Failing in master protocol casts fresh doubt on hydroxychloroquine even as WHO restarts trial

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Capping a fortnight’s worth of roller-coastering hydroxychloroquine news, a June 4 interim analysis of the University of Oxford’s RECOVERY study found that the malaria drug failed to benefit hospitalized COVID-19 patients. It is the most definitive readout of hydroxychloroquine in the indication to date.

Based on the review of the unblinded data, the investigators said Friday that they immediately stopped enrollment in RECOVERY’s hydroxychloroquine arm.

The change comes two days after WHO announced it had resumed testing in SOLIDARITY’s hydroxychloroquine arm. It had cited an association between the malaria drug and increased mortality reported in a May 22 Lancet article when it paused hydroxychloroquine evaluation on May 25 (see “WHO Restarts Hydroxychloroquine Testing”).

The journal published an Expression of Concern on Wednesday and retracted the paper the next day because the authors had failed to complete an independent audit of the study’s underlying raw data and could not “validate the primary data sources underlying” the conclusions.

Unlike the study in The Lancet, which was an observational analysis, RECOVERY is a large randomized, controlled study and one of three master protocol trials for COVID-19 that the U.K. has designated as a national priority (see “U.K. Sets the Bar for COVID-19 Master Protocols”).

Among 1,542 patients treated with hydroxychloroquine in RECOVERY, the 28-day mortality rate was 25.7% vs. 23.5% in the 3,132 patients who received standard of care (HR=1.11; 95% CI: 0.98,1.26; p=0.1). On other measures of clinical benefit including hospitalization duration, the researchers found no evidence of hydroxychloroquine efficacy.

In a statement, RECOVERY chief investigator Peter Horby and deputy chief investigator Martin Landray wrote, “These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalised with COVID-19.” Both are professors at Oxford.

Also on Thursday, The New England Journal of Medicine retracted a paper on hydroxychloroquine from the same group behind the study in The Lancet. The NEJM article had reported no significant association between COVID-19 mortality and pre-existing treatment with ACE inhibitors or angiotensin receptor blockers.

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