Covid-19 living Data

Hydroxychloroquine + Azithromycin vs Hydroxychloroquine (RCT)

Hospitalized patients

FOREST PLOTS -2022-04-12

Studies description

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
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 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.

Trial NCT04321278
Publication Furtado RHM, Lancet (2020) (published paper)
Dates: 28/03/2020 to 19/05/2020
Funding: Mixed (COALITION COVID-19 Brazil; EMS)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Brazil Follow-up duration (days): 29
Inclusion criteria	Patients who were at least 18 years and were admitted to hospital with suspected or confirmed COVID-19 with fewer than 14 days since symptom onset. Additionally, patients needed to have at least one of the following severity criteria: use of oxygen supplementation of more than 4 L/min flow use of high-flow nasal cannula use of non-invasive positive-pressure ventilation or use of mechanical ventilation.
Exclusion criteria	Refusal to provide consent for the study by the patient or their legal guardian Hypersensitivity to any of the drugs used in the study (Azithromycin or Hydroxychloroquine) Having either more than 48 hours under prior use of the study medications (Azithromycin or Hydroxychloroquine) symptom onset greater than 14 days long QT syndrome or severe ventricular arrhythmias QTc> = 480ms patients with do not resuscitate order or under exclusive palliative care know history of liver disease or cirrhosis or abnormal liver enzyme tests above three times the upper limit values (alanine aminotransferase -ALT and aspartate aminotransferase - AST) known history of retinopathy or macular degeneration known history of pancreatitis concomitant use of medications that alter the absorption or excretion of azithromycin or hydroxychloroquine use of medications known to prolong QTc interval use of psychoactive drugs, and breastfeeding and/or pregnancy women.
Interventions
	Treatment HCQ+AZM Azithromycin: 500 mg orally, by nasogastric tube or IV once a day for 10 days. Hydroxychloroquine: 400 mg orally or by nasogastric tube twice a day for 10 days
	Control Hydroxychloroquine 400 mg orally or by nasogastric tube twice a day for 10 days
Participants
	Randomized participants : HCQ+AZM=237 Hydroxychloroquine=210
	Characteristics of participants N= 447 Mean age : NR 286 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=225
Primary outcome
	In the register Evaluation of the clinical status [ Time Frame: 15 days after randomization ]
	In the report Clinical status, measured at 15 days using a six-level ordinal scale
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Not reported
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 all available versions of the published article, the study registry. statistical analysis plan and protocol were used in data extraction and risk of bias assessment. The study was terminated early due faster than anticipated enrolment. The study achieved the target sample size specified in the registry. There was no change from the trial registration in the intervention and control treatments nor the primary and secondary outcomes. The extraction and assessment were in accordance with the original statistical analysis plan using the intention-to-treat population (retrieved from the Supplementary Appendix) vs. the modified intention-to-treat population reported in the paper. Quote: "As of May 13, 2020, the protocol was amended so that the main analysis would be done in a modified ITT (mITT) population that included only patients diagnosed with COVID-19 confirmed through molecular methods or serological testing. This decision was made by the executive committee before the first interim analysis from the data safety monitoring board while masked to study results. The reason for this decision was to include in the primary analysis only those patients more likely to benefit from the study intervention, (ie, those ones with confirmed SARS-CoV-2 infection)."