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

Phase 4

Completed

• Conditions: COVID-19
• Interventions: Drug: Placebo; Drug: Hydroxychloroquine

• Registration Number: NCT04466540
• Lead Sponsor: Hospital Alemão Oswaldo Cruz

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.

Study Timeline

• Study Start: 2020-05-12
• Study First Submitted: 2020-07-03
• Study First Submitted QC: 2020-07-09
• Study First Posted: 2020-07-10
• Primary Completion: 2021-07-28
• Study Completion: 2021-09-28
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-04
• Last Update Posted: 2022-03-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1372

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	The placebo group will follow the same regimen of administration
Hydroxychloroquine (HCQ)	Hydroxychloroquine	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.

Primary Outcome Measures

Name	Time	Method
Hospitalization	30 days from randomization	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.

Secondary Outcome Measures

Name	Time	Method
Pneumonia	within 30 days from randomization	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
Uncontrolled asthma after ≥ 5 days of starting study medication	within 30 days from randomization	Affirmative answer in three or four items of the Global Initiative for Asthma (GINA) questionnaire
Need for Orotracheal Intubation	within 30 days from randomization	Clinical need for Orotracheal Intubation as assessed by the physician responsible for the case
Otitis media	within 30 days from randomization	Defined by clinical criteria - Fever (T\> 37.8o C) and otalgia + bulging of the tympanic membrane
Time to improve respiratory symptoms	within 30 days from randomization	Time to improve respiratory symptoms (cough, runny nose)
Hospitalization in the Intensive Care Unit	within 30 days from randomization	Admission to ICU due to clinical reasons related to COVID-19
Mortality	within 30 days from randomization	Death due to any cause that occurred within 30 days after inclusion in the study
Fever resolution time	within 30 days from randomization	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
Mechanical Ventilation Time	within 30 days from randomization	Number of days on mechanical ventilation until extubation or death

Trial Locations

Locations (69)

Centro de Pesquisas Clínicas Dr. Marco Mota HCOR; 🇧🇷 Maceió, Alagoas, Brazil

Hospital e Clínica São Roque; 🇧🇷 Ipiaú, Bahia, Brazil

Clínica Otorhinus; 🇧🇷 Salvador, Bahia, Brazil

Hospital da Bahia; 🇧🇷 Salvador, Bahia, Brazil

Hospital Santa Izabel; 🇧🇷 Salvador, Bahia, Brazil

Instituto Cárdio Pulmonar da Bahia; 🇧🇷 Salvador, Bahia, Brazil

Hospital SAMUR; 🇧🇷 Vitória Da Conquista, Bahia, Brazil

Hospital Maternidade São Vicente de Paulo; 🇧🇷 Barbalha, Ceará, Brazil

Hospital Unimed Cariri; 🇧🇷 Juazeiro Do Norte, Ceará, Brazil

Unimed Sul Capixaba; 🇧🇷 Cachoeiro De Itapemirim, Espírito Santo, Brazil

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