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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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SARS-CoV Infection, Severe Acute Respiratory Syndrome (SARS) Pneumonia

Intervention / Treatment
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* Drug: Chloroquine diphosphate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female participants aged over 18 years old Hospitalized 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.

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Dose Chloroquine Diphosphate (5 days) (Study stage 1) - Clorocovid 1<br>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<br>* 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).<br>* Other names: chloroquine;|
| Active Comparator: High Dose Chloroquine Diphosphate (10 days) (Study stage 1) - Clorocovid 1<br>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<br>* 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).<br>* Other names: chloroquine;|
| Placebo Comparator: Placebo (5 days) (Study stage 2) - Clorocovid 3<br>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<br>* 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).<br>* Other names: chloroquine;|
| Active Comparator: Low Dose Chloroquine Diphosphate (5 days) (Study stage 2) - Clorocovid 3<br>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<br>* 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).<br>* Other names: chloroquine;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-CoV Infection, Severe Acute Respiratory Syndrome (SARS) Pneumonia, Chloroquine Diphosphate, Clinical trial