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

Source PDF All Studies Meta AnalysisMeta

4th treatment shown to reduce risk in August 2020, now with p < 0.00000000001 from 105 studies, recognized in 23 countries.

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

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 111 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 at1,2.

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 data3,4. Authors appear to have used a mismatched dataset, incorrectly including data from neighboring municipalities5,6. Author's R code appears to incorrectly select patients7. Authors also do not appear to have read the original paper in full, missing details of the population analyzed8. They also appear to have missed the distinction between an individual's residential city and the location of their medical care5,9. 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 105 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 violations12,14.

Author's summary is discordant with reality - 64 studies show statistically significant positive results for one or more outcomes (including 27 RCTs)10,13,15-76.

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.

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

32 In Silico studies78-109

24 In Vitro studies77,110-132

14 In Vivo animal studies120,126,132-143

Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7144, Dengue111,145,146, HIV-1146, Simian virus 40147, Zika111,148,149, West Nile149, Yellow Fever150,151, Japanese encephalitis150, Chikungunya151, Semliki Forest virus151, Human papillomavirus131, Epstein-Barr131, BK Polyomavirus152, and Sindbis virus151.

Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins144,146,147,153, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing112, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination115,154, shows dose-dependent inhibition of wildtype and omicron variants110, exhibits dose-dependent inhibition of lung injury134,139, may inhibit SARS-CoV-2 via IMPase inhibition111, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation84, inhibits SARS-CoV-2 3CL^pro128, may inhibit SARS-CoV-2 RdRp activity103, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages133, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation155, may interfere with SARS-CoV-2's immune evasion via ORF8 binding79, may inhibit SARS-CoV-2 by disrupting CD147 interaction156-159, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19132,160, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage83, may minimize SARS-CoV-2 induced cardiac damage114,122, increases Bifidobacteria which play a key role in the immune system161, has immunomodulatory125 and anti-inflammatory143,162 properties, and has an extensive and very positive safety profile163.

Important missing comments or errors? Let us know.

1. github.com, github.com/gtuckerkellogg/itajai-reanalysis/commit/082bd50ec39c0c959aeea91b80fedd8cb5949397.github.com/gtuckerkellogg/itajai-reanalysis/commit/082bd50ec39c0c959aeea91b80fedd8cb5949397.

2. github.com (B), github.com/gtuckerkellogg/itajai-reanalysis/commit/92327372eb3c29ea8d3d792de713f14fb96b0d5c.github.com/gtuckerkellogg/itajai-reanalysis/commit/92327372eb3c29ea8d3d792de713f14fb96b0d5c.

3. twitter.com, twitter.com/filipe_rafaeli/status/1691850944428867971.twitter.com/filipe_rafaeli/status/1691850944428867971.

4. twitter.com (B), twitter.com/vox_populi_nl/status/1692288704478626016.twitter.com/vox_populi_nl/status/1692288704478626016.

5. twitter.com (C), twitter.com/lorenzoridolfi/status/1692580139001929992.twitter.com/lorenzoridolfi/status/1692580139001929992.

6. twitter.com (D), twitter.com/lorenzoridolfi/status/1692354800015294664.twitter.com/lorenzoridolfi/status/1692354800015294664.

7. twitter.com (E), twitter.com/lorenzoridolfi/status/1693304301911715937.twitter.com/lorenzoridolfi/status/1693304301911715937.

8. twitter.com (F), twitter.com/lorenzoridolfi/status/1694779980733874412.twitter.com/lorenzoridolfi/status/1694779980733874412.

9. twitter.com (G), twitter.com/lorenzoridolfi/status/1692558948769960399.twitter.com/lorenzoridolfi/status/1692558948769960399.

10. 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.

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

12. Reis et al., Effect of Early Treatment with Ivermectin among Patients with Covid-19, New England Journal of Medicine, doi:10.1056/NEJMoa2115869.nejm.org, doi.org.

13. Naggie et al., Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial, JAMA, doi:10.1001/jama.2022.18590.jamanetwork.com, doi.org.

14. Marinos et al., The TOGETHER Files 1: The Andrew Hill connection - How the principal investigator leaked interim results to a private ivermectin research group, Do Your Own Research, doyourownresearch.substack.com/p/the-together-files-1-the-andrew-hill.substack.com.

15. 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.

16. 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.

17. Mahmud et al., Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial, Journal of International Medical Research, doi:10.5061/dryad.qjq2bvqf6.sagepub.com, doi.org.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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, Journal of Medical Virology, doi:10.1002/jmv.26880.wiley.com, doi.org.

26. 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.

27. Mourya et al., Comparative Analytical Study of Two Different Drug Regimens in Treatment of Covid 19 Positive Patients in Index Medical College Hospital and Research Center, Indore, India, International Journal of Health and Clinical Research, 4:6, ijhcr.com/index.php/ijhcr/article/view/1263.ijhcr.com.

28. Merino et al., Ivermectin and the odds of hospitalization due to COVID-19: evidence from a quasi-experimental analysis based on a public intervention in Mexico City, Preprint, web.archive.org/web/20211218011849/https://files.osf.io/v1/resources/r93g4/providers/osfstorage/609085945533b4031ee1c789?action=download&direct&version=1.archive.org.

29. 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.

30. 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.

31. Mayer et al., Safety and Efficacy of a MEURI Program for the Use of High Dose Ivermectin in COVID-19 Patients, Frontiers in Public Health, doi:10.3389/fpubh.2022.813378.frontiersin.org, doi.org.

32. Borody et al., Combination Therapy For COVID-19 Based on Ivermectin in an Australian Population, TrialSite News, www.trialsitenews.com/a/combination-therapy-for-covid-19-based-on-ivermectin-in-an-australian-population.trialsitenews.com.

33. 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.

34. 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.

35. 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.

36. Siripongboonsitti et al., A Randomized Trial to Assess the Acceleration of Viral Clearance by the Combination Favipiravir/Ivermectin/Niclosamide in Mild-to-Moderate COVID-19 Adult Patients (FINCOV), Journal of Infection and Public Health, doi:10.1016/j.jiph.2024.03.030.sciencedirect.com, doi.org.

37. Wijewickrema et al., Efficacy and safety of oral ivermectin in the treatment of mild to moderate Covid-19 patients: a multi-centre double-blind randomized controlled clinical trial, BMC Infectious Diseases, doi:10.1186/s12879-024-09563-y.biomedcentral.com, doi.org.

38. Gorial et al., Effectiveness of Ivermectin as add-on Therapy in COVID-19 Management (Pilot Trial), medRxiv, doi:10.1101/2020.07.07.20145979.medrxiv.org, doi.org.

39. 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.

40. Soto-Becerra et al., Real-World Effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: Results of a target trial emulation using observational data from a nationwide Healthcare System in Peru, medRxiv, doi:10.1101/2020.10.06.20208066.medrxiv.org, doi.org.

41. Rajter et al., Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID-19 (ICON study), Chest, doi:10.1016/j.chest.2020.10.009.sciencedirect.com, doi.org.

42. Hashim et al., Controlled randomized clinical trial on using Ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq, Iraqi Journal of Medical Science, 19:1, www.iraqijms.net/upload/pdf/iraqijms60db8b76d3b1e.pdf.iraqijms.net.

43. Spoorthi et al., Utility of Ivermectin and Doxycycline combination for the treatment of SARSCoV-2, IAIM, 2020, 7:10, 177-182, iaimjournal.com/wp-content/uploads/2020/10/iaim_2020_0710_23.pdf.iaimjournal.com.

44. 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.

45. Okumuş et al., Evaluation of the Effectiveness and Safety of Adding Ivermectin to Treatment in Severe COVID-19 Patients, BMC Infectious Diseases, doi:10.1186/s12879-021-06104-9.biomedcentral.com, doi.org.

46. Shahbaznejad et al., Effects of Ivermectin in Patients With COVID-19: A Multicenter, Double-blind, Randomized, Controlled Clinical Trial, Clinical Therapeutics, doi:10.1016/j.clinthera.2021.04.007.sciencedirect.com, doi.org.

47. Lima-Morales et al., 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, doi:10.1016/j.ijid.2021.02.014.sciencedirect.com, doi.org.

48. 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.

49. Rezk et al., miRNA-223-3p, miRNA- 2909 and Cytokines Expression in COVID-19 Patients Treated with Ivermectin, Zagazig University Medical Journal, doi:10.21608/zumj.2021.92746.2329.ekb.eg, doi.org.

50. Ozer et al., Effectiveness and Safety of Ivermectin in COVID-19 Patients: A Prospective Study at A Safety-Net Hospital, Journal of Medical Virology, doi:10.1002/jmv.27469.wiley.com, doi.org.

51. Shimizu et al., Ivermectin administration is associated with lower gastrointestinal complications and greater ventilator-free days in ventilated patients with COVID-19: A propensity score analysis, Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2021.12.024.jiac-j.com, doi.org.

52. Thairu et al., A Comparison of Ivermectin and Non Ivermectin Based Regimen for COVID-19 in Abuja: Effects on Virus Clearance, Days-to-discharge and Mortality, Journal of Pharmaceutical Research International, doi:10.9734/jpri/2022/v34i44A36328.journaljpri.com, doi.org.

53. 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.

54. Rezai et al., Non-effectiveness of Ivermectin on Inpatients and Outpatients With COVID-19; Results of Two Randomized, Double-Blinded, Placebo-Controlled Clinical Trials, Frontiers in Medicine, doi:10.3389/fmed.2022.919708.frontiersin.org, doi.org.

55. Qadeer et al., Ivermectin A Potential Treatment In Covid-19, Related to Critical Illness, Pakistan Journal of Medical and Health Sciences, doi:10.53350/pjmhs2216824.pjmhsonline.com, doi.org.

56. 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.

57. Osati et al., Clinical manifestations and mortality among hospitalized COVID-19 patients in Tanzania, 2021-2022., medRxiv, doi:10.1101/2023.07.13.23292643.medrxiv.org, doi.org.

58. Hayward et al., Ivermectin for COVID-19 in adults in the community (PRINCIPLE): an open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes, Journal of Infection, doi:10.1016/j.jinf.2024.106130.sciencedirect.com, doi.org.

59. Varnaseri et al., Ivermectin as a Potential Addition to the Limited Anti-COVID-19 Arsenal: A Double-Blinded Clinical Trial, Jundishapur Journal of Health Sciences, doi:10.5812/jjhs-146703.brieflands.com, doi.org.

60. Shouman et al., Use of Ivermectin as a Potential Chemoprophylaxis for COVID-19 in Egypt: A Randomised Clinical Trial, Journal of Clinical and Diagnostic Research, doi:10.7860/JCDR/2021/46795.14529.jcdr.net, doi.org.

61. 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.

62. 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.

63. 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.

64. Hellwig et al., A COVID-19 Prophylaxis? Lower incidence associated with prophylactic administration of Ivermectin, International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106248.sciencedirect.com, doi.org.

65. 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.

66. 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.

67. IVERCOR PREP, Ivermectina en agentes de salud e IVERCOR COVID19, Preliminary Results, web.archive.org/web/20210226215453/https://twitter.com/Covid19Crusher/status/1365420061859717124.archive.org.

68. 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.

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

70. Tanioka et al., Why COVID-19 is not so spread in Africa: How does Ivermectin affect it?, medRxiv, doi:10.1101/2021.03.26.21254377.medrxiv.org, doi.org.

71. Seet et al., Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.04.035.ijidonline.com, doi.org.

72. Morgenstern et al., Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study, Cureus, doi:10.7759/cureus.17455.cureus.com, doi.org.

73. Mondal et al., Prevalence of COVID-19 Infection and Identification of Risk Factors among Asymptomatic Healthcare Workers: A Serosurvey Involving Multiple Hospitals in West Bengal, Journal of the Indian Medical Association, 119:5, onlinejima.com/read_journals.php?article=683.onlinejima.com.

74. Samajdar et al., Ivermectin and Hydroxychloroquine for Chemo-Prophylaxis of COVID-19: A Questionnaire Survey of Perception and Prescribing Practice of Physicians vis-a-vis Outcomes, Journal of the Association of Physicians India, 69:11, www.researchgate.net/publication/356294136_Ivermectin_and_Hydroxychloroquine_for_Chemo-Prophylaxis_of_COVID-19_A_Questionnaire_Survey_of_Perception_and_Prescribing_Practice_of_Physicians_vis-a-vis_Outcomes.researchgate.net.

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. 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.

77. 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.

78. Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.springer.com, doi.org.

79. Bagheri-Far et al., Non-spike protein inhibition of SARS-CoV-2 by natural products through the key mediator protein ORF8, Molecular Biology Research Communications, doi:10.22099/mbrc.2024.50245.2001.ac.ir, doi.org.

80. de Oliveira Só et al., In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease, Preprints, doi:10.20944/preprints202404.1825.v1.preprints.org, doi.org.

81. Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.scienceopen.com, doi.org.

82. Oranu et al., Validation of the binding affinities and stabilities of ivermectin and moxidectin against SARS-CoV-2 receptors using molecular docking and molecular dynamics simulation, GSC Biological and Pharmaceutical Sciences, doi:10.30574/gscbps.2024.26.1.0030.gsconlinepress.com, doi.org.

83. Zhao et al., Identification of the shared gene signatures between pulmonary fibrosis and pulmonary hypertension using bioinformatics analysis, Frontiers in Immunology, doi:10.3389/fimmu.2023.1197752.frontiersin.org, doi.org.

84. Vottero et al., Computational Prediction of the Interaction of Ivermectin with Fibrinogen, Molecular Sciences, doi:10.3390/ijms241411449.mdpi.com, doi.org.

85. 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.

86. Umar et al., Inhibitory potentials of ivermectin, nafamostat, and camostat on spike protein and some nonstructural proteins of SARS-CoV-2: Virtual screening approach, Jurnal Teknologi Laboratorium, doi:10.29238/teknolabjournal.v11i1.344.teknolabjournal.com, doi.org.

87. 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.

88. 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.

89. Parvez et al., Insights from a computational analysis of the SARS-CoV-2 Omicron variant: Host–pathogen interaction, pathogenicity, and possible drug therapeutics, Immunity, Inflammation and Disease, doi:10.1002/iid3.639.wiley.com, doi.org.

90. 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.

91. González-Paz et al., Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach, Biophysical Chemistry, doi:10.1016/j.bpc.2021.106677.sciencedirect.com, doi.org.

92. González-Paz (B) et al., Structural Deformability Induced in Proteins of Potential Interest Associated with COVID-19 by binding of Homologues present in Ivermectin: Comparative Study Based in Elastic Networks Models, Journal of Molecular Liquids, doi:10.1016/j.molliq.2021.117284.sciencedirect.com, doi.org.

93. Rana et al., A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection, Research Square, doi:10.21203/rs.3.rs-755838/v1.researchsquare.com, doi.org.

94. Muthusamy et al., Virtual Screening Reveals Potential Anti-Parasitic Drugs Inhibiting the Receptor Binding Domain of SARS-CoV-2 Spike protein, Journal of Virology & Antiviral Research, www.scitechnol.com/abstract/virtual-screening-reveals-potential-antiparasitic-drugs-inhibiting-the-receptor-binding-domain-of-sarscov2-spike-protein-16398.html.scitechnol.com.

95. Qureshi et al., Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1906750.tandfonline.com, doi.org.

96. Schöning et al., Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains, Research Square, doi:10.21203/rs.3.rs-379291/v1.researchsquare.com, doi.org.

97. 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.

98. Udofia et al., In silico studies of selected multi-drug targeting against 3CLpro and nsp12 RNA-dependent RNA-polymerase proteins of SARS-CoV-2 and SARS-CoV, Network Modeling Analysis in Health Informatics and Bioinformatics, doi:10.1007/s13721-021-00299-2.springer.com, doi.org.

99. 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.

100. 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.

101. Saha et al., The Binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2, Structural Chemistry, doi:10.1007/s11224-021-01776-0.researchsquare.com, doi.org.

102. 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.

103. Parvez (B) et al., Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach, International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2020.09.098.sciencedirect.com, doi.org.

104. 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.

105. 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.

106. Swargiary, A., Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: Evidence from in silico studies, Research Square, doi:10.21203/rs.3.rs-73308/v1.researchsquare.com, doi.org.

107. Maurya, D., A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients, American Chemical Society (ACS), doi:10.26434/chemrxiv.12630539.v1.chemrxiv.org, doi.org.

108. 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.

109. Suravajhala et al., Comparative Docking Studies on Curcumin with COVID-19 Proteins, Preprints, doi:10.20944/preprints202005.0439.v3.preprints.org, doi.org.

110. Shahin et al., The selective effect of Ivermectin on different human coronaviruses; in-vitro study, Research Square, doi:10.21203/rs.3.rs-4180797/v1.researchsquare.com, doi.org.

111. 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.

112. 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.

113. 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.

114. Liu et al., SARS-CoV-2 viral genes Nsp6, Nsp8, and M compromise cellular ATP levels to impair survival and function of human pluripotent stem cell-derived cardiomyocytes, Stem Cell Research & Therapy, doi:10.1186/s13287-023-03485-3.biomedcentral.com, doi.org.

115. 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.

116. 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.

117. Saha (B) et al., Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder, Pharmaceutics, doi:10.3390/pharmaceutics14071432.mdpi.com, doi.org.

118. Jitobaom (B) et al., Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations, BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8.biomedcentral.com, doi.org.

119. 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.

120. Zheng et al., Red blood cell-hitchhiking mediated pulmonary delivery of ivermectin: Effects of nanoparticle properties, International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121719.sciencedirect.com, doi.org.

121. 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.

122. Liu (B) et al., Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes, Stem Cell Reports, doi:10.1016/j.stemcr.2022.01.014.sciencedirect.com, doi.org.

123. Segatori et al., Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients, Viruses, doi:10.3390/v13102084.mdpi.com, doi.org.

124. Jitobaom (C) et al., Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2, Research Square, doi:10.21203/rs.3.rs-941811/v1.researchsquare.com, doi.org.

125. Munson et al., Niclosamide and ivermectin modulate caspase-1 activity and proinflammatory cytokine secretion in a monocytic cell line, British Society For Nanomedicine Early Career Researcher Summer Meeting, 2021, web.archive.org/web/20230401070026/https://michealmunson.github.io/COVID.pdf.archive.org.

126. Mountain Valley MD, Mountain Valley MD Receives Successful Results From BSL-4 COVID-19 Clearance Trial on Three Variants Tested With Ivectosol™, www.globenewswire.com/en/news-release/2021/05/18/2231755/0/en/Mountain-Valley-MD-Receives-Successful-Results-From-BSL-4-COVID-19-Clearance-Trial-on-Three-Variants-Tested-With-Ivectosol.html.globenewswire.com.

127. Yesilbag et al., Ivermectin also inhibits the replication of bovine respiratory viruses (BRSV, BPIV-3, BoHV-1, BCoV and BVDV) in vitro, Virus Research, doi:10.1016/j.virusres.2021.198384.sciencedirect.com, doi.org.

128. Mody et al., Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents, Communications Biology, doi:10.1038/s42003-020-01577-x.nature.com, doi.org.

129. Jeffreys et al., Remdesivir-ivermectin combination displays synergistic interaction with improved in vitro activity against SARS-CoV-2, International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2022.106542.sciencedirect.com, doi.org.

130. Surnar et al., Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19, ACS Pharmacol. Transl. Sci., doi:10.1021/acsptsci.0c00179.acs.org, doi.org.

131. 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.

132. Zhang et al., Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice, Inflammation Research, doi:10.1007/s00011-008-8007-8.springer.com, doi.org.

133. 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.

134. 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.

135. Uematsu et al., Prophylactic administration of ivermectin attenuates SARS-CoV-2 induced disease in a Syrian Hamster Model, The Journal of Antibiotics, doi:10.1038/s41429-023-00623-0.nature.com, doi.org.

136. 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.

137. 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.

138. Madrid et al., Safety of oral administration of high doses of ivermectin by means of biocompatible polyelectrolytes formulation, Heliyon, doi:10.1016/j.heliyon.2020.e05820.sciencedirect.com, doi.org.

139. Ma et al., Ivermectin contributes to attenuating the severity of acute lung injury in mice, Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113706.sciencedirect.com, doi.org.

140. 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.

141. 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.

142. 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.

143. Yan et al., Anti-inflammatory effects of ivermectin in mouse model of allergic asthma, Inflammation Research, doi:10.1007/s00011-011-0307-8.springer.com, doi.org.

144. Götz et al., Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import, Scientific Reports, doi:10.1038/srep23138.nature.com, doi.org.

145. Tay 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 Research, doi:10.1016/j.antiviral.2013.06.002.sciencedirect.com, doi.org.

146. Wagstaff et al., Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochemical Journal, doi:10.1042/BJ20120150.portlandpress.com, doi.org.

147. Wagstaff (B) et al., An AlphaScreen®-Based Assay for High-Throughput Screening for Specific Inhibitors of Nuclear Import, SLAS Discovery, doi:10.1177/1087057110390360.sciencedirect.com, doi.org.

148. 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.

149. Yang et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antiviral Research, doi:10.1016/j.antiviral.2020.104760.sciencedirect.com, doi.org.

150. Mastrangelo et al., Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug, Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dks147.oup.com, doi.org.

151. Varghese et al., Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses, Antiviral Research, doi:10.1016/j.antiviral.2015.12.012.sciencedirect.com, doi.org.

152. 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.

153. 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.

154. Scheim et al., Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19, International Journal of Molecular Sciences, doi:10.3390/ijms242317039.mdpi.com, doi.org.

155. Liu (C) et al., Crosstalk between neutrophil extracellular traps and immune regulation: insights into pathobiology and therapeutic implications of transfusion-related acute lung injury, Frontiers in Immunology, doi:10.3389/fimmu.2023.1324021.frontiersin.org, doi.org.

156. Shouman (B) et al., SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147, Cell Communication and Signaling, doi:10.1186/s12964-024-01718-3.biomedcentral.com, doi.org.

157. Scheim (B), D., Ivermectin for COVID-19 Treatment: Clinical Response at Quasi-Threshold Doses Via Hypothesized Alleviation of CD147-Mediated Vascular Occlusion, SSRN, doi:10.2139/ssrn.3636557.europepmc.org, doi.org.

158. Scheim (C), D., From Cold to Killer: How SARS-CoV-2 Evolved without Hemagglutinin Esterase to Agglutinate and Then Clot Blood Cells, Center for Open Science, doi:10.31219/osf.io/sgdj2.osf.io, doi.org.

159. Behl et al., CD147-spike protein interaction in COVID-19: Get the ball rolling with a novel receptor and therapeutic target, Science of The Total Environment, doi:10.1016/j.scitotenv.2021.152072.sciencedirect.com, doi.org.

160. 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.

161. Hazan et al., Treatment with Ivermectin Increases the Population of Bifidobacterium in the Gut, ACG 2023, acg2023posters.eventscribe.net/posterspeakers.asp.eventscribe.net.

162. 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.

163. 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.

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.

References

Adam, Journal says ivermectin study met standard for 'credible science'. Retraction Watch

Alein, Haro-Ramos, Frontline work and racial disparities in social and economic pandemic stressors during the first COVID-19 surge, Health Services Research

Aragon, epitools: Epidemiology tools. manual

Atif, Effects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus, PLoS Pathogens

Bandt, Boen, A prevalent misconception about sample size, statistical significance, and clinical importance, Journal of Periodontology

Bordalo, Gennaioli, Shleifer, Salience Theory of Choice Under Risk, The Quarterly Journal of Economics

Bordalo, Gennaioli, Shleifer, Salience and consumer choice, Journal of Political Economy

Bramante, Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19, The New England Journal of Medicine

Buffet, Mendoza-Sassi, Fysekidis, Inaccurate Real-World Data Does Not Provide Real-World Answers, American Journal of Therapeutics

Caly, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Research

Chee, Lim, Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial, JAMA Internal Medicine

Da Silva, Factors Contributing to Exacerbating Vulnerabilities in Global Clinical Trials, Frontiers in Pharmacology

Daniel, Lackland, Impact of COVID-19 on Clinical Research and Inclusion of Diverse Populations, Ethnicity & Disease

Dornels Freire De Souza, Feliciano Do Carmo, Machado, The burden of COVID-19 in Brazil is greater in areas with high social deprivation, Journal of Travel Medicine

Drummond, Da, Influência da desigualdade socioeconômica na distribuição das internações e dos óbitos por covid-19 em municípios brasileiros, 2020: um estudo ecológico Influência da desigualdade socioeconômica na distribuição das internações e dos óbitos por covid-19 em municípios brasileiros, 2020: um estudo ecológico, Epidemiologia e servicos de saude : revista do Sistema Unico de Saude do Brasil

Flaxman, Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe, Nature

Furlan, Caramelli, The regrettable story of the "Covid Kit" and the "Early Treatment of Covid-19" in Brazil

Gelman, Loken, The statistical crisis in science, American Scientist

González, The Pharmacokinetics and Interactions of Ivermectin in Humans-A Mini-review, The AAPS Journal

Grasselli, Hospital-Acquired Infections in Critically Ill Patients With COVID-19, Chest

Greenland, Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations, European Journal of Epidemiology

Hill, Retraction to: Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection, Open Forum Infectious Diseases

Janmohamed, Interventions to Mitigate COVID-19 Misinformation: A Systematic Review and Meta-Analysis, doi:10.1080/10810730.2021.2021460

Jaramillo, Clinical Trials Show Ivermectin Does Not Benefit COVID-19 Patients, Contrary to Social Media Claims

Keegan, Crown, Joseph, Diversity, Equity, and Inclusion in Clinical Trials, Surgical Oncology Clinics of North America

Kerr, Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching, Cureus

Kerr, Regular Use of Ivermectin as Prophylaxis for COVID-19 Led Up to a 92% Reduction in COVID-19 Mortality Rate in a Dose-Response Manner: Results of a Prospective Observational Study of a Strictly Controlled Population of 88,012 Subjects, Cureus

Kory, Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19, American Journal of Therapeutics

Laplante, Enrollment, retention, and strategies for including disadvantaged populations in randomized controlled trials: a systematic review protocol, Systematic Reviews

Lawrence, The lesson of ivermectin: meta-analyses based on summary data alone are inherently unreliable, Nature Medicine

Lee, Nunan, Immortal time bias

Leppink, Winston, Sullivan, Statistical significance does not imply a real effect, Perspectives on Medical Education

Long, Bui, Estimation of the incubation period of COVID-19 in Vietnam, PloS one

Martins-Filho, COVID-19 fatality rates related to social inequality in Northeast Brazil: a neighbourhood-level analysis, Journal of Travel Medicine

Men, Estimate the incubation period of coronavirus 2019 (COVID-19), Computers in biology and medicine

Meyerowitz-Katz, Unethical studies of ivermectin for covid-19, British Medical Journal Publishing Group Section: Editorial

Mueser, Granberg, The Monty Hall Dilemma Revisited: Understanding the Interaction of Problem Definition and Decision Making. Experimental

Naggie, Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial, JAMA

Nilima, Kumar, Moxidectin and Ivermectin Inhibit SARS-CoV-2 Replication in Vero E6 Cells but Not in Human Primary Bronchial Epithelial Cells, Antimicrobial Agents and Chemotherapy

Patrick, Walker, The impact of COVID-19 and strategies for mitigation and suppression in low-and middle-income countries, Science

Pennycook, Shifting attention to accuracy can reduce misinformation online, Nature

Peña-Silva, Pharmacokinetic considerations on the repurposing of ivermectin for treatment of COVID-19, British Journal of Clinical Pharmacology, doi:10.1111/bcp.14476

Popp, Ivermectin for preventing and treating COVID-19, Cochrane Database of Systematic Reviews

Reardon, Flawed ivermectin preprint highlights challenges of COVID drug studies

Reis, Effect of Early Treatment with Ivermectin among Patients with Covid-19, Publisher: Massachusetts Medical Society, doi:10.1056/NEJMoa2115869,null

Sackett, Bias in analytic research, Journal of Chronic Diseases

Saenen, Why Humans Fail in Solving the Monty Hall Dilemma: A Systematic Review

Sander Van Der Linden, Misinformation: susceptibility, spread, and interventions to immunize the public, Nature Medicine

Sheldrick, Meyerowitz-Katz, Tucker-Kellogg, Plausibility of Claimed Covid-19 Vaccine Efficacies by Age: A Simulation Study, American Journal of Therapeutics

Spencer, Heneghan, Chronological bias

Stacy, Uybico, Pavel, Gross, Recruiting Vulnerable Populations into Research: A Systematic Review of Recruitment Interventions, Journal of General Internal Medicine

Sundy, Yang, The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antiviral Research

Turner, Schaeffer ; William, Campbell, Mode of Action of Ivermectin

Tversky, Kahneman, Judgment under uncertainty: Heuristics and biases, Science

Wagstaff, Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochemical Journal

{ 'institution': [{'name': 'medRxiv'}], 'indexed': {'date-parts': [[2023, 8, 20]], 'date-time': '2023-08-20T05:10:34Z', 'timestamp': 1692508234189}, 'posted': {'date-parts': [[2023, 8, 15]]}, 'group-title': 'Infectious Diseases (except HIV/AIDS)', 'reference-count': 61, 'publisher': 'Cold Spring Harbor Laboratory', 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'accepted': {'date-parts': [[2023, 8, 15]]}, 'abstract': 'AbstractBackgroundTwo ' '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.MethodsStarting 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.ResultsUntreated ' '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.ConclusionsThe ' '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.', 'DOI': '10.1101/2023.08.10.23293924', 'type': 'posted-content', 'created': {'date-parts': [[2023, 8, 16]], 'date-time': '2023-08-16T05:25:23Z', 'timestamp': 1692163523000}, 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Published benefits of ivermectin use in Itajaí, Brazil for COVID-19 infection, hospitalisation, ' 'and mortality are entirely explained by statistical artefacts', 'prefix': '10.1101', 'author': [ { 'ORCID': 'http://orcid.org/0000-0003-4457-2855', 'authenticated-orcid': False, 'given': 'Robin', 'family': 'Mills', 'sequence': 'first', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-6146-1247', 'authenticated-orcid': False, 'given': 'Ana Carolina', 'family': 'Peçanha Antonio', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-8407-9251', 'authenticated-orcid': False, 'given': 'Greg', 'family': 'Tucker-Kellogg', 'sequence': 'additional', 'affiliation': []}], 'member': '246', 'reference': [ { 'key': '2023081903400475000_2023.08.10.23293924v1.1', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2405-7'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abc0035'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.3', 'doi-asserted-by': 'crossref', 'first-page': '100089', 'DOI': '10.1016/j.lana.2021.100089', 'article-title': 'The regrettable story of the “Covid Kit” and the “Early Treatment of ' 'Covid-19” in Brazil', 'volume': '4', 'year': '2021', 'journal-title': 'The Lancet Regional Health - Americas'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.4', 'doi-asserted-by': 'crossref', 'first-page': '104787', 'DOI': '10.1016/j.antiviral.2020.104787', 'article-title': 'The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 ' 'in vitro', 'volume': '178', 'year': '2020', 'journal-title': 'Antiviral Research'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.5', 'unstructured': 'Decree 11940 2020 of Itajaí SC. Regulamenta a Distribuição do ' 'Medicamento Ivermectina no Município de Itajaí. July 7, 2020. URL: ' 'https://web.archive.org/web/20221022092413/ ' 'https://leismunicipais.com.br/a/sc/i/itajai/decreto/2020/1194/11940/decreto-n-11940-2020-regulamenta-a-distribuicao-do-medicamento-ivermectina-no-municipio-de-itajai ' '(visited on 10/22/2022).'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.6', 'unstructured': '“The Brazilian city being turned into a coronavirus “lab experiment"”. ' 'In: Coda Story ' 'https://www.codastory.com/waronscience/brazil-covid19-ivermectin/ (Aug. ' '27, 2020).'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.7', 'doi-asserted-by': 'crossref', 'unstructured': 'Lucy Kerr et al. “Ivermectin Prophylaxis Used for COVID-19: A Citywide, ' 'Prospective, Observational Study of 223,128 Subjects Using Propensity ' 'Score Matching”. In: Cureus 14.1 (Jan. 15, 2022). Publisher: Cureus.', 'DOI': '10.7759/cureus.c61'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.8', 'doi-asserted-by': 'crossref', 'unstructured': 'Lucy Kerr et al. “Regular Use of Ivermectin as Prophylaxis for COVID-19 ' 'Led Up to a 92% Reduction in COVID-19 Mortality Rate in a Dose-Response ' 'Manner: Results of a Prospective Observational Study of a Strictly ' 'Controlled Population of 88,012 Subjects”. In: Cureus 14.8 (Aug. 31, ' '2022). Publisher: Cureus.', 'DOI': '10.7759/cureus.28624'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.9', 'unstructured': 'Catalina Jaramillo . “Clinical Trials Show Ivermectin Does Not Benefit ' 'COVID-19 Patients, Contrary to Social Media Claims”. In: FactCheck.org ' '(Sept. 15, 2022).'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.10', 'unstructured': '“Fact Check-Gaps in study claiming that ivermectin reduces risk of ' 'COVID-19 death by 92%”. In: Reuters (Sept. 20, 2022).'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.11', 'unstructured': '“Study claiming that ivermectin reduces COVID-19 mortality by 92% has ' 'important methodological problems”. In: Health Feedback (Sept. 7, ' '2022).'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.12', 'unstructured': 'Author Adam Marcus. Journal says ivermectin study met standard for ' '‘credible science’. Retraction Watch. Sept. 19, 2022. URL: ' 'https://retractionwatch.com/2022/09/19/journal-says-ivermectin-study-met-standard-for-credible-science/ ' '(visited on 04/25/2023).'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.13', 'unstructured': 'Sander van der Linden . “Misinformation: susceptibility, spread, and ' 'interventions to immunize the public”. In: Nature Medicine (Mar. 10, ' '2022). Publisher: Nature Publishing Group, pp. 1–8.'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.14', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-021-03344-2'}, { 'issue': '12', 'key': '2023081903400475000_2023.08.10.23293924v1.15', 'doi-asserted-by': 'crossref', 'first-page': '846', 'DOI': '10.1080/10810730.2021.2021460', 'article-title': 'Interventions to Mitigate COVID-19 Misinformation: A Systematic Review ' 'and Meta-Analysis', 'volume': '26', 'year': '2021', 'journal-title': 'Journal of Health Communication'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.16', 'unstructured': 'Catalog of Bias Collaboration , H Lee , and D Nunan . “Immortal time ' 'bias”. In: Catalog of Bias. May 16, 2020.'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.17', 'unstructured': 'Catalog of Bias Collaboration , EA Spencer , and C Heneghan . ' '“Chronological bias”. In: Catalog of Bias. July 18, 2017.'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.18', 'unstructured': 'Catalog of Bias Collaboration et al. “Attrition bias”. In: Catalog of ' 'Bias. July 20, 2017.'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.19', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/0021-9681(79)90012-2'}, { 'issue': '1', 'key': '2023081903400475000_2023.08.10.23293924v1.20', 'doi-asserted-by': 'crossref', 'first-page': '221', 'DOI': '10.1016/j.soc.2022.08.005', 'article-title': 'Diversity, Equity, and Inclusion in Clinical Trials', 'volume': '32', 'year': '2023', 'journal-title': 'Surgical Oncology Clinics of North America'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.21', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s11606-007-0126-3'}, { 'issue': '1', 'key': '2023081903400475000_2023.08.10.23293924v1.22', 'doi-asserted-by': 'crossref', 'first-page': '233', 'DOI': '10.1186/s13643-021-01790-7', 'article-title': 'Enrollment, retention, and strategies for including disadvantaged ' 'populations in randomized controlled trials: a systematic review ' 'protocol', 'volume': '10', 'year': '2021', 'journal-title': 'Systematic Reviews'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.23', 'doi-asserted-by': 'crossref', 'unstructured': 'Alein Y. Haro-Ramos et al. “Frontline work and racial disparities in ' 'social and economic pandemic stressors during the first COVID-19 surge”. ' 'In: Health Services Research (Jan. 31, 2023).', 'DOI': '10.1111/1475-6773.14136'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.24', 'first-page': '999', 'article-title': 'Factors Contributing to Exacerbating Vulnerabilities in Global Clinical ' 'Trials', 'volume': '8', 'year': '2017', 'journal-title': 'Frontiers in Pharmacology'}, { 'issue': '3', 'key': '2023081903400475000_2023.08.10.23293924v1.25', 'doi-asserted-by': 'crossref', 'first-page': '429', 'DOI': '10.18865/ed.30.3.429', 'article-title': 'Impact of COVID-19 on Clinical Research and Inclusion of Diverse ' 'Populations', 'volume': '30', 'year': '2020', 'journal-title': 'Ethnicity & Disease'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.26', 'doi-asserted-by': 'crossref', 'unstructured': 'Paulo Ricardo Martins-Filho et al. “COVID-19 fatality rates related to ' 'social inequality in Northeast Brazil: a neighbourhood-level analysis”. ' 'In: Journal of Travel Medicine 27.7 (Nov. 9, 2020), taaa128.', 'DOI': '10.1093/jtm/taaa128'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.27', 'doi-asserted-by': 'crossref', 'unstructured': 'Carlos Dornels Freire de Souza , Rodrigo Feliciano do Carmo , and ' 'Michael Ferreira Machado . “The burden of COVID-19 in Brazil is greater ' 'in areas with high social deprivation”. In: Journal of Travel Medicine ' '27.7 (Nov. 9, 2020), taaa145.', 'DOI': '10.1093/jtm/taaa145'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.28', 'doi-asserted-by': 'crossref', 'unstructured': 'Gabriela Drummond Marques da Silva et al. “Influência da desigualdade ' 'socioeconômica na distribuição das internações e dos óbitos por covid-19 ' 'em municípios brasileiros, 2020: um estudo ecológico Influência da ' 'desigualdade socioeconômica na distribuição das internações e dos óbitos ' 'por covid-19 em municípios brasileiros, 2020: um estudo ecológico”. In: ' 'Epidemiologia e servicos de saude : revista do Sistema Unico de Saude do ' 'Brasil 32.1 (2023). Place: Brazil, e2022303.', 'DOI': '10.1590/s2237-96222023000100021'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.29', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s10654-016-0149-3'}, { 'issue': '2', 'key': '2023081903400475000_2023.08.10.23293924v1.30', 'doi-asserted-by': 'crossref', 'first-page': '122', 'DOI': '10.1007/S40037-016-0256-6', 'article-title': 'Statistical significance does not imply a real effect', 'volume': '5', 'year': '2016', 'journal-title': 'Perspectives on Medical Education'}, { 'issue': '3', 'key': '2023081903400475000_2023.08.10.23293924v1.31', 'doi-asserted-by': 'crossref', 'first-page': '181', 'DOI': '10.1902/jop.1972.43.3.181', 'article-title': 'A prevalent misconception about sample size, statistical significance, ' 'and clinical importance', 'volume': '43', 'year': '1972', 'journal-title': 'Journal of Periodontology'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.32', 'doi-asserted-by': 'crossref', 'unstructured': 'M. J. Turner and J. M. Schaeffer . “Mode of Action of Ivermectin”. In: ' 'Ivermectin and Abamectin. Ed. by William C. Campbell . New York, NY: ' 'Springer, 1989, pp. 73–88.', 'DOI': '10.1007/978-1-4612-3626-9_5'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.33', 'doi-asserted-by': 'crossref', 'unstructured': 'Mohammed Atif et al. “Effects of glutamate and ivermectin on single ' 'glutamate-gated chloride channels of the parasitic nematode H. ' 'contortus”. In: PLoS Pathogens 13.10 (Oct. 2017). Publisher: PLOS.', 'DOI': '10.1371/journal.ppat.1006663'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.34', 'doi-asserted-by': 'publisher', 'DOI': '10.1042/BJ20120150'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.35', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2020.104760'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.36', 'doi-asserted-by': 'crossref', 'unstructured': 'Nilima Dinesh Kumar et al. “Moxidectin and Ivermectin Inhibit SARS-CoV-2 ' 'Replication in Vero E6 Cells but Not in Human Primary Bronchial ' 'Epithelial Cells”. In: Antimicrobial Agents and Chemotherapy 66.1 (Jan. ' '18, 2022). Publisher: American Society for Microbiology, e01543–21.', 'DOI': '10.1128/AAC.01543-21'}, { 'issue': '3', 'key': '2023081903400475000_2023.08.10.23293924v1.37', 'doi-asserted-by': 'crossref', 'first-page': '1589', 'DOI': '10.1111/bcp.14476', 'article-title': 'Pharmacokinetic considerations on the repurposing of ivermectin for ' 'treatment of COVID-19', 'volume': '87', 'year': '2021', 'journal-title': 'British Journal of Clinical Pharmacology'}, { 'issue': '1', 'key': '2023081903400475000_2023.08.10.23293924v1.38', 'doi-asserted-by': 'crossref', 'first-page': '42', 'DOI': '10.1208/s12248-007-9000-9', 'article-title': 'The Pharmacokinetics and Interactions of Ivermectin in Humans—A ' 'Mini-review', 'volume': '10', 'year': '2008', 'journal-title': 'The AAPS Journal'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.39', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/d41586-021-02081-w'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.40', 'doi-asserted-by': 'crossref', 'unstructured': 'Gideon Meyerowitz-Katz et al. “Unethical studies of ivermectin for ' 'covid-19”. In: BMJ 377 (Apr. 14, 2022). Publisher: British Medical ' 'Journal Publishing Group Section: Editorial, o917.', 'DOI': '10.1136/bmj.o917'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.41', 'doi-asserted-by': 'crossref', 'unstructured': 'Andrew Hill et al. “Retraction to: Meta-analysis of Randomized Trials of ' 'Ivermectin to Treat SARS-CoV-2 Infection”. In: Open Forum Infectious ' 'Diseases 9.3 (Mar. 2022), ofac056.', 'DOI': '10.1093/ofid/ofac056'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.42', 'doi-asserted-by': 'publisher', 'DOI': '10.1097/MJT.0000000000001377'}, { 'issue': '5', 'key': '2023081903400475000_2023.08.10.23293924v1.43', 'doi-asserted-by': 'crossref', 'first-page': 'e596', 'DOI': '10.1097/MJT.0000000000001415', 'article-title': 'Inaccurate Real-World Data Does Not Provide Real-World Answers', 'volume': '28', 'year': '2021', 'journal-title': 'American Journal of Therapeutics'}, { 'issue': '11', 'key': '2023081903400475000_2023.08.10.23293924v1.44', 'doi-asserted-by': 'crossref', 'first-page': '1853', 'DOI': '10.1038/s41591-021-01535-y', 'article-title': 'The lesson of ivermectin: meta-analyses based on summary data alone are ' 'inherently unreliable', 'volume': '27', 'year': '2021', 'journal-title': 'Nature Medicine'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.45', 'doi-asserted-by': 'crossref', 'unstructured': 'Kyle A. Sheldrick , Gideon Meyerowitz-Katz , and Greg Tucker-Kellogg . ' '“Plausibility of Claimed Covid-19 Vaccine Efficacies by Age: A ' 'Simulation Study”. In: American Journal of Therapeutics (2022).', 'DOI': '10.1097/MJT.0000000000001528'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.46', 'unstructured': 'Steven Chee Loon 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”. In: JAMA Internal ' 'Medicine (Feb. 18, 2022).'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.47', 'doi-asserted-by': 'crossref', 'unstructured': 'Gilmar Reis et al. “Effect of Early Treatment with Ivermectin among ' 'Patients with Covid-19”. In: New England Journal of Medicine 0.0 (Mar. ' '30, 2022). Publisher: Massachusetts Medical Society _eprint: ' 'https://doi.org/10.1056/NEJMoa2115869, null.', 'DOI': '10.1056/NEJMoa2115869'}, { 'issue': '16', 'key': '2023081903400475000_2023.08.10.23293924v1.48', 'doi-asserted-by': 'crossref', 'first-page': '1595', 'DOI': '10.1001/jama.2022.18590', 'article-title': 'Effect of Ivermectin vs Placebo on Time to Sustained Recovery in ' 'Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial', 'volume': '328', 'year': '2022', 'journal-title': 'JAMA'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.49', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2201662'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.50', 'doi-asserted-by': 'crossref', 'unstructured': 'Maria Popp et al. “Ivermectin for preventing and treating COVID-19”. In: ' 'Cochrane Database of Systematic Reviews 6 (2022). Publisher: John Wiley ' '& Sons, Ltd.', 'DOI': '10.1002/14651858.CD015017.pub3'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.51', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.185.4157.1124'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.52', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/qje/qjs018'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.53', 'doi-asserted-by': 'publisher', 'DOI': '10.1086/673885'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.54', 'doi-asserted-by': 'publisher', 'DOI': '10.1511/2014.111.460'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.55', 'unstructured': 'Peter Mueser and Donald Granberg . The Monty Hall Dilemma Revisited: ' 'Understanding the Interaction of Problem Definition and Decision Making. ' 'Experimental. University Library of Munich, Germany, 1999.'}, { 'issue': '1', 'key': '2023081903400475000_2023.08.10.23293924v1.56', 'doi-asserted-by': 'crossref', 'first-page': '128', 'DOI': '10.5334/pb.274', 'article-title': 'Why Humans Fail in Solving the Monty Hall Dilemma: A Systematic Review', 'volume': '58', 'year': '2018). = 2018', 'journal-title': 'Psychologica Belgica'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.57', 'unstructured': '“TCE pede explicações à prefeitura de Itajaí sobre distribuição de ' 'ivermectina; médicos dividem opinião sobre uso contra Covid-19”. In: ' 'globo.com (July 31, 2020), ' 'https://g1.globo.com/sc/santa–catarina/noticia/2020/07/31/tce–pede–explicacoes–a–prefeitura–de–itajai–sobre–compra–e–distribuicao–de–antiparasitario–medicos–dividem–opiniao–sobre–uso–contra–covid–19.ghtml.'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.58', 'doi-asserted-by': 'crossref', 'first-page': '106794', 'DOI': '10.1016/j.compbiomed.2023.106794', 'article-title': 'Estimate the incubation period of coronavirus 2019 (COVID-19)', 'volume': '158', 'year': '2023', 'journal-title': 'Computers in biology and medicine'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.59', 'doi-asserted-by': 'crossref', 'unstructured': 'Long V. Bui et al. “Estimation of the incubation period of COVID-19 in ' 'Vietnam.” In: PloS one 15.12 (2020). Place: United States, e0243889.', 'DOI': '10.1371/journal.pone.0243889'}, { 'issue': '2', 'key': '2023081903400475000_2023.08.10.23293924v1.60', 'doi-asserted-by': 'crossref', 'first-page': '454', 'DOI': '10.1016/j.chest.2021.04.002', 'article-title': 'Hospital-Acquired Infections in Critically Ill Patients With COVID-19', 'volume': '160', 'year': '2021). :', 'journal-title': 'Chest'}, { 'key': '2023081903400475000_2023.08.10.23293924v1.61', 'unstructured': 'Tomas J. Aragon . epitools: Epidemiology tools. manual. 2020.'}], 'container-title': [], 'original-title': [], 'link': [ { 'URL': 'https://syndication.highwire.org/content/doi/10.1101/2023.08.10.23293924', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 8, 19]], 'date-time': '2023-08-19T10:40:39Z', 'timestamp': 1692441639000}, 'score': 1, 'resource': {'primary': {'URL': 'http://medrxiv.org/lookup/doi/10.1101/2023.08.10.23293924'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2023, 8, 15]]}, 'references-count': 61, 'URL': 'http://dx.doi.org/10.1101/2023.08.10.23293924', 'relation': {}, 'published': {'date-parts': [[2023, 8, 15]]}, 'subtype': 'preprint'}

Download Image

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0