We are still talking about hydroxychloroquine, but maybe for the last time.

On a day when the well-respected RECOVERY Study from Great Britain reported there was no significant benefit to hydroxychloroquine in hospitalized patients, a paper was published in the International Journal of Infectious Disease suggesting that there might be benefit from hydroxychloroquine and the combination of that drug with azithromycin. 

First, the results from RECOVERY, funded by the U.K. government, sought to prospectively, randomly assign large numbers of patients to multiple potential treatments in the country’s National Health Service. The goal was to rapidly get answers as to what worked and what didn’t.

A total of 1,542 patients received hydroxychloroquine, and 3,132 received usual care. After 28 days of treatment, 25.7% of those on hydroxychloroquine and 23.5% of those who received usual care had died, meaning those on hydroxychloroquine were 11% more likely to die. That difference was not statistically significant. There also was “no beneficial effect” on how long patients stayed in the hospital, or on other outcomes.

As reported in STAT news, “Today’s preliminary results from the RECOVERY trial are quite clear – hydroxychloroquine does not reduce the risk of death among hospitalized patients with this new disease,” said University of Oxford epidemiologist Martin Landray, one of the study’s leaders. “This result should change medical practice worldwide and demonstrates the importance of large, randomized trials to inform decisions about both the efficacy and the safety of treatments.”

Despite this, the announcement was in a press release and not published. The authors plan to publish the data “soon.”

In contrast, another large study seemed to come to just the opposite conclusion. The International Journal of Infectious Diseases’ study was conducted at the Henry Ford Health System in southeastern Michigan. This is a large, six hospital integrated health system; the largest of hospitals is an 802-bed quaternary academic teaching hospital in urban Detroit, Michigan.

Importantly, this study was a retrospective observational study, rather than a prospective randomized study. However, the number of patients was impressive. There were 2,541 patients, with a median hospitalization of 6 days (IQR: 4-10 days), and a median age of 64 years (IQR:53-76 years). Fifty-one percent were male, 56% African American, and they had a median time to follow-up of 28.5 days (IQR:3-53). 

In-hospital mortality was primarily caused by respiratory failure (88%), but the overall death rate was lower than in the Recovery study at 18.1% (95% CI:16.6%-19.7%). Treatment group death rates were significantly different with hydroxychloroquine+azithromycin @ 20.1%, hydroxychloroquine alone @ 13.5%, azithromycin alone @ 22.4%, and patients on neither drug 26.4%. There was no cardiac toxicity from hydroxychloroquine 

The authors state that when controlling for COVID-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality. 

The last conclusion the Henry Ford researchers make is that “prospective trials are needed to examine this drug’s impact.” They got their wish on the same day in the announcement of the Recovery study!  

Given the mishmash of hydroxychloroquine trials, without similar controls, patient criteria or endpoints, it is unlikely another study will be performed. If on final review the RECOVERY data seem definitive, it will likely be the last word given the stronger power of a prospective, controlled trial.

Overall this dichotomy also highlights the disorder currently occurring in COVID-19 drug trials. As highlighted in STAT news today, many trials are fragmented and too small to give a definitive outcome. “If the goal was to optimize the likelihood of figuring out the best treatment options, the system is off course,” said Robert Califf, the head of clinical policy and strategy at Verily Life Sciences and Google Health and a former commissioner of the Food and Drug Administration.  

The findings show, he said, that too often studies are too small to answer questions, lack real control groups, and put too much emphasis on a few potential treatments, as occurred with hydroxychloroquine.