Covid-19 Living Data

Trial NCT04322123
Publication Cavalcanti AB, N Engl J Med (2020) (published paper)
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: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Brazil Follow-up duration (days): 15
Inclusion criteria	1. 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 criteria	1. 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 HCQ+AZM Hydroxychloroquine: 400 mg orally or via nasogastric tube twice a day for 7 days Azithromycin: 500 mg IV or orally once a day for 7 days Hydroxychloroquine 400 mg orally or via nasogastric tube twice a day for 7 days
	Control Standard care
Participants
	Randomized participants : HCQ+AZM=217 Hydroxychloroquine=221 Standard care=229
	Characteristics of participants N= 667 Mean age : NR 388 males Severity : Mild: n=387 / Moderate: n=278 / Severe: n=0 Critical: n=0 Number of vaccinated participants: NR
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 available	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: 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.