Safety and Efficacy of Hydroxychloroquine Associated With Azithromycin in SARS-Cov-2 Virus (COVID-19) (Coalition-I)

An Open-label, Randomized Controlled Trial of Hydroxychloroquine and Azithromycin for COVID-19 Infection on Hospitalized, Noncritical Patients

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.

Study Overview

• Status: Completed
• Conditions: Coronavirus Infections
• Intervention / Treatment: Drug: Hydroxychloroquine Oral Product; Drug: Hydroxychloroquine + azithromycin

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.

• Study Type: Interventional
• Enrollment (Actual): 667
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • BA
    • Feira De Santana, BA, Brazil
      • Hospital Geral Clériston Andrade
    • Salvador, BA, Brazil
      • Hospital Ana Nery - HAN/SESAB
    • Vitória Da Conquista, BA, Brazil
      • HHospital SAMUR
    • Vitória Da Conquista, BA, Brazil
      • Hospital Geral de Vitória da Conquista
  • DF
    • Brasilia, DF, Brazil
      • Hospital de Brasília
    • Brasília, DF, Brazil
      • Instituto de Cardiologia do Distrito Federal
  • ES
    • Colatina, ES, Brazil
      • Hospital Maternidade São José - UNESC - Fundação Social Rural de Colatina
  • MG
    • Nova Lima, MG, Brazil
      • Hospital Vila da Serra
    • São João Del Rei, MG, Brazil
      • Santa Casa de Misericórdia de São João Del Rei
  • PR
    • Londrina, PR, Brazil
      • Associação Evangélica Beneficente de Londrina - Hospital Evangélico de Londrina
  • RJ
    • Rio De Janeiro, RJ, Brazil
      • Instituto Estadual do Cérebro Paulo Niemeyer
  • RS
    • Caxias do Sul, RS, Brazil
      • Hospital Geral de Caxias do Sul
    • Porto Alegre, RS, Brazil
      • Hospital Santa Rita - Irmandade Santa Casa de Porto Alegre
    • Porto Alegre, RS, Brazil
      • Hospital São Francisco - Irmandade Santa Casa de Porto Alegre
  • S
    • São Paulo, S, Brazil
      • Hospital SEPACO
  • SC
    • Criciuma, SC, Brazil
      • Hospital Sao Jose
    • Florianópolis, SC, Brazil
      • Hospital Baía Sul - Baía Sul Medical Center
    • Joinville, SC, Brazil
      • Centro Hospitalar Unimed
  • SP
    • Barretos, SP, Brazil
      • Hospital de Amor - Unidade Barretos (Fundação PIO XII)
    • São Paulo, SP, Brazil
      • Hospital Sao Paulo - UNIFESP
    • São Paulo, SP, Brazil
      • Casa de Saude Santa Marcelina
    • São Paulo, SP, Brazil
      • Hospital Albert Einstein
    • São Paulo, SP, Brazil
      • Hospital Beneficência Portuguesa - Real e Benemérita Associação Portuguesa de Beneficência
    • São Paulo, SP, Brazil
      • Hospital BP Mirante - Real e Benemérita
    • São Paulo, SP, Brazil
      • Hospital das Clinicas da FMUSP
    • São Paulo, SP, Brazil
      • Hospital do Servidor Público Estadual - HSPE - IAMSPE
    • São Paulo, SP, Brazil
      • Hospital Sirio-Libanes
  • Sc
    • Florianópolis, Sc, Brazil
      • Hospital Nereu Ramos

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydroxychloroquine; Hydroxychloroquine after randomization, Hydroxychloroquine [400mg 2x/day, 12/12h] for 07 days.	Drug: Hydroxychloroquine Oral Product; Hydroxychloroquine 400 mg BID
Experimental: Hydroxychloroquine + azithromycin; Hydroxychloroquine + azithromycin. After randomization, Hydroxychloroquine [400mg 2x/day, 12/12h] + azithromycin [500mg 1x/day]) for 07 days.	Drug: Hydroxychloroquine + azithromycin; Hydroxychloroquine 400 mg BID + azithromycin 500 mg once a day
No Intervention: Control; standard treatment protocol for 2019-nCoV infection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of the clinical status	Evaluation of the clinical status of patients on the 15th day after randomization defined by the Ordinal Scale of 7 points.; Alive at home without limitations on activities; Alive at home without limitations on activities; In the hospital without oxygen; In the hospital using oxygen; In the hospital using high-flow nasal catheter or non-invasive ventilation; In hospital, on mechanical ventilation; Dead	15 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ordinal scale in 7 days	Evaluation of the clinical status of patients on the 7th day after randomization defined by the Ordinal Scale of 7 points.; Alive at home without limitations on activities; Alive at home without limitations on activities; In the hospital without oxygen; In the hospital using oxygen; In the hospital using high-flow nasal catheter or non-invasive ventilation; In hospital, on mechanical ventilation; Dead	7 days after randomization
Need of intubation and mechanical ventilation	Need of intubation and mechanical ventilation up to the 7th day after randomization	7 days after randomization
Use of mechanical ventilation during hospital stay	Use of mechanical ventilation during hospital stay	15 days after randomization
Use of non-invasive ventilation	Use of non-invasive ventilation up to the 7th day after randomization	7 days after randomization
Hospital Length of Stay	Hospital Length of Stay	28 days after randomization
All-cause mortality	All-cause mortality rates during hospital stay	28 days after randomization
Thromboembolic complications	Occurrence of thromboembolic complications such as: Deep vein thrombosis Pulmonary Embolism Stroke	15 days after randomization
Acute renal disfunction	Occurrence of renal dysfunction, defined as an increase in creatinine above 1.5 times the baseline value	15 days after randomization
Number of days alive and free of respiratory support up to 15 days	Number of days alive and free of respiratory support up to 15 days (DAFOR15), defined as the sum of days patients did not require supplementary oxygen, non-invasive ventilation, high-flow nasal catheter neither mechanical ventilation at 15 -days. Patients that perished during the 15-day window will receive zero DAFOR15.	15 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety outcome on corrected QT interval	Corrected QT interval	At day 3 and 7 after enrollment

Collaborators and Investigators

• Sponsor: Hospital do Coracao
• Collaborators: Hospital Israelita Albert Einstein; Hospital Sirio-Libanes; Brazilian Research In Intensive Care Network; EMS
• Investigators: Study Chair: Alexandre Biasi, PhD, Hospital do Coracao; Principal Investigator: Otavio Berwanger, Hospital Israelita Albert Einstein

Publications and helpful links

General Publications

• 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. Erratum In: N Engl J Med. 2020 Nov 19;383(21):e119.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2020
• Primary Completion (Actual): June 2, 2020
• Study Completion (Actual): June 2, 2020

Study Registration Dates

• First Submitted: March 24, 2020
• First Submitted That Met QC Criteria: March 24, 2020
• First Posted (Actual): March 26, 2020

Study Record Updates

• Last Update Posted (Actual): April 5, 2022
• Last Update Submitted That Met QC Criteria: April 3, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Coronavirus Infections; Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Azithromycin; Hydroxychloroquine
• Other Study ID Numbers: Brazil COVID Coalition I Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Study Data/Documents

1. Study Protocol
   Information comments: Preprint of the Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No