Safety and Efficacy of Hydroxychloroquine Associated With Azithromycin in SARS-Cov-2 Virus (COVID-19)

Study Overview
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Brief Summary
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Coronavirus (COVID-19) is a somewhat new and recognized infectious disease that is now spreading to several countries in the world, including Brazil. Hydroxychloroquine and azithromycin may be useful for treating those patients. COALITION I study aims to compared standard of care, hydroxychloroquine plus azithromycin and hydroxychloroquine monotherapy for treatment of hospitalized patients with COVID-19. COALITION I will recruit 630 patients with infection by COVID-19 (210 per arm). Ordinal endpoint of status at 15 days will be the primary endpoint.

Detailed Description
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The current pandemic associated with coronavirus disease 2019 (COVID-19) represents a major global health challenge. There are no effective therapies for the management of COVID-19 that have been proven to improve clinical outcomes in this high-risk group of patients. Hydroxychloroquine and its combination with azithromycin have been suggested to improve viral clearance, but its effect on clinical outcomes remains uncertain. This is an open-label pragmatic multicentre randomized (concealed) clinical trial of 7 days of hydroxychloroquine (400 mg BID) plus azithromycin (500 mg once daily), hydroxychloroquine 400 mg BID, or standard of care for moderately severe hospitalized patients with suspected or confirmed COVID-19 (in-patients with up to 4L/minute oxygen supply through nasal catheter). Patients are randomized in around 50 recruiting sites (630 patients with confirmed COVID-19; 1:1:1; 210 patients per arm). The primary endpoint is a 7-level ordinal scale measured at 15-days: 1) not hospitalized, without limitations on activities; 2) not hospitalized, with limitations on activities; 3) hospitalized, not using supplementary oxygen; 4) hospitalized, using supplementary oxygen; 5) hospitalized, using high-flow nasal cannula or non-invasive ventilation; 6) hospitalized, on mechanical ventilation; 7) death. Secondary endpoints are the ordinal scale at 7 days, need for mechanical ventilation and rescue therapies during 15 days, need of high-flow nasal cannula or non-invasive ventilation during 15 days, length of hospital stay, in-hospital mortality, thromboembolic events, occurrence of acute kidney injury, defined as an increase in creatinine above 1.5 times the baseline value and number of days free of respiratory support at 15 days. Secondary safety outcomes include prolongation of QT interval on electrocardiogram, ventricular arrhythmias, and liver toxicity. The main analysis will consider all patients with confirmed COVID-19 in the groups they were randomly assigned.

Official Title
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An Open-label, Randomized Controlled Trial of Hydroxychloroquine and Azithromycin for COVID-19 Infection on Hospitalized, Noncritical Patients

Conditions
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Coronavirus Infections

Intervention / Treatment
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* Drug: Hydroxychloroquine Oral Product
* Drug: Hydroxychloroquine + azithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with suspected or confirmed COVID-19 admitted to inpatient units and intensive care units Exclusion Criteria: Need for oxygen supplementation > 4 litters per min Patients using a high-flow nasal catheter Patients using non-invasive mechanical ventilation Patients using invasive mechanical ventilation Males and females aged < 18 years Pregnancy Allergy to chloroquine or derivatives Allergy to azithromycin Patients that have already received more than one dose of either azithromycin or hydroxychloroquine before enrollment Patients with respiratory symptoms for more than 14 days

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine<br>Hydroxychloroquine after randomization, Hydroxychloroquine [400mg 2x/day, 12/12h] for 07 days. | Drug: Hydroxychloroquine Oral Product<br>* Hydroxychloroquine 400 mg BID<br>|
| Experimental: Hydroxychloroquine + azithromycin<br>Hydroxychloroquine + azithromycin. After randomization, Hydroxychloroquine [400mg 2x/day, 12/12h] + azithromycin [500mg 1x/day]) for 07 days. | Drug: Hydroxychloroquine + azithromycin<br>* Hydroxychloroquine 400 mg BID + azithromycin 500 mg once a day<br>|
| No Intervention: Control<br>standard treatment protocol for 2019-nCoV infection. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the clinical status | Evaluation of the clinical status of patients on the 15th day after randomization defined by the Ordinal Scale of 7 points. Alive at home without limitations on activities Alive at home without limitations on activities In the hospital without oxygen In the hospital using oxygen In the hospital using high-flow nasal catheter or non-invasive ventilation In hospital, on mechanical ventilation Dead | 15 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ordinal scale in 7 days | Evaluation of the clinical status of patients on the 7th day after randomization defined by the Ordinal Scale of 7 points. Alive at home without limitations on activities Alive at home without limitations on activities In the hospital without oxygen In the hospital using oxygen In the hospital using high-flow nasal catheter or non-invasive ventilation In hospital, on mechanical ventilation Dead | 7 days after randomization | 
| Need of intubation and mechanical ventilation | Need of intubation and mechanical ventilation up to the 7th day after randomization | 7 days after randomization | 
| Use of mechanical ventilation during hospital stay | Use of mechanical ventilation during hospital stay | 15 days after randomization | 
| Use of non-invasive ventilation | Use of non-invasive ventilation up to the 7th day after randomization | 7 days after randomization | 
| Hospital Length of Stay | Hospital Length of Stay | 28 days after randomization | 
| All-cause mortality | All-cause mortality rates during hospital stay | 28 days after randomization | 
| Thromboembolic complications | Occurrence of thromboembolic complications such as: Deep vein thrombosis Pulmonary Embolism Stroke | 15 days after randomization | 
| Acute renal disfunction | Occurrence of renal dysfunction, defined as an increase in creatinine above 1.5 times the baseline value | 15 days after randomization | 
| Number of days alive and free of respiratory support up to 15 days | Number of days alive and free of respiratory support up to 15 days (DAFOR15), defined as the sum of days patients did not require supplementary oxygen, non-invasive ventilation, high-flow nasal catheter neither mechanical ventilation at 15 -days. Patients that perished during the 15-day window will receive zero DAFOR15. | 15 days |