USE OF REPOURPOSED DRUGS LOSARTAN AND IVERMECTIN IN PATIENTS WITH CANCER FOR PREVENTION OF COVID-19 SERIOUS EVENTS DURING PANDEMIC. A randomized, double-blind, placebo-controlled phase II study.
Main Article Content
Abstract
Introduction: Cancer patients are at higher risk of COVID-19 severe complications and also demonstrated a lower antibodies conversion after vaccination. Therefore, therapeutic approaches after COVID-19 infection are needed in this population. Repurposing drugs has emerged as an appealing strategy during pandemic, and drugs such as angiotensin 2 antagonists and ivermectin may have a role against COVID-19.
Objective: This trial evaluated losartan plus ivermectin aimed at decreasing the incidence of severe outcomes due to coronavirus infection among cancer patients.
Methods: This was a randomized, double-blind, and placebo-controlled phase II study. Cancer patients with recent diagnosis of mild to moderate COVID-19 were randomized to receive 50 mg of losartan for 15 days plus a single dose of 12 mg of ivermectin or placebo. The primary endpoint was the incidence of severe complications, defined as a need for admission to the intensive care unit (ICU), need for mechanical ventilation (MV), or death. Secondary endpoints were safety and adherence.
Results: Thirty-five patients were randomized to intervention arm and 34 to placebo arm. Seven (20%) patients in the losartan + ivermectin arm experienced severe outcomes versus 8 (23.5%) patients in the placebo arm (p = 1.00). No difference was observed in the need for intensive care unit (17.1% versus 17.6%; p = 1.00) or in the need for mechanical ventilation (17.1% versus 11.8%; p = 0.73). Four patients died in the losartan + ivermectin arm, while 3 in the placebo arm (11.4% versus 8.8%; p = 1.00). Severe adverse events and adherence were similar between groups.
Conclusions and Relevance: The combination of losartan and ivermectin did not improve severe COVID-19 outcomes among cancer patients. This is the first study registered on ClinicalTrials.gov that evaluates active treatment for COVID-19 exclusively for cancer patients. and more studies should be performed for a more aggressive approach in this high-risk population.
Keywords:
COVID-19, cancer, losartan, ivermectin, repurposing drugs
Article Details
How to Cite
EXMAN, Pedro et al.
USE OF REPOURPOSED DRUGS LOSARTAN AND IVERMECTIN IN PATIENTS WITH CANCER FOR PREVENTION OF COVID-19 SERIOUS EVENTS DURING PANDEMIC. A randomized, double-blind, placebo-controlled phase II study..
Medical Research Archives, [S.l.], v. 12, n. 4, apr. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5281>. Date accessed: 03 july 2024.
doi: https://doi.org/10.18103/mra.v12i4.5281.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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20. Tay MY, Fraser JE, Chan WK, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res. 2013;99(3):301-306. doi:10.1016/j.antiviral.2013.06.002
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26. Bertuzzi AF, Ciccarelli M, Marrari A, et al. Impact of active cancer on COVID-19 survival: a matched-analysis on 557 consecutive patients at an Academic Hospital in Lombardy, Italy. Br J Cancer. 2021;125(3):358-365. doi:10.1038/s41416-021-01396-9
27. Fu C, Stoeckle JH, Masri L, et al. COVID-19 outcomes in hospitalized patients with active cancer: Experiences from a major New York City health care system. Cancer. 2021; 127(18):3466-3475. doi:10.1002/cncr.33657
28. Pinato DJ, Tabernero J, Bower M, et al. Prevalence and impact of COVID-19 sequelae on treatment and survival of patients with cancer who recovered from SARS-CoV-2 infection: evidence from the OnCovid retrospective, multicentre registry study. Lancet Oncol. 2021;22(12):1669-1680. doi:10.1016/S1470-2045(21)00573-8
29. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020;369: m1985. Published 2020 May 22. doi:10.1136/bmj.m1985
30. Brar G, Pinheiro LC, Shusterman M, et al. COVID-19 Severity and Outcomes in Patients With Cancer: A Matched Cohort Study. J Clin Oncol. 2020;38(33):3914-3924. doi:10.1200/JCO.20.01580
31. Nader Marta G, Colombo Bonadio R, Nicole Encinas Sejas O, et al. Outcomes and Prognostic Factors in a Large Cohort of Hospitalized Cancer Patients With COVID-19. JCO Glob Oncol. 2021;7:1084-1092. doi:10.1200/GO.21.00087
32. Grivas P, Khaki AR, Wise-Draper TM, et al. Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium. Ann Oncol. 2021;32(6):787-800. doi:10.1016/j.annonc.2021.02.024
33. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022;386(15):1397-1408. doi:10.1056/NEJMoa2118542
34. Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022;386(4):305-315. doi:10.1056/NEJMoa2116846
35. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022;386(6):509-520. doi:10.1056/NEJMoa2116044
36. Reis G, Silva EASM, Silva DCM, et al. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med. 2022;386 (18):1721-1731. doi:10.1056/NEJMoa2115869
37. Lim SCL, Hor CP, Tay KH, et al. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial [published correction appears in JAMA Intern Med. 2022 Jun 1;182(6):690]. JAMA Intern Med. 2022;182(4):426-435. doi:10.1001/jamainternmed.2022.0189
38. Williams PB. Renin Angiotensin System Inhibition as treatment for Covid-19?. EClinicalMedicine. 2021;37:101023. doi:10.1016/j.eclinm.2021.101023
39. Palich R, Veyri M, Marot S, et al. Weak immunogenicity after a single dose of SARS-CoV-2 mRNA vaccine in treated cancer patients. Ann Oncol. 2021;32(8):1051-1053. doi:10.1016/j.annonc.2021.04.020
2. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin [published correction appears in Nature. 2020 Dec; 588(7836):E6]. Nature. 2020;579(7798):270-273. doi:10.1038/s41586-020-2012-7
3. Bajema KL, Oster AM, McGovern OL, et al. Persons Evaluated for 2019 Novel Coronavirus - United States, January 2020. MMWR Morb Mortal Wkly Rep. 2020;69(6):166-170. Published 2020 Feb 14. doi:10.15585/mmwr.mm6906e1
4. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China [published correction appears in Lancet. 2020 Jan 30;:]. Lancet. 2020;395(10223):497-506.
doi:10.1016/S0140-6736(20)30183-5
5. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513. doi:10.1016/S0140-6736(20)30211-7
6. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242. doi:10.1001/jama.2020.2648
7. Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis [published correction appears in Lancet Infect Dis. 2020 Apr 15;:] [published correction appears in Lancet Infect Dis. 2020 May 4;:]. Lancet Infect Dis. 2020;20 (6):669-677. doi:10.1016/S1473-3099(20)30243-7
8. Grasselli G, Pesenti A, Cecconi M. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response. JAMA. 2020; 323(16):1545-1546. doi:10.1001/jama.2020.4031
9. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy [published correction appears in JAMA. 2020 Apr 28;323(16):1619]. JAMA. 2020;323(18): 1775-1776. doi:10.1001/jama.2020.4683
10. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China [published correction appears in JAMA. 2021 Mar 16;325(11):1113]. JAMA. 2020;323(11):1061-1069. doi:10.1001/jama.2020.1585
11. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21(3): 335-337. doi:10.1016/S1470-2045(20)30096-6
12. Desai A, Sachdeva S, Parekh T, Desai R. COVID-19 and Cancer: Lessons From a Pooled Meta-Analysis. JCO Glob Oncol. 2020;6:557-559. doi:10.1200/GO.20.00097
13. Sharafeldin N, Bates B, Song Q, et al. Outcomes of COVID-19 in Patients With Cancer: Report From the National COVID Cohort Collaborative (N3C). J Clin Oncol. 2021;39 (20):2232-2246. doi:10.1200/JCO.21.01074
14. Monin L, Laing AG, Muñoz-Ruiz M, et al. Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study. Lancet Oncol. 2021;22(6):765-778. doi:10.1016/S1470-2045(21)00213-8
15. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020;382(17):1653-1659.
doi:10.1056/NEJMsr2005760
16. Alanagreh L, Alzoughool F, Atoum M. The Human Coronavirus Disease COVID-19: Its Origin, Characteristics, and Insights into Potential Drugs and Its Mechanisms. Pathogens. 2020;9(5):331. Published 2020 Apr 29. doi:10.3390/pathogens9050331
17. Duarte M, Pelorosso F, Nicolosi LN, et al. Telmisartan for treatment of Covid-19 patients: An open multicenter randomized clinical trial. EClinicalMedicine. 2021;37:100962. Published 2021 Jun 18. doi:10.1016/j.eclinm.2021.100962
18. Puskarich MA, Cummins NW, Ingraham NE, et al. A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19. EClinicalMedicine. 2021;37:100957. Published 2021 Jun 17. doi:10.1016/j.eclinm.2021.100957
19. Puskarich MA, Ingraham NE, Merck LH, et al. Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: A Randomized Clinical Trial [published correction appears in JAMA Netw Open. 2022 May 2; 5(5):e2215958]. JAMA Netw Open. 2022;5(3): e222735. Published 2022 Mar 1. doi:10.1001/jamanetworkopen.2022.2735
20. Tay MY, Fraser JE, Chan WK, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res. 2013;99(3):301-306. doi:10.1016/j.antiviral.2013.06.002
21. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012; 443(3):851-856. doi:10.1042/BJ20120150
22. Timani KA, Liao Q, Ye L, et al. Nuclear/ nucleolar localization properties of C-terminal nucleocapsid protein of SARS coronavirus. Virus Res. 2005;114(1-2):23-34. doi:10.1016/j.virusres.2005.05.007
23. Hiscox JA, Wurm T, Wilson L, Britton P, Cavanagh D, Brooks G. The coronavirus infectious bronchitis virus nucleoprotein localizes to the nucleolus. J Virol. 2001;75(1): 506-512. doi:10.1128/JVI.75.1.506-512.2001
24. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. doi:10.1016/j.antiviral.2020.104787
25. Hill A, Mirchandani M, Pilkington V. Ivermectin for COVID-19: Addressing Potential Bias and Medical Fraud. Open Forum Infect Dis. 2022;9(2):ofab645. Published 2022 Jan 17. doi:10.1093/ofid/ofab645.
26. Bertuzzi AF, Ciccarelli M, Marrari A, et al. Impact of active cancer on COVID-19 survival: a matched-analysis on 557 consecutive patients at an Academic Hospital in Lombardy, Italy. Br J Cancer. 2021;125(3):358-365. doi:10.1038/s41416-021-01396-9
27. Fu C, Stoeckle JH, Masri L, et al. COVID-19 outcomes in hospitalized patients with active cancer: Experiences from a major New York City health care system. Cancer. 2021; 127(18):3466-3475. doi:10.1002/cncr.33657
28. Pinato DJ, Tabernero J, Bower M, et al. Prevalence and impact of COVID-19 sequelae on treatment and survival of patients with cancer who recovered from SARS-CoV-2 infection: evidence from the OnCovid retrospective, multicentre registry study. Lancet Oncol. 2021;22(12):1669-1680. doi:10.1016/S1470-2045(21)00573-8
29. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020;369: m1985. Published 2020 May 22. doi:10.1136/bmj.m1985
30. Brar G, Pinheiro LC, Shusterman M, et al. COVID-19 Severity and Outcomes in Patients With Cancer: A Matched Cohort Study. J Clin Oncol. 2020;38(33):3914-3924. doi:10.1200/JCO.20.01580
31. Nader Marta G, Colombo Bonadio R, Nicole Encinas Sejas O, et al. Outcomes and Prognostic Factors in a Large Cohort of Hospitalized Cancer Patients With COVID-19. JCO Glob Oncol. 2021;7:1084-1092. doi:10.1200/GO.21.00087
32. Grivas P, Khaki AR, Wise-Draper TM, et al. Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium. Ann Oncol. 2021;32(6):787-800. doi:10.1016/j.annonc.2021.02.024
33. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022;386(15):1397-1408. doi:10.1056/NEJMoa2118542
34. Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022;386(4):305-315. doi:10.1056/NEJMoa2116846
35. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022;386(6):509-520. doi:10.1056/NEJMoa2116044
36. Reis G, Silva EASM, Silva DCM, et al. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med. 2022;386 (18):1721-1731. doi:10.1056/NEJMoa2115869
37. Lim SCL, Hor CP, Tay KH, et al. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial [published correction appears in JAMA Intern Med. 2022 Jun 1;182(6):690]. JAMA Intern Med. 2022;182(4):426-435. doi:10.1001/jamainternmed.2022.0189
38. Williams PB. Renin Angiotensin System Inhibition as treatment for Covid-19?. EClinicalMedicine. 2021;37:101023. doi:10.1016/j.eclinm.2021.101023
39. Palich R, Veyri M, Marot S, et al. Weak immunogenicity after a single dose of SARS-CoV-2 mRNA vaccine in treated cancer patients. Ann Oncol. 2021;32(8):1051-1053. doi:10.1016/j.annonc.2021.04.020