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Published benefits of ivermectin use in Itajaí, Brazil for COVID-19 infection, hospitalisation, and mortality are entirely explained by statistical artefacts

Mills et al., medRxiv, doi:10.1101/2023.08.10.23293924

Aug 2023

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Ivermectin for COVID-19

4th treatment shown to reduce risk in August 2020

^*, now known with p < 0.00000000001 from 102 studies, recognized in 22 countries.

Lower risk for mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ treatments. c19ivm.org

Highly flawed analysis with multiple basic errors, invalid assumptions, highly biased discussion, failure to correct any of the issues for over two months, major changes without explanation, and repeating known major errors.

There are major changes to all tables and figures, without explanation of why these changes were made. Code changes can be seen at github.com, github.com (B).

For example, authors claim that there were ""499 reported deaths - a citywide post-hospitalisation COVID death rate of 30.1% during the study period"", which is not possible based on official data twitter.com, twitter.com (B). Authors appear to have used a mismatched dataset, incorrectly including data from neighboring municipalities twitter.com (C), twitter.com (D). Author's R code appears to incorrectly select patients twitter.com (E). Authors also do not appear to have read the original paper in full, missing details of the population analyzed twitter.com (F). They also appear to have missed the distinction between an individual's residential city and the location of their medical care twitter.com (C), twitter.com (G). Authors assumptions are also invalid - participation for patients with symptoms may depend on multiple factors. For example, patients with more severe symptoms may be more likely to perceive serious risk and more likely to seek known effective treatment. Authors also only discuss potential biases in one direction - for example ignoring bias due to dropping out of the program. The assumption of no effect for treatment is contradicted by 17 out of 17 prophylaxis studies.

While the errors may be accidental, two factors increase the severity.

The extreme mismatch in deaths with the original paper should have been a sign to check. The cause of the mismatch should have been relatively easy to determine, and in case authors were still stuck, they could have asked the original authors. Such an extreme and easily identifiable error in mortality numbers undermines author's credibility.

Further, authors were notified of the mortality error within 12 hours of announcing the preprint on Twitter and acknowledged the error, initially claiming a rapid correction would be forthcoming. However, the paper had still not been withdrawn over two months after publication, and was still available without any warning, note, or even partial correction. Leaving known highly incorrect information for so long raises ethical concerns.

Discussion in this paper is highly biased, supporting concern over bias from the team. Authors claim that ""rigorous randomised clinical trials have largely not found clinical benefit for ivermectin use in COVID-19"", but in reality all 17 of 17 prophylaxis studies at the time showed statistically significant benefits of ivermectin, including all 4 of 4 RCTs.

Authors reference none of the other prophylaxis studies, and cherry pick a few non-prophylaxis studies, and even then they ignore the signs of efficacy in those studies. While it's common for authors to misrepresent research, excluding all 16 other studies and cherry picking a few non-prophylaxis studies stands out as one of the most extreme cases.

Authors cite only 4 of the 102 studies, all with major issues, and none reporting prophylaxis results. Further, the 4 studies cited all show signs of efficacy - Lim shows 69% lower mortality, close to statistical significance; Bramante showed 61% lower hospitalization for ivermectin vs. placebo (not reported by authors, without statistical significance); the co-principal investigator of Reis has stated ""there is a clear signal that IVM works in COVID patients""; and in Naggie the posterior probability ivermectin was effective was 99%, 98%, 97% for mean time unwell and clinical progression @14 and 7 days, all exceeding the pre-specified threshold for superiority (clinical progression results were changed without explanation between the preprint and journal version, the primary outcome was not reported, with a new post-hoc highly biased outcome created).

All 4 of the cited studies are low quality studies with major issues. For example, one trial reports impossible data, refuses to release data despite pledging to, broke blinding and shared interim results externally, had randomization failure, blinding failure, and numerous protocol violations Marinos, Reis.

Author's summary is discordant with reality - 62 studies show statistically significant positive results for one or more outcomes (including 25 RCTs) Abbas, Ahmed, Ahsan, Alam, Aref, Aref (B), Babalola, Behera, Behera (B), Bernigaud, Biber, Borody, Budhiraja, Bukhari, Cadegiani, Carvallo, Carvallo (B), Chaccour, Chahla, Chahla (B), Chowdhury, de Jesús Ascencio-Montiel, de la Rocha, Desort-Henin, Efimenko, Elalfy, Espitia-Hernandez, Faisal, Ghauri, Gorial, Hashim, Hayward, Hellwig, IVERCOR PREP, Kerr, Khan, Lim, Lima-Morales, Mahmud, Mayer, Merino, Mondal, Morgenstern, Mourya, Naggie, Okumuş, Osati, Ozer, Qadeer, Rajter, Rezai, Rezk, Samajdar, Seet, Shahbaznejad, Shimizu, Shouman, Siripongboonsitti, Soto-Becerra, Spoorthi, Tanioka, Thairu.

Further, author's discussion of preclinical data is highly cherry-picked and highly misleading, with inaccurate interpretation of the concentration required based on Caly (see discussion) and other studies, and no mention of the majority of proposed mechanisms and supporting data.

2.5 months later authors released an updated preprint which has very different data, but does not detail or mention the authors' errors. Note that an author pre-announced that there would be no change in the results on Twitter before it was possible to have made corrections. The analysis is unreliable because the conclusion came before the analysis, and the analysis includes assumptions that can be easily tweaked for any desired result. Moreover, many errors have clearly not been fixed. As before, the authors reference none of the other prophylaxis studies, and cherry pick a few low quality non-prophylaxis studies with many critical issues, and even then they ignore the signs of efficacy in those studies. While it's common for authors to misrepresent research, excluding all 16 other studies and cherry picking a few non-prophylaxis studies stands out as one of the most extreme cases. All 17 of 17 prophylaxis studies at the time showed statistically significant benefits of ivermectin, including all 4 of 4 RCTs, contradictory to the author's claims. Further, it is known that author's were aware of these errors.

Author's extreme bias, silent major changes without explanation, and failure to correct known errors suggests their goal is not to accurately evaluate the clinical evidence.

66 preclinical studies support the efficacy of ivermectin for COVID-19:

14 In Vivo animal studies Abd-Elmawla, Albariqi, Arévalo, Chaccour (B), de Melo, Errecalde, Gao, Ma, Madrid, Mountain Valley MD, Uematsu, Yan, Zhang, Zheng

Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Jitobaom, Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Jitobaom, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.

Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing Fauquet, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, Scheim, shows dose-dependent inhibition of wildtype and omicron variants Shahin, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 via IMPase inhibition Jitobaom, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, inhibits SARS-CoV-2 3CL^pro Mody, may inhibit SARS-CoV-2 RdRp activity Parvez (B), may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages Gao, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation Liu (C), shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), increases Bifidobacteria which play a key role in the immune system Hazan, has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.

1. Abbas et al., The Effect of Ivermectin on Reducing Viral Symptoms in Patients with Mild COVID-19, Indian Journal of Pharmaceutical Sciences, doi:10.36468/pharmaceutical-sciences.spl.416.ijpsonline.com, doi.org.

2. Abd-Elmawla et al., Suppression of NLRP3 inflammasome by ivermectin ameliorates bleomycin-induced pulmonary fibrosis, Journal of Zhejiang University-SCIENCE B, doi:10.1631/jzus.B2200385.springer.com, doi.org.

3. Ahmed et al., A five day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.11.191.sciencedirect.com, doi.org.

4. Ahsan et al., Clinical Variants, Characteristics, and Outcomes Among COVID-19 Patients: A Case Series Analysis at a Tertiary Care Hospital in Karachi, Pakistan, Cureus, doi:10.7759/cureus.14761.cureus.com, doi.org.

5. Alam et al., Ivermectin as Pre-exposure Prophylaxis for COVID-19 among Healthcare Providers in a Selected Tertiary Hospital in Dhaka – An Observational Study, European Journal of Medical and Health Sciences, doi:10.24018/ejmed.2020.2.6.599.ejmed.org, doi.org.

6. Albariqi et al., Pharmacokinetics and Safety of Inhaled Ivermectin in Mice as a Potential COVID-19 Treatment, International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121688.sciencedirect.com, doi.org.

7. Alvarado et al., Interaction of the New Inhibitor Paxlovid (PF-07321332) and Ivermectin With the Monomer of the Main Protease SARS-CoV-2: A Volumetric Study Based on Molecular Dynamics, Elastic Networks, Classical Thermodynamics and SPT, Computational Biology and Chemistry, doi:10.1016/j.compbiolchem.2022.107692.sciencedirect.com, doi.org.

8. Aminpour et al., In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds, Computation, doi:10.3390/computation10040051.mdpi.com, doi.org.

9. Aref et al., Clinical, Biochemical and Molecular Evaluations of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Reducing Upper Respiratory Symptoms of Mild COVID-19, International Journal of Nanomedicine, doi:10.2147/IJN.S313093.dovepress.com, doi.org.

10. Aref (B) et al., Possible Role of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Recovery of Post-COVID-19 Anosmia, Infection and Drug Resistance, doi:10.2147/IDR.S381715.dovepress.com, doi.org.

11. Arévalo et al., Ivermectin reduces in vivo coronavirus infection in a mouse experimental model, Scientific Reports, doi:10.1038/s41598-021-86679-0.nature.com, doi.org.

12. Babalola et al., Ivermectin shows clinical benefits in mild to moderate COVID19: A randomised controlled double-blind, dose-response study in Lagos, QJM: An International Journal of Medicine, doi:10.1093/qjmed/hcab035.oup.com, doi.org.

13. Barrows et al., A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection, Cell Host & Microbe, doi:10.1016/j.chom.2016.07.004.sciencedirect.com, doi.org.

14. Behera et al., Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study, PLoS ONE, doi:10.1371/journal.pone.0247163.plos.org, doi.org.

15. Behera (B) et al., Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers, Cureus 13:8, doi:10.7759/cureus.16897.cureus.com, doi.org.

16. Bello et al., Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857.tandfonline.com, doi.org.

17. Bennett et al., Role of a nuclear localization signal on the minor capsid Proteins VP2 and VP3 in BKPyV nuclear entry, Virology, doi:10.1016/j.virol.2014.10.013.sciencedirect.com, doi.org.

18. Bernigaud et al., Ivermectin benefit: from scabies to COVID-19, an example of serendipity, Annals of Dermatology and Venereology, doi:10.1016/j.annder.2020.09.231.sciencedirect.com, doi.org.

19. Biber et al., The effect of ivermectin on the viral load and culture viability in early treatment of non-hospitalized patients with mild COVID-19 – A double-blind, randomized placebo-controlled trial, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2022.07.003.sciencedirect.com, doi.org.

20. Borody et al., Combination Therapy For COVID-19 Based on Ivermectin in an Australian Population, TrialSite News, covidmedicalnetwork.com/media/TrialSite-media-release-19.10.2021.pdf.covidmedicalnetwork.com.

21. Boschi et al., SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects, bioRxiv, doi:10.1101/2022.11.24.517882.biorxiv.org, doi.org.

22. Bramante et al., Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19, NEJM, doi:10.1056/NEJMoa2201662.nejm.org, doi.org.

23. Budhiraja et al., Clinical Profile of First 1000 COVID-19 Cases Admitted at Tertiary Care Hospitals and the Correlates of their Mortality: An Indian Experience, medRxiv, doi:10.1101/2020.11.16.20232223.medrxiv.org, doi.org.

24. Bukhari et al., Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease, medRxiv, doi:10.1101/2021.02.02.21250840.medrxiv.org, doi.org.

25. Cadegiani et al., Early COVID-19 Therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in Outpatient Settings Significantly Improved COVID-19 outcomes compared to Known outcomes in untreated patients, New Microbes and New Infections, doi:10.1016/j.nmni.2021.100915.sciencedirect.com, doi.org.

26. Caly et al., The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Research, doi:10.1016/j.antiviral.2020.104787.sciencedirect.com, doi.org.

27. Carvallo et al., Usefulness of Topic Ivermectin and Carrageenan to Prevent Contagion of Covid 19 (IVERCAR), NCT04425850, clinicaltrials.gov/ct2/show/results/NCT04425850.clinicaltrials.gov.

28. Carvallo (B) et al., 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, doi:10.31546/2633-8653.1007.medicalpressopenaccess.com, doi.org.

29. Chaccour et al., 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, doi:10.1016/j.eclinm.2020.100720.thelancet.com, doi.org.

30. Chaccour (B) et al., Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats, Scientific Reports, doi:10.1038/s41598-020-74084-y.nature.com, doi.org.

31. Chahla et al., Randomized trials - Ivermectin repurposing for COVID-19 treatment of outpatients with mild disease in primary health care centers, Research, Society and Development, doi:10.33448/rsd-v11i8.30844.rsdjournal.org, doi.org.

32. Chahla (B) et al., Intensive Treatment With Ivermectin and Iota-Carrageenan as Pre-exposure Prophylaxis for COVID-19 in Health Care Workers From Tucuman, Argentina, American Journal of Therapeutics, doi:10.1097/MJT.0000000000001433.lww.com, doi.org.

33. Chellasamy et al., Docking and molecular dynamics studies of human ezrin protein with a modelled SARS-CoV-2 endodomain and their interaction with potential invasion inhibitors, Journal of King Saud University - Science, doi:10.1016/j.jksus.2022.102277.sciencedirect.com, doi.org.

34. Choudhury et al., Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach, Future Medicine, doi:10.2217/fvl-2020-0342.futuremedicine.com, doi.org.

35. Chowdhury et al., A Comparative Study on Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin Therapy on COVID-19 Patients, Eurasian Journal of Medicine and Oncology, doi:10.14744/ejmo.2021.16263.ejmo.org, doi.org.

36. Croci et al., Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin, International Journal of Biomaterials, doi:10.1155/2016/8043983.hindawi.com, doi.org.

37. De Forni et al., Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients, PLoS ONE, doi:10.1371/journal.pone.0276751.plos.org, doi.org.

38. de Jesús Ascencio-Montiel et al., A Multimodal Strategy to Reduce the Risk of Hospitalization/death in Ambulatory Patients with COVID-19, Archives of Medical Research, doi:10.1016/j.arcmed.2022.01.002.sciencedirect.com, doi.org.

39. de la Rocha et al., Ivermectin compared with placebo in the clinical course in Mexican patients with asymptomatic and mild COVID-19: a randomized clinical trial, BMC Infectious Diseases, doi:10.1186/s12879-022-07890-6.biomedcentral.com, doi.org.

40. de Melo et al., Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin, EMBO Mol. Med., doi:10.15252/emmm.202114122.embopress.org, doi.org.

41. Delandre et al., Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, Pharmaceuticals, doi:10.3390/ph15040445.mdpi.com, doi.org.

42. Descotes, J., Medical Safety of Ivermectin, ImmunoSafe Consultance, web.archive.org/web/20240313025927/https://www.medincell.com/wp-content/uploads/2021/03/Clinical_Safety_of_Ivermectin-March_2021.pdf.archive.org.

43. Desort-Henin et al., The SAIVE Trial, Post-Exposure use of ivermectin in Covid-19 prevention: Efficacy and Safety Results, ECCMID 2023 (results released 1/5/2023), www.medincell.com/wp-content/uploads/2024/03/Poster-SAIVE-April2023-OK3.pdf.medincell.com.

44. DiNicolantonio et al., Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19, Open Heart, doi:10.1136/openhrt-2020-001350.bmj.com, doi.org.

45. DiNicolantonio (B) et al., Anti-inflammatory activity of ivermectin in late-stage COVID-19 may reflect activation of systemic glycine receptors, Open Heart, doi:10.1136/openhrt-2021-001655.bmj.com, doi.org.

46. Efimenko et al., Treatment with Ivermectin Is Associated with Decreased Mortality in COVID-19 Patients: Analysis of a National Federated Database, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.12.096.sciencedirect.com, doi.org.

47. Elalfy et al., Effect of a combination of Nitazoxanide, Ribavirin and Ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-1, J. Med. Virol., doi:10.1002/jmv.26880.wiley.com, doi.org.

48. Errecalde et al., Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model, Journal of Pharmaceutical Sciences, doi:10.1016/j.xphs.2021.01.017.sciencedirect.com, doi.org.

49. Espitia-Hernandez et al., Effects of Ivermectin-azithromycin-cholecalciferol combined therapy on COVID-19 infected patients: A proof of concept study, Biomedical Research, 31:5, www.biomedres.info/biomedical-research/effects-of-ivermectinazithromycincholecalciferol-combined-therapy-on-covid19-infected-patients-a-proof-of-concept-study-14435.html.biomedres.info.

50. Eweas et al., Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2, Frontiers in Microbiology, doi:10.3389/fmicb.2020.592908.frontiersin.org, doi.org.

51. Faisal et al., Potential use of azithromycin alone and in combination with ivermectin in fighting against the symptoms of COVID-19, The Professional Medical Journal, doi:10.29309/TPMJ/2021.28.05.5867.theprofesional.com, doi.org.

52. Fauquet et al., Microfluidic Diffusion Sizing Applied to the Study of Natural Products and Extracts That Modulate the SARS-CoV-2 Spike RBD/ACE2 Interaction, Molecules, doi:10.3390/molecules28248072.mdpi.com, doi.org.

53. Francés-Monerris et al., Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection, Physical Chemistry Chemical Physics, doi:10.1039/D1CP02967C.rsc.org, doi.org.

54. Francés-Monerris (B) et al., Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent, ChemRxiv, doi:10.26434/chemrxiv.12782258.v1.chemrxiv.org, doi.org.

55. Gao et al., Ivermectin ameliorates acute myocarditis via the inhibition of importin-mediated nuclear translocation of NF-κB/p65, International Immunopharmacology, doi:10.1016/j.intimp.2024.112073.sciencedirect.com, doi.org.

56. García-Aguilar et al., In Vitro Analysis of SARS-CoV-2 Spike Protein and Ivermectin Interaction, International Journal of Molecular Sciences, doi:10.3390/ijms242216392.mdpi.com, doi.org.

57. Ghauri et al., Ivermectin Use Associated with Reduced Duration of Covid-19 Febrile Illness in a Community Setting, International Journal of Clinical Studies & Medical Case Reports, doi:10.46998/IJCMCR.2021.13.000320.ijclinmedcasereports.com, doi.org.

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70. Jitobaom et al., Identification of inositol monophosphatase as a broad‐spectrum antiviral target of ivermectin, Journal of Medical Virology, doi:10.1002/jmv.29552.wiley.com, doi.org.

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73. Kalhor et al., Repurposing of the approved small molecule drugs in order to inhibit SARS-CoV-2 S protein and human ACE2 interaction through virtual screening approaches, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2020.1824816.tandfonline.com, doi.org.

74. Kern et al., Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing, Frontiers in Pharmacology, doi:10.3389/fphar.2021.625678.frontiersin.org, doi.org.

75. Kerr et al., Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching, Cureus, doi:10.7759/cureus.21272.cureus.com, doi.org.

76. Khan et al., Ivermectin treatment may improve the prognosis of patients with COVID-19, Archivos de Bronconeumología, doi:10.1016/j.arbres.2020.08.007.archbronconeumol.org, doi.org.

77. Kosyna et al., The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways, Biological Chemistry, doi:10.1515/hsz-2015-0171.degruyter.com, doi.org.

78. Lehrer et al., Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2, In Vivo, 34:5, 3023-3026, doi:10.21873/invivo.12134.iiarjournals.org, doi.org.

79. Li et al., Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment, J. Cellular Physiology, doi:10.1002/jcp.30055.wiley.com, doi.org.

80. Lim 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, JAMA, doi:10.1001/jamainternmed.2022.0189.jamanetwork.com, doi.org.

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Important missing comments or errors? Let us know.

Mills et al., 15 Aug 2023, retrospective, Brazil, preprint, 3 authors, study period 7 July, 2020 - 2 December, 2020. Contact: dbsgtk@nus.edu.sg.

This Paper Ivermectin All

Published benefits of ivermectin use in Itajaí, Brazil for COVID-19 infection, hospitalisation, and mortality are entirely explained by statistical artefacts

Robin Mills, Ana Carolina Peçanha Antonio, Greg Tucker-Kellogg

doi:10.1101/2023.08.10.23293924

Background Two recent publications by Kerr et al. (Cureus 14(1):e21272; Cureus 14(8): e28624) reported dramatic effects of prophylactic ivermectin use for both prevention of COVID-19 and reduction of COVID-19-related hospitalisation and mortality, including a dose-dependent effect of ivermectin prophylaxis. These papers have gained an unusually large public influence: they were incorporated into debates around COVID-19 policies and may have contributed to decreased trust in vaccine efficacy and public health authorities more broadly. Both studies were based on retrospective observational analysis of city-wide registry data from the city of Itajaí, Brazil from July-December 2020. Methods Starting with initially identified sources of error, we conducted a revised statistical analysis of available data, including data made available with the original papers and public data from the Brazil Ministry of Health. We identified additional uncorrected sources of bias and errors from the original analysis, including incorrect subject exclusion and missing subjects, an enrolment time bias, and multiple sources of immortal time bias. In models assuming no actual effect from ivermectin use, we conducted Monte Carlo simulations to estimate the contribution of these biases to any observed effect. Results Untreated statistical artefacts and methodological errors alone lead to dramatic apparent risk reduction associated with Ivermectin use in both studies. The magnitude of apparent risk reduction from these artefacts is comparable to the results reported by the studies themselves, including apparent protection from infection, hospitalisation, and death, and including the reported apparent dose-response relationship. Conclusions The inference of ivermectin efficacy reported in both papers is unsupported, as the observed effects are entirely explained by untreated statistical artefacts and methodological errors. Our re-analysis calls for caution in interpreting highly publicised observational studies and highlights the importance of common sources of bias in clinical research.

Author contributions RM conducted the research required to uncover all fallacies mentioned in the manuscript (delayed registrations, missing data, incorrect inclusion of prior infections, all biases). GTK independently uncovered the immortal time bias, enrolment bias, and attrition bias. RM and GTK wrote the simulation and analysis code. GTK in particular, RM, and ACPA contributed to writing and reviewing the manuscript. ACPA acquired the data from the Brazilian Health Ministry. ACPA has been in frequent contact with Itajaí City Hall in an attempt to get access to missing raw data. RM has been in frequent contact with the KC22 and KB22 authors in an attempt to discuss the issues in their work before publishing this manuscript.

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