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Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

Trial Design and Oversight

We tested this three-group in 55 hospitals in Brazil. The test was designed by the executive committee (see Supplementary Addendum, Is available with the full text of this article at and approved by the Brazilian National Health Research Commission, the Brazilian Health Regulatory Agency (ANVISA), and ethical committees at participating sites. The trial was funded by participating hospitals and research institutes in the coalition Kovid-19 Brazil (see) Supplementary Addendum). EMS Pharma provided additional funding and logistic support for the trial and also donated and supplied test drugs. EMS Pharma had no role in the decision to conduct the trial, analyze or submit the manuscript for publication. The test was overseen by an independent international data and security monitoring committee. The Executive Committee pledges for the completeness and accuracy of the data and for the integrity of the lawsuit Make a contract (Available at

The participants

We enrolled patients who were either actively screened by the test team or referred to us who were 18 years of age or older and suspected or confirmed 14 or fewer days after symptom onset. Was hospitalized with Kovid-19. Reasons for exclusion from the test included the use of supplemental oxygen at a rate of more than 4 liters per minute at a level of at least 40% administered by a canker cannula or by a venturi mask; Use of supplemental oxygen administered by high-flow nasal cannula or by invasive or noninvasive ventilation; And history of severe ventricular tachycardia or electrocardiographic findings with a corrected QT interval (QTc) of at least 480 msec. Complete information is provided on the inclusion and exclusion criteria, including criteria regarding previous use of hydroxychloroquine or azithromycin. Supplementary Addendum. All patients were provided with written or electronic informed consent prior to randomization.

Randomization, intervention, and follow-up

Patients randomly receive standard care (control group) in a 1: 1: 1 ratio, twice daily for 7 days (hydroxychloroquine-alone group) at a dose of 400 mg to receive standard care plus hydroxychloroquine, or standard care plus Hydroxychloroquine was assigned in aq. Azithromycin twice daily dose of 400 mg at a dose of 500 mg once a day for 7 days. Randomization was performed in blocks of six and stratified according to the use or non-use of supplemental oxygen at the time of randomization. Randomization was performed centrally through an electronic case-report form system (RedCap), as described Supplementary Addendum.12

The current standard of care for Kovid-19 was at the discretion of the treating physicians. The use of glucocorticoids, other immunomodulators, antibiotic agents, and antiviral agents were permitted (see) Supplementary Addendum). Investigators were provided with guidance on how to adjust or interrupt treatment according to side effects and laboratory abnormalities.

In electronic case-report form, data were collected from randomization to day 15. For those patients who were discharged before day 15, a structured telephone call to the patient or patient’s family was conducted on 15 or after by an interviewer to assess the critical situation and return to routine activities Was unaware of the assigned test group.


The primary outcome was a clinical condition at 15 days, assessed with the use of a seven-tier ordinal scale. Scores on the scale were defined as follows: a score of 1 indicates no hospitalization with no limitations on activities; 2, are not hospitalized, but have limitations on activities; 3, hospitalization and not receiving supplemental oxygen; 4, hospitalization and receiving supplemental oxygen; 5, hospitalization and received oxygen supplementation administered by a high flow nasal cannula or noninvasive ventilation; 6, hospitalization and receiving mechanical ventilation; And 7, death.

Secondary outcomes included clinical status over 7 days, assessed with the use of a six-level ordinal scale (see and see below Supplementary Addendum); An indication for intubation within 15 days; Randomization and receipt of supplemental oxygen administered by a high-flow nasal cannula or non-sensory ventilation between 15 days; Duration of hospital stay; Death in hospital; Thromboembolic complications; acute kidney injury; And the number of days alive up to 15 days and free of respiratory support. A day alive and free from respiratory aids was defined as any day in which the patient did not receive supplemental oxygen or invasive or noninvasive mechanical ventilation, randomly to day 15. Patients who died during the 15-day window were assigned a value of 0 are alive and free of respiratory aids in this evaluation. Safety results are listed in Supplementary Addendum. All test results were evaluated by on-site investigators who were aware of the workings of the test-group (only for patients discharged before 15 days and who assessed for the primary outcome via a blind telephone interview Were made, except). No formal decision of the test results was made.

Sample-size calculation and protocol changes

We originally planned the trial to include 630 patients, using the intention-to-treat analysis population as the primary outcome, with a six-stage ordinal outcome. Supplementary Addendum. However, before the first interim analysis was conducted, we changed the primary-outcome assessment to a seven-level ordinal scale and the main analysis ranged from the intention-to-treat population of the population to the modified intention-to-treat population in which only patients Included were the confirmation of the Kovid-19 diagnosis with reverse-transcriptase-polymerase-chain-reaction (RT-PCR) testing (using the test available at each site).

The change in the use of the seven-tier ordinal scale was adopted because on April 10, 2020 (after the first enrolled patient’s 15-day follow-up), we established the ability to obtain 15-day information on the limitations on the activities of the blind. With the use of telephone interviews. So we added another level to the six-level sequential outcome, dividing the first level (not hospitalized) into two levels (level 1, not hospitalized and no limitation on activities; and level 2, hospitalization Not admitted but with limits on activities). Changes in the revised intention-to-treat population were adopted, because under the hypothesis that treatment would have a beneficial effect on the primary outcome for patients who were confirmed to be involved, the inclusion of unconfirmed cases predicted effect sizes and potency Will decrease. As a related change, we added external adjudication of unconfirmed cases that were classified as probable, not probable, or perhaps not Kovid-19 (see) Supplementary Addendum).

The sample size was modified with the use of the first distribution of seven-tier sequential results of 15 observed among the first 120 patients, with the following ratios of patients with level 1 of 1: 60%, 19%, 7% , 1%, 1%, 5% and 7% respectively. With 630 patients who had undergone randomization and 510 patients were included in the modified intention-to-treat analysis, we calculated that the trial would have 80% power between the groups (two-by-two comparisons) Odd ratio of 0.5 will be for detection. Significance level of 5% and with Bonferroni adjustment for multiple comparisons (α = 5%, divided by 3 for each comparison).13

Statistical analysis

The primary outcome was analyzed by mixed ordinal logistic regression with random intercept according to site, assuming proportional odds. We all report two-by-two comparisons. Binary outcomes were evaluated with the use of a mixed logistic-regression model, excluding in-hospital mortality, which was evaluated with the Cox proportional-hazards model. Consistent results were evaluated via generalized linear regression or mixed models for repeated outcomes as appropriate. All models were adjusted for age and supplemental oxygen use at admission.

We also performed a sensitivity analysis that included all patients who underwent a randomization (intention-to-treat population) and a sensitivity analysis for the primary outcome of the following groups: patients with definite, probable or probable Kovid-19; And patients with definite or potential Kovid-19. Two additional populations were considered. An efficacious population included patients with a definitive diagnosis who received at least one dose of the prescribed test drug. The safety population consisted of patients according to medications received during the randomized treatment period, regardless of the assigned test group or the outcome of the Kovid-19 trial.

We planned three interim analyzes when 120 patients, 315 patients, and 504 patients had completed a 15-day follow-up. However, only the first interim analysis was conducted. It was only after the trial-recruitment ended that the second and third interim analyzes were available because of the rapid-expected enrollment in the primary-results. After discussion with the Data and Security Monitoring Committee, the second and third interim analyzes were canceled. The Data and Safety Monitoring Committee used Haybittle-Peto14 Constraining limits with a p-value range of less than 0.001 to constrain testing for safety and a p-value threshold of less than 0.0001 to constrain testing for efficacy. We did not adjust the final values ​​of hypothesis testing for sequential analysis.

The analysis was performed with the use of R software (R core team).15 The P value for the primary outcome was adjusted with the use of the Bonferroni correction. No P values ​​have been reported for secondary outcomes; The width of the confidence interval for secondary outcomes has not been adjusted for multiple comparisons, so the interval should not be used to estimate fixed treatment effects. The P values ​​of safety analyzes were not adjusted given the importance of identifying potential signs of damage. Additional details about statistical analysis are provided in Supplementary Addendum.

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