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

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; SARS-CoV 2; COVID; Corona Virus Infection; Coronavirus
• Intervention / Treatment: Drug: Chloroquine; Drug: Hydroxychloroquine; Other: standard care

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Parana
    • Curitiba, Parana, Brazil, 82530200
      • Centro de Estudos e Pesquisa em Emergencias Clinicas e Terapia Intensiva

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intervention; 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; 5 days of treatment with Chloroquine + Standard Care; Drug: Hydroxychloroquine; 5 days of treatment with Hydroxychloroquine + Standard Care
ACTIVE_COMPARATOR: Control; Standard treatment available and recomended by the Brazilian Guidelines for COVID-19.	Other: standard care; Standard Care according to Brazilian Guidelines for treating COVID-19

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arrhythmia	Safety outcome: Any kind of arrhythmia identified by the attending physician at the time of the intercurrence, confirmed by an electrocardiogram (ECG), sometime until the 28th day	28 days after randomization

Collaborators and Investigators

• Sponsor: Centro de Estudos e Pesquisa em Emergencias Medicas e Terapia Intensiva

Publications and helpful links

General Publications

• Rea-Neto A, Bernardelli RS, Camara BMD, Reese FB, Queiroga MVO, Oliveira MC. An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients. Sci Rep. 2021 Apr 27;11(1):9023. doi: 10.1038/s41598-021-88509-9.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 16, 2020
• Primary Completion (ACTUAL): August 20, 2020
• Study Completion (ACTUAL): September 3, 2020

Study Registration Dates

• First Submitted: June 2, 2020
• First Submitted That Met QC Criteria: June 5, 2020
• First Posted (ACTUAL): June 9, 2020

Study Record Updates

• Last Update Posted (ACTUAL): May 12, 2021
• Last Update Submitted That Met QC Criteria: May 10, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; COVID; SARS-COV-2; CORONAVIRUS; VIRAL PNEUMONIA
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Coronavirus Infections; Pneumonia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Amebicides; Chloroquine; Hydroxychloroquine
• Other Study ID Numbers: CLOROTRIAL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No