Randomized trials - Ivermectin repurposing for COVID-19 treatment of outpatients with mild disease in primary health care centers
Keywords:COVID-19; Ivermectin; Drug repurposing; Outpatient care; Primary Health Care.
Objective: to evaluate the therapeutic intervention with Ivermectin in outpatients with COVID-19 mild disease, to increase medical discharge and prevent the progression to moderate or severe disease. Methods: Randomized Trial, n= 254. The subjects were divided into experimental (EG: n= 110) and control groups (CG: n= 144). The EG received Ivermectin orally 0.6 mg/kg weight in two doses. All participants were by physical examination COVID-19 diagnosed with negative RT-PCR at the beginning and the end of protocol. Differences between the variables were determined using the Chi-square test (p<0.05). The contagion risk (Odds Ratio) was calculated using software STATA. Results: Both groups were similar in age, sex, and comorbidities. A significant reduction in the percentage of participants with symptoms (PPS) was observed in the EG and CG when the clinical evaluation of symptoms was performed from 5th to 9th day (p= 0.0005). When the clinical evaluation was performed from 10th to 14th day there was no significant difference. A higher proportion of medical discharge was observed in EG (98.2%) vs. CG (86.1%) (p= 0.0007). EG showed 8 times more chance of receiving medical discharge than CG (OR 8.71, 95% CI: 1·99 – 38.12, p= 0.004). The treatment effect with Ivermectin to obtain medical discharge from outpatient care was analyzed by logistic regression. Then, the chance to obtain medical discharge was independent of variables sex, age, and comorbidities. Conclusion: This work supports the potential efficacy of Ivermectin in outpatient care with mild COVID-19 as a potentially useful intervention of public health consideration.
Ashburn, T. T. & Thor, K. B. (2004). Drug repositioning: identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery [Internet].; 3(8):673–83. https://doi.org/10.1038/nrd1468
Bottan, N. L., Vera-Cossio, D. A., & Hoffmann, B. (2020). The unequal impact of the coronavirus pandemic: evidence of seventeen development countries [Internet]. https://publications.iadb.org/publications/english/document/The-Unequal-Impact-of-the-Coronavirus-Pandemic-Evidence-from-Seventeen-Developing-Countries.pdf
Bryant, A., Lawrie, T. A., Dowswell, T., Fordham, E. J., Mitchell, S., Hill, S. R., et al. (2021). Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. American Journal of Therapeutics. 28: e434–60. 10.1097/MJT.0000000000001442
Chaccour, C., Casellas, A., Blanco-Di Matteo, A., et al. (2021). 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, placebo-controlled, randomized clinical trial. EClinicalMedicine, 32:100720.
Chahla, R. E., Medina Ruiz, L., Ortega, E. S., et al. (2021). Prophylaxis Covid-19 in Healthcare Agents by Intensive Treatment with Ivermectin and Iota-carrageenan (Ivercar-Tuc). American Journal of Therapeutics, 28 (5). https://clinicaltrials.gov/ct2/show/NCT04701710?term=ivermectin&cond=Covid19&cntry=AR&city=Tucuman&draw=2&rank=1
Chahla, R. E., Medina Ruiz, L., Mena, T., et al. (2021). Cluster Randomised Trials – Ivermectin Repurposing for COVID-19 Treatment of Outpatient with Mild Disease in Primary Health Care Centers. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04784481#wrapper
Chahla, R. E., Medina Ruiz, L., Mena, T., et al. (2021). Cluster Randomised Trials – Ivermectin Repurposing for COVID-19 Treatment of Outpatient with Mild Disease in Primary Health Care Centers. Research Square. https://doi.org/10.21203/rs.3.rs-495945/v1
Chahla, R.E., Medina Ruiz, L., Mena, T., et al. (2021). Cluster Randomised Trials – Ivermectin Repurposing for COVID-19 Treatment of Outpatient with Mild Disease in Primary Health Care Centers. Research Square. https://doi.org/10.21203/rs.3.rs-495945/v2
Chahla, R. E., Medina Ruiz, L., Mena, T., et al. (2021). Cluster Randomised Trials – Ivermectin Repurposing for COVID-19 Treatment of Outpatient with Mild Disease in Primary Health Care Centers. medRxiv. https://www.medrxiv.org/content/medrxiv/early/2021/03/30/2021.03.29.21254554.full.pdf
Chahla, R. E., Medina Ruiz, L., Mena, T., et al. (2021). Cluster Randomised Trials – Ivermectin Repurposing for COVID-19 Treatment of Outpatient with Mild Disease in Primary Health Care Centers. medRxiv. https://www.medrxiv.org/content/10.1101/2021.03.29.21254554v1.full.pdf
Chahla, R. E., Medina Ruiz, L., Mena, T., et al. (2021). Cluster Randomised Trials – Ivermectin Repurposing for COVID-19 Treatment of Outpatient with Mild Disease in Primary Health Care Centers. medRxiv. https://www.medrxiv.org/content/10.1101/2021.03.29.21254554v1
Chong, C. R., & Sullivan, D. J. (2007). New uses for old drugs. Nature, 448(7154):645– https://doi.org/10.1038/448645a
Caly, L., Wagstaff, K. M., & Jans, D. A. (2012). Nuclear trafficking of proteins from RNA viruses: potential target for antivirals? Antiviral Research, 95(3):202–6.
Caly, L., Druce, J. D., Catton, M. G., Jans, D. A., & Wagsta, K. M. (2020). The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research, 178:104787.
Carvallo, H., Hirsch, R., Alkis, P., & Contreras, V. (2020). Study of the Efficacy and Safety of Topical Ivermectin + Iota-Carrageenan in the Prophylaxis against COVID-19 in Health Personnel. Journal of Biomedical Research and Clinical Investigation, 2(1).
Carvallo, H., Hirsch, R., & Farinella, M. E. (2020). Safety and efficacy of the combined use of ivermectin, dexamethasone, enoxaparin and aspirin against COVID 19. medRxiv the preprint server for health sciences; https://doi.org/10.1101/2020.09.10.20191619
Cassará, F. P. (2020). Ivermectina asociada a iota-Carragenina aplicada localmente en la cavidad bucal, en la profilaxis de la enfermedad COVID-19 en el personal de salud. Estudio IVERCAR01. 1–23.
Dyall, J., Coleman, C. M., Hart, B. J., et al. (2014). Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrobial Agents and Chemotherapy, 58(8):4885–93.
Edwards, G., Dingsdale, A., Helsby, N., Orme, M. L. E., & Breckenridge, A. M. (1988). The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution. European Journal of Clinical Pharmacology, 35:681– 4. 10.1007/BF00637608
Elgazzar, A., Hany, B., & Youssef, S. A. (2020). Efficacy and Safety of Ivermectin for Treatment and prophylaxis of COVID-19 Pandemic. Research Square [Internet], 1–9. https://doi.org/10.21203/rs.3.rs-100956/v1
Krolewiecki, A., Lifschitz, A., Moragas, M., et al. (2020). Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial. SSRN Electronic Journal [Internet]. 10.2139/ssrn.3714649
Lima-Morales, R., Méndez-Hernández, P., Flores, Y. N., et al. (2021). Effectiveness of a multidrug therapy consisting of ivermectin, azithromycin, montelukast and acetylsalicylic acid to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico. International Journal of Infectious Diseases, 105: 598-605.
Liu, Z., Fang, H., Reagan, K., et al. (2013). In silico drug repositioning-what we need to know. Drug Discovery Today. Elsevier Ltd, 18: 110–5.
López-Medina, E., López, P., Hurtado, I. C., et al. (2021). Effect of Ivermectin on Time to Resolution of Symptoms Among Adults with Mild COVID-19: A Randomized Clinical Trial. Journal American Medical Association. 1–10. http://www.ncbi.nlm.nih.gov/pubmed/33662102
Marshall, J. C., Murthy, S., Diaz, J., et al. (2020). A minimal common outcome measure set for COVID-19 clinical research. Lancet Infectious Diseases, 20(8): e192–7.
Mayer, M. A., Krolewiecki, A., Ferrero, A., Bocchio, M., Barbero, J., Miguel, M., Paladini, A., Delgado, C., Ojeda, J. R., Elorza, C., Bertone, A., Fleitas, P. E., Vera, G., & Kohan, M. R. (2022) Safety and Efficacy of a MEURI Program for the Use of High Dose Ivermectin in COVID-19 Patients. Frontiers in Public Health, 10:813378. 10.3389/fpubh.2022.813378
Ministerio de Salud de la Nación Argentina. Criteria for defining COVID-19 cases [Internet]. 2020. https://www.argentina.gob.ar/salud/coronavirus- COVID-19/definicion-de-caso
Ministerio de Salud Pública de la Provincia de Tucumán. Protocolo de Investigación I.D.D.E.A - TUC. 2020. https://msptucuman.gov.ar/wordpress/wp-content/uploads/2020/10/SPROTOCOLO-DE-INV-IDDEA.pdf
Neil, M., Fenton, N., Kow, C. S., Hasan, S. S., Popp, M., Stegemann, M., et al. (2021). Bayesian hypothesis testing and hierarchical modeling of ivermectin effectiveness. American Journal of Therapeutics. 28:CD015017. 10.1097/MJT.0000000000001450
Osterberg, L., & Blaschke, T. (2005). Adherence to Medication. The New England Journal of Medicine, 353(5):487–97.
Padhi, S., Pati, A., & Panda, A. K. (2021). Effect of ivermectin in the treatment of COVID-19: a trial sequential analysis highlighted the requirement of additional randomized controlled trials. Clinical Infectious Diseases. ciab692. 10.1093/cid/ciab692
Rodríguez Chamorro, MÁ., García-Jiménez, E., Amariles, P., Rodríguez Chamorro, A., & Faus, M. J. (2008). Revisión de tests de medición del cumplimiento terapéutico utilizados en la práctica clínica. Atención primaria, 40(8):413–7. 10.1157/13125407
Roman, Y. M., Burela, P. A., Pasupuleti, V., Piscoya, A., Vidal, J. E., & Hernandez, A. V. (2021). Ivermectin for the treatment of COVID-19: a systematic review and meta-analysis of randomized controlled trials. Clinical of Infectious Diseases. 10.1101/2021.05.21.21257595
Rubin, J. E., & Crowe, S. E. (2020). COVID-19 Symptoms: Longitudinal Evolution and Persistence in Outpatient Settings. Annals of Internal Medicine, 172(1): ITC1–14.
WHO-adverse reaction terminology (WHO-ART). In: Dictionary of Pharmaceutical Medicine. Springer Vienna; 2009. p. 192–3.
World Health Organization (WHO). Ethical issues related to study design for trials on therapeutics for Ebola Virus Disease. WHO Ethics Work Gr Meet. (2014) 1–7.
WHO. What we know about long-term effects of COVID-19. The latest on the COVID- 19 global situation and long-term sequelae. 2020; (September). https://www.who.int/docs/default-source/coronaviruse/risk-comms-updates/update-36- long-term-symptoms.pdf?sfvrsn=5d3789a6_2
Wu, Z., & Mc Googan, J. M. (2020). Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese Center for Disease Control and Prevention. Journal American Medical Association, 323(13):1239–42.
Zhou, F., Yu, T., Du, R., et al. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 395(10229):1054–62. http://dx.doi.org/10.1016/S0140-6736(20)30566-3
How to Cite
Copyright (c) 2022 Rossana Elena Chahla; Luis Medina Ruiz; Teresa Mena; Yolanda Brepe; Paola Terranova; Eugenia Silvana Ortega; Guillermo Gabriel Barrenechea; Daniel Gustavo Goroso; María de los Ángeles Peral de Bruno
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
1) Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
2) Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
3) Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.