azithromycin in a handful of patients. But several observational studies and randomized controlled trials, which are considered the gold standard for determining whether a drug is effective, have found no benefit.
Gallagher thinks it's time to move on to investigating other potential therapies for non-hospitalized COVID-19 patients.
"If a therapy is going to be successful in treating outpatient COVID-19, it will be something else," he said. "It's time to expend our resources elsewhere."
