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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: > 65 years; Hypertension; Diabetes mellitus; Asthma; COPD or other chronic lung diseases; Smoking; Immunosuppression; Obesity (Defined as BMI equal to or greater than 30 Kg/m2). Exclusion Criteria: Patients under 18 years old; Hospitalization at the first medical care; Positive test for influenza at the first medical care; Known hypersensitivity to hydroxychloroquine / chloroquine; Previous diagnosis of retinopathy or macular degeneration; 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; Evidence of known liver disease, reported by the patient; Evidence of known chronic kidney disease, reported by the patient; Patients with pancreatitis; Baseline ECG with QTc interval ≥ 480ms; Chronic use of hydroxychloroquine/chloroquine for other reasons; Pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Pragmatic, double-blind, placebo-controlled randomized parallel-group, two-arm clinical trial (with allocation ratio 1:1)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine (HCQ)<br>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<br>* Hydroxychloroquine pharmaceutical form will be tablets of 400 mg.<br>|
| Placebo Comparator: Placebo<br>The placebo group will follow the same regimen of administration | Drug: Placebo<br>* Hydroxychloroquine placebo<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Severe Acute Respiratory Syndrome - Coronavirus-2, Hydroxychloroquine, COALITION Brazil V 2019, Outpatients