COVID-19
Conditions
Keywords
COVID-19, Severe Acute Respiratory Syndrome - Coronavirus-2, Hydroxychloroquine, COALITION Brazil V 2019, Outpatients
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.
Interventions
DRUGHydroxychloroquine
Hydroxychloroquine pharmaceutical form will be tablets of 400 mg.
DRUGPlacebo
Hydroxychloroquine placebo
Sponsors
EMS S/A
Hospital do Coracao
Hospital Israelita Albert Einstein
Hospital Sirio-Libanes
Hospital Moinhos de Vento
Brazilian Research In Intensive Care Network
Hospital Alemão Oswaldo Cruz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Randomization (1:1) is generated by a validated software and performed in permuted blocks of size 8. Concealment of the randomization list is maintained through a 24-hour, centralized, automated, internet-based randomization system. Furthermore, as placebo-controlled study, the placebo will have the same structural characteristics as the active drug and will be dispensed in cartridges that do not allow the identification of what is being given
Intervention model description
Pragmatic, double-blind, placebo-controlled randomized parallel-group, two-arm clinical trial (with allocation ratio 1:1)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Otitis media | within 30 days from randomization | Defined by clinical criteria - Fever (T\> 37.8o C) and otalgia + bulging of the tympanic membrane |
| 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 |
| 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 |
| Need for Orotracheal Intubation | within 30 days from randomization | Clinical need for Orotracheal Intubation as assessed by the physician responsible for the case |
| Mechanical Ventilation Time | within 30 days from randomization | Number of days on mechanical ventilation until extubation or death |
| Mortality | within 30 days from randomization | Death due to any cause that occurred within 30 days after inclusion in the study |
Other
| Measure | Time frame | Description |
|---|---|---|
| Reduced visual acuity | within 30 days from randomization | Change in visual acuity or new diagnosis of retinal disease not previously documented |
| Diarrhea | within 30 days from randomization | Change in bowel habit greater than three (3) diarrheal episodes per day during the use of hydroxychloroquine medication and 3 days after its end |
| Anorexia | within 30 days from randomization | Change in appetite during medication use hydroxychloroquine and 3 days after the end of treatment |
| Emotional lability | within 30 days from randomization | Perception of change in emotional lability (mood swings) during hydroxychloroquine use and 3 days after the end of treatment |
| Time to hospitalization after randomization | within 30 days from randomization | Time from randomization to hospitalization |
| Assessment of the patient clinical status at the time of hospitalization | within 30 days from randomization | Clinical and vital signs assessed when admitted to hospital |
| Palpitations | within 30 days from randomization | 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; |
| Hypoglycemia | within 30 days from randomization | 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 |
Countries
Brazil
Outcome results
None listed