Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients

Haliton Alves de Oliveira Junior

Centro Internacional de Pesquisa, Hospital Alemão Oswaldo Cruz, São Paulo, SP – Brazil

Cleusa P. Ferri

Centro Internacional de Pesquisa, Hospital Alemão Oswaldo Cruz, São Paulo, SP – Brazil

Icaro Boszczowski

Centro Internacional de Pesquisa, Hospital Alemão Oswaldo Cruz, São Paulo, SP – Brazil

Gustavo B. F. Oliveira

Centro Internacional de Pesquisa, Hospital Alemão Oswaldo Cruz, São Paulo, SP – Brazil

Alexandre B. Cavalcanti

Instituto de Pesquisa HCor, São Paulo, SP – Brazil

Brazilian Research in Intensive Care Network (BRICnet), São Paulo, SP – Brazil

Regis G. Rosa

Brazilian Research in Intensive Care Network (BRICnet), São Paulo, SP – Brazil

Hospital Moinhos de Vento, Porto Alegre, PR – Brazil

Renato D. Lopes

Brazilian Clinical Research Institute (BCRI), São Paulo, SP – Brazil

Duke University Medical Center – Duke Clinical Research Institute, Durham – USA

Luciano C. P. Azevedo

Brazilian Research in Intensive Care Network (BRICnet), São Paulo, SP – Brazil

Instituto de Ensino e Pesquisa do Hospital Sírio-Libanês, São Paulo, SP – Brazil

Viviane C. Veiga

Brazilian Research in Intensive Care Network (BRICnet), São Paulo, SP – Brazil

Beneficência Portuguesa de São Paulo, São Paulo, SP – Brazil

Otavio Berwanger

Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, SP – Brazil

Álvaro Avezum on behalf of COPE - COALITION V COVID-19 trial investigators

Centro Internacional de Pesquisa, Hospital Alemão Oswaldo Cruz, São Paulo, SP – Brazil

Mailing Address: Álvaro Avezum • Hospital Alemão Oswaldo Cruz – International Research Center – Rua João Julião, 331. CEP 01323-903, Sao Paulo, SP – Brazil. E-mail: aavezum@haoc.com.br

Author Contributions

Conception and design of the research: Oliveira Junior HA, Ferri CP; Boszczowski I, Oliveira GBF, Rosa RG, Lopes RD, Veiga VC, Berwanger O, Avezum A, Cavalcanti AB; Acquisition of data: Oliveira Junior HA, Boszczowski I, Oliveira GBF, Avezum A; Analysis and interpretation of the data: Oliveira Junior HA, Oliveira GBF, Avezum A; Obtaining financing: Oliveira Junior HA, Oliveira GBF, Avezum A; Writing of the manuscript: Oliveira Junior HA, Ferri CP, Oliveira GBF, Avezum A; Critical revision of the manuscript for intellectual content: Oliveira Junior HA, Ferri CP, Oliveira GBF, Rosa RG, Lopes RD, Veiga VC, Berwanger O, Avezum A, Cavalcanti AB.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

COVID-19 status	Definition
Confirmed	Individual with laboratory confirmation of COVID-19 (RT-PCR SARS-CoV-2 virus detection), preferably collected between the 4th and 7th days of symptom onset by nasopharyngeal/oropharyngeal swabs, regardless of signs and symptoms.
Confirmed	Immunological test (rapid test or classic serology to detect IgM/IgG antibodies) in a sample collected after the 7th day of symptom onset, analyzed by a validated method.
Suspected	Patient who meets at least one of the following criteria*:
	Patient with acute respiratory disease (fever AND at least one sign/symptom of respiratory disease, for example, cough or dyspnea) AND a travel history or residing in a location that reports community transmission of COVID-19 during the 14 days prior to the onset of symptoms;
	Patient with acute respiratory disease AND having been in contact with a confirmed or probable case (with acute respiratory disease without laboratory confirmation) of COVID-19 in the 14 days prior to the onset of symptoms.

General Criteria
	Adults (> 18 years) seeking medical care with suspected or confirmed COVID-19, with ≤ 7 days from symptom onset, presenting with mild symptoms without clear indication for hospitalization and at least one of the following risk factors for clinical complications:
Inclusion Criteria
1.	Age > 65 years;
2.	Hypertension;
3.	Diabetes mellitus;
4.	Asthma;
5.	Chronic obstructive pulmonary disease or other chronic lung diseases;
6.	Smoking;
7.	Immunosuppression;
8.	Obesity (defined as body mass index ≥ 30 kg/m2).
Exclusion Criteria
1.	Immediate hospitalization after first medical care;
2.	Positive test for influenza at the first medical care;
3.	Known hypersensitivity to hydroxychloroquine/chloroquine;
4.	Previous diagnosis of retinopathy or macular degeneration;
5.	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 antiarrhythmic drugs or other drugs that can increase the bioavailability of hydroxychloroquine or enhance its effect;
6.	Evidence of known liver disease, reported by the patient;
7.	Evidence of known chronic kidney disease, reported by the patient;
8.	Patients with pancreatitis;
9.	Baseline electrocardiogram with QTc interval ≥ 480 ms;
10.	Chronic use of hydroxychloroquine/chloroquine for other reasons;
11.	Pregnancy.

Item	Definition
Initiation visit	All researchers will participate in a site initiation visit (web-based training) before the start of the study to ensure consistency of study procedures, including collection of the data.
Contact	Researchers will be able to call the Study Coordinating Center to solve issues or problems that may arise.
Data cleaning	Data cleaning to identify inconsistencies will be conducted periodically (approximately every 15 days). Centers will be notified about inconsistencies to provide correction.
Statistical validation	Statistical techniques for identifying errors will be carried out during the study. These analyses will include identification of missing data, inconsistent data, protocol deviations, adverse events reported incorrectly (data considered inconsistent with centralized medical review), and systematic error assessment.
Data review	The Coordinating/Sponsoring Center will review detailed reports monthly on screening, inclusion, follow-up, consistencies, and completeness of the data, and will take immediate action to solve any problems.

Brasil