The New England Journal of Medicine (NEJM) yesterday published the results of two randomized, controlled trials on two medications for the treatment of COVID-19, one supporting previous studies that found that Gilead Sciences' antiviral drug remdesivir helps patients recover faster and one adding to mounting evidence that the antimalarial drug hydroxychloroquine is no better than a placebo at preventing death in hospital patients.
Faster recovery, fewer interventions for remdesivir
The first study, by the Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group, randomly assigned 1,062 hospitalized COVID-19 patients with lower respiratory tract infections to receive either a placebo or 200 milligrams (mg) of intravenous remdesivir followed by 100 mg daily for as many as 9 days. The double-blind trial took place from Feb 21 to Apr 19 at 60 sites and 13 subsites in the United States, Europe, and Asia.
The 532 patients assigned to remdesivir recovered after a median of 10 days, while the 516 who received a placebo took 15 days to improve (rate ratio for recovery, 1.29). Median recovery time in the 957 severely ill patients who received remdesivir was 11 days, versus 18 days with placebo (rate ratio for recovery, 1.31).
The rate ratio for recovery in patients receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO; having oxygen added to their blood outside their body) at study enrollment was 0.98.
Of the 285 patients on mechanical ventilation or ECMO at enrollment, patients receiving remdesivir needed these interventions for fewer days than those receiving a placebo (median, 17 days vs 20 days), and 13% of patients in the remdesivir group advanced to needing mechanical ventilation or ECMO, versus 23% of those in the placebo group.
Preliminary study findings were published in late May in NEJM. The study is sponsored by the US National Institute of Allergy and Infectious Diseases.
Death rate by disease severity
An analysis that used a proportional-odds model with an eight-category number scale found that patients assigned to remdesivir were 1.5 times more likely than those who received a placebo to see clinical improvement at 15 days. Kaplan-Meier estimates of death by day 15 were 6.7% for remdesivir and 11.9% for placebo (hazard ratio [HR], 0.55) and 11.4% for remdesivir and 15.2% for placebo at 29 days (HR, 0.73).
Between-group differences in the death rate varied widely by baseline disease severity; the largest difference was observed in patients requiring extra oxygen (HR, 0.30).
Of the remdesivir group, 131 of 532 patients (24.6%) had serious adverse events, as did 163 of 516 patients (31.6%) in the placebo group. Remdesivir was most beneficial when given early in the illness, but the benefit was sustained in most analyses of the duration of symptoms. Forty-seven patients (8.8%) in the remdesivir group experienced acute respiratory failure requiring endotracheal intubation, compared with 15.5% in the placebo group.
In total, 53.3% of the patients were white, 23.5% were Hispanic or Latino, 21.3% were black, 12.7% were Asian, and 12.7% were designated as other, or their race was not reported. Most patients had one underlying illness (25.9%) or two or more (54.5%). The most common underlying conditions were high blood pressure (50.2%), obesity (44.8%), and type 2 diabetes (30.3%).
"Our data also suggest that treatment with remdesivir may have prevented the progression to more severe respiratory disease, as shown by the lower proportion of serious adverse events due to respiratory failure among patients in the remdesivir group, as well as a lower incidence of new oxygen use among patients who were not receiving oxygen at enrollment and a lower proportion of patients needing higher levels of respiratory support during the study," the authors wrote.
The researchers said that studies are under way assessing remdesivir in combination with immune response modifiers. "Given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient for all patients," they said. "A variety of therapeutic approaches including novel antivirals, modifiers of the immune response or other intrinsic pathways, and combination approaches are needed to continue to improve outcomes in patients with Covid-19."
On May 1, the US Food and Drug Administration (FDA) issued an emergency use authorization allowing use of remdesivir for treating adults and children hospitalized with COVID-19.
No difference in deaths, hospital stay for hydroxychloroquine
The second study, by the Randomized Evaluation of COVID-19 Therapy (RECOVERY) Collaborative Group, compared hydroxychloroquine with usual care in 1,561 hospitalized adults with coronavirus. Participant enrollment began on Mar 25 and closed on Jun 5 after a preliminary analysis showed that hydroxychloroquine was ineffective.
Of the 1,561 patients randomly assigned to receive hydroxychloroquine, 421 (27.0%) died within 28 days, compared with 790 of the 3,155 patients (25.0%) assigned to usual care (rate ratio, 1.09). The authors said the study findings suggest that patients receiving hydroxychloroquine were less likely than those in the placebo group to be released from the hospital within 28 days (59.6% vs 62.9%; rate ratio, 0.90).
Of patients not receiving mechanical ventilation at study enrollment, more patients who received hydroxychloroquine advanced to needing mechanical ventilation or dying than those who received usual care (30.7% vs 26.9%; risk ratio, 1.14). The rate of deaths due to cardiac events occurred in just 0.4 percentage points more patients in the hydroxychloroquine group than in the usual care group, but there was no difference between the two groups in incidence of new major heart rhythm abnormalities. Hydroxychloroquine treatment carries a risk of cardiovascular toxicity.
The most common underlying illnesses were diabetes (27%), heart disease (26%), and chronic lung disease (22%).
The authors concluded that hydroxychloroquine is not an effective treatment for hospitalized COVID-19 patients and that it could result in longer hospital stays and a higher risk of mechanical ventilation than usual care.
"The lower boundary of the confidence limit for the primary outcome ruled out any reasonable possibility of a meaningful mortality benefit," the authors wrote. "The results were consistent across subgroups according to age, sex, race, time since illness onset, level of respiratory support, and baseline-predicted risk."
Sponsored by the University of Oxford, the ongoing RECOVERY trial is testing several possible COVID-19 treatments at 176 hospitals in the United Kingdom. The hydroxychloroquine treatment arm, along with the corticosteroid dexamethasone and lopinavir-ritonavir arms, were stopped early after showing no benefit.
Trials of the antibiotic azithromycin, the immunosuppressive drug tocilizumab, convalescent plasma (which contains antibodies from recovered COVID-19 patients), and Regeneron's monoclonal antibody cocktail REGN-CoV2 are ongoing.
Previous studies have produced mixed results, with most finding no benefit from hydroxychloroquine. The FDA revoked its emergency use authorization for hydroxychloroquine and chloroquine in June, less than 3 months after issuing it, because it was unlikely to be effective in the treatment of COVID-19.
