Therapeutic Application of Chloroquine in Clinical Trials for COVID-19

Divya RSJB Rana; Santosh Dulal

is the (which was not peer-reviewed) The copyright holder for this preprint . hydroxychloroquine in COVID-19 patients. A non-randomized open-label clinical trial in France that enrolled hospitalized COVID-19 patients to the hydroxychloroquine (20 patients) and control arms (16 patients) concluded a positive effect of hydroxychloroquine or hydroxychloroquine plus azithromycin based on viral negativity at day 6 (15) . Patients who didn't consent for hydroxychloroquine, had exclusion criteria (allergy to hydroxychloroquine, retinopathy, G6PD deficiency, QT prolongation and breast feeding/pregnacy) and were admitted to hospitals not using hydroxychloroquine, were grouped in the controlled arm. Six patients in the case arm also received azithromycin to prevent bacterial superinfection. Though the study had small sample size, was not randomized and didn't carry an intention-to-treat analysis, it concluded positive effects for hydroxychloroquine arm in spite of lesser proportion of "asymptomatic" patients (10% in hydroxychloroquine arm vs. 25% in control arm) and higher average age (51.2 years in hydroxychloroquine arm vs 37.3 years in control arm) in the intervention arm. Moreover, a secondary analysis (16) covering up for the weak statistical analyses by original authors found the azithromycin and hydroxychloroquine combination are was better compared to the control arm. Another study carried an open label randomized clinical trial in 30 Chinese COVID-19 patients treated with either hydroxychloroquine (15 patients) or conventional methods (15 patients) (17) . The study concluded no apparent benefit of hydroxychloroquine treatment compared to conventional treatment (86.7% treatment arm vs 93.3% control arm had negative viral conversion on day 7, p>0.05). But the authors reported using interferon alfa in all of the patients and 80% patients in each arm were treated with other antiviral therapies. Moreover, the authors cautioned the high recovery rate in control arm due to enrollment of mild cases could impact the comparison of efficacy of treatment arm. The third published study (as a preprint at the time of writing this manuscript) from the Renmin Hospital of Wuhan University, Wuhan, China, (ChiCTR2000029559) claimed to find an positive effect of hydroxychloroquine in a double-blind randomized control design. 80.6% (25/31) patients in the treatment arm (400 mg hydroxychloroquine/day for 5 days) had improved pneumonia compared to 54.8% (17/31) in the control arms, along with other better outcome measures in the treatment arm (18) . Patients in both of the arms were reported to have been treated with other antivirals and antibiotics. A recent review found the inclusion of chloroquine/hydroxychloroquine based therapy in the national guidelines of China, Korea, Netherlands, Italy, Canada and Belgium (19) . More recently, the US Food and Drug Administration has allowed an emergency use authorization for these drugs against COVID-19 when used by a valid health care provider (20) .