Recruitment for most trials of HCQ prophylaxis was severely impeded by incorrect interpretations of the evidence from the early, mostly post-exposure prophylaxis, trials. The findings from the first reported trials were widely (and incorrectly) portrayed as definite evidence of the lack of effectiveness of HCQ, simply because they were not “statistically significant” when taken individually. Thus, the common confusion between the concepts “no effect” and “no statistical significance” led many to prematurely conclude that HCQ had no prophylactic effect when the correct conclusion was that the effect estimate was too imprecise.

Concerns about potentially deleterious effects of treatment with HCQ and backslash against unsubstantiated claims in the lay media may have also affected the timely completion of the prophylaxis trials.

In one study, conversations with investigators in participating hospitals confirmed that recruitment was difficult because of toxicity concerns. Of four eligible trials labelled as “completed” or “terminated” in clinicaltrials.gov but without posted results, at least one had to be terminated because of poor recruitment, and another was closed after recruitment of one patient because researchers considered that the risk/benefit balance of HCQ was unfavorable.

Yet these safety concerns were unwarranted as demonstrated by the findings of the randomized trials included in our meta-analysis.