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

• ClinicalTrials.gov Identifier: NCT04323527
• Recruitment Status: Completed
• First Posted: March 26, 2020
• Last Update Posted: August 9, 2021
• 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
• Information provided by (Responsible Party): Fundação de Medicina Tropical Dr. Heitor Vieira Dourado

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
SARS-CoV Infection; Severe Acute Respiratory Syndrome (SARS) Pneumonia	Drug: Chloroquine diphosphate	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 278 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 23, 2020
• Actual Primary Completion Date: May 7, 2020
• Actual Study Completion Date: June 7, 2020

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: chloroquine

Outcome Measures

Primary Outcome Measures :

1. Mortality rate reduction of 50% by day 28 [ Time Frame: 28 days after randomization ]
   proportion of deaths at day 28 between groups compared

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Brazil

Hospital e Pronto Socorro Delphina Rinaldi Abdel Aziz

Manaus, Amazonas, Brazil, 69093-415

Sponsors and Collaborators

Fundação de Medicina Tropical Dr. Heitor Vieira Dourado

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, Mourão MPG, Brito-Sousa JD, Baía-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.

• Responsible Party: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
• ClinicalTrials.gov Identifier: NCT04323527
• Other Study ID Numbers: CAAE: 30152620.1.0000.0005
• First Posted: March 26, 2020
• Last Update Posted: August 9, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

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

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Fundação de Medicina Tropical Dr. Heitor Vieira Dourado:

COVID-19; SARS-CoV Infection; Severe Acute Respiratory Syndrome (SARS) Pneumonia; Chloroquine Diphosphate; Clinical trial

Additional relevant MeSH terms:

Chloroquine; Chloroquine diphosphate; Pneumonia; Severe Acute Respiratory Syndrome; Syndrome; Disease; Pathologic Processes; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Amebicides; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Antimalarials; Antirheumatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Filaricides