Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial

Abstract

Objectives: To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk of worsening. Methods: We conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: need for supplemental oxygen, age 75 years, age between 60 and 74 years and presence of at least one co-morbidity. Severely ill patients requiring oxygen therapy >3 L/min or intensive care were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800 mg hydroxychloroquine on day 0 followed by 400 mg per day for 8 days or a placebo. The primary end point was a composite of death or start of invasive mechanical ventilation within 14 days following randomization. Secondary end points included mortality and clinical evolution at days 14 and 28, and viral shedding at days 5 and 10. Results: The trial was stopped after 250 patients were included because of a slowing down of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years (interquartile range 58 e86 years) and 151/250 (60.4%) patients required oxygen therapy. The primary end point occurred in 9/ 124 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group

Efficacy and Safety of Hydroxychloroquine for Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis

“…Our comprehensive search yielded 9378 citations with an additional 927 citations identified through other sources, including backwards citation tracking. After removing duplicates and applying our inclusion and exclusion criteria ( Figure 1 ), we identified thirteen RCTs ( n = 18,540) [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

“…All RCTs included adult populations. Placebo was the comparator in three RCTs (Self et al [ 24 ], Dubee et al [ 25 ], Ulrich et al [ 28 ]) while usual care was the comparator in the other RCTs. The total dose of hydroxychloroquine in the RCTs varied between 2000 and 12,400 mg with follow up times between 5 and 30 days.…”

“…Seven RCTs [ 16 , 17 , 22 , 24 , 26 , 27 , 28 ] had some concerns of bias, three due to the randomization process, [ 16 , 24 , 28 ] one due to randomization and deviation from intended interventions [ 26 ], two due to deviations from intended target, [ 22 , 27 ] and one due to selection of the reported results. [ 17 ] Two RCTs had low risk of bias in all categories [ 21 , 25 ] ( Figure 2 ).…”

“…In comparison to the control group, HCQ non-significantly increased all-cause mortality by 7% (RR 1.07, 95%CI 0.92–1.25, I 2 = 0%, Figure 3 ) at day 14 in seven RCTs [ 16 , 20 , 22 , 24 , 25 , 27 , 28 ] and by 8% (RR 1.08, 95%CI 1.00–1.16, I 2 = 0%, Figure 4 ) at day 30 in seven RCTs [ 19 , 21 , 23 , 24 , 25 , 27 , 28 ]. HCQ did not impact the need for mechanical ventilation at 14 or 30 days ( Supplementary Figures S1 and S2 ), high-flow nasal cannula or non-invasive ventilation at 14 days ( Supplementary Figure S3 ), need for ICU admission ( Supplementary Figure S4 ) and need of oxygen support at 14 days ( Supplementary Figure S5 ) in comparison to the control group.…”

“…HCQ non-significantly increased the composite endpoint of clinical recovery by 26% in two RCTs [ 23 , 25 ] but with high heterogeneity (RR 1.26, 95%CI 0.87–1.83, I 2 = 76%, Supplementary Figure S6 ) while HCQ also significantly increased the composite endpoint of clinical worsening by 14% in two RCTs [ 21 , 25 ] with no noted heterogeneity (RR 1.14, 95%CI 1.11–1.18, I 2 = 0%, Supplementary Figure S7 ).…”