Clinical trial NCT04322123: Safety and Efficacy of Hydroxychloroquine Associated With Azithromycin in SARS-Cov-2 Virus (COVID-19)
Official title: An Open-label, Randomized Controlled Trial of Hydroxychloroquine and Azithromycin for COVID-19 Infection on Hospitalized, Noncritical Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Coronavirus Infections
Lead sponsor: Hospital do Coracao
Sponsor class: OTHER
Collaborators: name: Hospital Israelita Albert Einstein
name: Hospital Sirio-Libanes
name: Brazilian Research In Intensive Care Network
name: EMS
First posted: 2020-03-26
Enrollment: 667
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Coronavirus (COVID-19) is a somewhat new and recognized infectious disease that is now spreading to several countries in the world, including Brazil. Hydroxychloroquine and azithromycin may be useful for treating those patients.

COALITION I study aims to compared standard of care, hydroxychloroquine plus azithromycin and hydroxychloroquine monotherapy for treatment of hospitalized patients with COVID-19.

COALITION I will recruit 630 patients with infection by COVID-19 (210 per arm). Ordinal endpoint of status at 15 days will be the primary endpoint.

Detailed description: The current pandemic associated with coronavirus disease 2019 (COVID-19) represents a major global health challenge. There are no effective therapies for the management of COVID-19 that have been proven to improve clinical outcomes in this high-risk group of patients. Hydroxychloroquine and its combination with azithromycin have been suggested to improve viral clearance, but its effect on clinical outcomes remains uncertain.

This is an open-label pragmatic multicentre randomized (concealed) clinical trial of 7 days of hydroxychloroquine (400 mg BID) plus azithromycin (500 mg once daily), hydroxychloroquine 400 mg BID, or standard of care for moderately severe hospitalized patients with suspected or confirmed COVID-19 (in-patients with up to 4L/minute oxygen supply through nasal catheter). Patients are randomized in around 50 recruiting sites (630 patients with confirmed COVID-19; 1:1:1; 210 patients per arm).

The primary endpoint is a 7-level ordinal scale measured at 15-days: 1) not hospitalized, without limitations on activities; 2) not hospitalized, with limitations on activities; 3) hospitalized, not using supplementary oxygen; 4) hospitalized, using supplementary oxygen; 5) hospitalized, using high-flow nasal cannula or non-invasive ventilation; 6) hospitalized, on mechanical ventilation; 7) death. Secondary endpoints are the ordinal scale at 7 days, need for mechanical ventilation and rescue therapies during 15 days, need of high-flow nasal cannula or non-invasive ventilation during 15 days, length of hospital stay, in-hospital mortality, thromboembolic events, occurrence of acute kidney injury, defined as an increase in creatinine above 1.5 times the baseline value and number of days free of respiratory support at 15 days. Secondary safety outcomes include prolongation of QT interval on electrocardiogram, ventricular arrhythmias, and liver toxicity. The main analysis will consider all patients with confirmed COVID-19 in the groups they were randomly assigned.

Eligibility criteria: Inclusion Criteria:

* Patients with suspected or confirmed COVID-19 admitted to inpatient units and intensive care units

Exclusion Criteria:

* Need for oxygen supplementation \> 4 litters per min
* Patients using a high-flow nasal catheter
* Patients using non-invasive mechanical ventilation
* Patients using invasive mechanical ventilation
* Males and females aged \< 18 years
* Pregnancy
* Allergy to chloroquine or derivatives
* Allergy to azithromycin
* Patients that have already received more than one dose of either azithromycin or hydroxychloroquine before enrollment
* Patients with respiratory symptoms for more than 14 days

Primary outcomes:
measure: Evaluation of the clinical status
timeFrame: 15 days after randomization
Secondary outcomes:
measure: Ordinal scale in 7 days
timeFrame: 7 days after randomization
measure: Need of intubation and mechanical ventilation
timeFrame: 7 days after randomization
measure: Use of mechanical ventilation during hospital stay
timeFrame: 15 days after randomization
measure: Use of non-invasive ventilation
timeFrame: 7 days after randomization
measure: Hospital Length of Stay
timeFrame: 28 days after randomization
measure: All-cause mortality
timeFrame: 28 days after randomization
measure: Thromboembolic complications
timeFrame: 15 days after randomization
measure: Acute renal disfunction
timeFrame: 15 days after randomization
measure: Number of days alive and free of respiratory support up to 15 days
timeFrame: 15 days
Other outcomes:
measure: Safety outcome on corrected QT interval
timeFrame: At day 3 and 7 after enrollment
Locations:
city: Feira De Santana
country: Brazil
facility: Hospital Geral Clériston Andrade
state: BA
city: Salvador
country: Brazil
facility: Hospital Ana Nery - HAN/SESAB
state: BA
city: Vitória Da Conquista
country: Brazil
facility: HHospital SAMUR
state: BA
city: Vitória Da Conquista
country: Brazil
facility: Hospital Geral de Vitória da Conquista
state: BA
city: Brasilia
country: Brazil
facility: Hospital de Brasília
state: DF
city: Brasília
country: Brazil
facility: Instituto de Cardiologia do Distrito Federal
state: DF
city: Colatina
country: Brazil
facility: Hospital Maternidade São José - UNESC - Fundação Social Rural de Colatina
state: ES
city: Nova Lima
country: Brazil
facility: Hospital Vila da Serra
state: MG
city: São João Del Rei
country: Brazil
facility: Santa Casa de Misericórdia de São João Del Rei
state: MG
city: Londrina
country: Brazil
facility: Associação Evangélica Beneficente de Londrina - Hospital Evangélico de Londrina
state: PR
city: Rio De Janeiro
country: Brazil
facility: Instituto Estadual do Cérebro Paulo Niemeyer
state: RJ
city: Caxias do Sul
country: Brazil
facility: Hospital Geral de Caxias do Sul
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital Santa Rita - Irmandade Santa Casa de Porto Alegre
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital São Francisco - Irmandade Santa Casa de Porto Alegre
state: RS
city: Criciuma
country: Brazil
facility: Hospital São José
state: SC
city: Florianópolis
country: Brazil
facility: Hospital Baía Sul - Baía Sul Medical Center
state: SC
city: Florianópolis
country: Brazil
facility: Hospital Nereu Ramos
state: Sc
city: Joinville
country: Brazil
facility: Centro Hospitalar Unimed
state: SC
city: Barretos
country: Brazil
facility: Hospital de Amor - Unidade Barretos (Fundação PIO XII)
state: SP
city: São Paulo
country: Brazil
facility: Casa de Saúde Santa Marcelina
state: SP
city: São Paulo
country: Brazil
facility: Hospital Albert Einstein
state: SP
city: São Paulo
country: Brazil
facility: Hospital Beneficência Portuguesa - Real e Benemérita Associação Portuguesa de Beneficência
state: SP
city: São Paulo
country: Brazil
facility: Hospital BP Mirante - Real e Benemérita
state: SP
city: São Paulo
country: Brazil
facility: Hospital das Clínicas da FMUSP
state: SP
city: São Paulo
country: Brazil
facility: Hospital do Servidor Público Estadual - HSPE - IAMSPE
state: SP
city: São Paulo
country: Brazil
facility: Hospital São Paulo - UNIFESP
state: SP
city: São Paulo
country: Brazil
facility: Hospital Sírio-Libanês
state: SP
city: São Paulo
country: Brazil
facility: Hospital SEPACO
state: S
Study officials:
affiliation: Hospital do Coração
name: Alexandre Biasi, PhD
role: STUDY_CHAIR
affiliation: Hospital Israelita Albert Einstein
name: Otavio Berwanger
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, Damiani LP, Marcadenti A, Kawano-Dourado L, Lisboa T, Junqueira DLM, de Barros E Silva PGM, Tramujas L, Abreu-Silva EO, Laranjeira LN, Soares AT, Echenique LS, Pereira AJ, Freitas FGR, Gebara OCE, Dantas VCS, Furtado RHM, Milan EP, Golin NA, Cardoso FF, Maia IS, Hoffmann Filho CR, Kormann APM, Amazonas RB, Bocchi de Oliveira MF, Serpa-Neto A, Falavigna M, Lopes RD, Machado FR, Berwanger O; Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med. 2020 Nov 19;383(21):2041-2052. doi: 10.1056/NEJMoa2019014. Epub 2020 Jul 23.