Hydroxychloroquine alone or in combination with azithromycin to prevent major clinical events in hospitalised patients with coronavirus infection (COVID-19): rationale and design of a randomised, controlled clinical trial

IntroductionHydroxychloroquine and its combination with azithromycin have been suggested to improve viral clearance in patients with COVID-19, but its effect on clinical outcomes remains uncertain. Methods and analysisWe describe the rationale and design of an open-label pragmatic multicentre randomised (concealed) clinical trial of 7 days of hydroxychloroquine (400 mg BID) plus azithromycin (500 mg once daily), hydroxychloroquine 400 mg BID, or standard of care for moderately severe hospitalised patients with suspected or confirmed COVID-19 (in-patients with up to 4L/minute oxygen supply through nasal catheter). Patients are randomised in around 50 recruiting sites and we plan to enrol 630 patients with COVID-19. The primary endpoint is a 7-level ordinal scale measured at 15-days: 1)not hospitalised, without limitations on activities; 2)not hospitalised, with limitations on activities; 3)hospitalised, not using supplementary oxygen; 4)hospitalised, using supplementary oxygen; 5)hospitalised, using high-flow nasal cannula or non-invasive ventilation; 6)hospitalised, on mechanical ventilation; 7)death. Secondary endpoints are the ordinal scale at 7 days, need for mechanical ventilation and rescue therapies during 15 days, need of high-flow nasal cannula or non-invasive ventilation during 15 days, length of hospital stay, in-hospital mortality, thromboembolic events, occurrence of acute kidney injury, and number of days free of respiratory support at 15 days. Secondary safety outcomes include prolongation of QT interval on electrocardiogram, ventricular arrhythmias, and liver toxicity. The main analysis will consider all patients with confirmed COVID-19 in the groups they were randomly assigned. Ethics and disseminationThis study has been approved by Brazils National Ethic Committee (CONEP) and National Health Surveillance Agency (ANVISA). An independent data monitoring committee will perform interim analyses and evaluate adverse events throughout the trial. Results will be submitted for publication after enrolment and follow-up are complete, as well as presented and reported to local health agencies. ClinicalTrials.gov identifierNCT04322123 O_LSTStrengths and limitations of this studyC_LSTO_LIPragmatic randomised controlled trial of 7 days of hydroxychloroquine plus azithromycin, hydroxychloroquine or standard of care for moderately severe in-patients with suspected or confirmed COVID-19 C_LIO_LIMulticentre: around 50 recruiting sites in Brazil with planned enrolment of 630 patients (1:1:1) C_LIO_LIThe primary endpoint is a 7-level ordinal scale ([1] not hospitalised, without limitations on activities; [2] not hospitalised, with limitations on activities; [3] hospitalised, not using supplementary oxygen; [4] hospitalised, using supplementary oxygen; [5] hospitalised, using high-flow nasal cannula or non-invasive ventilation; [6] hospitalised, on mechanical ventilation; [7] death) measured at 15 days. C_LIO_LIOpen label design (no placebo) C_LI