Limitations and Strengths of the First Clinical Trial of Hydroxychloroquine to Prevent COVID-19 Disease

[Authors: Clara Pons y Elena Marbán, predoctoral researchers at ISGlobal]

In recent weeks, hydroxychloroquine (HCQ) has been the focus of various studies published in the scientific literature concerning SARS-CoV-2 infection and COVID-19 disease. For more than 25 years, HCQ has been used to treat and prevent specific diseases such as systemic lupus erythematosus and rheumatoid arthritis, even in pregnant women. This fact, together with in vitro evidence of its antiviral action against SARS-CoV and SARS-CoV-2, has profiled hydroxychloroquine as a candidate drug to assess its efficacy in the treatment and prevention of SARS-CoV-2.

The publication of an observational study in The Lancet, in which the authors used data from a questionable source, suggesting that HCQ and chloroquine are associated with higher in-hospital mortality of COVID-19 patients, created controversy in the scientific and general media, which led the authors of this study to retract this study in The Lancet itself.

More recently, on 3 June, the results of the first clinical trial on the efficacy of HCQ to prevent postexposure to the SARS-CoV-2 virus were published. This article, published in The New England Journal of Medicine, is the first quality scientific evidence for the medical community concerning the efficacy of HCQ to prevent COVID-19 disease. Its results show that HCQ does not prevent symptoms compatible with COVID-19 following high-risk exposures to the disease.

The results of the first clinical trial on the efficacy of hydroxychloroquine against COVID-19 have been published in The New England Journal of Medicine: It shows that HCQ does not prevent symptoms compatible with COVID-19 following high-risk exposures to the disease

This study, performed in the United States and Canada, is a randomised, double-blind, placebo-controlled trial, so its results do not, a priori, suffer from the major biases associated with other study designs. In addition, the strategy the study team followed to recruit and monitor the participants, which was performed remotely through the internet, made it possible to obtain the results within a relatively short period of time after the start of the pandemic. However, in spite of these strengths, the study is not exempt from limitations that must be taken into account when drawing conclusions.

Firstly, the scarcity of PCR tests to detect SARS-CoV-2 infection in the United States led the study team to change the definition from a PCR-confirmed case to having an illness compatible with COVID-19. A team of external experts reviewed the symptoms reported by each participant to decide whether or not they were clinically compatible with the disease. This may lead to a diagnostic bias since just over 20% of the cases were PCR-confirmed. Therefore, one cannot rule out the symptoms being due to other aetiologies in a large number of participants.

The authors mention this limitation in the article, as well as the fact that it was offset by randomisation, which would cause the same proportion of diagnostic errors to be shared between the two parts of the study. However, this will have affected the statistical power of the study by requiring a sample size that would probably have to be far larger in order to assess the study’s main objective. This makes the study unable to confirm the efficacy of HCQ to prevent asymptomatic or mild infections. Moreover, the predictive power of the definition of a case based on an illness compatible with COVID-19 used in the United States has not been proven, specifically due to the unavailability of PCR tests.

The study is not exempt from limitations. Firstly, the scarcity of PCR tests to detect SARS-CoV-2 infection in the United States led the study team to change the definition from a PCR-confirmed case to having an illness compatible with COVID-19

Another major limitation of the clinical trial by Boulware et al is monitoring of the participants through the internet, which makes the results less precise. The participants reported the symptoms they presented through internet surveys; they never had contact with healthcare professionals to assess their condition and confirm their symptoms. The efficacy data are therefore based on the participants’ perceptions and present a major information bias due to potential misclassification of the subjects.

Moreover, the study does not rule out the possibility of HCQ being effective in populations at high risk of contracting COVID-19 disease, since the study population was exclusively made up of young, healthy subjects. Hence, these findings would not be applicable to other populations such as immunosuppressed patients, hospitalised patients and pregnant women, for example.

The efficacy data are therefore based on the participants’ perceptions and present a major information bias due to potential misclassification of the subjects

Finally, in spite of it not strictly being a limitation of this clinical trial, the HCQ dose used as a treatment and its duration is very different from that used in other clinical trials currently underway. The study team opted for a loading dose of 800 mg of HCQ followed by 600 mg in 6 to 8 hours, then a maintenance dose of 600 mg daily for four additional days. This study does not rule out that a strategy with a lower daily dose but with a longer duration may be effective in preventing the transmission of the infection and the progression of the disease.

In spite of the major step taken by publication of this clinical trial, the aforementioned limitations in its execution mean that the results are not conclusive in determining whether or not HCQ is effective in the prevention and treatment of SARS-CoV-2 infection. In order to decide this, we must await the results of further well-designed and well-executed studies to guide decision-making concerning the use of HCQ in this pandemic with the greatest possible scientific robustness. Therefore, we conclude that HCQ must be used in the research environment until firm conclusions are obtained concerning its efficacy and safety in all possible contexts.