Efficacy of Chloroquine or Hydroxychloroquine in Treating Pneumonia Caused by SARS-Cov-2 - COVID-19

Study Overview
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Brief Summary
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Facing the challenge of finding an efficient treatment for COVID-19, the viral pneumonia caused by the Coronavirus SARS-Cov-2, this study intended to test if Chloroquine or Hydroxychloroquine, two drugs with strong in-vitro antiviral role proven by numerous studies and with a well defined safety profile established, for efficacy in treating COVID-19 and improving an ordinal primary outcome composed by a 9-levels scale, which was recomended by the World Health Organization.

Detailed Description
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This is a Phase 3, Pragmatic, Multicentric Randomized Controled Trial of efficacy to test the effect of either Chloroquine or Hydroxychloroquine for 5 days in the recomended dose standardized by brazilian Ministry of Health. Patients were randomized (1:1) using stratified randomization by hospital and severity at the moment of randomization (stipulated by use of mechanical ventilation or not) into two arms: Intervention and Control. Intervention group recieved a loading dose of 900mg of Chloroquine or 800mg of Hydroxycloroquine in the first day, followed by 450mg of chloroquine of 400mg of hydroxychloroquine. Primary and secondary outcomes were evaluated on the 5th, 7th, 10th, 14th, 28th day after randomization. Although the outcomes presented in the latest version were updated late on ClinicalTrials.org, on October 23, 2020, these outcomes were already present in the trial protocol approved by the Brazilian National Commission for Ethics in Research on April 8, 2020 (approval number: 3960331) and amending the protocol, approved by the same National Commission on May 25, 2020 (approval number: 4044848)

Official Title
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Multicentric Pragmatic Randomized Controled Trial to Evaluate the Efficacy Chloroquine or Hydroxychloroquine for Five Days in Treating Pneumonia Caused by SARS-Cov-2 - COVID-19

Conditions
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Coronavirus, COVID, COVID-19, SARS-CoV 2, Corona Virus Infection

Intervention / Treatment
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* Drug: Chloroquine
* Drug: Hydroxychloroquine
* Other: standard care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult Males and non-pregnant females that accept and sign the informed consent. Hospitalized with COVID-19 suspection that has collected the confirmatory test To have at least one of thes symptoms: Fever, coughing, throat ache or runny nose. To have at least one of these findings: radiological findings that indicates COVID-10 (bilatareal ground grass images); O2 saturation lower than 94% without supplementation and crackles in lung auscultation; Need of O2 supplementation; Need of Mechanical Ventilation. Female patients must also agree to use efficient counterceptive methods during the evaluation period. Exclusion Criteria: Patients with psoriasis or other exfoliative disease, porphyria, epilepsy, myasthenia gravis, advanced liver failure or glucose-6-phosphate dehydrogenase deficiency. ALT / AST> 5 times the upper limit of normal. Severe chronic kidney disease in stage 4 or requiring dialysis (ie, eGFR <30). Pregnancy or breastfeeding. Early transfer to another hospital that is not a study site within 72 hours. Severe heart disease and / or a history of cardiac arrhythmia. Allergy to Chloroquine and / or Hydroxychloroquine.

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: Two arms - Intervention and Control Intervention received unblinded treatment with Chloroquine or Hyroxycloroquine for 5 days, as well as standard treatment available and recomended by the Brazilian Guidelines for COVID-19. Control group received just the standard treatment available and recomended by the Brazilian Guidelines for COVID-19.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Treatment with either Chloroquine or Hydroxychloroquine according to what was available in the hospital: Chloroquine - 900mg on the first day, followed by 450mg in the next 4 days. Hydroxychloroquine - 800mg on the first day, followed by 450mg in the next 4 days. + Standard treatment available and recomended by the Brazilian Guidelines for COVID-19. | Drug: Chloroquine<br>* 5 days of treatment with Chloroquine + Standard Care<br>Drug: Hydroxychloroquine<br>* 5 days of treatment with Hydroxychloroquine + Standard Care<br>|
| Active Comparator: Control<br>Standard treatment available and recomended by the Brazilian Guidelines for COVID-19. | Other: standard care<br>* Standard Care according to Brazilian Guidelines for treating COVID-19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| World Health Organization (WHO) 9-levels ordinal scale (from 0-8) | Evaluation of the clinical status of patients on the 14th day after randomization defined by the 9-levels ordinal scale, with lower scores meaning better outcomes. | 14 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| World Health Organization (WHO) 9-levels ordinal scale (from 0-8) | Evaluation of the clinical status of patients on the 5th, 7th, 10th and 28th day after randomization defined by the 9-levels ordinal scale, with lower scores meaning better outcomes. | 5, 7, 10 and 28 days after randomization | 
| Mortality | All-cause mortality at 28 days after randomization | 28 days after randomization | 
| Ventilation free days | Number of days without need of Mechanical Ventilation at 28 days after randomization | 28 days after randomization | 
| ICU Lenght of Stay | ICU Lenght of Stay on survivors at 28 days after randomization | 28 days after randomization | 
| Hospital Lenght of Stay | Hospital Lenght of Stay on survivors at 28 days after randomization | 28 days after randomization | 
| Acute Kidney Disease incidence | Acute Kidney Disease incidence measured by Kidney Disease Improving Global Outcomes (KDIGO) stage 3 sometime until the 28th day after randomization. | 28 days after randomization | 
| Percentage of patients needing dialysis | Percentage of patients needing dialysis sometime until the 28th day. | 28 days after randomization | 
| Coagulopathy incidence | Presence of coagulopathy sometime until the 28th day (platelets < 150000 and/or INR >1.5 and/or KPTT > 35 seconds). | 28 days after randomization | 
| Mean of C Reactive Protein Levels | Mean of C Reactive Protein Levels on the 5th, 7th, 10th, 14th and 28th day after randomization, during period of hospitalization | 5, 7, 10, 14 and 28 days after randomization | 
| Sequential Organ Failure Assessment (SOFA) scores | Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) on the 5th, 7th, 10th, 14th and 28th day after randomization, during period of hospitalization. | 5, 7, 10, 14 and 28 days after randomization | 
| Neutrophils/lymphocytes ratio | Neutrophils/lymphocytes ratio on the 5th, 7th, 10th, 14th and 28th day after randomization, during period of hospitalization. | 5, 7, 10, 14 and 28 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VIRAL PNEUMONIA, CORONAVIRUS, COVID-19, COVID, SARS-COV-2