Hydroxychloroquine shows no benefit in RECOVERY trial

A 10-day course of the antiviral drug remdesivir was superior to placebo for shortening the time to recovery in adults hospitalized with Covid-19, according to the final report from the randomized, placebo-controlled Adaptive Covid-19 Treatment Trial (ACTT-1).

Patients who received remdesivir in the study were more likely than placebo-treated patients to show clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2-1.9, after adjustment for disease severity) and mortality at day 29 was 11.4% and 15.2% among remdesivir- and placebo-treated patients, respectively.

The final ACTT-1 findings, published Oct. 8 in New England Journal of Medicine, were consistent with preliminary study results from the trial, published in May, and they suggest that treatment with the antiviral drug may prevent the progression to more severe respiratory disease, wrote researcher John H. Beigel, MD, of the National Institute of Allergy and Infectious Diseases, and colleagues.

Based on those early findings, the FDA issued an Emergency Use Authorization (EUA) in May allowing the drug’s use in patients hospitalized with Covid-19.

In the ACTT-1 trial, patients treated with the antiviral drug had a lower rate of serious adverse events due to respiratory failure and a subset of patients who were not receiving oxygen at enrollment had a lower incidence of new oxygen use.

Treatment with the antiviral drug was also associated with fewer days on oxygen among patients receiving oxygen at enrollment and shorter duration of mechanical ventilation or ECMO among those receiving the interventions at enrollment.

In addition to the ACTT-1 final results, results from a large study evaluating the efficacy of the malaria and rheumatoid arthritis drug hydroxychloroquine were published in the same issue of NEJM.

The RECOVERY trial of Covid-19 therapies failed to show a lower incidence of death at day 28 in hospitalized patients with Covid-19 treated with hydroxychloroquine, compared to placebo.

Patients in the hydroxychloroquine arm of the study who were not on mechanical ventilation at enrollment also had a higher incidence of new mechanical ventilation compared to patients in the placebo group.

President Trump’s Covid-19 diagnosis has brought both drugs back into the national media spotlight this week.

Remdesivir is among the drugs the president is reportedly taking during his illness, along with the immune-system calming steroid dexamethasone and an experimental monoclonal antibody cocktail manufactured by Regeneron Pharmaceuticals.

He is not taking hydroxychloroquine, even though he promoted the drug for months and claimed last spring that he was taking it to prevent infection with the SARS-CoV-2 virus.

In July, the FDA warned of safety issues, including new onset heart arrhythmia, associated with the use of hydroxychloroquine for the treatment of Covid-19, and the agency revoked its EUA for use of the drug in certain hospitalized patients.

The ACTT-1 study included 1,062 patients hospitalizedwith Covid-19 exhibiting evidence of lower respiratory infection who were randomly assigned to treatment with either intravenous remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days.

Among the main study findings:

  • Remdesivir-treated patients had a median recovery time of 10 days (95% CI, 9-11 days), compared to 15 days (95% CI, 13-18 days) among placebo-treated patients (rate ratio for recovery, 1.29; 95% CI, 1.12-1.49; P<0.001).
  • Analysis involving a proportional odds model with an eight-category ordinal scale revealed that remdesivir-treated patients were more likely to show clinical improvement at day 15.
  • Kaplan-Meier estimates of mortality at day 15 were 6.7% with remdesivir and 11.9% with placebo. At day 29, 11.4% of remdesivir patients had died, compared to 15.2% of placebo-treated patients (hazard ratio, 0.73; 95% CI, 0.52-1.03).
  • Serious adverse events were reported in 131 of the 532 patients treated with remdesivir (24.6%) compared to 163 of the 516 patients treated with placebo (31.6%).
  • Remdesivir-treatment was associated with fewer days of subsequent oxygen use and shorter subsequent duration of mechanical ventilation or ECMO.

“Cumulatively, these findings suggest that treatment with remdesivir may not only reduce the disease burden but may also decrease the use of scarce health care resources during this pandemic,” the researchers wrote. “The benefit in recovery persisted when adjustment was made for glucocorticoid use, which suggests that the benefit of dexamethasone as shown in the RECOVERY trial may be additive to that of remdesivir.”

They noted that the observed benefit associated with remdesivir was greatest in patients receiving low-flow oxygen (baseline ordinal score of 5).

The newly reported findings from the hydroxychloroquine arm of the RECOVERY trial indicate that the drug “is not an effective treatment for hospitalized patients with Covid-19, but do not address its use as prophylaxis or in patients with less severe SARS-CoV-2 infection managed in the community,” wrote researcher Martin J. Landray, PhD, of the University of Oxford, UK, and colleagues.

The RECOVERY trial was designed to evaluate the efficacy of various drugs being used to treat patients hospitalized with Covid-19 and it includes patients treated at 176 hospitals in the United Kingdom.

The hydroxychloroquine analysis included 1,561 patients randomized to receive the drug and 3,155 receiving usual care without hydroxychloroquine. The primary outcome was death at 28 days.

Enrollment of patients in the hydroxychloroquine group was closed in early June after an interim analysis showed lack of efficacy associated with the drug’s use.

At 28 days, 27% of patients in the hydroxychloroquine group had died, compared to 25% of patients in the usual care group (rate ratio, 0.90; 95% CI, 0.83-0.98).

Patients treated with hydroxychloroquine not receiving mechanical ventilation at baseline were more likely than those in the usual care group to require mechanical ventilation during the study (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03-1.27).

A small excess of cardiac death (0.4 percentage points) was seen in the hydroxychloroquine group, but no difference was seen between the two groups in new-onset cardiac arrhythmia.

The RECOVERY Trial also failed to support the use of lopinavir-ritonavir in patients hospitalized with Covid-19, as previously reported by BreakingMED.

  1. A 10-day course of the antiviral drug remdesivir was superior to placebo for shortening the time to recovery in adults hospitalized with Covid-19, according to the final report from the ACTT-1 trial.
  2. No benefit was seen for treatment with hydroxychloroquine in the RECOVERY trial.

Salynn Boyles, Contributing Writer, BreakingMED™

The ACTT-1 study was funded by the National Institute of Allergy and Infectious Diseases and others.

The RECOVERY study was funded by the UK Research and Innovation, National Institute for Health Research and others.

ACTT-1 corresponding author John Beigel reported no relevant disclosures. RECOVERY corresponding researcher Martin Landray reported reports grants from UK Research and Innovation, grants from National Institute for Health Research, grants from Health Data Research UK, non-financial support from Roche, non-financial support from AbbVie, during the conduct of the study; grants from Novartis, grants from Boehringer Ingelheim, grants from Merck Sharp & Dohme, outside the submitted work.

 

Cat ID: 125

Topic ID: 79,125,521,791,932,125,190,926,192,927,151,725,928,925,934