Hydroxychloroquine sulphate (Plaquenil) an analog of chloroquine has an established track record for treating malaria and has demonstrated in vitro activity against the SARS-CoV and therefore being considered as possible treatment for COVID-19. Recently, findings from a just-released manuscript by Gautret et al. (2020)1 summarizing findings from an ongoing study to evaluate hydroxychloroquine in patients with COVID-19 made news. The aim of this perspective is to summarize the study design, main results and to highlight limitations. Note that there is a wealth of information on the known toxicity associated with hydroxychloroquine and chloroquine, which are not covered in this perspective.
The study by Gautret and colleagues is an ongoing, single arm, non-randomized coordinated by The Mediterranee Infection University Hospital Institute in Marseille in response to the current COVID-19 pandemic. Patients enrolled in the study were recruited and managed in Marseille; however, non-randomized controls (described below) were obtained from centers located in Marseille, Nice and elsewhere in Southern France. Patients hospitalized with COVID-19, at least 12 years of age with PCR confirmed SARS-CoV-2 carriage from a nasopharyngeal sample at time of hospital admission were eligible to participate. Having a certain level of disease severity was not an enrollment criterion. Pregnant or breastfeeding women, persons with known allergy to hydroxychloroquine or chloroquine, known G6PD deficiency or QT prolongation were ineligible. The main study outcome is virological clearance on day 6 post-enrollment. Secondary outcomes (not reported in this paper) include virological clearance over the entire observation period, clinical measures including body temperature, length of hospitalization, mortality and respiratory rate and adverse effects. Study assessments occur daily for up to 14 days. Patients providing informed consent and enrolling in the study received hydroxychloroquine sulfate at a dose of 200 mg three time daily for ten days. Patients refusing treatment or had an exclusion criterion serve as controls for purposes of the analyses presented in this manuscript.
The authors present findings from 26 patients enrolled to study and received hydroxychloroquine and 16 non-randomized controls who did not receive hydroxychloroquine. Among the 26 patients enrolled to receive hydroxychloroquine; 6 were reported by the authors as lost to follow-up during the study for the following reasons: three patients were transferred to an intensive care unit on days 2, 3, and 4 respectively all being PCR positive prior to transfer; one patient who was reportedly PCR negative on day 2 died on day 3; one patient who was PCR negative on days 1-2 left the hospital on day 3; and one patient prematurely discontinued treatment on day 3 due to nausea and was PCR positive up until discontinuation. Compared to the non-randomized controls, the patients treated with hydroxychloroquine patients were, on average, older with a reported mean age of 51 (+/- 19) years vs. 37 years (+/- 24). Forty-five percent of hydroxychloroquine-treated patients were males compared to 37.5% male in the non-randomized control. Reported time between symptom onset and study inclusion was 4.1 (+/- 2.6) days in the 20 hydroxychloroquine-treated patients. The authors report a mean onset time of 3.9 (+/-2.8) in the non-randomized control but it is unclear how this was determined since these patients were not enrolled into the study. In addition, time was missing in 37.5% (6/16) of the non-randomized controls and in 10% (2/20) hydroxychloroquine patients, therefore creating uncertainty as to if the groups were similar in time since symptom onset.
The authors report that on day 6, the proportion of hydroxychloroquine-treated patients with a negative PCR was 70% (14/20) compared to 12.5% (2/16) in the non-randomized control group. In the subset of hydroxychloroquine-treated patients who also received azithromycin, the proportion with negative PCR on day 6 was 100% (6/6).
The fundamental weakness of this study is the lack of randomization to treatment, which not only balances groups with respect to measured and unmeasured pre-treatment demographics and other characteristics, but also ensures randomness in treatment assignment. In the absence of randomization, bias associated with treatment assignment is present distorting the repor...
(All Rights Reserved)