Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

Abstract

Objective: To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19).

Design: Multicentre, open label, randomised controlled trial.

Setting: 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020.

Participants: 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone).

Interventions: Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively).

Main outcome measure: Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone.

Results: Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval -10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events.

Conclusions: Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients.

Trial registration: ChiCTR2000029868.

Fig 1

Screening, randomisation, and follow-up of trial participants

Fig 2

Kaplan-Meier curves of time to negative conversion of SARS-CoV-2 on real time reverse transcription polymerase chain reaction (RT-PCR) test in standard of care (SOC) plus hydroxychloroquine (HCQ) versus SOC in intention to treat population. Data are shown for 75 patients assigned to SOC plus HCQ and 75 assigned to SOC. Overall probability of negative conversion by 28 days was 85.4% (95% CI 73.8% to 93.8%) in SOC plus HCQ group and 81.3% (71.2% to 89.6%) in SOC group (P=0.34). Difference between groups was 4.1% (95% CI –10.3% to 18.5%). Median time to negative conversion was 8 (95% CI 5 to 10) days in SOC plus HCQ group and 7 (5 to 8) days SOC group (hazard ratio 0.85, 95% CI 0.58 to 1.23; P=0.34 by log rank test). Data from patients who did not have negative conversion were censored (tick marks) at last visit date

Fig 3

Kaplan-Meier curves of time to alleviation of clinical symptoms with standard of care (SOC) plus hydroxychloroquine (HCQ) versus SOC alone in intention to treat population. Data shown are for 55 patients with symptoms assigned to SOC plus HCQ and 64 assigned to SOC. Probability of alleviation of symptoms by 28 days was similar (P=0.97) in patients with SOC with (59.9%, 95% confidence interval 45.0% to 75.3%) and without HCQ (66.6%, 39.5% to 90.9%). Difference between groups was –6.6% (95% CI –41.3% to 28.0%). Median time to alleviation of clinical symptoms was similar in SOC plus HCQ group and SOC group (19 v 21 days; hazard ratio 1.01, 95% confidence interval 0.59 to 1.74; P=0.97 by log rank test). Data from patients who did not have alleviation of symptoms were censored (tick marks) at last visit date