Five RCTs recently published in mainstream scientific journals that confirm major, statistically significant benefits of ivermectin against COVID-19

Source: Trial Site News

Abstract

Major benefits of ivermectin (IVM) treatment for COVID-19 have been known since the results of 20 such randomized controlled trials (RCTs) were reported, as compiled in January 2021. Of the eight of these RCTs that tracked mortality or morbidity in patients with serious cases, seven showed statistically significant clinical improvements.

The pooled mortality reduction in these eight RCTs was 78% in the treatment vs. controls groups, and the RCT that used the highest dose of IVM reported a 92% reduction in mortality (p < 0.001). Three RCTs for IVM prevention of COVID-19 and two animal studies of IVM at low human-equivalent doses likewise reported pronounced efficacy.

Here we note the recent publication of RCTs for IVM treatment or prevention of COVID-19 in mainstream scientific journals that confirm these previously reported findings.

Background

The consistently observed, major benefits of ivermectin (IVM) for COVID-19 treatment have been known since a January 2021 meta-study compiled results of 20 such randomized clinical trials (RCTs).¹ Of the eight of these RCTs that tracked mortality or morbidity in patients with moderate or severe symptoms (4 double-blind,^2-5 1 single-blind,⁶ and 3 non-blinded^7-9), seven showed statistically significant clinical improvements (all but Podder et al.⁸). The pooled mortality reduction in these eight RCTs for the IVM treatment group vs. controls was 78% (mortality of 2.1% for IVM, 9.5% for controls). The RCT that used the highest dose of IVM, 1,600 μg/kg total, had 2 vs. 24 deaths in the treatment vs. control group (n=200 each),⁷ a 92% reduction in mortality (p < 0.001). 

Complementing these IVM treatment studies, three RCTs evaluated IVM for prevention in subjects exposed to COVID-19 patients. These studies reported relative COVID-19 incidences of 20%, 16% and 13% compared with incidences in controls, with even lower relative incidences for serious such cases. In addition, two animal studies of IVM treatment at low human-equivalent doses for SARS-CoV-2 in hamsters¹⁰ and for a closely related betacoronavirus in mice¹¹ likewise found major, highly statistically significant treatment benefits.

Yet some skeptical reviewers had dismissed this overwhelming RCT evidence for clinical efficacy of IVM against COVID-19, claiming insufficient quality of the studies,^12,13 as had been indicated by the lack of publication of any in mainstream scientific journals. The recent publication of five such RCTs for IVM in top-tier journals, including Lancet eClinicalMedicine¹⁴ and BMC infectious diseases,¹⁵ all reporting major, statistically significant clinical benefits against COVID-19, dismantles these skeptical critiques.

Five recently published studies in mainstream scientific journals

Among these five recently published RCTs was a prevention study of April 2021 by Seet et al.¹⁶ IVM was administered to 617 subjects, with 2,420 other subjects assigned to either a control group or to one of three other preventative regimens. The subjects were then tracked for onset of COVID-19 symptoms and positive nasopharyngeal PCR tests over a 42-day period. IVM at a dose of 12 mg was given just once on day one, while the three other preventative regimens were each administered daily during this 42-day period. Yet IVM at this single low dose yielded the best clinical results, reducing incidence of symptomatic COVID-19 by 50% (p=0.003) and of ARDS symptoms by 49% (p=0.012) with respect to controls. IVM at that single low dose, however, yielded only a non-significant 8% reduction in relative incidence of positive PCR tests.

Of the four recently published RCTs that studied IVM treatment of COVID-19, Chaccour et al., as previously released in preprint, monitored outcomes for 40 generally young patients with mild COVID-19 symptoms.¹⁴ A single dose of IVM at 400 μg/kg significantly reduced the duration of hyposmia/anosmia (p<0.001), but gave only a modest reduction in viral load. Shahbaznejad et al. reported that IVM in a single dose of 200 μg/kg reduced duration of COVID-19 symptoms and hospitalization (p=0.02 for each).¹⁷ IVM also reduced duration of coughing (p=0.02) and of shortness of breath (p<0.05). No conclusions could be drawn regarding mortality, since only one patient died, within 24 hours of hospitalization in critical condition, a 78-year old woman in the treatment group with a history of diabetes and heart failure.

Mahmud et al. administered a single dose of IVM at 12 mg plus doxycycline at 100 mg twice daily for five days.¹⁸ The IVM treatment group had statistically significant clinical benefits v. controls by four different measures, p=0.001 to 0.003, and had a reduced percentage of positive PCR tests at 14 days with p=0.002. Okumus et al. administered IVM at 200 μg/kg for five consecutive days, in addition to the standard of care used for both the treatment and control groups, which included azithromycin.¹⁵ At the end of the five-day study follow-up period, spO2 was increased; CRP, ferritin and D-dimer blood levels were reduced; and percentage of PCR-negative tests were increased vs. controls, all to statistical significance (p=0.032, 0.02, 0.005, 0.03, and 0.01, respectively).

More pronounced reduction by single-agent IVM of COVID-19 morbidity v. infectivity

The findings of two of these five recently published RCTs, Chaccour et al.¹⁴ and Seet et al.,¹⁶ both fit a pattern established in a prior RCT³ and two animal studies^10,11 of more pronounced alleviation by IVM as a single agent of COVID-19-related symptoms and morbidities than reductions in viral load. Indeed, one RCT of IVM at an unusually high dose, 3,000 μg/kg total over 5 consecutive days, yielded a statistically significant reduction in viral load in COVID-19 patients vs. controls only for the subgroup of treated patients (45%) in which the highest levels of plasma IVM levels were obtained.¹⁹ 

This disparity between reduction in morbidity vs. infectivity by IVM for COVID-19 may be explainable by the indicated clinically operative biological mechanism of IVM as reported in seven molecular modeling studies.^20-26 Those studies found that IVM bound strongly to regions of SARS-CoV-2 viral spike protein, one subdomain of which (RBD) controls viral binding and replication via host cell ACE2 receptors, with another subdomain (NTD) governing viral attachments to sialic acid (SA) binding sites on blood, endothelial and other host cells.²⁷ The latter such attachments of SARS-CoV-2 to SA binding sites on red blood cells (RBCs) are responsible for the clumping that is observed in vitro when virus is mixed with RBCs in this hemagglutinating virus. Whereas the common cold human betacoronavirus strains contain an enzyme, hemagglutinin esterase (HE), that releases viral-RBC clumps, the three virulent betacoronavirus strains—SARS-CoV-2, SARS-CoV, and MERS—lack HE.²⁷ IVM, if it is found to bind to NTD sites on SARS-CoV-2 spike protein, might thus limit viral virulence by blocking such hemagglutinating bindings.

The biological mechanism of IVM that is operative clinically against COVID-19 remains to be confirmed, as do indications of its greater reduction of morbidity than of infectivity per the studies noted. The recent publication of the five RCTs noted in top tier scientific journals, however, positively confirms the major, statistically significant clinical benefits of IVM, as previously reported in several prior such RCTs, for COVID-19 treatment and prevention.

References

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2. Babalola O, Bode C, Ajayi A, et al. Ivermectin shows clinical benefits in mild to moderate COVID19: A randomised controlled double blind dose response study in Lagos. medRxiv. 2021;doi:10.1101/2021.01.05.21249131.

3. Kirti R, Roy R, Pattadar C, et al. Ivermectin as a potential treatment for mild to moderate COVID-19 – A double blind randomized placebo-controlled trial. medRxiv. 2021;doi: 10.1101/2021.01.05.21249310.

4. Mahmud R. Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection (NCT04523831). https://clinicaltrials.gov/ct2/show/results/NCT04523831?view=results. Updated October 9, 2020. Accessed April 2, 2021.

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8. Podder CS, Chowdhury N, Sina MI, et al. Outcome of ivermectin treated mild to moderate COVID-19 cases; a single-centre, open-label, randomised controlled study. IMC J Med Sci. 2020;14(2):002.

9. Okumus N. Ivermectin for Severe COVID-19 Management (NCT04646109). https://clinicaltrials.gov/ct2/show/results/NCT04646109?view=results. Updated January 27, 2021. Accessed April 21, 2021.

10. Melo GD, Lazarini F, Larrous F, et al. Anti-COVID-19 efficacy of ivermectin in the golden hamster. bioRxiv. 2020;doi:10.1101/2020.11.21.392639.

11. Arévalo AP, Pagotto R, Pórfido JL, et al. Ivermectin reduces in vivo coronavirus infection in a mouse experimental model. Scientific Reports. 2021;11(1):7132.

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14. Chaccour C, Casellas A, Blanco-Di Matteo A, 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. 2021;10.1016/j.eclinm.2020.100720.

15. Okumuş N, Demirtürk N, Çetinkaya RA, et al. Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients. BMC Infectious Diseases. 2021;21(1):411.

16. Seet RCS, Quek AML, Ooi DSQ, 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. 2021;106:314-322.

17. Shahbaznejad L, Davoudi A, Eslami G, et al. Effect of ivermectin on COVID-19: A multicenter double-blind randomized controlled clinical trial. Clinical Therapeutics. 2021;https://doi.org/10.1016/j.clinthera.2021.04.007.

18. Mahmud R, Rahman MM, Alam I, et al. Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial. Journal of International Medical Research. 2021;49(5):03000605211013550.

19. Krolewiecki A, Lifschitz A, Moragas M, et al. Antiviral effect of high-dose ivermectin in adults with COVID-19: a pilot randomised, controlled, open label, multicentre trial. SSRN. http://ssrn.com/abstract=3714649. Published 2020. Accessed November 23, 2020.

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22. Suravajhala R, Parashar A, Malik B, et al. Comparative Docking Studies on Curcumin with COVID-19 Proteins. Preprints.org. 2020;doi:10.20944/preprints202005.0439.v2.

23. Nallusamy S, Mannu J, Ravikumar C, et al. Shortlisting Phytochemicals Exhibiting Inhibitory Activity against Major Proteins of SARS-CoV-2 through Virtual Screening. Research Square. 2020;doi:10.21203/rs.3.rs-31834/v1.

24. Kalhor H, Sadeghi S, Abolhasani H, 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. 2020;10.1080/07391102.2020.1824816:1-16.

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26. Toor HG, Banerjee DI, Lipsa Rath S, et al. Computational drug re-purposing targeting the spike glycoprotein of SARS-CoV-2 as an effective strategy to neutralize COVID-19. Eur J Pharmacol. 2021;890:173720.

27. Scheim DE. From cold to killer: How SARS-CoV-2 evolved without hemagglutinin esterase to agglutinate, then clot blood cells in pulmonary and systemic microvasculature. http://ssrn.com/abstract=3706347. Published 2020. Accessed March 30, 2021.

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