Chloroquine Diphosphate for the Treatment of Severe Acute Respiratory Syndrome Secondary to SARS-CoV2 (CloroCOVID19)

Efficacy and Safety of Chloroquine Diphosphate for the Treatment of Hospitalized Patients With Severe Acute Respiratory Syndrome Secondary to SARS-CoV2: a Phase IIb, Double-blind, Randomized Adaptive Clinical Trial

In December 2019, the Municipal Health Committee of Wuhan, China, identified an outbreak of viral pneumonia of unknown cause. This new coronavirus was called SARS-CoV-2 and the disease caused by that virus, COVID-19. Recent numbers show that 222,643 infections have been diagnosed with 9115 deaths, worldwide. Currently, there are no approved therapeutic agents available for coronaviruses. In this scenario, the situation of a global public health emergency and evidence about the potential positive effect of chloroquine (CQ) in most coronaviruses, including SARS-CoV-1, and recent data on small trials on SARS-CoV-2, the investigators intend to investigate the efficacy and the safety of CQ diphosphate in the treatment of hospitalized patients with severe acute respiratory syndrome in the scenario of SARS-CoV2. Preliminary in vitro studies and uncontrolled trials with low number of patients of CQ repositioning in the treatment of COVID-19 have been encouraging. The main hypothesis is that CQ diphosphate will reduce mortality in 50% in those with severe acute respiratory syndrome infected by the SARS-COV2. Therefore, the main objective is to assess whether the use of chloroquine diphosphate reduces mortality by 50% in the study population. The primary outcome is mortality in day 28 of follow-up. According to local contingency plan, developed by local government for COVID-19 in the State of Amazonas, the Hospital Pronto-Socorro Delphina Aziz, located in Manaus, is the reference unit for the admission of serious cases of the new virus. The unit currently has 50 ICU beds, with the possibility of expanding to 335 beds, if needed. The hospital also has trained multiprofessional human resources and adequate infrastructure. In total, 440 participants (220 per arm) will receive either high dose chloroquine 600 mg bid regime (4x150 mg tablets, every 12 hours, D1-D10) or low dose chloroquine 450mg bid regime (3x150mg tablets + 1 placebo tablet every 12 hours on D1, 3x150mg tablets + 1 placebo followed by 4 placebo tablets 12h later from D2 to D5, and 4 placebo tablets every 12 hours, D6-D10). Placebo tablets were used to standardize treatment duration and blind research team and patients. All drugs administered orally (or via nasogastric tube in case of orotracheal intubation). Both intervention and placebo drugs will be produced by Farmanguinhos. Clinical and laboratory data during hospitalization will be used to assess efficacy and safety outcomes.

Study Overview

• Status: Completed
• Conditions: SARS-CoV Infection; Severe Acute Respiratory Syndrome (SARS) Pneumonia
• Intervention / Treatment: Drug: Chloroquine diphosphate

• Study Type: Interventional
• Enrollment (Actual): 278
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Amazonas
    • Manaus, Amazonas, Brazil, 69093-415
      • Hospital e Pronto Socorro Delphina Rinaldi Abdel Aziz

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:

1. Male and female participants aged over 18 years old
2. Hospitalized

3. presenting:

   • respiratory rate higher than 24 breathing incursions per minute AND/OR
   • heart rate higher than 125 beats per minute (in the absence of fever) AND/OR
   • peripheral oxygen saturation lower than 90% in ambient air AND/OR
   • shock (defined as mean arterial pressure less than 65 mmHg, requiring vasopressor or oliguria or lowering level of consciousness)

Exclusion Criteria:

• None.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low Dose Chloroquine Diphosphate (5 days) (Study stage 1) - Clorocovid 1; Low dose chloroquine group consists of 450 mg bid (3 tablets of 150 mg + 1 placebo tablet, every 12 hours) on D1, 3x150mg tablets + 1 placebo followed by 4 placebo tablets 12h later from D2 to D5, and 4 placebo tablets every 12 hours, D6-D10 . Oral administration or via nasogastric tube in case of orotracheal intubation. (this was the first stage of the original study and was approved by the Brazilian IRB on 23/March/2020).	Drug: Chloroquine diphosphate; 150mg chloroquine diphosphate tablets. Note: Tablets used in the study were Chloroquine Diphosphate (produced by Farmanguinhos/Fiocruz), and the dosing stated in the clinicaltrials.gov refers to chloroquine base (in mg).; Other Names: chloroquine
Active Comparator: High Dose Chloroquine Diphosphate (10 days) (Study stage 1) - Clorocovid 1; High dose chloroquine group consists of 600 mg bid (4 tablets of 150 mg, every 12 hours) for 10 days. Oral administration or via nasogastric tube in case of orotracheal intubation. (this was the first stage of the original study and was approved by the Brazilian IRB on 23/March/2020).	Drug: Chloroquine diphosphate; 150mg chloroquine diphosphate tablets. Note: Tablets used in the study were Chloroquine Diphosphate (produced by Farmanguinhos/Fiocruz), and the dosing stated in the clinicaltrials.gov refers to chloroquine base (in mg).; Other Names: chloroquine
Placebo Comparator: Placebo (5 days) (Study stage 2) - Clorocovid 3; Placebo group consists of 3 placebo tablets bid (day 1), and 3 placebo tablets once daily from D2 to D5. Oral administration or via a nasogastric tube in case of orotracheal intubation. (this was a second stage of the original study and was approved by the Brazilian IRB on 03/May/2020).	Drug: Chloroquine diphosphate; 150mg chloroquine diphosphate tablets. Note: Tablets used in the study were Chloroquine Diphosphate (produced by Farmanguinhos/Fiocruz), and the dosing stated in the clinicaltrials.gov refers to chloroquine base (in mg).; Other Names: chloroquine
Active Comparator: Low Dose Chloroquine Diphosphate (5 days) (Study stage 2) - Clorocovid 3; Low dose chloroquine group consisted of 450 mg bid (3 tablets of 150 mg) on D1, and 3x150mg tablet once daily from D2 to D5. Oral administration or via a nasogastric tube in case of orotracheal intubation. (this was a second stage of the original study and was approved by the Brazilian IRB on 03/May/2020).	Drug: Chloroquine diphosphate; 150mg chloroquine diphosphate tablets. Note: Tablets used in the study were Chloroquine Diphosphate (produced by Farmanguinhos/Fiocruz), and the dosing stated in the clinicaltrials.gov refers to chloroquine base (in mg).; Other Names: chloroquine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality rate reduction of 50% by day 28	proportion of deaths at day 28 between groups compared	28 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute mortality on days 7 and 14	number of deaths at days 7 and 14 between groups compared	7 and 14 days after first dose
Improvement in overall subject's clinical status assessed in standardized clinical questionnaires on days 14 and 28	clinical status	14 and 28 days after first dose
Improvement in daily clinical status assessed in standardized clinical questionnaires during hospitalization	clinical status	during and after intervention, up to 28 days
Duration of supplemental oxygen (if applicable)	supplemental oxygen	during and after intervention, up to 28 days
Duration of mechanical ventilation (if applicable)	mechanical ventilation	during and after intervention, up to 28 days
Absolute duration of hospital stay in days	hospitalization	during and after intervention, up to 28 days
Prevalence of grade 3 and 4 adverse events	adverse events grade 3 and 4	during and after intervention, up to 28 days
Prevalence of serious adverse events	adverse events	during and after intervention, up to 28 days
Change in serum creatinine level	increase or decrease in serum creatinine compared to baseline	during and after intervention, up to 28 days
Change in serum troponin I level	increase or decrease in serum troponin I compared to baseline	during and after intervention, up to 28 days
Change in serum aspartate aminotransferase level	increase or decrease in serum aspartate aminotransferase compared to baseline	during and after intervention, up to 28 days
Change in serum CK-MB level	increase or decrease in serum aspartate aminotransferase compared to baseline	during and after intervention, up to 28 days
Change in detectable viral load in respiratory tract swabs	virus clearance from respiratory tract secretion	during and after intervention, up to 28 days
Viral concentration in blood samples	viremia in blood detected through RT-PCR	during and after intervention, up to 28 days
Absolute number of causes leading to participant death (if applicable)	death	during and after intervention, up to 28 days

Collaborators and Investigators

• Sponsor: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
• Collaborators: Marcus Vinícius Guimarães de Lacerda; Mayla Gabriela Silva Borba; Wuelton Marcelo Monteiro; Gisely Cardoso de Melo; Fernando Fonseca de Almeida e Val; Felipe Gomes Naveca; Maria Paula Gomes Mourão; Ludmila Abrahão Hajjar; Jorge Souza Mendonça

Publications and helpful links

General Publications

• Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, Mourao MPG, Brito-Sousa JD, Baia-da-Silva D, Guerra MVF, Hajjar LA, Pinto RC, Balieiro AAS, Pacheco AGF, Santos JDO Jr, Naveca FG, Xavier MS, Siqueira AM, Schwarzbold A, Croda J, Nogueira ML, Romero GAS, Bassat Q, Fontes CJ, Albuquerque BC, Daniel-Ribeiro CT, Monteiro WM, Lacerda MVG; CloroCovid-19 Team. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open. 2020 Apr 24;3(4):e208857. doi: 10.1001/jamanetworkopen.2020.8857.

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2020
• Primary Completion (Actual): May 7, 2020
• Study Completion (Actual): June 7, 2020

Study Registration Dates

• First Submitted: March 19, 2020
• First Submitted That Met QC Criteria: March 25, 2020
• First Posted (Actual): March 26, 2020

Study Record Updates

• Last Update Posted (Actual): August 9, 2021
• Last Update Submitted That Met QC Criteria: August 2, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; SARS-CoV Infection; Clinical trial; Severe Acute Respiratory Syndrome (SARS) Pneumonia; Chloroquine Diphosphate
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease; Severe Acute Respiratory Syndrome; Syndrome; Pneumonia; Physiological Effects of Drugs; Anti-Infective Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Amebicides; Filaricides; Antinematodal Agents; Anthelmintics; Chloroquine; Chloroquine diphosphate
• Other Study ID Numbers: CAAE: 30152620.1.0000.0005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: all patient data will be shared after study publication
• IPD Sharing Time Frame: after study publication
• IPD Sharing Access Criteria: upon request to researchers
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No