QPROTECT 01 Sept 2020
Description
Hydroxychloroquine (HC) ± azithromycin (AZ) is widely used for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its disease Covid-19. The Qatar Prospective RCT of Expediting Coronavirus Tapering (Q-PROTECT) aimed to assess virologic cure rates of HC±AZ in cases of low-acuity SARS-CoV-2 infection. It is not the case that virologic cure is more important than clinical outcomes, but Q-PROTECT’s laboratory-assessed endpoints fill a gap in the blinded-RCT Covid-19 evidence base. Specifically, a blinded RCT could inform national decisions on utility of HC±AZ to expedite viral clearance and thus reduce transmission. Q-PROTECT employed a prospective, placebo-controlled design with blinded randomization to three parallel arms: placebo, oral HC (600 mg daily for one week), or oral HC plus oral AZ (500 mg day one, 250 mg daily on days two through five). At enrollment, subjects had mild or no symptoms and were within a day of testing positive for SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (PCR). For all PCR testing, the primary endpoint of day six virologic cure (as well as the secondary endpoint of day 14 cure) was defined as being met if the machine’s cycle threshold (Ct) interpretation algorithm reported a result of negative. For subjects who did not achieve day six virologic cure, the semi-quantitative secondary endpoint of Ct increase (i.e. drop in viral load) was assessed. Restriction of semi-quantitative endpoint assessment to non-cured subjects was necessary due to the non-reporting of a Ct for cured subjects (PCR assay did not extend beyond Ct of 40). After six days, intent-to-treat (ITT) analysis of the primary dichotomous endpoint of virologic cure was assessed using binomial exact 95% confidence intervals (CIs) and χ2 testing. (ClinicalTrials.gov NCT04349592, trial status closed to new participants.) The study enrolled 456 subjects (152 in each of three groups: HC+AZ, HC, placebo) between 13 April and 1 August 2020. Day six PCR results were available for all 152 HC+AZ subjects, 149/152 (98·0%) HC subjects, and 147/152 (96·7%) placebo subjects. ITT analysis of subjects with day six PCR results found no difference (p = 0·821) in groups’ proportions achieving virologic cure: HC+AZ 16/152 (10·5%, 95% CI 6·1-16·5%), HC 19/149 (12·8%, 95% CI 7·9-19·2%), placebo 18/147 (12·2%, 95% CI 7·4-18·7%). The day 14 cure assessment also showed no association (p = 0·072) between study group and viral cure: HC+AZ 30/149 (20·1%, 95% CI 14·0-27·5%), HC 42/146 (28·8%, 95% CI 21·6-36·8%), placebo 45/143 (31·5%, 95% CI 24·0-39·8%). There were no serious adverse events. The investigators conclude that HC±AZ shows no sign of usefulness in the population studied, and that there is low likelihood of undiscovered drug benefits outweighing therapeutic risks.