Covid-19 Living Data

Trial NCT04322123
Publication Cavalcanti AB, N Engl J Med, 2020
Dates: 3/29/2020 to 5/17/2020
Funding: Mixed (The trial was funded by the hospitals and research institutes participating in Coalition Covid-19 Brazil (see the Supplementary Appendix). EMS Pharma provided additional funding and logistic support for the trial and als)

Methods
	RCT
	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 1 Hydroxychloroquine (400mg) Co-Intervention: Standard care Duration : 7 days Definition of Standard care: The treatment and control groups received the current standard of care treatment for COVID-19, which included daily monitoring with clinical assessment by the attending physician, routine laboratory tests (blood count, urea, creatinine, liver enzymes and bilirubin, c-reactive protein) at the discretion of the attending physician, respiratory therapy and motor physiotherapy, surveillance of vital parameters according to the patient's location (inpatient unit or ICU) at least once per period (which may be more frequent in some situations and institutions), addition of ventilatory support measures, such as increased oxygen flow, use of non-invasive positive pressure ventilation or oxygen supplementation via high-flow nasal cannula, as recommended by the attending physician, prophylaxis of stress ulcers (if indicated) and venous thromboembolism according to the protocol of each institution and addition of other therapies such as antibiotics, corticosteroids, other immunomodulators (e.g., tocilizumab), other antivirals (e.g., oseltamivir for suspected influenza coinfection), as recommended by the attending physician. Remdesivir is not available in Brazil and was not used.
	Treatment 2 Hydroxychloroquine + Azithromycin (400mg/500mg) Co-Intervention: Standard care Duration : 7 days Definition of Standard care: The treatment and control groups received the current standard of care treatment for COVID-19, which included daily monitoring with clinical assessment by the attending physician, routine laboratory tests (blood count, urea, creatinine, liver enzymes and bilirubin, c-reactive protein) at the discretion of the attending physician, respiratory therapy and motor physiotherapy, surveillance of vital parameters according to the patient's location (inpatient unit or ICU) at least once per period (which may be more frequent in some situations and institutions), addition of ventilatory support measures, such as increased oxygen flow, use of non-invasive positive pressure ventilation or oxygen supplementation via high-flow nasal cannula, as recommended by the attending physician, prophylaxis of stress ulcers (if indicated) and venous thromboembolism according to the protocol of each institution and addition of other therapies such as antibiotics, corticosteroids, other immunomodulators (e.g., tocilizumab), other antivirals (e.g., oseltamivir for suspected influenza coinfection), as recommended by the attending physician. Remdesivir is not available in Brazil and was not used.
	Treatment 3 Hydroxychloroquine (400mg) Duration : 7 days Definition of Standard care: The treatment and control groups received the current standard of care treatment for COVID-19, which included daily monitoring with clinical assessment by the attending physician, routine laboratory tests (blood count, urea, creatinine, liver enzymes and bilirubin, c-reactive protein) at the discretion of the attending physician, respiratory therapy and motor physiotherapy, surveillance of vital parameters according to the patient's location (inpatient unit or ICU) at least once per period (which may be more frequent in some situations and institutions), addition of ventilatory support measures, such as increased oxygen flow, use of non-invasive positive pressure ventilation or oxygen supplementation via high-flow nasal cannula, as recommended by the attending physician, prophylaxis of stress ulcers (if indicated) and venous thromboembolism according to the protocol of each institution and addition of other therapies such as antibiotics, corticosteroids, other immunomodulators (e.g., tocilizumab), other antivirals (e.g., oseltamivir for suspected influenza coinfection), as recommended by the attending physician. Remdesivir is not available in Brazil and was not used.
Participants
	Randomized 450 participants (n₁=229 / n₂= 221)
	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 language other than 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	High
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.