Clinical trial NCT04323527: Chloroquine Diphosphate for the Treatment of Severe Acute Respiratory Syndrome Secondary to SARS-CoV2
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: SARS-CoV Infection
Severe Acute Respiratory Syndrome (SARS) Pneumonia
Keywords: COVID-19
SARS-CoV Infection
Severe Acute Respiratory Syndrome (SARS) Pneumonia
Chloroquine Diphosphate
Clinical trial
Lead sponsor: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Sponsor class: OTHER
Collaborators: name: Marcus Vinícius Guimarães de Lacerda
name: Mayla Gabriela Silva Borba
name: Wuelton Marcelo Monteiro
name: Gisely Cardoso de Melo
name: Fernando Fonseca de Almeida e Val
name: Felipe Gomes Naveca
name: Maria Paula Gomes Mourão
name: Ludmila Abrahão Hajjar
name: Jorge Souza Mendonça
First posted: 2020-03-26
Enrollment: 278
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Mortality rate reduction of 50% by day 28
timeFrame: 28 days after randomization
Secondary outcomes:
measure: Absolute mortality on days 7 and 14
timeFrame: 7 and 14 days after first dose
measure: Improvement in overall subject's clinical status assessed in standardized clinical questionnaires on days 14 and 28
timeFrame: 14 and 28 days after first dose
measure: Improvement in daily clinical status assessed in standardized clinical questionnaires during hospitalization
timeFrame: during and after intervention, up to 28 days
measure: Duration of supplemental oxygen (if applicable)
timeFrame: during and after intervention, up to 28 days
measure: Duration of mechanical ventilation (if applicable)
timeFrame: during and after intervention, up to 28 days
measure: Absolute duration of hospital stay in days
timeFrame: during and after intervention, up to 28 days
measure: Prevalence of grade 3 and 4 adverse events
timeFrame: during and after intervention, up to 28 days
measure: Prevalence of serious adverse events
timeFrame: during and after intervention, up to 28 days
measure: Change in serum creatinine level
timeFrame: during and after intervention, up to 28 days
measure: Change in serum troponin I level
timeFrame: during and after intervention, up to 28 days
measure: Change in serum aspartate aminotransferase level
timeFrame: during and after intervention, up to 28 days
measure: Change in serum CK-MB level
timeFrame: during and after intervention, up to 28 days
measure: Change in detectable viral load in respiratory tract swabs
timeFrame: during and after intervention, up to 28 days
measure: Viral concentration in blood samples
timeFrame: during and after intervention, up to 28 days
measure: Absolute number of causes leading to participant death (if applicable)
timeFrame: during and after intervention, up to 28 days
Other outcomes:
Locations:
city: Manaus
country: Brazil
facility: Hospital e Pronto Socorro Delphina Rinaldi Abdel Aziz
state: Amazonas
Study officials:
References:
citation: 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.