Do We Still Need More Randomized Trials for Hydroxychloroquine?

A series of randomized trials of hydroxychloroquine (HCQ) have indicated that it doesn’t work against COVID-19 as a single agent or with antibiotics (1, 2, 3, 4, 5, 6,and 7). HCQ proponents have criticized these trials putting forward many arguments. Two of the main arguments are that the doses were too high and that HCQ was not administered with zinc. In response to that, HCQ skeptics like me have argued that we should then wait for the results of randomized trials of lower doses of HCQ or HCQ with zinc. Some (but not all) HCQ proponents reply to this by stating that randomized trials are not necessary because numerous observational (non-randomized trials) have shown that HCQ works. When it is pointed out to them that these observational trials have the potential to be biased due to their non-randomized nature, these HCQ proponents reply that randomized trials have shortcomings too, and that the observational trials that have been performed are all the evidence we need.

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So how do we resolve this argument? It occurred to me that I would look at some of the observational trials that HCQ proponents defend, and see what the authors of these trials have to say about the matter. Here are their comments:
 
Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19
This is the controversial Henry Ford study. The authors state that: “Our results also require further confirmation in prospective, randomized controlled trials that rigorously evaluate the safety and efficacy of hydroxychloroquine therapy for COVID-19 in hospitalized patients.”
 
COVID-19 outpatients – early risk-stratified treatment with zinc plus low dose hydroxychloroquine and azithromycin: a retrospective case series study  (Click on Get pdf)
This is the study by the controversial HCQ apologist Vladimir Zelenko. He and his coauthors state that one of the limitations of their study is that it is a: “Retrospective case series study with findings that have to be validated in prospective controlled clinical trials.”
 
Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide observational study of 8075 participants
This is the large nationwide study from Belgium. The authors state that: “Although observational studies, even of large scale, do not provide final conclusions on treatment efficacy, their results are important to consider in order to guide clinical trials. Well-designed prospective studies combined with large, randomised control trials should provide definitive evidence about the clinical impact of HCQ in severe hospitalised and in mild ambulatory COVID-19 patients.”
 
Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study
This is the large study from Italy. The authors state that: “Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19.”
 
The Effect of Early Hydroxychloroquine-based Therapy in COVID-19 Patients in Ambulatory Care Settings: A Nationwide Prospective Cohort Study
This is a large study from Saudi Arabia. The authors state that: “Additional large randomised controlled trials are recommended to further support this conclusion, particularly in older populations.”
 
Effect of combination therapy of hydroxychloroquine and azithromycin on mortality in COVID-19 patients
This is a smaller study from Italy. The authors state that: “There are also several limitations to acknowledge. A first limitation relates to the study design, as we performed a single-center observational study, which does not allow to completely correct for confounders. Only a randomized double-blind clinical trial would provide more solid evidence.”
 
Risk Factors for Mortality in Patients with COVID-19 in New York City
This is a New York study involving several hospitals and ambulatory practices. The authors state that: “Due to the inherent limitations of our retrospective study design, there was no conclusive determination on the efficacy of hydroxychloroquine in patients with COVID-19. More robust studies such as randomized clinical trials are needed.”
 
​Effectiveness of hydroxychloroquine in COVID-19 disease: A done and dusted deal?
Another study from Italy. The authors state that:
“…we believe that hydroxychloroquine should be further tested in randomised trials. When best to start treatment is also a question that needs to be addressed in ad-hoc randomized studies.”

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So the authors of all the above observational studies often cited by some HCQ proponents as definite proof that HCQ works and that we don’t need randomized trials, acknowledge the need for randomized trials or accept that randomized trials would provide more robust confirmatory information. And how couldn’t they? The randomized trial is the gold standard of clinical medicine. The majority of scientists and doctors know and accept this. And in case you are wondering, the observational studies that yielded a negative result for HCQ also make the same kind of statements (for example: A, B, C, D, E, and F).
 
The majority of the authors of the studies mentioned above are not “for” or “against” HCQ. They just wanted to find if the drug worked, and they did what they could with what they had during the difficult setting of a pandemic. I respect that, but as they acknowledge (and I have repeatedly pointed out in my blog), to firmly establish or confirm that HCQ works in a given treatment modality or dosage, we need the randomized trials.
 
Clinical trials image from pixabay by mcmurryjulie is free for commercial use.
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