Trial NCT04322123
Publication Cavalcanti AB, N Engl J Med, 2020
Dates: 3/29/2020 to 5/17/2020
Funding: Mixed (Hospitals and research institutes participating in Coalition Covid-19 Brazil; EMS Pharma)
Conflict of interest: COI

Methods
RCT
Location : Multicenter / Brazil
Follow-up duration (days): 15
Inclusion criteria1. Patients who were 18 years of age or older and were hospitalized with suspected or confirmed COVID-19. 2. Fewer than 14 days since symptom onset.
Exclusion criteria1. Need for oxygen supplementation >4 L/min via nasal cannula or 40% via Venturi mask; 2. Need for oxygen supplementation via high-flow nasal cannula; 3. Need for non-invasive ventilation; 4. Need for invasive mechanical ventilation; 5. Previous use of chloroquine, hydroxychloroquine, azithromycin, or any other macrolide for more than 24 hours before enrollment; 6. History of severe ventricular cardiac arrhythmia or electrocardiogram with corrected QT interval (QTc) ≥480 ms; 7. History of liver cirrhosis; 8. Chronic renal failure (estimated glomerular filtration rate <30 mL/min/1.73 m2); 9. Known retinopathy or macular degeneration; 10. History of pancreatitis; 11. Less than 18 years of age; 12. Known allergy to chloroquine or hydroxychloroquine; 13. Known allergy to azithromycin; 14. Pregnancy or breastfeeding.
Interventions
Treatment 1
Hydroxychloroquine (400mg)
Co-Intervention: Standard care
Duration : 7 days
Control
Standard care
Treatment 3
Hydroxychloroquine + Azithromycin (400mg/500mg)
Co-Intervention: Standard care
Duration : 7 days
Participants
Randomized
667 participants n1=221/ n2=229/ n3=217
Characteristics of participants
N=667
Mean age : 50.1
388 males
Severity : Mild: n=387 / Moderate: n=278/ Severe: n=0 Critical: n=0
Primary outcome
In the register
Evaluation of the clinical status of patients on the 15th day after randomization defined by the Ordinal Scale of 7 points.
In the report
Clinical status at 15 days, evaluated with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition)
Documents
avalaible

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing stated

Yes
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment "In addition to the published report and supplementary file, the study registry, protocol and SAP were used in data extraction and risk of bias assessment. The study achieved the target sample size reported in the registry. There is no change from the trial registration in the intervention and control treatments. All outcomes from the registry are reported in the paper.
Quote: ""We had originally planned for the trial to include 630 patients, using the intention-to-treat analysis population, with a six-level ordinal outcome as the primary outcome, as described in the Supplementary Appendix. However, before the first interim analysis was conducted, we changed the primary-outcome assessment to the seven-level ordinal scale and the main analysis population from the intention-to-treat population to a modified intention-to-treat population that included only patients with a diagnosis of Covid-19 that had been confirmed by reverse-transcriptase- polymerase-chain-reaction (RT-PCR) testing (using the test available at each site).""
Comment: Furthermore, safety analysis on a safety population of 4 arms was performed - hydrxychloroquine plus azithromycin (n=239), hydroxychloroquine only (n=199), azithromycin only (n=50)and neither hydroxychloroquine nor azithromycin (n=177). Data could not be accurately extracted from this safety population, therefore adverse events data from ITT population were used. "