Ivermectin compared with placebo in the clinical course in Mexican patients with asymptomatic and mild COVID-19: a randomized clinical trial
Carmen De La Rocha, Marco A Cid-López, Blanca I Venegas-López, Sandra C Gómez-Méndez, Adriana Sánchez-Ortiz, Alma M Pérez-Ríos, Ricardo A Llamas-Velázquez, Aidé I Meza-Acuña, Bárbara Vargas-Íñiguez, Daniela Rosales-Galván, Alejandra Tavares-Váldez, Nizdali Luna-Gudiño, Cinthia V Hernández-Puente, Jovana Milenkovic, Cecilia Iglesias-Palomares, Miriam Méndez-Del Villar, Gerardo A Gutiérrez-Dieck, Carlos G Valderrábano-Roldán, Jennefer Mercado-Cerda, Jocelyn G Robles-Bojórquez, Arieh R Mercado-Sesma
BMC Infectious Diseases, doi:10.1186/s12879-022-07890-6
Background: Despite the development and application of vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) around the world, the scientific community is still trying to find some therapies to avoid or ameliorate the fatal evolution of the Coronavirus disease 2019 . Since the publication of the potential use of ivermectin as a treatment against the disease, a pleiad of information about it has been published. However, the evidence is not strong or weak enough to conclude its usefulness in the clinical evolution of patients infected with SARS-CoV-2. We evaluate the efficacy and safety of ivermectin in the treatment of Mexican patients with asymptomatic and mild COVID-19 in a three-day administration in comparison to placebo.
Methods: A randomized, double-blind, placebo-controlled trial was carried out in 66 adults with asymptomatic and mild COVID-19. Patients were randomly assigned 1:1 ratio to ivermectin plus acetaminophen or placebo plus acetaminophen. The primary endpoint was the proportion of subjects without a disease progression to severity according to COVID-19 guidelines by the National Institutes of Health (NIH) since randomization to 14 days. Results: None of the participants presented progression to a severe state in either group. Viral load was measured on Days 1, 5, and 14. No significant differences were observed in baseline or 14-day between groups (p = 0.720 and 0.362, respectively). However, on Day 5, a significant difference in viral load was observed between groups (p = 0.039). The frequency of symptoms was similar between groups, and no significant differences were observed. The most frequent symptom was cough. One severe adverse event associated with SARS-CoV-2 infection was observed in the ivermectin group.
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12879-022-07890-6. Additional file 1. CONSORT checklist.
Additional file 2. Supplementary tables. Author contributions dlRC, MSAR and CLM: Conceptualization, methodology, formal analysis, investigation, writing original draft visualization, and validation. VLB and GMSC: writing review and editing. HPCV, MJ, SOA, PRAM, LVRA, MAAI, VIB, IPC, and RGD: resources, formal analysis, software and methodology. TVA, LGN, MVM GDGA, VRCG, MCJ and RBJG: writing review, conceptualization, funding acquisition and supervision. All authors contributed to the interpretation of the results, provided critical revisions. All authors read and approved the final manuscript.
Funding Investigación Biomédica para el Desarrollo de Fármacos S.A. de C.V. covered all the expenses generated during the study. This trial was supported Investigación Biomédica para el Desarrollo de Fármacos S.A. de C.V. The funding source participated in study design, data collection, data analysis, data interpretation, or writing of the report, since most of the team are affiliated, but no commercial purposes are intended with this trial results.
Declarations Ethics approval and consent to participate The protocol was approved by the local ethics, biosafety and investigation committees and the Mexican health ministry COFEPRIS: 203301410A0055. The study is registered on ClinicalTrials.gov: NCT04407507...
Ahmed, Karim, Ross, A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness, Int J Infect Dis
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res
Canga, Prieto, Liébana, Martínez, Vega et al., The pharmacokinetics and interactions of ivermectin in humans-a minireview, AAPS J
Chaccour, Casellas, Blanco-Di Matteo, The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: a pilot, double-blind, placebocontrolled, randomized clinical trial, EClinicalMedicine
Crump, Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise and exceed expectations, J Antibiot
Garg, Paliwal, Gupta, Encephalopathy in patients with COVID-19: a review, J Med Virol
Hariyanto, Halim, Gunawan, Kurniawan, Ivermectin and outcomes from Covid-19 pneumonia: a systematic review and metaanalysis of randomized clinical trial studies, Rev Med Virol, doi:10.1002/rmv.2265
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
Kim, An, Kim, Hwang, Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: a systematic review and network meta-analysis, PLoS Med
Liu, Yan, Wan, Viral dynamics in mild and severe cases of COVID-19, Lancet Infect Dis
López-Medina, López, Hurtado, Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial, JAMA
Merck, Co, Stromectrol, FDA approved package insert
Mohan, Tiwari, Suri, Ivermectin in mild and moderate COVID-19 (RIVET-COV): a randomized, placebo-controlled trial, Prepr Res Sq, doi:10.21203/rs.3.rs-191648/v1
Okumuş, Demirtürk, Çetinkaya, Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients, BMC Infect Dis
Popp, Stegemann, Metzendorf, Gould, Kranke et al., Ivermectin for preventing and treating COVID-19, Cochrane Database System Rev
Pott-Junior, Paoliello, Miguel, Use of ivermectin in the treatment of Covid-19: a pilot trial, Toxicol Rep
Samaha, Mouawia, Fawaz, Effects of a single dose of ivermectin on viral and clinical outcomes in asymptomatic SARS-CoV-2 infected subjects: a pilot clinical trial in lebanon, Viruses
Schmith, Zhou, Lohmer, The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19, Clin Pharmacol Ther
Shahbaznejad, Davoudi, Eslami, Effects of ivermectin in patients with COVID-19: a multicenter, double-blind, randomized, controlled clinical trial, Clin Ther, doi:10.1016/j.clinthera.2021.04.007
Wölfel, Corman, Guggemos, Virological assessment of hospitalized patients with COVID-2019, Nature
Yang, Atkinson, Wang, The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antiviral Res
Ye, Ren, Lv, Encephalitis as a clinical manifestation of COVID-19, Brain Behav Immun