WHO Pauses Hydroxychloroquine Arm Of COVID-19 Clinical Trial – After Lancet Study Finds Higher Mortality Rate Among Patients Getting The Drug

This story was updated 4 June to reflect the Lancet study’s retraction.

WHO Chief Scientist Soumya Swaminathan provides reasoning behind pausing hydroxychloroquine arm of the Solidarity Trial.

Enrollment of new patients in the hydroxychloroquine (HCQ) arm of the World Health Organization’s Global COVID-19 Solidarity Trial will be put on pause, as the trial’s oversight committee reviews all available data on COVID-19 and hydroxychloroquine, WHO Director-General Dr. Tedros Adhanom Ghebreyesus said on Monday.

The WHO decision on Saturday came just a day after a major observational study published in The Lancet found a higher mortality rate in COVID-19 patients who have received hydroxochloroquine, chloroquine, or a combination of either drug and azithromycin, as compared to COVID-19 patients who did not receive any treatments.

The Lancet paper was later retracted on 4 June by three of the authors due to concerns about the “veracity of the primary data sources.”

“The executive group [composed of experts from 10 countries involved in the trial] has implemented a temporary pause of the hydroxychloroquine arm within the Solidarity trial,” said Dr Tedros speaking at a WHO press conference. “The group has agreed to review a comprehensive analysis and critical reappraisal of all evidence available globally. The review will consider data collected so far in the Solidarity trial, and important, robust randomized available data to evaluate the potential benefits and harms from this drug.”

WHO Experts Clarify Reasoning Behind Hydroxycholoroquine Arm Suspension

Still, WHO experts said that mortality conclusions could not be definitively drawn from an observational study, such as the one reported by The Lancet. WHO’s Chief scientist Soumya Swaminathan acknowledged that unlike randomized controlled trials such as the one WHO is conducting observational studies can yield misleading results.

“We know that the evidence from observational studies, however large they may be, is still subject to inherent bias. What’s really important is to have well-conducted randomised control studies, done in large numbers,” said WHO Chief Scientist Soumya Swaminathan, also speaking at the press briefing.

WHO Emergencies head Mike Ryan also underlined that WHO’s decision to suspend the hydroxychloroquine arm of the WHO Solidarity Trial was not due to any negative preliminary results that had already been flagged in the ongoing WHO study.

Rather, the decision was a “proactive” one made to “err on the side of caution,” said Swaminathan.

“There were also a lot of questions coming from our own principal investigators in countries, and we knew that the regulatory agencies in many countries were also discussing these data…So the steering committee decided that in the light of this uncertainty that we should be proactive, err on the side of caution and suspend enrollment temporarily into the hydroxychloroquine arm,” she told reporters.

As one part of the review, the trial’s independent data safety monitoring board will be analyzing data collected so far to see if there are any “signals” that the drug is failing, and send them to the trial’s advisory committee for further review, said WHO Health Emergencies Executive Director Mike Ryan.

“We will expect that if there is no signal of failing, and we don’t have any problems, we will try to use the drug,” said Ryan.

Dr Tedros highlighted that hydroxychloroquine, which has been widely approved for use for malaria and the autoimmune disease Lupus, is still safe to use in patients with those diseases.

Researchers Criticise The Lancet Study Design
Analysis of HCQ studies finds that randomised control studies (green) are more likely to find the drug has a positive effect on COVID-19, compared to observational studies (red)
(Credit: Didier Raoult et al.)

Other researchers have also criticised The Lancet study’s design. While the study had analyzed a large body of data from 671 hospitals in 6 continents, there could still be bias in the analysis that is obscuring the true effects of the drug.

In smaller RCTs for example, positive results for hydroxychloroquine had been found. Treatment failure had so far mainly been identified only in observational studies, according to an analysis by Didier Raoult, director of the Marseille University Hospital Institute for Infectious Diseases ( IHU Méditerranée Infection).

One major critique is that The Lancet study does not adequately adjust for the fact that many of the patients in the study are more likely to be severely ill, and are already at increased risk of death.

Critics contend that The Lancet study primarily observes patients experiencing more severe disease who began receiving HCQ later in disease progression, while the drug has shown promise when given earlier or used as a preventative treatment. For example, India now recommends the prophylactic use of hydroxycholoroquine to protect against COVID-19 infection in all healthcare and frontline workers, following results from a small observation trial that found the likelihood of infection was lower in those who took the drug.

“Another poorly designed interpretation of a hydroxychloroquine data set for COVID-19. A larger poorly designed “trial” only leads to larger erroneous conclusions,” tweeted Steven Phillips, a Yale-educated internal medicine doctor who specializes in zoonotic infectious diseases.

About two-thirds of the patients in The Lancet study were from North America, where delays in testing mean that patients aren’t identified until 5 to 7 days after they begin showing symptoms, says Phillips.

“HCQ early COVID-19 treatment isn’t embraced in the US. It’s given only to the sickest patients, without contrary evidence in this study. To state that the baseline disease severity between treatment & control is equal was incorrect,” he added.

For example, one measure used in The Lancet study to determine baseline disease severity is the “quick sequential organ failure assessment”(qSOFA) score. There is little difference between qSOFA scores across different disease severities, so the score is “proving a bad stratifier for COVID,” tweeted antimalarial pharmacology researcher James Watson, a lead scientist at the Mahidol Oxford Tropical Medicine Research Unit (MORU).

“So a quick conclusion is that they have just inadequately adjusted for disease severity, which is driving the treatment allocation [of HCQ or no HCQ],” added Watson.

“I agree with one thing the authors said: ‘Randomized clinical trials will be required before any conclusion can be reached regarding benefit or harm of these agents in COVID-19 patients,'” Phillips tweeted in conclusion.

Image Credits: Matthieu Million, Yanis Roussel, Didier Raoult.