Clinical trial NCT04466540: Randomized Placebo-controlled Trial of Hydroxychloroquine in Outpatient Cases With Coronavirus Disease 2019 (COVID-19)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COVID-19
Keywords: COVID-19
Severe Acute Respiratory Syndrome - Coronavirus-2
Hydroxychloroquine
COALITION Brazil V 2019
Outpatients
Lead sponsor: Hospital Alemão Oswaldo Cruz
Sponsor class: OTHER
Collaborators: name: EMS S/A
name: Hospital do Coracao
name: Hospital Israelita Albert Einstein
name: Hospital Sirio-Libanes
name: Hospital Moinhos de Vento
name: Brazilian Research In Intensive Care Network
First posted: 2020-07-10
Enrollment: 1372
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Pragmatic, double-blind, placebo-controlled randomized parallel-group, two-arm clinical trial (with allocation ratio 1:1)
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Hospitalization
timeFrame: 30 days from randomization
Secondary outcomes:
measure: Uncontrolled asthma after ≥ 5 days of starting study medication
timeFrame: within 30 days from randomization
measure: Pneumonia
timeFrame: within 30 days from randomization
measure: Otitis media
timeFrame: within 30 days from randomization
measure: Fever resolution time
timeFrame: within 30 days from randomization
measure: Time to improve respiratory symptoms
timeFrame: within 30 days from randomization
measure: Hospitalization in the Intensive Care Unit
timeFrame: within 30 days from randomization
measure: Need for Orotracheal Intubation
timeFrame: within 30 days from randomization
measure: Mechanical Ventilation Time
timeFrame: within 30 days from randomization
measure: Mortality
timeFrame: within 30 days from randomization
Other outcomes:
measure: Hypoglycemia
timeFrame: within 30 days from randomization
measure: Palpitations
timeFrame: within 30 days from randomization
measure: Reduced visual acuity
timeFrame: within 30 days from randomization
measure: Diarrhea
timeFrame: within 30 days from randomization
measure: Anorexia
timeFrame: within 30 days from randomization
measure: Emotional lability
timeFrame: within 30 days from randomization
measure: Time to hospitalization after randomization
timeFrame: within 30 days from randomization
measure: Assessment of the patient clinical status at the time of hospitalization
timeFrame: within 30 days from randomization
Locations:
city: Maceió
country: Brazil
facility: Centro de Pesquisas Clínicas Dr. Marco Mota HCOR
state: Alagoas
city: Ipiaú
country: Brazil
facility: Hospital e Clínica São Roque
state: Bahia
city: Salvador
country: Brazil
facility: Clínica Otorhinus
state: Bahia
city: Salvador
country: Brazil
facility: Hospital da Bahia
state: Bahia
city: Salvador
country: Brazil
facility: Hospital Santa Izabel
state: Bahia
city: Salvador
country: Brazil
facility: Instituto Cárdio Pulmonar da Bahia
state: Bahia
city: Vitória Da Conquista
country: Brazil
facility: Hospital SAMUR
state: Bahia
city: Barbalha
country: Brazil
facility: Hospital Maternidade São Vicente de Paulo
state: Ceará
city: Juazeiro Do Norte
country: Brazil
facility: Hospital Unimed Cariri
state: Ceará
city: Cachoeiro De Itapemirim
country: Brazil
facility: Unimed Sul Capixaba
state: Espírito Santo
city: Goiânia
country: Brazil
facility: Hospital das Clínicas Universidade Federal de Goiás
state: Goiás
city: Passos
country: Brazil
facility: Santa Casa de Misericórdia de Passos
state: Minas Agerais
city: Belo Horizonte
country: Brazil
facility: Hospital Júlia Kubitschek
state: Minas Gerais
city: Belo Horizonte
country: Brazil
facility: Instituto da Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa
state: Minas Gerais
city: Carangola
country: Brazil
facility: Casa de Caridade de Carangola
state: Minas Gerais
city: Poços De Caldas
country: Brazil
facility: Hospital Maternidade e Pronto Socorro Santa Lucia
state: Minas Gerais
city: São João Del Rei
country: Brazil
facility: Hospital da Unimed
state: Minas Gerais
city: São João Del Rei
country: Brazil
facility: Santa Casa de Misericórdia de São João Del Rei
state: Minas Gerais
city: Uberaba
country: Brazil
facility: Hospital de Clínicas da Universidade Federal do Triangulo Mineiro
state: Minas Gerais
city: Uberlândia
country: Brazil
facility: Hospital de Clínicas da Universidade Federal de Uberlândia
state: Minas Gerais
city: Campo Largo
country: Brazil
facility: Hospital do Rocio
state: Paraná
city: Maringá
country: Brazil
facility: Clínica Clinilive
state: Paraná
city: Maringá
country: Brazil
facility: Hospital Universitário Regional de Maringá
state: Paraná
city: Recife
country: Brazil
facility: PROCAPE
state: Pernambuco
city: Recife
country: Brazil
facility: Real Hospital Português de Beneficência em Pernambuco
state: Pernambuco
city: Sairé
country: Brazil
facility: SECRETARIA MUNICIPAL DE SAÚDE DE SAIRÉ (Unidade Mista Olília Mendonça Souto Maior)
state: Pernambuco
city: Niterói
country: Brazil
facility: Complexo Hospitalar de Niterói
state: Rio De Janeiro
city: Volta Redonda
country: Brazil
facility: Hospital Unimed Volta Redonda
state: Rio De Janeiro
city: Bento Gonçalves
country: Brazil
facility: Associação Dr. Bartholomeu Tacchini
state: Rio Grande Do Sul
city: Passo Fundo
country: Brazil
facility: Hospital São Vicente de Paulo
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Santa Casa de Misericórdia de Porto Alegre (ISCMPA)
state: Rio Grande Do Sul
city: Santa Maria
country: Brazil
facility: Universidade Federal de Santa Maria
state: Rio Grande Do Sul
city: Porto Velho
country: Brazil
facility: CEPEM Centro de Pesquisa de Medicina Tropical de Rondônia
state: Rondônia
city: Monte alto
country: Brazil
facility: Irmandade de Misericórdia Do Hospital Da Santa Casa de Monte Alto
state: Salto Alto
city: Blumenau
country: Brazil
facility: Maestri e Kormann Consultoria Medico Cientifica
state: Santa Catarina
city: Brusque
country: Brazil
facility: Imigrantes Hospital e Maternidade
state: Santa Catarina
city: Criciúma
country: Brazil
facility: Hospital São José
state: Santa Catarina
city: Joinville
country: Brazil
facility: Hospital Regional Hans Dieter Schmidt
state: Santa Catarina
city: Araras
country: Brazil
facility: Santa Casa de Araras
state: São Paulo
city: Barretos
country: Brazil
facility: Hospital de Amor
state: São Paulo
city: Barretos
country: Brazil
facility: Santa Casa de Misericórdia de Barretos
state: São Paulo
city: Barueri
country: Brazil
facility: Alphacor Cardiologia Clinica E Diagnóstica LTDA
state: São Paulo
city: Botucatu
country: Brazil
facility: Faculdade de Medicina de Botucatu, UNESP
state: São Paulo
city: Caraguatatuba
country: Brazil
facility: Hospital Regional do Litoral Norte
state: São Paulo
city: Cordeirópolis
country: Brazil
facility: Hospital de Cordeirópolis
state: São Paulo
city: Itapevi
country: Brazil
facility: Centro de Combate ao Coronavírus de Itapevi
state: São Paulo
city: Jundiaí
country: Brazil
facility: Dux Medicina
state: São Paulo
city: Matão
country: Brazil
facility: Hospital Carlos Fenando Malzoni
state: São Paulo
city: Monte alto
country: Brazil
facility: Centro de Atendimento Para O Enfrentamento A Covid-19 Da Prefeitura Municipal de Monte Altoprefeitura de Monte Alto
state: São Paulo
city: Ribeirão Preto
country: Brazil
facility: Faculdade de Medicina de Ribeirão Preto
state: São Paulo
city: Ribeirão Preto
country: Brazil
facility: Unimed Ribeirão Preto
state: São Paulo
city: Santos
country: Brazil
facility: Hospital Casa de Saúde de Santos
state: São Paulo
city: São José Do Rio Preto
country: Brazil
facility: Kaiser Clínica e Hospital Dia
state: São Paulo
city: São José Dos Campos
country: Brazil
facility: Hospital Policlin
state: São Paulo
city: São José Dos Campos
country: Brazil
facility: Hospital Regional de São José dos Campos
state: São Paulo
city: Votuporanga
country: Brazil
facility: Santa Casa de Misericórdia de Votuporanga
state: São Paulo
city: Lençois Paulista
country: Brazil
facility: ESF Dr. João Paccola Primo
city: Rio De Janeiro
country: Brazil
facility: Cardioclinica da Ilha do Governador
city: São Paulo
country: Brazil
facility: International Research Center - Hospital Alemão Oswaldo Cruz
city: São Paulo
country: Brazil
facility: Hospital do Coração
city: São Paulo
country: Brazil
facility: Hospital Israelita Albert Einstein
city: São Paulo
country: Brazil
facility: Hospital Leforte
city: São Paulo
country: Brazil
facility: Hospital Moriah
city: São Paulo
country: Brazil
facility: Hospital Samaritano
city: São Paulo
country: Brazil
facility: Hospital Santa Paula
city: São Paulo
country: Brazil
facility: Hospital São Camilo Pompéia
city: São Paulo
country: Brazil
facility: Hospital São Paulo - UNIFESP
city: São Paulo
country: Brazil
facility: Hospital Sírio-Libanês
Study officials:
affiliation: International Research Center - Hospital Alemão Oswaldo Cruz
name: Álvaro Avezum, Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.