United Kingdom Pauses Massive Hydroxychloroquine Trial After Finding “No Benefit” For COVID-19 Patients; The Lancet Retracts Hydroxychloroquine Paper
Electron microscope image of SARS-CoV-2, the virus that causes COVID-19

In a series of flip-flops on Friday, the United Kingdom suspended the enrollment of new patients into the hydroxychloroquine arm of its massive RECOVERY trial, one of the largest randomised COVID-19 clinical trials in the world, after preliminary data showed “no benefit” for COVID-19 patients receiving the drug.

The suspension of the trial came just a day after the academic journal The Lancet retracted a widely disseminated  observational hydroxychloroquine study that found an increased risk of mortality and cardiac problems in COVID-19 patients taking the drug, in a highly unusual move. The paper’s withdrawal was requested by three authors who had concerns about the reliability of the underlying data.

“‘We have concluded that there is no beneficial effect of hydroxychloroquine in patients hospitalised with COVID-19. We have therefore decided to stop enrolling participants to the hydroxychloroquine arm of the RECOVERY trial with immediate effect,” Peter Horby and Martin Landray, chief investigators of the RECOVERY Trial, said in a press statement released Friday.

Preliminary results from the trial showed no significant difference in the proportion of deaths in COVID-19 patients taking hydroxychloroquine compared to those who received standard care. Among 1542 patients receiving the drug, 25.7% died after 28 days, compared to 23.5% of the 3132 patients who received standard treatment.

“There was also no evidence of beneficial effects on hospital stay duration or other outcomes,” said the principal investigators. “These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalised with COVID-19.”

The full results of the trial will be released “as soon as possible,” said the researchers.

Soumya Swaminathan explains reasoning for continuing WHO hydroxychloroquine trial.

Despite the pause on the RECOVERY Trial, the World Health Organization is continuing the hydroxychloroquine arm of its multicountry Solidarity Trial, which WHO temporarily suspended last week to review preliminary mortality data. After finding no increased risk of mortality in COVID-19 patients taking hydroxychloroquine, the WHO Solidarity Trial oversight committee decided to resume the trial without altering the protocol on Wednesday, according to WHO Chief Scientist Soumya Swaminathan.

“We will continue for now,” said Swaminathan, when asked whether the new RECOVERY Trial results affected WHO’s decision.  “We will wait to see the final data analysis, and the publication that’s going to come out of it and certainly our committee will be considering these results as we go on.”

Swaminathan did note, however, that “Solidarity and RECOVERY are two of the larger trials and moreover, they have very very similar study designs.”

Addressing the confusion around whether hydroxychloroquine is harmful, beneficial, or has no effect for COVID-19 patients, WHO Health Emergencies Executive Director Mike Ryan said, “With a story of such huge public interest with 24 hour coverage of those issues, the normal process of science can sometimes appear confusing.

“It is quite normal to have slightly different results coming out from different trials, and that is why the scientific world normally wants more than one trial for any particular drug or vaccine to really confirm that what you’re seeing is actually a true effect,” added WHO COVID-19 Technical Lead Maria Van Kerkhove.

Lancet Withdraws Controversial Hydroxychloroquine Study Finding No Benefit & Increased Risk of Mortality in COVID-19 Patients

After causing an uproar in the two weeks since its release, the Lancet study was retracted at the request of three out of four of the paper’s authors, after concerns arose around the accuracy of the underlying data.

The three authors requested an independent, third-party peer review of the data collected by Surgisphere, the company that supplied the data for the original analysis.

Surgisphere, however, refused to release the full dataset for audit by an independent panel of experts, citing confidentiality and agreements with clients prevented data sharing. This occurred despite the other three authors obtaining the consent of Sapan Desai, second author on the paper and CEO of Surgisphere, for the independent review.

“As a result, we can no longer vouch for the veracity of the primary data sources,” the authors Mandeep Mehra, Frank Ruschitzka, and Amit Patel wrote in a statement published in the Lancet.

The independent review aimed to evaluate the origin of the database elements, to confirm the completeness of the database, and to replicate the analyses presented in the paper.

The WHO Director-General had referred to the study when WHO suspended its hydroxychloroquine arm of the Solidarity trial for review two weeks ago, and France rolled back recommendations for the broader use of the drug to treat severe COVID-19 patients in the wake of the study’s publication.

But soon after Lancet study was published, it drew criticism from other researchers – many of whom were concerned about the design of the analysis and the underlying data sources.

The independent review of the study was meant to address these criticisms, but could not be completed, said the three study authors who retracted the study.

“That is good science, that is doing the right thing,” Ryan said of the paper’s withdrawal at a WHO press briefing Friday. “Occasionally, when a paper is published inadvertently, and subsequently the data that supports that publication is found to be questionable or called in question, then it is the responsible thing to do for the journal to retract their paper.

“I know it sometimes can give the impression that the science community is confused or give mixed messages and for that we all collectively apologize.

“In the vast, vast majority of cases in peer reviewed journals, those papers are not retracted. It’s an incredible success rate.”

Image Credits: National Institute of Allergy and Infectious Diseases, NIH.