Randomized Placebo-controlled Trial of Hydroxychloroquine in Outpatient Cases With Coronavirus Disease 2019 (COVID-19) (COALITION-V)

Pragmatic, Double-blind, Placebo-controlled Randomized Clinical Trial, Evaluating Hydroxychloroquine for Prevention of Hospitalization and Respiratory Complications in Non-hospitalized Patients With Confirmed or Probable COVID-19

In December 2019, a group of patients with pneumonia of unknown cause was identified in Wuhan, in the Hubei province, China. Despite the need of target specific therapeutic options for COVID-19, until now there is no proof of effectiveness of any specific intervention. Some limited observational trials and also evidence from randomized trials have shown no benefit of hydroxychloroquine in inpatient context. Thus, studies evaluating interventions in an outpatient setting in non-severe patients can provide important information related to prognosis and safety. In this way, the present study will evaluate the effectiveness and safety of the use of hydroxychloroquine in COVID-19 outpatients by means of a Randomized, double-blind, placebo-controlled trial

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: Placebo

Detailed Description

Pragmatic, double-blind, placebo-controlled randomized parallel-group, two-arm clinical trial (with allocation ratio 1:1), evaluating hydroxychloroquine (800 mg at 1st day, and 400 mg from day 2 to 7) for prevention of hospitalization and respiratory complications in non-hospitalized confirmed or suspected COVID-19 cases. Key inclusion criteria are adults (equal to or greater tahn 18 years) seeking medical care with suspected or confirmed COVID-19, with time between symptoms and inclusion ≤ 07 days, presenting mild symptoms, without indication of hospitalization and at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; Chronic Obstructive Pulmonary Disease (COPD) or other chronic lung diseases; smoking; immunosuppression; obesity (Defined as BMI equal to or greater than 30 Kg/m2). Primary endpoint is to assess if the treatment with hydroxychloroquine is able to avoid hospitalization due to a COVID-19-related clinical reason within 30 days of randomization in an outpatient setting. Hospitalization is considered to be hospital stay for a period > 24h or an additional hospitalized calendar day. The primary endpoint is centrally adjudicated by an independent clinical events committee blinded to the assigned treatment groups. Secondary endpoints include uncontrolled asthma after ≥ 5 days of starting study medication; pneumonia; otitis media; fever resolution time; time to improve respiratory symptoms; hospitalization in the Intensive Care Unit; need for orotracheal intubation; mechanical ventilation time; mortality. Safety outcomes will be hypoglycemia; palpitations; reduced visual acuity; diarrhea; anorexia; and emotional lability. The evaluation of the primary outcome (hospitalization within 30 days) will be performed for the included population following the principle of intention-to-treat (ITT), which will consist of all randomized cases. A modified intention-to-treat analysis (mITT), in which cases definitely confirmed as negative for COVID-19 will be excluded, will also be performed.

• Study Type: Interventional
• Enrollment (Actual): 1372
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • Lençois Paulista, Brazil
    • ESF Dr. João Paccola Primo
  • Rio De Janeiro, Brazil
    • Cardioclinica da Ilha do Governador
  • São Paulo, Brazil
    • Hospital Santa Paula
  • São Paulo, Brazil
    • Hospital Israelita Albert Einstein
  • São Paulo, Brazil
    • Hospital Sirio-Libanes
  • São Paulo, Brazil, 01323-903
    • International Research Center - Hospital Alemão Oswaldo Cruz
  • São Paulo, Brazil
    • Hospital do Coracao
  • São Paulo, Brazil
    • Hospital Leforte
  • São Paulo, Brazil
    • Hospital Moriah
  • São Paulo, Brazil
    • Hospital Samaritano
  • São Paulo, Brazil
    • Hospital São Camilo Pompeia
  • São Paulo, Brazil
    • Hospital Sao Paulo - UNIFESP
  • Alagoas
    • Maceió, Alagoas, Brazil
      • Centro de Pesquisas Clínicas Dr. Marco Mota HCOR
  • Bahia
    • Ipiaú, Bahia, Brazil
      • Hospital e Clínica São Roque
    • Salvador, Bahia, Brazil
      • Clínica Otorhinus
    • Salvador, Bahia, Brazil
      • Hospital da Bahia
    • Salvador, Bahia, Brazil
      • Hospital Santa Izabel
    • Salvador, Bahia, Brazil
      • Instituto Cardio Pulmonar da Bahia
    • Vitória Da Conquista, Bahia, Brazil
      • Hospital SAMUR
  • Ceará
    • Barbalha, Ceará, Brazil
      • Hospital Maternidade São Vicente de Paulo
    • Juazeiro Do Norte, Ceará, Brazil
      • Hospital Unimed Cariri
  • Espírito Santo
    • Cachoeiro De Itapemirim, Espírito Santo, Brazil
      • Unimed Sul Capixaba
  • Goiás
    • Goiânia, Goiás, Brazil
      • Hospital das Clínicas Universidade Federal de Goiás
  • Minas Agerais
    • Passos, Minas Agerais, Brazil
      • Santa Casa de Misericórdia de Passos
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil
      • Hospital Júlia Kubitschek
    • Belo Horizonte, Minas Gerais, Brazil
      • Instituto da Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa
    • Carangola, Minas Gerais, Brazil
      • Casa de Caridade de Carangola
    • Poços De Caldas, Minas Gerais, Brazil
      • Hospital Maternidade e Pronto Socorro Santa Lúcia
    • São João Del Rei, Minas Gerais, Brazil
      • Hospital da Unimed
    • São João Del Rei, Minas Gerais, Brazil
      • Santa Casa de Misericórdia de São João Del Rei
    • Uberaba, Minas Gerais, Brazil
      • Hospital de Clínicas da Universidade Federal do Triângulo Mineiro
    • Uberlândia, Minas Gerais, Brazil
      • Hospital de Clínicas da Universidade Federal de Uberlândia
  • Paraná
    • Campo Largo, Paraná, Brazil
      • Hospital do Rocio
    • Maringá, Paraná, Brazil
      • Clínica Clinilive
    • Maringá, Paraná, Brazil
      • Hospital Universitário Regional de Maringá
  • Pernambuco
    • Recife, Pernambuco, Brazil
      • Procape
    • Recife, Pernambuco, Brazil
      • Real Hospital Português de Beneficência em Pernambuco
    • Sairé, Pernambuco, Brazil
      • SECRETARIA MUNICIPAL DE SAÚDE DE SAIRÉ (Unidade Mista Olília Mendonça Souto Maior)
  • Rio De Janeiro
    • Niterói, Rio De Janeiro, Brazil
      • Complexo Hospitalar de Niteroi
    • Volta Redonda, Rio De Janeiro, Brazil
      • Hospital Unimed Volta Redonda
  • Rio Grande Do Sul
    • Bento Gonçalves, Rio Grande Do Sul, Brazil
      • Associação Dr. Bartholomeu Tacchini
    • Passo Fundo, Rio Grande Do Sul, Brazil
      • Hospital São Vicente de Paulo
    • Porto Alegre, Rio Grande Do Sul, Brazil
      • Hospital Moinhos de Vento
    • Porto Alegre, Rio Grande Do Sul, Brazil
      • Santa Casa de Misericórdia de Porto Alegre (ISCMPA)
    • Santa Maria, Rio Grande Do Sul, Brazil
      • Universidade Federal de Santa Maria
  • Rondônia
    • Porto Velho, Rondônia, Brazil
      • CEPEM Centro de Pesquisa de Medicina Tropical de Rondônia
  • Salto Alto
    • Monte alto, Salto Alto, Brazil
      • Irmandade de Misericórdia Do Hospital Da Santa Casa de Monte Alto
  • Santa Catarina
    • Blumenau, Santa Catarina, Brazil
      • Maestri e Kormann Consultoria Medico Cientifica
    • Brusque, Santa Catarina, Brazil
      • Imigrantes Hospital e Maternidade
    • Criciúma, Santa Catarina, Brazil
      • Hospital Sao Jose
    • Joinville, Santa Catarina, Brazil
      • Hospital Regional Hans Dieter Schmidt
  • São Paulo
    • Araras, São Paulo, Brazil
      • Santa Casa de Araras
    • Barretos, São Paulo, Brazil
      • Hospital de Amor
    • Barretos, São Paulo, Brazil
      • Santa Casa de Misericórdia de Barretos
    • Barueri, São Paulo, Brazil
      • Alphacor Cardiologia Clínica e Diagnóstica LTDA
    • Botucatu, São Paulo, Brazil
      • Faculdade de Medicina de Botucatu, Unesp
    • Caraguatatuba, São Paulo, Brazil
      • Hospital Regional do Litoral Norte
    • Cordeirópolis, São Paulo, Brazil
      • Hospital de Cordeirópolis
    • Itapevi, São Paulo, Brazil
      • Centro de Combate ao Coronavírus de Itapevi
    • Jundiaí, São Paulo, Brazil
      • Dux Medicina
    • Matão, São Paulo, Brazil
      • Hospital Carlos Fenando Malzoni
    • Monte alto, São Paulo, Brazil
      • Centro de Atendimento Para O Enfrentamento A Covid-19 Da Prefeitura Municipal de Monte Altoprefeitura de Monte Alto
    • Ribeirão Preto, São Paulo, Brazil
      • Faculdade de Medicina de Ribeirão Preto
    • Ribeirão Preto, São Paulo, Brazil
      • Unimed Ribeirão Preto
    • Santos, São Paulo, Brazil
      • Hospital Casa de Saúde de Santos
    • São José Do Rio Preto, São Paulo, Brazil
      • Kaiser Clinica e Hospital Dia
    • São José Dos Campos, São Paulo, Brazil
      • Hospital Policlin
    • São José Dos Campos, São Paulo, Brazil
      • Hospital Regional de São José dos Campos
    • Votuporanga, São Paulo, Brazil
      • Santa Casa de Misericórdia de Votuporanga

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:

It will be considered eligible those adults (equal to or greater than 18 years) seeking medical care with suspected or confirmed COVID-19, with time between symptoms and inclusion ≤ 07 days, presenting mild symptoms, without indication of hospitalization and at least 1 risk factor for complication:

1. > 65 years;
2. Hypertension;
3. Diabetes mellitus;
4. Asthma;
5. COPD or other chronic lung diseases;
6. Smoking;
7. Immunosuppression;
8. Obesity (Defined as BMI equal to or greater than 30 Kg/m2).

Exclusion Criteria:

1. Patients under 18 years old;
2. Hospitalization at the first medical care;
3. Positive test for influenza at the first medical care;
4. Known hypersensitivity to hydroxychloroquine / chloroquine;
5. Previous diagnosis of retinopathy or macular degeneration;
6. Previous diagnosis of Long QT-syndrome, history of sudden death in close family members (parents and siblings), decompensated heart failure, unstable coronary artery disease, use of anti-arrhythmic drugs or other drugs that can increase the hydroxychloroquine bioavailability or enhance its effect;
7. Evidence of known liver disease, reported by the patient;
8. Evidence of known chronic kidney disease, reported by the patient;
9. Patients with pancreatitis;
10. Baseline ECG with QTc interval ≥ 480ms;
11. Chronic use of hydroxychloroquine/chloroquine for other reasons;
12. Pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydroxychloroquine (HCQ); HCQ group participants will receive a dose of 400mg twice daily (BID) in the first day, and a dose of 400 mg once daily (OD) from the second day of treatment, in a total of 7 days.	Drug: Hydroxychloroquine; Hydroxychloroquine pharmaceutical form will be tablets of 400 mg.
Placebo Comparator: Placebo; The placebo group will follow the same regimen of administration	Drug: Placebo; Hydroxychloroquine placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospitalization	To assess if the treatment is able to avoid hospitalization due to a COVID-19-related clinical reason within 30 days of randomization in an outpatient setting. Hospitalization is considered to be hospital stay for a period > 24h or an additional hospitalized calendar day.	30 days from randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Uncontrolled asthma after ≥ 5 days of starting study medication	Affirmative answer in three or four items of the Global Initiative for Asthma (GINA) questionnaire	within 30 days from randomization
Pneumonia	Defined by clinical-radiological criteria - a history of cough and one or more of the following symptoms: sputum, dyspnea, chest pain, sweating or fever (T> 37.8o C) + Chest CT scan showing ground-glass opacity, focal consolidations or mixed opacities (including reverse halo sign), uni or bilateral	within 30 days from randomization
Otitis media	Defined by clinical criteria - Fever (T> 37.8o C) and otalgia + bulging of the tympanic membrane	within 30 days from randomization
Fever resolution time	Day 0 of fever resolution will be defined as the first afebrile day (T <37.5o C) after inclusion in the study followed by at least two consecutive days. The temperature will be obtained through the participant report in the patient's diary	within 30 days from randomization
Time to improve respiratory symptoms	Time to improve respiratory symptoms (cough, runny nose)	within 30 days from randomization
Hospitalization in the Intensive Care Unit	Admission to ICU due to clinical reasons related to COVID-19	within 30 days from randomization
Need for Orotracheal Intubation	Clinical need for Orotracheal Intubation as assessed by the physician responsible for the case	within 30 days from randomization
Mechanical Ventilation Time	Number of days on mechanical ventilation until extubation or death	within 30 days from randomization
Mortality	Death due to any cause that occurred within 30 days after inclusion in the study	within 30 days from randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypoglycemia	Change in the frequency of hypoglycemic episodes in diabetic patients using hypoglycemic medication, perceived by clinical signs or symptoms or measured in a capillary or blood glucose device	within 30 days from randomization
Palpitations	Presence of cardiac arrhythmias in patients without known history of prolongation of the measure between Q wave and T wave in the heart's electrical cycle (QTc) or pre-existing heart disease;	within 30 days from randomization
Reduced visual acuity	Change in visual acuity or new diagnosis of retinal disease not previously documented	within 30 days from randomization
Diarrhea	Change in bowel habit greater than three (3) diarrheal episodes per day during the use of hydroxychloroquine medication and 3 days after its end	within 30 days from randomization
Anorexia	Change in appetite during medication use hydroxychloroquine and 3 days after the end of treatment	within 30 days from randomization
Emotional lability	Perception of change in emotional lability (mood swings) during hydroxychloroquine use and 3 days after the end of treatment	within 30 days from randomization
Time to hospitalization after randomization	Time from randomization to hospitalization	within 30 days from randomization
Assessment of the patient clinical status at the time of hospitalization	Clinical and vital signs assessed when admitted to hospital	within 30 days from randomization

Collaborators and Investigators

• Sponsor: Hospital Alemão Oswaldo Cruz
• Collaborators: Hospital Israelita Albert Einstein; Hospital Moinhos de Vento; Hospital do Coracao; Hospital Sirio-Libanes; Brazilian Research In Intensive Care Network; EMS S/A
• Investigators: Principal Investigator: Álvaro Avezum, Ph.D, International Research Center - Hospital Alemão Oswaldo Cruz

Publications and helpful links

General Publications

• Avezum A, Oliveira GBF, Oliveira H, Lucchetta RC, Pereira VFA, Dabarian AL, D O Vieira R, Silva DV, Kormann APM, Tognon AP, De Gasperi R, Hernandes ME, Feitosa ADM, Piscopo A, Souza AS, Miguel CH, Nogueira VO, Minelli C, Magalhaes CC, Morejon KML, Bicudo LS, Souza GEC, Gomes MAM, Fo JJFR, Schwarzbold AV, Zilli A, Amazonas RB, Moreira FR, Alves LBO, Assis SRL, Neves PDMM, Matuoka JY, Boszczowski I, Catarino DGM, Veiga VC, Azevedo LCP, Rosa RG, Lopes RD, Cavalcanti AB, Berwanger O; COPE - COALITION COVID-19 Brazil V Investigators. Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE - Coalition V): A double-blind, multicentre, randomised, controlled trial. Lancet Reg Health Am. 2022 Jul;11:100243. doi: 10.1016/j.lana.2022.100243. Epub 2022 Mar 31.
• Oliveira Junior HA, Ferri CP, Boszczowski I, Oliveira GBF, Cavalcanti AB, Rosa RG, Lopes RD, Azevedo LCP, Veiga VC, Berwanger O, Avezum A. Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients. Arq Bras Cardiol. 2022 Feb;118(2):378-387. doi: 10.36660/abc.20210832. English, Portuguese.

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2020
• Primary Completion (Actual): July 28, 2021
• Study Completion (Actual): September 28, 2021

Study Registration Dates

• First Submitted: July 3, 2020
• First Submitted That Met QC Criteria: July 9, 2020
• First Posted (Actual): July 10, 2020

Study Record Updates

• Last Update Posted (Actual): March 7, 2022
• Last Update Submitted That Met QC Criteria: March 4, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; Outpatients; Hydroxychloroquine; Severe Acute Respiratory Syndrome - Coronavirus-2; COALITION Brazil V 2019
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 30415320.8.1001.0070

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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