Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with severe manifestations of SARS-CoV-2 infection
Luis Enrique Bermejo Galan, Nayara Melo Dos Santos, Jucineide Mauro Shosuka Asato, Jucineide Vieira Araújo, Adriana De Lima Moreira, Aléxia Mahara Marques Araújo, Artur Diogenes Pinheiro Paiva, Diego Guilherme Santos Portella, Frank Silas Saldanha Marques, Gabriel Melo Alexandre Silva, Joana De Sousa Resende, Marycassiely Rodrigues Tizolim, Poliana Lucenados Santos, Steffi Ferreira Buttenbender, Stephanye Batista De Andrade, Roberto Carlos Cruz Carbonell, Juliana Gomes Da Rocha, Ruy Guilherme Silveira De Souza, Allex Jardim Da Fonseca
Pathogens and Global Health, doi:10.1080/20477724.2021.1890887
Objective: Given the urgent need for strategies to minimize the damage caused by this pandemic, this study performed a randomized, double-blind phase 2 study to assess the safety of the effectiveness of chloroquine (CQ), hydroxychloroquine (HCQ) or ivermectin in severe forms of COVID-19, in addition to identifying predictors of mortality in this group of patients. Methods: Phase 2, double-blind, randomized study to assess the safety and efficacy of enteral CQ, HCQ or ivermectin in patients hospitalized for SARS-CoV-2 infection, admitted to a Reference Hospital in Roraima (Brazil) in may 2020. Patients were randomized in a 1:1:1 ratio. The endpoints were need of supplemental O 2 , invasive ventilation, admission in ICU and death. The study was approved by an independent IRB. Results: 168 patients were randomized. The mean age was 53.4 years (±15.6), most participants were male (n = 95; 58.2%). Therapy with corticosteroid, anticoagulant or antibiotics was a decision of the attending physicians, and there was no difference between the groups. The mortality was similar in three groups (22.2%; 21.3% and 23.0%) suggesting ineffectiveness of the drugs. No difference in the incidence of serious adverse events were observed. To be older than 60 years of age, obesity, diabetes, extensive pulmonary involvement and low SaO 2 at hospital admission due to independent risk factors for mortality. Conclusion: Although CQ, HCQ or ivermectin revealed a favorable safety profile, the tested drugs do not reduce the need for supplemental oxygen, ICU admission, invasive ventilation or death, in patients hospitalized with a severe form of COVID-19.
References
Baj, Karakuła-Juchnowicz, Teresiński, COVID-19: specific and non-specific clinical manifestations and symptoms: the current state of knowledge, J Clin Med
Barrows, Campos, Powell, A Screen of FDA-approved drugs for inhibitors of Zika virus infection, Cell Host Microbe
Brazil, Uso da Cloroquina como terapia adjuvante no tratamento de formas graves do COVID-19
Caly, Druce, Catton, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res
Cavalcanti, Zampieri, Rosa, Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2019014Chen, Liu, Liu, A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19
Cipriani, Zorzi, Ceccato, Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin, Int J Cardiol
Da, Xue, Yi, Ban, None
Deng, Liu, Liu, Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: a retrospective study, Chin Med J (Engl)
Du, Liang, Yang, Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study, Eur Respir J
Gao, Tian, Breakthrough, YX. Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends
Geleris, Sun, Platt, Observational study of hydroxychloroquine in hospitalized patients with Covid-19, N Engl J Med
Guan, Ni, Hu, Clinical characteristics of coronavirus disease 2019 in China, N Engl J Med
Götz, Magar, Dornfeld, Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import, Sci Rep
Heidary, Gharebaghi, Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen, J Antibiot
Huang, Wang, Li, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet
Kern, Mittenbühler, Vesting, Obesityinduced TNFα and IL-6 signaling: the missing link between obesity and inflammation-driven liver and colorectal cancers, Cancers
Kumar, Mukherjee, Harne, Novelty in the gut: a systematic review and meta-analysis of the gastrointestinal manifestations of COVID-19, BMJ Open Gastroenterol
Lee, Lee, Ivermectin inhibits porcine reproductive and respiratory syndrome virus in cultured porcine alveolar macrophages, Arch Virol
Mao, Qiu, He, Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis, Lancet Gastroenterol Hepatol
Mraz, Haluzik, The role of adipose tissue immune cells in obesity and low-grade inflammation, J Endocrinol
Petrosillo, Viceconte, Ergonul, SARS and MERS: are they closely related?, Clin Microbiol Infect
Porcheddu, Serra, Kelvin, Similarity in case fatality rates (CFR) of COVID-19/SARS-COV-2 in Italy and China, J Infect Dev Ctries
Pujadas, Chaudhry, Mcbride, SARS-CoV-2 viral load predicts COVID-19 mortality, Lancet Respir Med
Ruiz-Irastorza, Ramos-Casals, Brito-Zeron, Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review, Ann Rheum Dis
Sharun, Dhama, Patel, Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19
Tang, Cao, Han, Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial, BMJ
Velavan, Meyer, The COVID-19 epidemic, Trop Med Int Health
Wagstaff, Sivakumaran, Heaton, Ivermectin is a specific inhibitor of importin α/βmediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochem J
Wu, Wu, Liu, The SARS-CoV-2 outbreak: what we know, Int J Infect Dis
Xu, Han, Liu, Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus, PLoS Negl Trop Dis
Yang, Atkinson, Wang, The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antiviral Res
Yang, Yu, Xu, Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study, Lancet Respir Med
Yao, Ye, Zhang, In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis
Ye, Wang, Mao, The pathogenesis and treatment of the `cytokine storm' in COVID-19, J Infect
Yiu, Graham, Stengel, Dynamics of a cytokine storm, PLoS One
Zhao, Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies, Int J Antimicrob Agents
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