Safety and Efficacy of Hydroxychloroquine Associated With Azithromycin in SARS-CoV2 Virus (Coalition Covid-19 Brasil II)

Study Overview
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Brief Summary
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The Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV2) is a new and recognized infectious disease of the respiratory tract. Around 20% of those infected have severe pneumonia and currently there is no specific or effective therapy to treat this disease. Therapeutic options using malaria drugs chloroquine and hydroxychloroquine have shown promising results in vitro and in vivo test. But those efforts have not involved large, carefully-conducted controlled studies that would provide the global medical community the proof that these drugs work on a significant scale. In this way, the present study will evaluate the effectiveness and safety of the use of hydroxychloroquine combined with azithromycin compared to hydroxychloroquine monotherapy in patients hospitalized with pneumonia by SARS-CoV2 virus.

Detailed Description
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The Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV2) is a new and recognized infectious disease of the respiratory tract that is now spreading to several countries in the world, including Brazil. Mortality rates after infection are higher in adults over 60 and with a history of comorbidities. The most serious patients need care in intensive care units (ICU). Most of the time they depend on mechanical ventilation support due to acute respiratory distress syndrome (ARDS). Infection rates are higher than the capacity for intensive care, which represents a serious problem in medical care. Around 20% of those infected have severe pneumonia and so far it does not have a specific therapy, or even, an effective clinical management. Therapeutic options using malaria drugs chloroquine and hydroxychloroquine have shown promising results in vitro and in vivo test. A recent, small, non-randomized study with hydroxychloroquine in 36 patients infected with SARS-Cov-2 proved to be promising in the ability to reset the viral load in 6 days after starting treatment. Thus, the present study will evaluate the effectiveness and safety of the use of hydroxychloroquine combined with azithromycin compared to hydroxychloroquine monotherapy in the clinical evolution by the ordinal scale of 6 points in adult patients hospitalized with pneumonia caused by infection by the SARS-CoV2 virus in Brazil.

Official Title
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Evaluation of the Safety and Clinical Efficacy of Hydroxychloroquine Associated With Azithromycin in Patients With Pneumonia Caused by Infection by the SARS-CoV2 Virus - Coalition COVID-19 Brasil II - SEVERE - Patients

Conditions
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Coronavirus Infections, Pneumonia, Viral

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females aged > 18 years; Suspected or confirmed infection by SARS-CoV2; Presenting with one of the following: Need for oxygen supplementation > 4 L/min, or Need for high-flow nasal canula, or Need for non-invasive ventilation, or Need for mechanical ventilation. Exclusion Criteria: Refusal to provide written informed consent (either the patient or a legal representative); Hypersensitivity to any of the drugs used in the study (Azithromycin or Hydroxychloroquine); Patients with more than 48 hours of prior study medication use; Patients with onset of symptoms longer than 14 days; Patients with long QT syndrome or severe ventricular arrhythmias, not protected by an implantable cardioverter defibrillators (ICD).; QTc>= 480ms; Do not resuscitate order or exclusive palliative care; Patients with liver disease or cirrhosis or abnormal liver enzyme tests above three times the upper limit values (alanine aminotransferase -ALT and aspartate aminotransferase - AST); Patients with known retinopathy or macular degeneration; Patients with history of pancreatitis; Patients with concomitant use of medications that alter the absorption or excretion of azithromycin or hydroxychloroquine; Breastfeeding women; 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: Intervention Group: Hydroxychloroquine + azithromycin. After randomization, Hydroxychloroquine [400mg 2x/day, 12/12h] + azithromycin [500mg 1x/day]) for 10 days. Standard treatment is according to the treatment protocol for 2019-nCoV infection. Active Control Group: Hydroxychloroquine. After randomization, Hydroxychloroquine [400mg 2x/day, 12/12h] for 10 days. Standard treatment is according to the treatment protocol for 2019-nCoV infection.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine + azithromycin<br>Hydroxychloroquine [400mg 2x/day, 12/12h] + azithromycin [500mg 1x/day] | Drug: Hydroxychloroquine + azithromycin<br>* Intervention Group: Hydroxychloroquine + azithromycin. After randomization, Hydroxychloroquine [400mg 2x/day, 12/12h] + azithromycin [500mg 1x/day]) for 10 days. Standard treatment is according to the treatment protocol for 2019-nCoV infection.<br>* Other names: HCQ+AZI;|
| Active Comparator: Hydroxychloroquine<br>Hydroxychloroquine [400mg 2x/day, 12/12h] | Drug: Hydroxychloroquine<br>* Active Control Group: Hydroxychloroquine. After randomization, Hydroxychloroquine [400mg 2x/day, 12/12h] for 10 days. Standard treatment is according to the treatment protocol for 2019-nCoV infection.<br>* Other names: HCQ;|

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 6 points (score ranges from 1 to 6, with 6 being the worst score) | 15 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | All-cause mortality rates at 29 days after randomization | 29 days after randomization | 
| Evaluation of the clinical status | Evaluation of the clinical status of patients on the 7th and 29th day after randomization defined by the Ordinal Scale of 6 points (score ranges from 1 to 6, with 6 being the worst score) | 7 and 29 days after randomization | 
| Number of days free from mechanical ventilation | Number of days free from mechanical ventilation at 29 days after randomization | 29 days after randomization | 
| Duration of mechanical ventilation | Number of days that the patient was on mechanical ventilation after randomization | 29 days after randomization | 
| Duration of hospitalization | Length of hospital stay on survivors | 29 days after randomization | 
| Other secondary infections | Presence of other secondary infections | 29 days after randomization | 
| Time from treatment start to death | Time from treatment start to death | 29 days after randomization | 
| Medium and long-term outcomes of SARS-CoV2 infection on morbimortality, daily life activities, mental health, and quality of life | Morbimortality, daily life activities, mental health, and quality of life | 3, 6, 9 and 12 months | 
| Assess whether the tested therapies may be affected by leucocyte phenotype | Leucocyte transcriptome | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV2 virus, 2019-nCOV, COVID-19, hydroxychloroquine, azithromycin