Third part of a timeline of ivermectin-related events in theCOVID-19 pandemic

See Part 1 and Part 2

Mika Turkia M.Sc.
mika.turkia@alumni.helsinki.fi
September 30, 2021

Abstract

This review presents a third part extending two previous parts of a timeline describing ivermectin-related events in the COVID-19 pandemic, with this third part covering a period from July 2021 to September 2021.

Among the most notable developments during the period were allegations that a clinical trial about prophylaxis and late treatment of COVID-19 with ivermectin by Elgazzar et al. carried out in Egypt in mid-2020was fraudulent, with some of the introduction plagiarized and the patient data claimed to appear fabricated.

The government of Egypt initiated an investigation on the issue, the results of which were not available bythe end of the period.

Ivermectin skeptics noted that the retraction of the Elgazzar et al. trial, along with suspicions about failed randomization in another trial by Niaee et al., seemed to invalidate the various meta-analyses which had included these trials. Ivermectin proponents argued that the retraction did not affect the conclusions of their meta-analyses. Later, the validity of an Argentinian prophylaxis trial by Carvallo et al. was questioned; as an observational trial it had not been included in the meta-analyses.

Among new trial results were the results of ’Together’ trial led by a Canadian university but carried out in Brazil. The primary endpoint was extended emergency room observation or hospitalization, and the secondary endpoint was mortality. Fluvoxamine produced a statistically significant result for the first endpoint but not for the second. In 677 treated patients vs 678 controls ivermectin indicated some risk reduction but the differences were not statistically significant. One of the authors concluded that ivermectin had ’noeffect whatsoever’ on their endpoints. On the other hand, a intervention program in La Pampa province of Argentina with 3,269 treated and 18,149 untreated indicated mortality rates of 1.5% vs 2.1% (p=0.029),and in subjects over 40 years 2.7% vs 4.1% (p=0.005). A Cochrane meta-analysis concluded that all aspects regarding ivermectin’s efficacy for either treatment or prophylaxis were currently unknown.

After a 24-fold increase in ivermectin prescriptions from US pharmacies compared to the pre-pandemic baseline, US Food and Drug Administration (FDA), American Medical Association, American Pharmacists Association and American Society of Health-System Pharmacists campaigned against ivermectin, calling for‘an immediate end’ to prescribing, dispensing and using it. However, this campaigning also resulted in an increased public awareness of ivermectin.

A prominent social media figure with over ten million followers revealed that he had been prescribed ivermectin for COVID-19. The fact was subsequently propagated internationally by the news media which represented ivermectin as a dangerous ‘horse dewormer’. Several international news outlets published a false story about emergency rooms in Oklahoma being full of people having overdosed ivermectin, blocking out other patients including gunshot victims.

A Japanese doctor who had treated 500 patients with ivermectin reported having received death threats after telling about his methods on a television program. A group of British scientists which had published a meta-analysis about ivermectin reported having received death threats after questioning the efficacy of ivermectin. An ivermectin discussion forum was flooded with pornographic images and incoherent babbling.

A hospital was harassed for not administering ivermectin.

An Indian physician claimed that due to the World Health Organization’s opposition to ivermectin, India’s second wave had been countered by an almost nationwide covert use of early treatment protocols including ivermectin. Another physician reported that in one city in Amazonas, Brazil, a mass distribution of ivermectin had resulted in the city having no hospitalized COVID-19 patients during the surge of the gamma variant in the first half of 2021.

Frontline COVID-19 Critical Care Alliance (FLCCC) faced criticism for its ivermectin advocacy and communication style. With regard to treatment protocols, the addition of dual anti-androgen therapy to FLCCC’sMATH+ hospital treatment protocol was said to have restored the protocol’s efficacy against the delta variant in intensive care unit patients. FLCCC also published a scoping review of the pathophysiology ofCOVID-19, emphasizing the role of platelet activation with the release of serotonin and the activation and degranulation of mast cells contributing to the hyper-inflammatory state.

In an overview, the period from April 2020 to March 2021 could be characterized as a period of argumentation and attempted rationality, the period from April 2021 to June 2021 as a period of emotion and campaigning,and the period from July 2021 to September 2021 as a period of chaos.

Current best practices for meta-analyses were found to be unsound. A new approach based on individual patient data analysis was proposed.

Introduction

The period covering the first part of the timeline from April 2020 to March 2021 [1] could be characterized as a period of research, argumentation and rationality. During the period, smaller-scale research and experimentation of ivermectin for COVID-19 was pursued and eventually, alliances and groups of clinicians and researchers were formed to promote combination treatment protocols that included ivermectin. However, at the end of the period, first the European Medicine Agency (EMA) and second the World Health Organization(WHO) advised against the use of ivermectin except in clinical trials.

The second period from April 2021 to June 2021 [2] could be characterized as a period of emotion and campaigning. During the period, a failure of the approach based on argumentation led to a disillusionment of clinicians and researchers in favor of ivermectin treatments and stopped communication between the proponents and administrative agencies. Instead, ivermectin proponents turned directly to the public and the clinicians. The analysis related to the second part of the timeline focused on possible structural corruption and the role of the WHO.

The third period from July 2021 to September 2021 covered in this paper might best be characterized as a period of chaos, initiated by accusations of plagiarism and data fabrication in one of the early ivermectin trials [3]. As the trial was included in published meta-analyses of ivermectin’s efficacy [4,5,6], the allegations undermined the believability of these meta-analyses, although the authors of the meta-analyses at first stated that the exclusion did not essentially change the results of the analyses. Later, one of the groups diverged from this view.

The history, indications and safety of ivermectin have been described in the previous parts. Some events preceding July 2021 not included in the previous parts of the timeline have been included.

March 2020

On March 25, Waltner-Toews et al. wrote that COVID-19 requires a new approach to science [7]. They referred to ‘post-normal science’ (PNS) developed in the 1990s by Silvio Funtowicz and Jerome R. Ravetz which represented a novel approach for the use of science on issues where ‘facts are uncertain, values in dispute, stakes high and decisions urgent’ [8]. As an example, PNS recommended that models to predict and control the future should be replaced by models to map our ignorance about the future; it also stressed the importance of trust, participation and transparency, all of which had been lacking during the COVID-19pandemic. Waltner-Toews et al. wrote that ‘everywhere, we are seeing a total breakdown of the epistemic consensus required to make normal science “work”. This is happening not only in the fields you might expect– behavioral psychology, sociology, and ethics – but also in virology, genetics, and epidemiology. In other words, when “applied scientists” and “professional consultants” are no longer in their comfort zones but find themselves in a post-normal context, fitness for purpose changes meaning. And even in established fields, disagreements can’t be hidden (or consensus enforced) from broad audiences: are the present draconian measures justified or not? More data (even “reliable data”) and better predictive models cannot resolve the“distribution of sacrifice” which involves, among other things, the arbitration of dilemmas that appear at every scale. Hiding behind some general notion of science or the “lack of data” – as if data had the power to resolve these dilemmas – is feckless, feeble and confused’.

November 2020

On November 29, an article by Cherkes et al. in the clinical practice guidelines and recommendations section of an Ukrainian journal Proceedings of the Shevchenko Scientific Society – Medical Sciences gave a detailed description of FLCCC’s MATH+ hospital treatment protocol [9].

April 2021

On April 14, an article by Seet et al. described an open-label randomized trial (n=3,037) describing a 42-day prophylaxis regimen with four different medications, one of which was povidone iodine throat spray(n=735), compared to 500 mg per day of oral vitamin C (n=619), indicated 44.7% lower risk of severe disease (5.7% vs 10.3%, RR 0.55, p=0.05) and 31.1% lower risk of infection (46.0% vs 70.0%, RR 0.69,p=0.01) [10,11]. A single 12 mg dose of ivermectin (n=617) did not produce a statistically significant difference. Hydroxychloroquine produced a slightly smaller risk reduction than povidone iodine.

May 2021

On May 11, two Norwegian doctors presented data on ivermectin trials to the Norwegian government [12].

On May 26, an investigational monoclonal antibody for mild to moderate COVID-19, sotrovimab, was issued an emergency use authorization by the US Food and Drug Administration (FDA). Sotrovimab was to be administered as a single intravenous infusion of 500 mg over 30 minutes within 10 days of symptom onset [13].

The wholesale price of a single dose was USD 2,100 [14].

On May 28, Bloomberg Law discussed YouTube’s censorship practices [15]. YouTube chief executive officer Susan Wojcicki commented that ‘the complex nature of misinformation online presents a number of challenges for platforms such as YouTube and I welcome your suggestions as to what we can do better’.

June 2021

On June 1, a commentary by Chosidow et al. asked whether ivermectin would be a potential treatment forCOVID-19 [16].

On June 4, an article by Payne et al. about evidence-based approach to early outpatient treatment considered zinc gluconate, melatonin and vitamin D feasible options but repeated the usual objections to ivermectin[17].

On June 7, an article by Sajidah et al. discussed the host nuclear transport machinery in detail [18].

On June 10, Kumar et al. discussed the role of vitamins and minerals as immunity boosters in COVID-19, pointing out for example the protective roles of calcium, magnesium, copper, iodine, selenium, manganese,cobalt and sulfur, and the possibly harmful effect of iron [19].

On June 14, an article by Duru et al. described an in silico study suggesting that ivermectin bound well toSARS-CoV-2 spike glycoprotein [20].

On June 17, an article by Yanagida et al. concluded that ivermectin had low proarrhythmic risk [21].

On June 18, an article by Mart´ınez investigated the antioxidant properties of several pharmaceuticals, positing the idea that oxide reduction balance might help explain the toxicity or efficacy of these drugs, and noting that ivermectin and molnupiravir, two powerful COVID-19 drugs, were not good electron acceptors,and the fact that they were not as effective oxidants as other studied molecules might be an advantage [22].

On June 18, a commentary by Taibbi discussed politicization and censorship of ivermectin in the US [23,24].

On June 18, a Norwegian newspaper Aftenposten interviewed two Norwegian proponents of FLCCC protocols, one of whom was FLCCC founding member Eivind Hustad Vinjevoll [25] and the other Anders Bugge.

The Norwegian Medicines Agency remained unconvinced, stating that it was not their task to assess unapproved treatments: they only followed the recommendations of US National Institutes of Health and the World Health Organization.

On June 21, referring to lack of evidence and low quality of trials, eleven Norwegian senior physicians disagreed with Vinjevoll’s and Bugge’s views [26].

On June 22, Huang et al. summarized recent advances in the exploration of ivermectin’s anticancer properties [27].

On June 27, Salvador et al. published a protocol of a prospective observational study aiming to evaluate the effectiveness and safety of a single-dose ivermectin for treatment of uncomplicated strongyloidiasis in immunosuppressed patients [28].

On June 28, Bugge replied to the Norwegian senior physicians [29].

On June 28, an article by Roman et al. presented a meta-analysis of ten randomized controlled trials(RCTs) including 1,173 patients with mild or moderate disease [30]. The authors wrote that in comparison to standard of care or placebo, ivermectin did not reduce all-cause mortality, length of stay or viral clearance.

They concluded that ivermectin was not a viable option to treat COVID-19 patients. The article was based on a previous preprint [31,32]. The CovidAnalysis group noted that in addition to numerous uncorrected errors,the preprint and the PDF of the article stated that the authors had no conflicts of interest, yet Pasupuleti’saffiliation listed in the abstract on the journal’s website was a company delivering brand and portfolio commercial strategy for biotech and pharma, working with 24 of the top 25 pharmaceutical companies as well as hundreds of biotechs globally [33,34]. The company also stated that they were working withthe European Federation of Pharmaceutical Industries (EFPIA) to support their activities, and that the company’s regulatory consultancy practice in the US was preparing a number of emergency use authorizations to the FDA [35].

On June 28, an article by Patterson et al. presented a model for predicting COVID-19 severity and chronicity [36]. A score measuring severity of COVID-19 was defined as (IL-6 + sCD40L / 1000 + VEGF / 10 + 10 * IL-10) / (IL-2 + IL-8). A score measuring chronicity (long haul symptoms) was defined as (IFN-γ+ IL-2) / CCL4-MIP-1β. CCL4 (chemokine ligands 4), also called MIP-1β(macrophage inflammatory protein-1β),was related to the C-C chemokine receptor type 5 (CCR5) pathway. About VEGF, see also [37,38,39,40].

On June 30, Thailand’s FDA and Chiang Mai University’s faculty of pharmacy warned against using ivermectin for COVID-19 [41].

On June 30, an article by Nippes et al. reviewed research on the presence of chloroquine, hydroxychloroquine, azithromycin, ivermectin, dexamethasone, remdesivir, favipiravir and some HIV antivirals in the environment, and presented treatment technologies for each drug [42].

On June 30, Syed interviewed FLCCC’s Marik about treatments and the origin of SARS-CoV-2 [43].

July 2021

On July 1, HART group consisting of UK doctors compared adverse events reported to the WHO of ivermectin (20 deaths and 5,484 adverse events since 1992), remdesivir (534 deaths and 6,707 adverse events since 2020) and COVID-19 vaccines (6,667 deaths and 1,198,200 adverse events since 2020) [44]. They also suggested that some of the ongoing studies were designed to fail and actually aimed at stalling the adoption of ivermectin.

On July 1, Vice magazine wrote about ivermectin advocates, saying that ‘proponents of a dubious COVID19 cure have signaled they’re ready for a long fight against what they see as censorship in medicine and media’ [45].

On July 2, an article by Vallejos et al. described a low dose RCT with 501 relatively low-risk outpatients in Argentina which did not produce statistically significant results (NCT04529525) [46,47].

On July 2, an article by Adegboro et al. reviewed the antiviral effects of ivermectin [48].

On July 2, a Twitter post reported that a video featuring Nobel prize winner Satoshi ¯Omura discussing Japanese ivermectin emergency use authorization bill had been removed by YouTube for violating their terms of service [49].

On July 2, a blog post by Crawford investigated the details and the background of the meta-analysis by Roman et al., noting that the meta-analysis came at a politically contentious moment, the language and behavior appeared political, the work was error-laden, took research out of its true context, used numbers that didn’t seem to come from the actual studies, chose papers testing ivermectin under the least favorable circumstances, gave unexplained and inappropriate weights to the small amount of data that stood as outliers to the bigger picture, and extracted an unfavorable conclusion from a massive average mortality reduction that did not quite reach statistical significance while consistently complaining about the low quality of evidence represented by the studies [50]. Crawford asked whether these were ‘just mistakes’, adding that ‘a medical journal published all this – just in time to push back the Lawrie case. Think on all that for a moment’.

On July 3, an open letter signed by 43 researchers and clinicians requested retraction of the meta-analysis by Roman et al. [51,52].

On July 6, an article by Hill et al. (submitted on January 20) presented a meta-analysis including eleven RCTs of moderate/severe infection [5]. The analysis indicated 56% reduction in mortality (3% vs 9%, RR0.44, 95% CI 0.25-0.77, p=0.004), favorable clinical recovery and reduced hospitalization. In contrast to the preprint stating that ivermectin should be validated in larger studies before the results are sufficient for review by regulatory authorities [53], the published version said that a network of large clinical trials was in progress to validate the results seen to date.

On July 6, a TrialSite news report suggested that the WHO might have been attempting to limit the use of ivermectin to neglected tropical diseases only [54,55,56]. The report also discussed the apparent lack of objectivity of Wikipedia, noting that it had, among other omissions, mentioned the rejection of FLCCC’s review by Frontiers of Pharmacology but failed to mention that it had later been published in the American Journal of Therapeutics, failed to mention the meta-analysis by the BIRD group, and failed to mention USNIH’s transitioning to a neutral stance on ivermectin. The report asked why any positive aspects would be omitted unless there was an explicit goal to completely discredit this possible therapeutic option and researchers looking into the matter.

On July 6, Yahoo News UK published a news story featuring ivermectin in a positive light [57].

On July 6, WHO announced that it had updated its patient care guidelines to include interleukin-6 receptor blockers tocilizumab (by Roche) and sarilumab (by Regeneron Pharmaceuticals and Sanofi) [58]. The strong recommendation was based on findings from a prospective and a living network meta-analysis including data(also prepublication data) from over 10,000 patients enrolled in 27 clinical trials. The meta-analyses were said to show that in severely or critically ill patients these drugs reduced the odds of death by 13% and the odds of mechanical ventilation by 28% compared to standard of care, with high certainty of evidence [59]. WHO said tocilizumab and sarilumab were the first drugs found to be effective against COVID-19 since corticosteroids were recommended in September 2020 [58]. WHO director-general Tedros Adhanom Ghebreyesus said, however, that the drugs would remain inaccessible to most, and called on manufacturers to reduce prices and make supplies available to low-and middle-income countries. Ghebreyesus also encouraged companies to agree to transparent, non-exclusive voluntary licensing agreements using WHO’s Covid-19 Technology Access Pool (C-TAP) platform and the Medicines Patent Pool, or to waive exclusivity rights. Rochwerg et al. noted that compared with other treatments IL-6 receptor blockers were expensive but the the recommendation did not take account of cost effectiveness [59]. They also acknowledged that access to these drugs was challenging in many parts of the world and that the recommendation could exacerbate health inequity. However, the strong recommendation aimed at providing a stimulus to improve global access to these treatments.

On July 6, an article by WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) WorkingGroup presented a meta-analysis on the efficacy of tocilizumab and sarilumab [60]. Absolute mortality risk was 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for standard of care or placebo, with especially sarilumab showing very low efficacy. Regarding conflicts of interests, one of the authors reported being involved with two patents owned by Genentech/Roche, one on treating COVID-19with an IL-6 antagonist, and another for tocilizumab and remdesivir combination therapy for COVID-19pneumonia. Two other authors reported being co-inventors of a filed patent covering the use of low-dose tocilizumab for treatment of viral infections. Nine other authors also reported associations with Roche.

Seven authors reported associations with Sanofi. Three reported being employees of and owning stock in Regeneron, and two reported other associations with it. Also associations with, for example, Merck Sharp and Dohme, Gilead Sciences, ViiV Healthcare, Janssen, Cilag, Thera technologies, Lilly, Biohope, Gebro, Bristo lMyers Squibb, Abbvie, Pfizer, Novartis, PharmaMar, GlaxoSmithKline, Boehringer Ingelheim, Celgene,Alexion, Inatherys, AB Science, Argenx, Oncoarendi, Biogen, Ose Pharmaceutical, Shionogi, Genetech, EliLilly, Swedish Orphan Biovitrum AB, Sanofi Genzyme, Aspen Pharmacare, Crist´alia and AM Pharma were reported.

On July 6, a press release by M´edecins Sans Fronti`eres (MSF) noted that the Swiss pharmaceutical company Roche continued to have de facto market exclusivity and tocilizumab was likely to remain unaffordable and inaccessible for most of the world [61]. MSF wrote that Roche had kept the price of tocilizumab very high in most countries (USD 410 in Australia, USD 646 in India and USD 3,625 in the US per dose of 600mg for COVID-19, while the manufacturing cost was estimated to be around USD 60).

On July 6, an article by Malin et al. presented a key summary of German national treatment guidance for COVID-19 inpatients [62]. The guideline recommended corticosteroids, prophylactic anti-coagulation, and optionally tocilizumab. Convalescent plasma, azithromycin, ivermectin and vitamin D3were recommended against. With regard to ivermectin, it was said that achievable tissue concentrations seemed to be far below the half maximal inhibitory concentration in vitro, that in February 2021 only one peer-reviewed RCT with 72 patients was available for consideration, and that the numerous preprints did not report clinically relevant endpoints or presented with significant methodological issues and a high risk of bias.

On July 6, a commentator asked why WHO targeted IL-6 instead of going upstream to block NF-kB [63] which in turn inhibits IL-6 (ivermectin is an NF-kB antagonist [64]) [65,66].

On July 6, the US president Biden proposed the creation of the Advanced Research Projects Agency for Health (ARPA-H), a new organization under the NIH, aimed at facilitating and accelerating more innovation and breakthroughs in fundamental biomedical and health research [67].

On July 6, an article by Margolin et al. described a small controlled trial (n=113) that suggested benefits from supplementation with zinc, zinc ionophores quina plant bark extract and quercetin, vitamins C, D3and E, and L-lysine [68].

On July 7, an article by Cadegiani et al. about an open-label observational prospective outpatient study indicated 98.0% lower risk of hospitalization (0% vs 19.7%, RR 0.02, p<0.001) and 94.2% lower risk of ventilation (0% vs 6.6%, RR 0.06, p=0.005) [69,70,71]. The authors said treatments showed overwhelming improvements; therefore, it had become ethically questionable to conduct further studies employing full placebo arms in early COVID-19.

On July 7, a preprint by Hazan et al. described a retrospective late treatment study with 24 outpatients and a synthetic control arm calculated from the US Centers for Disease Control and Prevention (CDC)database [72]. The study used a combination therapy protocol with ivermectin, doxycycline, zinc, vitaminD and vitamin C, resulting in 100% survival and cure in unselected ambulatory ‘moderate to severely’ illCOVID-19 outpatients, with some initially presenting with SpO2values as low as 73% and 77%. Despite a symptom to treatment delay of over nine days, mean SpO2values rose from 86.5 to 93.1 in the first 24 hours.

On July 8, an article by Muthusamy et al. described an in silico study identifying 32 anti-parasitic compounds effectively inhibiting the receptor binding domain of the SARS-CoV-2 spike protein [73]. The most effective compounds, in a descending order, were selamectin, ivermectin, artefenomel, moxidectin, posaconazole, imidocarb, piperaquine, cepharantine, betulinic acid and atovaquone.

On July 9, Cameron et al. proposed a two-axis model to describe variability in decision-making among critical care physicians [74]. The authors emphasized the necessity for a better understanding of the root causes of physician-attributable differences in patient management in order to foster a better collaborative and educational environment to help critical care systems adapt to emerging ideas. The first axis of the model measured interventionism (early, aggressive treatment) versus minimalism (’wait and see’) preferences. The second axis measured individualism versus collectivism.

On July 12, a preprint by Neil et al. described a Bayesian meta-analysis of ivermectin’s effectiveness in COVID-19 [75].

On July 13, a news report in the Atlantic by Mazer discussed FDA’s recent approval of Alzheimer’s disease medicine aducanumab [76]. It said aducanumab was approved despite scant evidence of benefit, and against the nearly unanimous advice of the agency’s expert advisers, with ten members against approval and one being uncertain [77]. Aducanumab was priced at USD 56,000 a patient per year. The estimated cost of treating all patients with it was larger than NASA’s yearly budget. The article said that ‘the actions of drug regulators, like those of industrial polluters, are often freighted with unacknowledged externalities .. . the FDA specifically does not really worry about those larger societal issues and doesn’t really worry about cost. . . instead, the agency is judged by how many drugs it can approve’.

On July 14, an opinion by Flam said that high hopes for ivermectin owe more to politics than to science[78].

On July 14, Mathachan et al. reviewed current uses of ivermectin in dermatology, tropical medicine andCOVID-19 [79].

On July 15, an article by Ravikirti et al. describing a clinical trial in India on patients with mild to moderate disease (n=112) using 12 mg of ivermectin on two consecutive days did not produce statistically significant results [80].

On July 15, referring to a 2020 preprint by Elgazzar et al. [3], a news article by Davey in the Guardian said that a huge study supporting ivermectin as COVID-19 treatment had been withdrawn over ethical concerns [81]. The article described ivermectin being promoted by right wing figures, then interviewed a person described as a medical student, Jack Lawrence, who had analyzed the preprint and the associated dataset for an assignment as a part of his master’s degree. He had found that the introduction section appeared plagiarized, raw data apparently contradicted the study protocol on several occasions, there were errors in data formatting, and the dataset didn’t match the numbers in the preprint. He also described that ivermectin hype was ‘dominated by a mix of right-wing figures, anti-vaxxers and outright conspiracists’.

A data analyst Nick Brown had helped Lawrence to analyze the data. He said that the main error was that at least 79 of the patient records were obvious clones of other records. An epidemiologist, Gideon Meyerowitz-Katz, commented that the data appeared totally faked, and since the study had been included in most meta-analyses, if removed, the conclusions of these meta-analyses would have their conclusions entirely reversed. Yet another researcher said the data appeared fabricated. Lawrence concluded that ‘something is clearly broken in a system that can allow a study as full of problems as the Elgazzar paper to run unchallenged for seven months . . . thousands of highly educated scientists, doctors, pharmacists, and at least four major medicines regulators missed a fraud so apparent that it might as well have come with a flashing neon sign’.

On July 15, a post by Lawrence on an online disinformation website discussed retraction of the preprint by Elgazzar et al. [82]. Jack Lawrence introduced himself on his blog as a journalist and a disinformation researcher [83].

On July 15, a blog post by Brown analyzed details of the study by Elgazzar et al [84].

On July 15, a blog post by Meyerowitz-Katz pictured ivermectin for COVID-19 research as ‘potentially the most consequential medical fraud ever committed’ [85].

On July 15, the Covid Analysis group removed Elgazzar et al. from their meta-analysis. Since the study was a preprint, the analysis of 37 peer-reviewed studies (n=11,352) in the July 15 version 99 of 60 studies [86] remained unchanged, indicating 88% efficacy in prophylaxis (95 % CI 70%-95%), 74% efficacy in early treatment (95% CI 58%-84%) and 42% efficacy in late treatment (95% CI 19%-58%). Since Elgazzar etal. only concerned prophylaxis and late treatment, also the early treatment results remained unchanged, indicating 64% reduction in mortality (95% CI 15%-85%). In comparison to the previous, July 9 version 98 of 62 studies [87] (Elgazzar study included prophylaxis (n=200) and late treatment (n=400) parts), the new version indicated the same or slightly improved prophylaxis efficacy but slightly widened confidence intervals, with all studies indicating 85% (95% CI 75%-91%) vs 85% (95% CI 75%-92%) efficacy, and RCTs indicating83% (95% CI 39%-95%) vs 84% (95% CI 25%-96%) efficacy. For late treatment, the new version indicated lower efficacy, with all studies indicating 46% (95% CI 30%-59%) vs 43% (95% CI 26%-56%) efficacy, and RCTs indicating 40% (95% CI 11%-60%) vs 29% (95% CI 3%-48%) efficacy.

On July 16, FLCCC and BIRD gave a joint statement saying that there was no scientific basis to state that the removal of one study from meta-analyses would ‘reverse results’, yet the Guardian article had reported it as a fact [88]. They also said that according to the most recent analyses by BIRD, excluding the Elgazzar data from the meta-analyses by Bryant and Hill did not change the conclusions of these reviews, with the findings still clearly favoring ivermectin for both prevention and treatment. They added that even the prestigious Institute Pasteur in France had confirmed that the evidence was sound [89].

On July 16, Hill tweeted that ‘after removal of Elgazzar trial from ivermectin meta-analysis, borderline significant effects still seen for hospitalization and survival, but small number of endpoints. More evidence still needed from large ongoing randomized trials – must be continued’ [90].

On July 16, a news article said that a study that had ‘lit up the right-wing sphere of COVID deniers had been retracted over questionable methods’, adding that it was ‘just totally faked’ [91].

On July 16, a South African news article reviewed the retraction [92]. It also featured video interviews of patients, doctors and officials which concentrated on the black market of ivermectin in South Africa and the possible dangers of counterfeit medications.

On July 16, an opinion by Razak, the rector of International Islamic University of Malaysia, aimed at ‘setting the pace for a more courageous narrative’ about ivermectin’s possibilities in COVID-19 [93].

On July 17, the United Arab Emirates announced the treatment results for intravenously administered monoclonal antibody sotrovimab, produced by GlaxoSmithKline, in treating mild to moderate COVID-19cases among high-risk outpatients [94]. 6,175 patients were administered sotrovimab in Abu Dhabi between30 June and 13 July. Within 14 days, 97 percent of recipients achieved full recovery. There were zero deaths. 1 percent were admitted to ICU.

On July 17, a news report by Weisser described that early in the pandemic in Indonesia, an enterprising philanthropist Haryoseno made ivermectin available to the masses for free or at low cost, which resulted in Indonesia having an extremely low COVID-19 mortality rate. On June 12, 2021, however, in line withthe WHO recommendation, the ministry of health decided to disallow ivermectin and threatened Haryoseno with a fine and a ten-year jail sentence. Subsequently, the supply of ivermectin dried up and mortality increased five-fold [95]. About Australia, the report noted that clinician Mark Hobart had been reported to the Australian Health Practitioner Regulation Agency (AHPRA) which had decided that there had been no infringement. Subsequently, federal health minister had written that off-label ivermectin prescribing was not regulated or controlled by the Therapeutic Goods Administration (TGA) but was at the discretion ofthe prescribing physician. The physicians had formed Covid Medical Network [96], the members of which predominantly followed a ‘triple-therapy protocol’ developed by Thomas Borody, consisting of ivermectin, zinc and doxycycline [97]. The report also said that although the research on ivermectin for COVID-19 had originated from Australia, the researchers had been starved of resources and the discovery ignored.

On July 20, BBC wrote about Indonesia, saying that local media reports had incorrectly stated that theIndonesian authorities had granted ivermectin emergency approval [98]. The reports had been based on a July 15 statement issued by the Food and Drugs Authority of Indonesia (BPOM) in which ivermectin had been listed together with other drugs, two of which had had emergency approval. Shortly afterwards the head of BPOM had told local media that no emergency approval had been given to ivermectin. It had been listed because it was undergoing clinical trials at eight hospitals, the results of which were not expected until October.

On July 20, Med Page Today wrote about retraction of the preprint by Elgazzar et al. [99].

On July 20, a Swedish medical newspaper published an opinion by three Swedish doctors suggesting that Sweden should follow the example of the Czech Republic, Slovakia and other countries which had adopted ivermectin [100].

On July 22, Los Angeles Times wrote that ‘ivermectin, another bogus treatment, becomes a darling ofconspiracy-mongers’ [101]. In addition to reviewing the main points behind the retraction of the Elgazzaret al. preprint the columnist delved into an analysis of ivermectin politics, saying it was rather different from hydroxychloroquine controversy, as ‘the political underpinning of the ivermectin craze involves a conspiracy-infused attack on the pharmaceutical and medical establishment. In this it resembles the antivaccine movement .. . like anti-vaxxers, ivermectin advocates claim that information about the drug is being “suppressed,” generally by agents of Big Pharma; the core idea is that because drug companies can’t make very much money out of a drug available in generic form, they prefer to foist vaccines, on which they canmake billions of dollars in profits, on the innocent public . . . let’s be clear: information about the drug isn’t being “suppressed” for political reasons. It’s being treated as what it is: dangerous misinformation’.

On July 23, an interview of science writer Matt Ridley in the Wall Street Journal said that science had lost the public’s trust and that the politicization of science had led to a loss of confidence in science as an institution, and whereas the distrust may have been justified it left a vacuum that was often filled by lessrigorous approaches to knowledge [102]. Ridley pointed to a distinction between ‘science as a philosophy’ and‘science as an institution’, with the former wanting to remain open-minded, and the latter wanting to present a unified and authoritative voice, fostering a naive belief in the supremacy of scientists in understanding the world, luring politicians to affiliate themselves with this alleged power. Regardless, scientists often deliberately published things that fit with their political prejudices, ignored things that didn’t, or presented models based on rather extreme assumptions. Pessimistic predictions often being more popular in the media introduced a bias. A third conceptualization of or a type of identification with the concept of science,‘science as a profession’, had become off-puttingly arrogant and political, permeated by motivated reasoning and confirmation bias, with increasing numbers of scientists falling prey to groupthink [103]. According to Ridley, the tendency of scientific establishment ‘to turn into a church, enforcing obedience to the latest dogma and expelling heretics and blasphemers’ had previously been kept in check by the fragmented natureof the scientific enterprise but social media was eliminating the space for heterodoxy, leaving those believingin science as a philosophy increasingly estranged from science as an institution.

On July 23, an article by Mansour et al. described a preclinical tolerance study on the safety of inhaled lyophilized ivermectin formulation indicating 127-fold increase in drug aqueous solubility but also safety issues [104].

On July 24, World Ivermectin Day was organized by the BIRD group, the FLCCC, TrialSite News and 15 other affiliates [105]. Panel discussions included Shabnam Palesa Mohamed in conversation with PinkyN.J. Ngcakani (South Africa) and Wahome Ngare (Kenya); Erin Stair in conversation with Hector Carvallo(Argentina), Lucy Kerr (Brazil) and Flavio Cadegiani (Brazil); Shabnam Palesa Mohamed in conversation with Pierre Kory (US), Ira Bernstein (Canada) and Sabine Hazan (United States); Vincent Rey Vicente(US) in conversation with Iggy Agbayani, Homer Lim and Allan Landrito (Philippines), and PriyamadhabaBahera, Binod Kumar Patro, Biswa Mohan Padhy and Rashmi Ranjan Mohanty (India); Daniel O’Connorin conversation with Juan Bertoglio (Chile) and Matjaˇz Zwitter (Slovenia); Daniel O’Connor in conversationwith Juan Chamie (US), Pierre Kory (US) and Nathi Mdladla (South Africa).

On July 25, a preprint by Ontai et al. described a nationwide implementation of multi-drug COVID-19inpatient and outpatient treatment protocol CATRACHO in Honduras since May 3, 2020 [106,107]. The inpatient protocol consisted of dexamethasone, colchicine, tocilizumab, ivermectin, zinc, azithromycin andheparin. There were two outpatient protocols, one consisting of mouthwash, azithromycin, ivermectin andzinc, and the other consisting of prednisone, colchicine and rivaroxaban. The results indicated a case fatalityrate (CFR) decrease from May 3,2020 baseline of 9.3% to 3.0%, or from June 10, 2020 baseline of 5.0% to3.0%. Mexico used as a control country failed to show a similar decline.

On July 27, upon receiving a Special Benevolence Award from Tan Sri Lee Kim Yew of Malaysia on World Ivermectin Day, Kory of the FLCCC gave a lecture outlining the history of ivermectin in COVID-19 [108,109].

He mentioned that the MATH+ protocol had been adopted as the standard protocol in Ukraine, and thatthe hospital mortality rate there was the lowest of the countries in the area.

On July 27, press releases by Cochrane Deutschland and the University of W¨urzburg stated that there was no evidence of ivermectin’s efficacy [110,111].

On July 27, the university hospital of St. Anny in Brno in the Czech Republic published a report about their ivermectin treatment, saying it had been well tolerated and likely had a positive effect on COVID19 [112]. Ivermectin had been available at hospitals and for outpatient treatment since late 2020. Head of internal cardioangiology clinic Michal Rezek described the results of their analysis of 150 patients with a mean age of 63 years (32-93 years, median 65 years) treated between December 2020 and January 2021 with two doses of 0.2 mg/kg of ivermectin. 117 patients had required oxygenation and corticosteroids, 42 had required high-flow oxygen, and 17 had received also remdesivir. 18 patients had needed mechanical ventilation, six of which had died. Hospital mortality had been 10%, with the average age of the deceased being 75 years. There had been no control group. The hospital intended to continue ivermectin treatment and was preparing a RCT in collaboration with Masaryk University and Czech Clinical Research InfrastructureNetwork (CZECRIN) [113]. Lack of COVID-19 patients was mentioned as a possible obstacle to the trial. Rezek said a combination antiviral therapy with ivermectin and remdesivir was likely more effective than single-agent therapies.

On July 28, a Cochrane review by Popp et al. concluded that its authors were uncertain about the efficacy and safety of ivermectin for treatment or prophylaxis of COVID-19 [114]. With regard to late treatment(inpatients), the authors were uncertain whether ivermectin compared to placebo or standard of care reduced or increased mortality (RR 0.60, 95% CI 0.14-2.51, 2 studies, n=185, very low certainty), mechanical ventilation (RR 0.55, 95% CI 0.11-2.59, 2 studies, 185 participants, very low certainty), need for supplemental oxygen (0 participants required supplemental oxygen, one study, 45 participants, very low certainty), adverse events within 28 days (RR 1.21, 95% CI 0.50-2.97, one study, 152 participants, very low certainty), or viral clearance at day seven (RR 1.82, 95% CI 0.51-6.48, 2 studies, 159 participants, very low certainty). With regard to outpatients, the authors were uncertain about mortality up to 28 days (RR 0.33, 95% CI 0.018.05, 2 studies, 422 participants, very low certainty), mechanical ventilation (RR 2.97, 95% CI 0.12-72.47,one study, 398 participants, very low certainty) and symptoms resolution up to 14 days (RR 1.04, 95% CI0.89-1.21, one study, 398 participants, low certainty). With regard to prophylaxis there was only one eligible study, with mortality up to 28 days being the only outcome eligible for primary analysis; the authors were uncertain whether ivermectin reduced or increased mortality compared to no treatment (zero participants died, one study, 304 participants, very low certainty). The Covid Analysis group criticized the meta-analysis for being ’a very biased meta analysis designed to exclude almost all studies’ [115].

On July 28, an opinion in the Wall Street Journal questioned FDA’s negative stance on ivermectin [116]. The next day the authors wrote that they had not been aware of the retraction of the Elgazzar et al. study, yet stated that ‘the broader point stands: there’s strong evidence of ivermectin’s efficacy in COVID-19’ [117].

On July 28, GlaxoSmithKline (GSK) and Vir Biotechnology announced a joint procurement agreement with European Commission to supply up to 220,000 doses of sotrovimab [118], a contract worth USD 462 million at the wholesale price of USD 2,100 per dose. The agreement enabled participating European Union member states to quickly purchase sotrovimab, following local emergency authorization or authorization at the EUlevel, to treat high-risk patients with COVID-19 who might benefit from early treatment with sotrovimab.

On July 29, an article in Times of India explained a much higher rate of infections in the state of Kerala bylower COVID-19 seropositivity [119].

On July 30, a Czech Republic newspaper published a timeline of ivermectin-related events in the CzechRepublic [120].

On July 30, an article by Rella et al. suggested that in the current conditions the vaccines-only pandemic response may create vaccine-resistant strains [121,122].

On July 31, Kiekens interviewed George Fareed about outpatient treatment protocols for newly infected andfor long haul COVID-19 syndrome (LHCS) patients, implemented jointly with Brian Tyson on thousands of patients in the US [123]. For neurological LHCS symptoms in some instances, Fareed suggested a two to three-day high-dose ivermectin treatment as suggested by Alessandro Santin [124].

August 2021

On August 2, a news article from Israel reported on a clinical trial by Biber et al. (NCT04429711) [125], saying that ivermectin could help reduce the length of infection for less than a USD 1 per day, and that only 13%of ivermectin-treated patients were infectious after six days, compared with 50% of patients in the placebo group [126]. Schwartz, the leader of the trial, said that three journals had rejected the paper: ‘No one even wanted to hear about it. You have to ask how come when the world is suffering’.

On August 2, an open letter by Covid Medical Network stressed the importance of early treatment and noted that the federal health minister had acknowledged and even encouraged off-label prescribing of some treatments including ivermectin [127].

On August 2, an article by Reardon in Nature said that shocking revelations of widespread flaws in the data of a preprint study by Elgazzar et al. dampened ivermectin’s promise and highlighted the challenges of investigating drug efficacy during a pandemic [128]. Gideon Meyerowitz-Katz, an Australian epidemiologist,said he had lost all faith in the results of ivermectin trials published to date.

On August 2, an article by Sengthong et al. said that repeated ivermectin treatment induced ivermectin resistance in Strongyloides ratti infected rats [129].

On August 3, an article by Santin et al. reviewed the current status of ivermectin research, mentioning that the indicated biological mechanism of ivermectin, competitive binding with SARS-CoV-2 spike protein, was ikely non-epitope specific, possibly yielding full efficacy against emerging viral mutant strains [130].

On August 3, BBC wrote about the mystery of rising infections in India’s Kerala [131]. The southern Indian state of Kerala, with barely 3% of India’s population, accounted for more than half of the country’s new COVID-19 infections. Kerala was testing more than double the people per million compared to the rest of the country. Antibody tests survey revealed that only 43% people above the age of six in Kerala had been exposed to the infection, compared to 68% nationwide. Kerala had fully vaccinated more than 20% of its eligible population and 52% had received a single jab (70% of people over 45 years) which was much higher than the national average. BBC wrote that the state appeared to be testing widely, reporting cases honestly and vaccinating quickly, ensuring that future waves of infection would be less severe. Yet Kerala was said to be at an early stage in runaway exponential growth of cases. More forceful enforcement of rolling lockdowns was suggested as a solution.

On August 3, George Fareed discussed early treatments on Fox News television [132].

On August 5, an article by Behera et al. described a prospective cohort study (n=3,532) in India, indicatingthat two doses of oral ivermectin (0.3 mg/kg/dose given 72 hours apart) as chemoprophylaxis among healthcare workers reduced the risk of COVID-19 infection by 83% in the following month (6% vs 15%, adjustedrelative risk 0.17; 95% CI, 0.12-0.23) [133].

On August 5, a preprint by Rana et al. described an in silico study showing strong binding affinity ofivermectin and doxycycline for SARS-CoV-2 main protease 3CLpro, and increased binding affinity for thecombination of both [134,135].

On August 5, a Finnish technology magazine wrote about ivermectin, saying that according to FLCCC,there was already an effective medication for COVID-19 but it was rarely used [136]. A head of unit at theFinnish Medicines Agency (FIMEA) commented that doctors were allowed to prescribe it off-label, providedthat the patient was informed about it not being officially approved for COVID-19. The official commentedthat ‘in an international comparison the Finnish medical community is quite conservative about adoptingnew treatments without a sufficiently strong evidence base’. Also, a process to officially adopt ivermectin forCOVID-19 could only be initiated by a producer of ivermectin or the European Medicine Agency (EMA).

On August 6, an article by Kow et al. reviewed sample size calculations in ivermectin trials, indicating thatexisting trials had been very underpowered [137].

On August 6, US National Institutes of Health (NIH) Collaboratory published a video interview of EdwardJ. Mills, the head researcher of Together adaptive platform trial [138]. Mills discussed interim results of their outpatient trial which included fluvoxamine and ivermectin (0.4 mg/kg for three days). For ivermectin,the risk reduction for extended emergency room observation or hospitalization was 9% (86/677 vs 95/678,RR 0.91, 95% CI 0.69-1.19) and for mortality 18% (RR 0.82, 95% CI 0.44-1.52); these were not statistically significant. Mills commented that ivermectin had had ’no effect whatsoever’ on their primary and secondary endpoints. For fluvoxamine, the risk reduction for extended emergency room observation or hospitalization was 31% (74/742 vs 107/738, RR 0.69, 95% CI 0.52-0.91) and for mortality 29% (17/742 vs 24/738, RR0.71, 95% CI 0.39-1.29); the first endpoint was statistically significant while the second was not. The trial was done at ten locations in Minas Gerais, Brazil. It was unclear whether over-the-counter ivermectin usehad been an exclusion criteria. At the time the gamma variant was prevalent and assumed to cause higher viral loads and a more severe disease than most other variants. The Covid Analysis group criticized various aspects of the trial [139].

On August 6, a report on SARS-CoV-2 variants by Public Health England indicated that concerning deathswithin 28 days of positive specimen date between February 1 and August 2 there had been 71 deaths in people under 50 years and 670 in people over 50 years [140]. In the first group, 18% had been vaccinatedtwice and 68% were unvaccinated. In the second group, 58% had been vaccinated twice and 31% were unvaccinated.

On August 6, a podcast by Nature discussed ivermectin [141].

On August 9, a commentary by US medical doctor using a pseudonym Justus R. Hope described a ‘blackouton any conversation about how ivermectin beat COVID-19 in India’ [142,143]. It claimed that the US newsmedia were trying to confuse the public with false information by saying the deaths in India were ten times greater than official reports. Using August 5 numbers as examples the author said that in ivermectin-using states of India such as Uttar Pradesh with a population 240 million of which 4.9% were fully vaccinated there were 26 daily cases and three deaths, in Delhi with a population of 31 million of which 15% were fully vaccinated there were 61 daily cases and two deaths, in Uttarakhand with a population of 11.4 million of which 15% were fully vaccinated there were 24 daily cases with zero deaths. In states not using ivermectin such as Tamil Nadu with a population of 78.8 million of which 6.9% were fully vaccinated there were 1,997daily cases with 33 deaths. In the US with a population of 331 million of which 50.5% were fully vaccinated there were 127,108 daily cases with 574 deaths. He compared FDA’s and WHO’s ban on ivermectin to Pope’sban on all books and letters that argued the Sun was the center of the universe instead of Earth, adding that the US government was ‘all-in with vaccines with the enthusiasm of a 17th century Catholic church’.

On August 10, a news story by Yahoo! Japan reported that a Japanese clinician Kazuhiro Nagao, appearingon the Fuji TV television program, had suggested that ivermectin should be distributed to all Japanese nationals in advance to be taken after COVID-19 infection, and that COVID-19 should be in the same administrative category as seasonal influenza in order to avoid delays and make early treatment possible [144].

On August 10, a news report from La Pampa province of Argentina described minister of health MarioRub´en Kohan releasing the latest results of the implementation of a monitored intervention program on the use of 0.6 mg/kg of ivermectin for five days in 3,269 treated patients versus 18,149 untreated patients[145,146]. The risk of death was 27.4% lower (RR 0.73) and the risk of death or ICU admission was 38.0%lower (RR 0.62). For people over 40 years of age the risk of death was 33.4% lower (RR 0.67). For people over 40 years of age and with comorbidities the risk of death was 44.0% lower (RR 0.56).

On August 11, Los Angeles Times wrote about ivermectin having ‘no effect whatsoever’ in the Togethertrial [147]. The head researcher Mills said that ‘in our specific trial we do not see the treatment benefit that a lot of the advocates believe should have been seen’. He complained that many researchers had faced unprecedented abuse from advocates of specific treatments.

On August 11, an article by Cobos-Campos et al. reviewed ivermectin for COVID-19 [148].

On August 12, vaccine expert Geert Vanden Bossche, who on May 24, 2021 had proposed mass chemoprophylaxis with ivermectin [149], demanded stopping of COVID-19 mass vaccination [150]. A rationale for the demand was the increased infectiousness of new variants already noted with respect to the alpha and delta variants, both more infective than the original variant, and the delta variant being significantly more infective than the alpha variant. Bossche expected this trajectory to continue, possibly resulting in an uncontrollable situation. In Bossche’s view, the increased infectivity had resulted from a natural selection of increasingly vaccine immunity escaping variants in the vaccinated part of the population. In other words, mass vacci11nation had created an evolutionary pressure for development of these variants which were then transferred to the non-vaccinated population. In addition, vaccine-induced antibodies possibly competed with natural antibody based, variant-nonspecific immunity, possibly rendering the population more vulnerable to some vaccine immunity escaping variants. The issue was also taken up by other researchers [151].

On August 12, a preprint by Elavarasi et al. described a retrospective study about hospitalized patients in India which did not show a statistically significant result [152].

On August 12, an article by Pedroso et al. described that self-prescribed use of early ivermectin treatment by 45 healthcare workers in Brazil was associated with a lower rate of seroconversion in a dose-dependentresponse [153].

On August 13, an article by Zhou et al. suggested that ivermectin might be a new potential anticancer drug therapy for human colorectal cancer and other cancers [154].

On August 13, on NIH Collaboratory, Smith discussed the history of proposed therapies for COVID-19 andthe adaptive platform trial ACTIV-2 [155].

On August 14, a Japanese clinician Kazuhiro Nagao wrote in a blog post that he had been harassed and had received death threats after appearing on TV and telling about treating 500 COVID-19 patients with ivermectin with no deaths [156,157].

On August 14, Kiekens interviewed an Italian physician Andrea Stramezzi about his early treatment protocol and his telehealth treatment method [158]. He was using hydroxychloroquine as a part of the outpatient protocol due to its easy availability. According to Stramezzi, it was useful in the first few days. Initially in the pandemic it had been provisionally recommended [159], then banned [160]. Stramezzi had initiated a legal proceeding about the ban, initially winning the case but subsequently losing an appeal. Regardless,the judge had decreed that physicians were free to prescribe medications off-label at their discretion. In addition, the protocol had included anti-inflammatories such as aspirin, and bromhexine. Also vitamins C and D were used, although Stramezzi did not consider high levels of vitamin D sufficient to prevent COVID19. Additionally, vitamin K was administered separately from vitamin D due to their antagonism. A later addition, ivermectin, useful also in later stages to reduce replication of the virus, needed to be imported from the neighboring countries. Stramezzi said that about 10% of Italians had a genetic vulnerability toSARS-CoV-2 induced hyperinflammation. For this group, prevention with corticosteroids and enoxaparin was necessary. He said that there were approximately 1,500 physicians in Italy working with the similar protocols, exchanging information with each other. The public’s awareness of early treatments in Italy was still low because health authorities did not recommend it or talk about it, instead just recommendingparacetamol and waiting for severe pneumonia to emerge before contacting healthcare facilities. Stramezzisaid they had met Sileri, a physician/researcher and deputy minister of health (M5s) [161,162], for an hour.

Sileri had said he was aware of the therapeutical options, had treated a hundred patients himself, and hadco-authored an article about the genetic defect [163]. Also, the parliament of Italy had voted in favor ofearly treatments [164]. Regardless, after several months nothing had happened with regard to adoption of these treatments. Stramezzi was developing a free mobile phone app for doctors who had too many patients or who were unsure of how to treat COVID-19: the app would give suggestions for a suitable treatment protocol.

On August 16, a letter to the editor by Chahla et al. in the American Journal of Therapeutics described a randomized controlled trial (n=234) in Argentina with ivermectin and iota-carrageenan as pre-exposureprophylaxis for health care workers (NCT04701710) [165,166,167]. The treated group (n=117) received 6mg ivermectin every seven days, and six nasal sprays of iota-carrageenan per day for 4 weeks. The risk ofCOVID-19 infection was 84.0% lower (3.4% vs 21.4%, RR 0.16, p=0.001), and the risk of moderate or severe disease was 95.2% lower (0.0% vs 8.5%, RR 0.05, p=0.002). The authors hypothesized that the combination treatment formed a double viral barrier: first, carrageenan behaved as a mucolytic agent in a barrier of sulfated polysaccharides with negative charge in the nasal cavity; second, ivermectin decreased viral load by systemic cellular action.

On August 16, an article by Winter examined the ongoing discussion about ivermectin [168].

On August 17, an article by Gonz´alez-Paz et al. described an in-silico elastic network model analysis of ivermectin components (avermectin-B1a and avermectin-B1b) providing a biophysical and computational perspective of proposed multi-target activity of ivermectin for COVID-19 [169,170].

On August 17, Associated Press reported that ’dozens of people in Oregon have contacted the state’s poisoncenter after self-medicating against COVID-19 with a drug used to treat parasites, with five becoming hospitalized and two of them winding up in intensive care units’ [171].

On August 18, Los Angeles Times wrote that fluvoxamine may actually work against COVID-19 [172].

On August 19, an article by Gonz´alez-Paz et al. described an in silico analysis of the components of ivermectin (avermectin-B1a and avermectin-B1b), suggesting different and complementary inhibitory activity of each component, with an affinity of avermectin-B1b for viral structures, and of avermectin-B1a for host structures [173,174].

On August 20, an article by Amaya-Aponte reviewed ivermectin in COVID-19 [175].

On August 20, the investigational monoclonal antibody sotrovimab was granted a provisional approval forthe treatment of COVID-19 in Australia [176].

On August 20, a letter by Popp et al. in the BMJ said that the different assessments between Popp et al’sCochrane meta-analysis and the one by Bryant et al. were partly due to baseline data of included studies:Bryant et al. pooled heterogeneous patient populations, interventions, comparators and outcomes whereasPopp et al. did not; thus, according to Popp et al., Bryant et al. compared apples and oranges, ‘serving a large bowl of a colorful fruit salad’ [177]. The authors accused Bryant et al. of ‘creating pseudotrustworthiness for substances that cannot be considered effective and safe treatment options nor game changers, at this stage’.

On August 21, an article by Karvanen et al. described a new algorithm for causal effect identification: do search based on do-calculus [178]. The algorithm might allow for improving clinical trial result analysis [179,180,181].

On August 21, due to overlap and confusion with the I-MATH+ prophylaxis and early outpatient treatment protocol, the FLCCC discontinued its I-MASS mass prophylaxis and home treatment protocol introduced a few months earlier [182].

On August 21, the US Food and Drug Administration (FDA) tweeted about ivermectin, stating that ‘You are not a horse. You are not a cow. Seriously, y’all. Stop it.’ [183]. The tweet linked to FDA’s March 2021advisory against ivermectin [184].

On August 21, a Slovenian newspaper reviewed ivermectin, mentioning two previous articles published in the same newspaper written by a Slovenian ivermectin proponent Matjaˇz Zwitter [185,186].

On August 21, a blog post by Meyerowitz-Katz discussed a study by Cadegiani et al. [69], claiming that thedata in a spreadsheet uploaded by the authors didn’t look real: ’data for this study may not be fake, but it is at least incredibly suspicious’ [187,188].

On August 21, a preprint by Izcovich et al. presented a systematic review about bias as a source of inconsistency in ivermectin trials [189]. Based on a review of 29 RCTs with 5,592 cases the authors concluded that previous reports about ivermectin’s benefits were based on potentially biased results, and further research was needed.

On August 22, an Indian geriatrician, preventive cardiologist and anti-aging specialist Lenny Da Costa described ivermectin use in India [190,191]. According to Costa, beginning from March 2020, India distributed an outpatient home treatment kit containing hydroxychloroquine, azithromycin, doxycycline, ivermectin and vitamin C. In March 2021, ignoring evidence from India, WHO stated that ivermectin should not be used.

The statement was given by an Indian epidemiologist, WHO chief scientist Soumya Swaminathan. A group of Indian physicians filed a legal case against her. To protect Swaminathan, Indian central government removedivermectin from official recommendations. However, state governments were responsible for guidelines for medical care in the states, not the central government; most states continued the use of ivermectin. Costasaid that no-one had stopped using ivermectin but they did not advertise the fact. According to Costa,during the deadly second wave in April-May 2021, India’s most populous state, Uttar Pradesh, reduced the number of daily cases from 60,000 to 15,000 in a month by distributing ivermectin for everyone for free. Clinicians did not wait for RT-PCR test results; instead, medication was started immediately on the presentation of symptoms. Prescriptions were given for free by telemedicine (WhatsApp). Ivermectin prevented people from infecting others, especially family members. Also, numerous physicians had been using ivermectin since March 2020 for prophylaxis, with none of them getting infected. On June 29, 2021, the government of Uttar Pradesh announced a home treatment kit for children, containing paracetamol, multivitamins and ivermectin. Costa claimed that India’s success in controlling the second wave was primarily due to an early administration of ivermectin, doxycycline, zinc and other medications used for early treatment.

On August 23, a medical doctor writing under a pseudonym Justus R. Hope continued on India’s ‘ivermectin blackout’ [192,193]. On August 15, Kerala, a state reportedly not using ivermectin, with a population of approximately 3% of India’s population, had accounted for 56% of India’s new cases and 25% of India’s new deaths. Delhi, a state with nearly the same population size as Kerala but using ivermectin, accounted for 0.2% of new cases and 0% of deaths. Uttar Pradesh, with a population almost eight times larger than

Kerala, accounted for 0.09% of new cases and 0.2% of deaths. Hope wrote that Kerala ranked in the top five most vaccinated of India’s 29 states, adding that Kerala’s failure in comparison to most other states of India could be explained by the facts that Kerala had not used ivermectin for early treatment whereas most other states had, and that ivermectin lowered the viral load and inhibited transmission whereas vaccination did not, giving a false sense of security. Those with prior infection, negative test result, or at least one vaccine dose (56% of adults) had been exempted from lockdown [194]. Hope called Kerala’s comparatively highvaccination rate its most problematic feature leading to rampant viral transmission. Kerala had adopted ivermectin in April but restricted its use to severe cases with additional risk factors. On August 5, Kerala had removed ivermectin from state guidelines completely. In contrast, Uttar Pradesh had been the first stateto introduce large-scale prophylactic and therapeutic use of ivermectin. The state had treated all contacts of an infected patient prophylactically with ivermectin. The lesson, Hope said, was that ivermectin could make up for the low use of vaccination but vaccination could not make up for the low use of ivermectin.

On August 23, ABC News report written by a medical toxicology fellow and an emergency medicine physician in New York stated that health officials had said that a potentially dangerous, unproven deworming drugs hould not be used to treat COVID-19 [195]. The report blamed social media for informing people about the medication ‘not authorized by independent regulators at the FDA’ (see e.g. [196]). Not a single trial to prove ivermectin’s usefulness existed and an interviewee advised that people ‘don’t have to go with something that doesn’t have a scientific basis’.

On August 23, CBS News reported that officials had warned against using anti-parasite drug for COVID19 [197].

On August 24, Mother Jones magazine interviewed Boulware, an ivermectin researcher, involved in a University of Minnesota trial (NCT04510194) [198,199]. Boulware had received hostile messages calling him ’are embodied Josef Mengele’ from people believing that ivermectin was a miracle cure and placebo-controlled trials were therefore unethical. Another researcher at Washington University in St. Louis commented on the polarization, saying that if she tweeted something about vaccines as positive, she was being attacked by people pro early treatment, and if she tweeted about potential treatments, she provoked the ire of vaccine advocates who ‘kind of seem to suppress any information about early treatment, maybe because they feel like it’s going to make people think they don’t need to be vaccinated’. The article also described Steve Kirsch’s frustration with the government’s unwillingness to recommend treatments on the basis of small trials with encouraging results. Researchers also worried that the recent reports of ivermectin self-dosing could scare people off of enrolling in any kind of treatment trials in the future.

On August 25, an article by Mohan et al. described a trial (RIVET-COV, n=157) investigating the effect of single-dose oral ivermectin (12 or 24 mg) in mild and moderate COVID-19 which indicated no statistically significant effects on viral load or RT-PCR negativity [200].

On August 25, on the social media platform Reddit, subreddit r/ivermectin which had been a public, uncensored discussion forum initiated a year before for discussions related to ivermectin research and treatments,was flooded with tens of horse-themed pornographic cartoon images, in reference to ivermectin as ‘horse paste’, as well as hundreds of sexual, offensive or irrelevant comments. The moderator said the attack had been coordinated by a group of moderators of other, large subreddits, yet refused to remove the irrelevant content, referring to his disbelief in censorship [201].

On August 25, in a FLCCC weekly update, endocrinologist and researcher Fl´avio Cadegiani described his experience in the state of Amazonas in Brazil during a gamma variant outbreak in 2021 (the gamma variantwas considered to cause a more severe disease than the delta variant) [202]. The research group had visitedvarious cities with hospitals overwhelmed with COVID-19 patients. However, in the city of Coari located afew hundred kilometers west from Manaus there had been no hospitalized COVID-19 patients at all. At first Cadegiani had been unable to get an explanation to the situation but later, in private, a health official had revealed that the city had been providing ivermectin for its whole population for two months already. As to the question why the explanation had not been given immediately the official replied that she had been afraid of being accused of giving unapproved treatments. Cadegiani said the experience had been shocking.

He added that secondary endpoints in single-agent trials were important indicators of possible efficacy as a component in a multi-agent treatment protocol.

On August 25, in the FLCCC weekly update, Kory and Marik discussed the addition of dual anti-androgentherapy (dutasteride 2 mg on day one followed by 1 mg daily for ten days [203], and spironolactone 100 mg twice daily for ten days [204]) to their delta variant early treatment protocol which at the time included twelve components [202]. They stated the addition provided ‘massive improvements’.

On August 26, Krolewiecki et al. published additional details about their trial on the antiviral effect of high-dose ivermectin in COVID-19 [205].

On August 26, Centers for Disease Control and Prevention (CDC) reported that ivermectin prescriptionsfrom US pharmacies had increased 24-fold from the pre-pandemic baseline [206]. Ivermectin-related calls to poison control centers had increased five-fold, respectively. The report gave two examples of adverse effects:one patient becoming disoriented after taking tablets of unknown strength (5 tablets per day for five days),and another patient presenting with confusion, drowsiness, visual hallucinations, tachypnea and tremors after drinking an injectable form of veterinary ivermectin.

On August 26, Newsweek interviewed Joe Varon of the FLCCC saying that since a year ago he had treated thousands of COVID-19 patients in the US with off-label ivermectin in combination with other pharmaceuticals in the FLCCC treatment protocols [207]. During the pandemic Varon had been widely featured in the US media but the reporters had chosen to not mention ivermectin.

On August 26, a news story in Vice magazine complained that Facebook did not properly censor ivermectin content and Facebook’s ivermectin groups were ‘unhinged and out of control’ [208,209].

On August 28, Newsweek reported about a far-right political commentator’s use of ivermectin for his COVID19 infection [210].

On August 28, Newsweek reported that a Republican representative from Texas had appeared to speak in support of unproven treatments for COVID-19, including ivermectin, a drug often used as a dewormer for cows and horses [211]. The representative was also said to have praised president Trump and have raised concerns about vaccines.

On August 29, Anthony Fauci warned against using ivermectin for COVID-19 [212].

On August 29, Cohen wrote in Forbes that ivermectin had become embedded in a ‘cultural war’, commenting that ‘of all drugs right-wingers would have gravitated to, ivermectin and hydroxychloroquine are most unusual candidates, in that they’re largely used in humans in developing nations for conditions rarely seen in the US’ [213]. Ivermectin for COVID-19 was pictured as unproven misinformation harming public health, and the politicization of the issue had been to the detriment of efforts to contain the pandemic, taking attention away from clinically confirmed instruments such as vaccines. The author worried that there were a surprising number of people in the medical profession who believed in ivermectin, such as the physician advisor to Florida’s governor. Cohen said that ‘these contrarians are not waiting for the completion of confirmatory studies to disseminate their advice to the gullible minions to take ivermectin off-label, even if doing so may endanger lives’.

On August 30, Newsweek reported that an US hospital had refused to administer FLCCC member FredWagshul’s prescription for a patient, after which a judge had ordered the hospital to administer it [214]. The next day, a regional US newspaper interviewed Wagshul who attributed the lack of adoption of ivermectinto ‘propaganda, money and big pharma’ [215].

On August 30, a report by German news agency said that ivermectin trials have been of a low quality and that Cochrane Deutschland and the University of W¨urzburg considered ivermectin inefficacious [216].

On August 30, a video interview of Fernando Valerio describes Honduras’ treatment protocols in detail [217].

On August 31, a preprint by Omrani et al. presented a systematic review and meta-analysis of effectiveness of ivermectin/doxycycline combination, concluding that based on low-quality evidence, the combination was accompanied with a shorter time of clinical recovery but did not significantly reduce all-cause mortality, viral clearance, and hospital stay [218].

On August 31, Pfeiffer described patients’ experiences in US hospitals [219].

On August 31, Kory of the FLCCC accused the US National Institutes of Health (NIH) of being the main agent in the ‘war against ivermectin’ due to not having given a recommendation for ivermectin [220]. Healso stated the FDA was only ‘running interference for [NIH] by telling jokes and lies’.

On August 31, a Swedish newspaper G¨oteborgs-Posten wrote about veterinary ivermectin use in the US [221].

On August 31, a preprint describing a randomized controlled trial of community-level surgical mask promotion in rural Bangladesh with 111,525 individuals in the intervention arm and 155,268 individuals in the control arm indicated 14% relative reduction in COVID-19-like symptoms, with absolute reductions of 7.5%vs 8.6%. Divided by age groups, differences were not statistically significant in people under 50. In people between 50-60 years there was a reduction of 23%, and in people over 60 a reduction of 35%, respectively.

The impact of the intervention faded after five months [222].

September 2021

On September 1, ABC News wrote that due to lack of evidence and increase in reports related to ivermectin toxicity, the American Medical Association, American Pharmacists Association and American Society of Health-System Pharmacists had called for an ‘immediate end’ to prescribing, dispensing or using the deworming drug ivermectin to treat or prevent COVID-19 [223].

On September 1, Washington Post wrote that people using ivermectin for prophylaxis had been shocked about having ended up being hospitalized for COVID-19 [224]. The story mentioned the rise in prescriptions and FDA’s tweet and warned about overdoses. Numerous interviewees advised against ivermectin, with the most critical comparing it to ‘snake oil’. Overall, a part of the population preferring ivermectin and vitamin cocktails over vaccines was seen to indicate ‘a broader problem: a public health crisis made worse by many people’s distrust of medical authorities while they rely on often faulty information from some ofthe country’s most influential people, which is amplified through social media’. Ivermectin was said to have gained particular traction in conservative circles. Wagshul of the FLCCC was quoted saying that ivermectin was more effective than vaccines against variants given waning immunity. A researcher working on an ongoingclinical trial on ivermectin in the US ([225,226]) commented that ‘there’s either people that believe it totally is a cure-all and works or that it is highly dangerous . . . and the reality is, neither extreme is true’.

On September 1, a letter by Keehner et al. in the New England Journal of Medicine reported about a dramatic decline in vaccine effectiveness from June to July in a highly vaccinated health system workforce in California, likely due to the emergence of the delta variant, waning of immunity over time, and the end of masking requirements in California [227].

On September 1, KFOR News published a news story in which a rural Oklahoma doctor, Jason McElyea,claimed that local emergency rooms were so backed up with patients having overdosed ivermectin that gunshot victims had hard time getting to the facilities [228]. In addition, ivermectin overdose patients were completely clogging ambulance services: McElyea was quoted saying that ‘all of their ambulances are stuck at the hospital waiting for a bed to open so they can take the patient in and they don’t have any, that’s it. . . if there’s no ambulance to take the call, there’s no ambulance to come to the call’.

On September 1, 2021 the subreddit r/ivermectin was ‘quarantined’ by the Reddit platform but that did notstop the flood of offensive posts. Alternative forums were created but they seemed to fail to capture largeaudiences (e.g. [229]). Another subreddit, r/IVMScience appeared to have stalled after August 23, 2021,with the moderator’s account deleted.

On September 1, podcaster Joe Rogan, with 11.1 million followers on YouTube, 13.2 million followers on Instagram and a USD 100 million contract to publish his podcast exclusively on Spotify, revealed on Instagram that he had got COVID-19 and had been treated with monoclonal antibodies, ivermectin, azithromycin, prednisone, nicotinamide adenine dinucleotide drip and a vitamin drip for three days in a row [230]. Rogan’s statement was widely taken up by news media [231,232,233]. On July 1, 2021, in the context of an unrelated controversy, a journalist at the New York Times had called Rogan ‘too big to cancel . . . one of the most consumed media products on the planet – with the power to shape tastes, politics, medical decisions’ [234].

On September 1, a letter to the editor by Bryant et al. commented on the recent report in the Guardian [81]discussing the effect of the removal of the Elgazzar et al. trial on the meta-analysis by Bryant at al. [4].

The authors stated that ‘while quantitative measures of effect do of course change on removal of any study,the overall findings of a significant mortality advantage in ivermectin treatment, and in prophylaxis, remain robust to removal of the disputed data. The claim that conclusions are “entirely reversed” cannot be sustained on the evidence’ [235].

On September 1, Due˜nas-Gonz´alez et al. discussed repurposing of ivermectin as a novel anticancer [236].

On September 2, Newsweek published a version of McElyea’s story, saying people taking the horse de-wormer medication were filling up the area’s emergency rooms [237]. The report mentioned FDA’s ‘stern warnings’against ivermectin, the unavailability of ambulances, and gunshot victims’ difficulties.

On September 2, Rolling Stone wrote about how Joe Rogan ‘became a cheerleader for ivermectin . . . no one has been more successful at promoting ivermectin than Rogan’ [238].

On September 2, a major Finnish newspaper Helsingin Sanomat republished a news article written by Finnish News Agency (STT) about an US podcast host Joe Rogan treating his COVID-19 infection with a ‘dewormer intended for horses’ warned against by ‘medical officials’ [239]. The article described that after his diagnosis Rogan begun taking ‘all kinds of potions’ including ivermectin, which, according to Washington Post and the Guardian, was used as a dewormer for horses. However, ‘some representatives of conservative media’had ‘advertised the controversial dewormer’. In addition to mentioning the negative stance of the European

Medicine Agency (EMA), the article also cited FDA’s tweet saying: ‘You are not a horse. You are not a cow.

Seriously, y’all. Stop it’. According to the article, calls about ivermectin exposure to poison control centers in the US jumped to five times over normal levels in July 2021. Rogan was also described having spread ‘lies’about COVID-19 and being against vaccines. The leading infectious diseases expert Anthony Fauci was said to have criticized Rogan’s earlier statements. Up to the 1990s, STT, founded in 1887, was often consideredt he ‘official’ national news source. Helsingin Sanomat, the most widely distributed newspaper in Finland,essentially holds a monopoly in the metropolitan area. The article was also republished by the most widely distributed yellow press media Ilta-Sanomat belonging to the same concern as Helsingin Sanomat [240]. In addition, the story was posted in some regional newspapers [241], essentially reaching the whole population of the country.

On September 2, a competing Finnish yellow press newspaper wrote about Rogan’s use of dewormer, saying that it had no proven efficacy and it could be dangerous, even deadly [242]. Rogan was said to regularly ‘flirt with misinformation’. The article also described FDA warnings and retraction of the Elgazzar et al. trial.

On September 2, citing insufficient evidence of efficacy, leading health experts in Sri Lanka urged people to stop using ivermectin for COVID-19; however, a local trial was ongoing [243].

On September 2, Marik and Kory published a reanalysis of the data of their earlier meta-analysis [6],saying that the summary point estimates were largely unaffected when the study by Elgazzar et al. was removed [244].

On September 2, a letter to the editor by Neil et al. said that their Bayesian analysis provided sufficientconfidence that ivermectin was an effective treatment for COVID-19, also after the exclusion of Elgazzar et al. study [245].

On September 2, a Cochrane review concluded that the authors were uncertain whether the investigational monoclonal antibody sotrovimab had an effect on mortality (RR 0.33, 95% CI 0.01-8.18) and invasive mechanical ventilation requirement or death (RR 0.14, 95% CI 0.01-2.76). Treatment with sotrovimab was said to possibly reduce the need for oxygenation (RR 0.11, 95 % CI 0.02-0.45), hospital admission or death by day 30 (RR 0.14, 95% CI 0.04-0.48) [246].

On September 2, an article by Alves et al. in the BMJ about poorly designed studies contributing to misinformation in Brazil said that ’much like a poorly written sequel to a blockbuster, the ivermectin narrative appears to be a subsidiary of the rationale that gave the world the HCQ pseudo-solution to COVID-19: cheap, readily available answer to the biggest sanitary crisis of our time’ [247]. The authors argued that public communication of science (i.e. news reporting) should be evidence based: any interaction between scientists and press should aim at summarizing and contextualizing the most important findings of an article for the general public, preserving context and limitations of the research, promoting transparency,integrity and scientific literacy. Also, research findings should be published without delay and include full datasets. Otherwise, the authors said, public communication may be only fueling polarization and an eventual implementation of harmful, inefficient or wasteful public health policies.

On September 2, an article by Chaudhry et al. presented a systematic review about the role of ivermectin in hospitalized patients [248].

On September 2, a report in BuzzFeed news questioned the validity of two prophylaxis trials by Carvallo etal. in Argentina [249]. The report claimed that the reported numbers, genders and ages of trial participants had slight inconsistencies. Carvallo was said to have declined to share the raw data even to his coauthors, the timeline and ethical approvals of the trials were unclear, as well as who had performed the statistical analyses.

It was also unclear which hospitals had been involved and in which ways. Carvallo denied accusations of fraud.

On September 3, an article by Okogbenin et al. described a retrospective study in Nigeria, with 300 patients treated with ivermectin, zinc, vitamin C and azithromycin, reporting zero mortality [250].

On September 3, a rapid response by Bryant et al. to Popp et al. [177] stated that their Bryant et al. metaanalysis was a non-commissioned research paper that strictly followed PRISMA systematic review guidelines,and that Popp et al. itself contained several misleading items, including using death instead of infection for the prophylaxis outcome, specifying outcome measures not found in the included trials but ignoring the outcome measures found in the trials, subsequently stating that they found ‘no data’ [251]. The authors concluded that in a pandemic context, the benefits of ivermectin almost certainly outweighed any risks.

On September 3, a blog post by Meyerowitz-Katz discussed the study by Carvallo et al. [252], pointing outissues that indicated possible fraud, yet noted that the study was not a randomized controlled trial and thus

not included in most meta-analyses or given the same credence, and it did not change recommendations forofficial medical organizations. However, Meyerowitz-Katz added, ’it perhaps had an even bigger impact onpeople actually taking ivermectin than previously fraudulent research. This paper showed a 100% benefit,it was enormously popular on social media, and it was given a huge amount of credence by promoters ofivermectin for nearly a year. It is not a stretch to say that this one study has perhaps caused hundreds ofthousands or even millions of people to take ivermectin as a prophylactic drug to prevent COVID-19’ [253].

On September 3, South African Health Products Regulatory Authority (SAHPRA) repeated its warnings against the use of ivermectin, saying its stance was aligned to that of US FDA [254].

On September 3, Yahoo News published a version of McElyea’s story, mentioning that he was an emergency room physician affiliated with multiple hospitals in Sallisaw, Oklahoma, and that the situation was so dire that even people with gunshot wounds have to wait their turn to get treatment [255]. McElyea added that people were suffering real ramifications from taking a dosage meant for a full-sized horse, including ‘scary’instances of vision loss, nausea, and vomiting.

On September 3, Rolling Stone magazine published a version of McElyea’s story [256].

On September 4, the Guardian published a version of McElyea’s story [257].

On September 4, BBC published a version of McElyea’s story [258].

On September 4, the administration of Northeastern Health Systems (NHS) Sequoyah posted a statement saying that although McElyea was not an employee of NHS Sequoyah, he was affiliated with a medical staffing group that provided coverage for the emergency room at Sallisaw but he had not worked there in over two months [259,260]. The administration clarified that NHS Sequoyah had not treated any patients due to complications related to taking ivermectin, including not treating any patients for ivermectin overdose. They added that all patients who had visited the emergency room had received medical attention as appropriate,and the hospital had not needed to turn away any patients seeking emergency care.

On September 4, KXMX interviewed a hospital administrator of NHS Sequoyah who stated that the hospital being overloaded by ivermectin patients was ‘simply not the case in Sallisaw .. . we have not seen or had anypatients in our ER or hospital with ivermectin overdose . . . we have not had any patients with complaints or issues related to ivermectin . . . we are not overrun with patients with ivermectin related issues’ [261].

The administrator added that McElyea had treated patients in the Sallisaw emergency room but not in the past several months, and added that she wanted the public to know that McElyea did not speak for NHSSequoyah.

On September 4, NPR wrote that poison control centers are fielding a surge of ivermectin overdose calls [262,263].

On September 4, Reuters published a fact-check article saying that ‘outrage has spread online that Afghan refugees entering the United States will receive the drug ivermectin although it does not have U.S. approval as a COVID-19 treatment. However, the posts miss the vital context that refugees are given ivermectin for infections unrelated to the novel coronavirus . . . ivermectin is administered as a presumptive treatment forintestinal parasite’ [264]. The ‘outrage’ was said to have been caused by ivermectin being administered to refugees but being largely unavailable for US citizens willing to use it for COVID-19.

On September 4, an article by Associated Press published in Indian Express said that efforts to stamp out use of parasite drug ivermectin for COVID-19 in US were growing [265]. It said that ivermectin was being‘promoted by Republican lawmakers, conservative talk show hosts and some doctors, amplified via social media to millions of Americans who remain resistant to getting vaccinated’, with the American Medical Association, two US pharmacist groups, FDA, CDC and WHO advising against it.

On September 5, the Guardian added an amendment to the end of their article, quoting parts of the statementby NHS Sequoyah, saying that the hospital had not treated any patients related to taking ivermectin,including overdose [266].

On September 5, a ‘fact check’ by Shore News Network called the McElyea story ‘completely false’, mentioning that the publishers had not issued retractions, saying that ‘the left continues to push a media narrativethat conservatives and Republicans are creating an ivermectin health crisis’ [267].

On September 6, a preprint by Buonfrate et al. described randomized controlled trial in Italy with results indicating statistically insignificant dose dependent viral load reduction (NCT04438850) [268]. The authors said that ivermectin remained safe with dosing regimes of 0.6 mg/kg and 1.2 mg/kg for five days. The study was terminated early due to lack of eligible patients.

On September 6, a blog post by an US doctor working on new models for mental health care called theMcElyea story ‘too good to check’, saying that ’the media has tried to spread the word that the scientific consensus [about ivermectin for COVID-19] remains skeptical. In the process, they may have gone a littleoverboard and portrayed it as the world’s deadliest toxin that will definitely kill you and it will all somehow be Donald Trump’s fault’ [269,270].

On September 6, a report by News On 6 said ‘a false report has Oklahoma trending nationally . . . the doctor at the center of the story told News 9 he was misquoted, and the story was wrong’. McElyea clarifiedthat ‘as the story ran, it sounded like all of Oklahoma hospitals were filled with people who have overdosed on ivermectin and that’s not the case, . . . the cases we are seeing, people who are overdosing on ivermectin,they are taking full strength cattle doses and coming in and that is something that could be avoided’.

The report mentioned another hospital in the area, Integris Grove, having stated that they had seen ‘a handful of ivermectin patients in their emergency rooms . . . while our hospitals are not filled with people who have taken ivermectin, such patients are adding to the congestion already caused by COVID-19 and other emergencies’. The report concluded with a mention that the Oklahoma Center for Poison and Drug Information had received 12 ivermectin-related calls last month [271].

On September 6, Soave analyzed the media reporting, saying that the media fell for a viral hoax about ivermectin overdoses straining rural hospitals [272]. He commented that McElyea clearly stated that ivermectin overdoses were a problem and claimed that some hospitals were dealing with strain in general but he neveractually connected these two issues. Instead, the KFOR’s journalist had added that framing; she had notresponded to a request for comment. If other media outlets had called the doctor or the hospitals they would have easily uncovered the error. Soave added that while the mainstream media had vigorously condemned COVID-19 misinformation in social media, readers could also encounter it in mainstream media such as Rolling Stone, New York Times or Associated Press (AP) which had recently reported that 70 percent of calls to Mississippi’s poison hotline were from people who had taken ivermectin while the actual figure was 2 percent [273] (AP was a member of the Trusted News Initiative (TNI) [274]).

On September 6, another judge reversed the earlier decision concerning administration of ivermectin prescribed by Wagshul to a patient in a US hospital, saying there ‘was no doubt that the medical and scientific communities do not support the use of ivermectin as a treatment for COVID-19’ [275]. The judge addedt hat ‘COVID-19 has ravaged the world. However, the rule of law must be followed once the court system is involved. The law in its purest form shall have neither hatred nor sympathy to anyone or anything. It shall stand unwavering in its truth, justice, and fairness to call’ [276]. A spokesperson for the hospital described the ruling as ‘positive in regards to the respect for science and the expertise of medical professionals’, adding that they implore the community ‘to do what we know works: wear a mask, become fully vaccinated and use social distancing whenever possible’. She added that the hospital appreciated scientific rigor and did not believe they should be ordered to administer medications ’against medical advice’.

On September 6, a German magazine for pharmacists reported about American Pharmacists Association’s recent demand to stop off-label ivermectin prescribing [277]. The article mentioned the ongoing PRINCIPLEtrial by University of Oxford.

On September 7, Fox News reported that McElyea was an employee of an agency that staffs emergencydepartments [278]. The report also mentioned that while NHS Sequoyah had stated they had not treatedany ivermectin patients, Integris Grove Hospital, had seen a handful’. Integris added that ‘there is a lotof media attention surrounding remarks reportedly made by Dr. McElyea. While we do not speak on hisbehalf, he has publicly said his comments were misconstrued and taken out of context’.

On September 7, a CNN reporter Daniel Dale tweeted about McElyea case, saying local media had misrepresented the interview of McElyea, national and international media had failed to do due diligence, and readers and critics had jumped to conclusions. He concluded that ‘lots of people involved here – certainly the local outlet/the big aggregating outlets/the prominent tweeters on the left, but also some critics on the right – could’ve done a better job pursuing facts/waiting for facts before coming to conclusions’ [279]. CNN published a ‘fact-check’ report with similar content [280].

On September 7, an Austrian newspaper wrote that the misconception that horse dewormer ivermectin wouldhelp against COVID-19 is widespread internationally and also in Austria [281]. The article mentioned thatno poisonings had been reported in Austria, and that Czech Republic had adopted ivermectin in hospitals.

A toxicologist commented that ivermectin was still dangerous and there was insufficient data on the safety of chronic consumption.

On September 7, the title of a January 2021 article in a German women’s magazine, originally asking whether ivermectin might be useful, was updated to ‘People are not horses’ [282].

On September 7, a Swedish newspaper Svenska Dagbladet wrote that instead of being vaccinated Americans are taking ivermectin as the latest alternative treatment for COVID-19, the only problem being that it was intended for treating parasites in horses and cows [283].

On September 7, Joe Rogan complained that CNN had reported that he had been taking ‘horse dewormer’;Rogan stated that ‘I literally got it from a doctor’ [284].

On September 7, wealthy Chinese exile Guo Wengui was said to be using his online misinformation network to promote the use of unproven treatments for COVID-19 [285].

On September 8, an article by Cruciani et al. presented a systematic review and meta-analysis of ivermectin for prophylaxis and treatment of COVID-19 [286]. Based on an analysis of eleven RCTs, the authors concluded that there was limited evidence for the benefit of ivermectin.

On September 8, a letter published in the Guardian by Hill, the main author of one of the meta-analyses about ivermectin [5], said that after his team had questioned the clinical benefits of ivermectin the team and his family had received daily death threats. As social media platforms had not reacted he had stopped using social media but abuse by email had continued. Hill described the situation as shocking, affecting many scientists, and said that scientists must be protected from anti-vaxxer abuse, possibly by police action [287].

On September 8, Wired magazine wrote about Together trial results, quoting the head researcher saying that ivermectin proponents had ignored their fluvoxamine findings, only being interested in ivermectin,‘feeling strongly’ about it but not about other possible options [288]. The article also mentioned US NIH’s ongoing ACTIV-6 ivermectin trial, into which people could sign up at home. A co-chair of the trial’s steering committee said that there was no data on ivermectin’s benefit but since people were using it, the point of their trial was to get a definitive answer.

On September 8, the Guardian worried about some Australian clinics’ off-label prescribing of ‘unapproved’ivermectin [289]. The president of the Royal Australian College of General Practitioners (RACGP) said that while RACGP did not consider its role to be looking over the shoulders of every GP, the advice from the health experts to not use ivermectin was ‘100% clear’. However, she added, ‘the status of other drugs, suchas sotrovimab, is very different. That is an example of a new drug for the treatment of Covid-19 that haspassed through the rigorous testing safety procedures of the Therapeutic Goods Administration’.

On September 9, Geert Vanden Bossche summarized the negative effects of mass vaccination as follows: itwill, first, eventually drive dominant propagation of super variants that are highly infectious and increasinglyresist vaccine-induced neutralizing antibodies; second, erode innate immune defense in the non-vaccinated(due to high infectious pressure exerted by enhanced circulation of more infectious variants); and third,erode naturally acquired immunity (due to increasing viral resistance to neutralizing spike protein specificantibodies). Of these, the second and third consequences together prevent herd immunity from being established.

Yet the solution, according to Bossche, would be induction of herd immunity by starting from scratch against the more infectious variants. This could be achieved by providing multidrug early treatment for the infected which would result in enhanced rates of recovery from disease and rise in the number of people who develop life-long protective immunity. Also, mass antiviral treatment with any drug that would effectively reduce viral infectious pressure would be required to prevent innate antibodies in previously asymptotically infected individuals from being suppressed by short-lived, spike protein specific antibodies and thus enable the healthy, unvaccinated part of the population to deal with all SARS-CoV-2 variants; these massantiviral campaigns might need to include pets and live-stock and be combined with lockdown rules foras long as titers of these short-lived antibodies were measurable (6-8 weeks).

Boscche said that a larger unvaccinated population would circulate also less infectious variants, attenuating circulation of more infectious variants. However, the above methods would still be unlikely to sufficiently reduce transmission among healthy individuals; therefore ultimately an immune intervention able to prevent infection in all susceptible age groups would be required, and as long as such an intervention, likely based on natural killer cell based vaccines, would not be available, repeated antiviral chemoprophylaxis might be necessary. However, as along term strategy the chemoprophylaxis would not be feasible, as overuse could promote viral resistance to the compound.

About his personal intentions Bossche wrote that ‘one can always do more, write morearticles, bring more scientific evidence to the table, do more interviews and podcasts, reply to more questionsand destroy more of the nonsense divulgated by scientifically incompetent experts or illiterate fact-checkers.

However, I’ve decided to not continue along this path as I knew from the very start that this big alliance of stakeholders would not listen and as the primary purpose of my endeavors has always been to share, as broadly as possible, my scientific insights on why this [mass vaccination] experiment is an incredible blunder, so that none the involved experts, key opinion leaders, public health authorities or peers from industry could ever pretend that this was unknown and simply unpredictable’ [290].

He said that he had a history of going against ‘groupthink’, for example speaking against the results of Gavi The Vaccine Alliance’s phase III Ebola vaccine trials conducted by the World Health Organization (WHO) and published in a peer-reviewed journal. Bossche said the results falsely concluded that the vaccine had 100% efficacy, whereas according to Bossche’s analysis ‘the truth looked extremely different’ [291]. He added that to him it seemed that ‘many of our experts and scientists, even including a substantial number of renowned professors, are so stuck within their small silos that they have simply lost touch with reality’.

On September 9, Hill responded to a tweet by the BIRD group which had said that according to Hill, the conclusions of the meta-analysis by Hill et al. remain clearly in favor of ivermectin even after exclusion ofElgazzar et al. trial [292,293]. Hill stated: ‘Misleading information from the BIRD group. In our analysis there is no significant survival benefit for ivermectin in randomized trials after exclusion of apparently fraudulent and biased studies’ [292]. Later on the same days he responded with ‘more misleading information from the BIRD group misquoting our research’ to another tweet by the BIRD group which had said that‘Hill’s work also shows that ivermectin not only reduces the risk of death, it clears the virus from the bloodstream faster than controls, thus ivermectin reduces the time that an infected person can transmit the virus’ [294].

On September 9, Joe Rogan discussed the ‘horse dewormer’ narrative, referring to regulatory capture in theUS [295].

On September 10, a news report in the BMJ discussed US court rulings and ivermectin prescriptions [296].

On September 10, the BIRD group announced that their meta-analysis by Bryant et al. [4] had reached a position in the top ten of 18.9 million articles tracked by Altmetric [297,298].

On September 10, Hill tweeted that the ‘survival benefit of ivermectin disappears when only trials at low risk of bias are analyzed. The reported survival effects are entirely driven by studies at high risk of bias or medical fraud’ [299]. An accompanying graph indicated slightly over 50% benefit (p=0.01) with Elgazzar et al. study included, slightly under 40% benefit (p=0.05) without it but including studies with a high risk for bias, and approximately 4% benefit (p=0.90) with only low risk studies included.

On September 10, a blog article discussing failed communication attempts between ivermectin skeptics and proponents commented that ‘what you are witnessing is just the most absurd example of a decades-long war on re-purposed (aka “non-profitable”) medicines’ [300,301,302].

On September 10, Hindustan Times wrote about a clinical trial (RIVET-COV) with 157 patients with mild to moderate disease carried out by All India Institute of Medical Sciences (AIIMS) which indicated that ivermectin did not reduce the viral load or duration of symptoms [303]. Mohan said that ‘all the ivermectin being prescribed or being taken by people left, right, and centre will definitely not show any effect’; therefore ivermectin should not be used outside clinical trials, although he added that their trial did not investigate possible effect on mortality.

On September 11, TrialSite News wrote about US NIH’s refusal to release information on who had been involved in its decision to recommend neither for nor against ivermectin [304]. However, US CDC had released the names of the members of the working group [305]. According to TrialSite News, three of the nine members, Adimora, Bedimo and Glidden, had disclosed a financial relationship with Merck & Co/MSD.

Another member, Naggie, had later received USD 155 million funding for US NIH’s ACTIV-6 trial which included ivermectin, fluvoxamine and fluticasone (NCT04885530) [306].

On September 11, TrialSite News wrote that Australia’s Therapeutic Good Administration (TGA) had formally placed a national prohibition on off-label prescribing of ivermectin to all general practitioners,citing interruption of vaccination as a factor in the decision [307].

On September 12, a three-day International Covid Summit started in Rome [308,309], with presentationsin the Roman Senate held also in Italian and Spanish and translated into sign language. Lecturers included Roberta Ferrero, Francesca Donato, Albert Bagnai, Luigi Icardi, Ivan Vilibor Sincic, Joseph Tritto, Robert Malone, Mauro Rango, Christof Plothe, David Anderson, Ira Bernstein, Fabio Burigana, Steven Hatfill,Roberto Accinelli, Tess Lawrie, Oswaldo Castaneda, Rosanna Chifari, Antonietta Gatti, Andrea Stramezzi, Peter Mccullough, George Fareed, Pierre Kory, Roberta Lacerda, Carlos Maggi, Bruce Patterson, DilipPawar, Victor Villa, Mattia Perroni and Francesco Matozza. In addition, the summit featured groups of researchers and clinicians from Italy, Croatia, Czech Republic, Poland, Romania, Bulgaria, Tanzania, South Africa, Nigeria, Mali, Spain, UK, France, Brazil, Bolivia, Argentina, Paraguay, Peru, Canada and US. Several treatment protocols including McCullough et al’s sequenced multidrug protocol [310] and FLCCC’s MATH+protocol were discussed.

On September 13, a Dominican Republic newspaper described details of an early 2020 ivermectin trial by Morgenstern et al. [311,312].

On September 13, a story in Rolling Stone ridiculed ‘anti-vaxxers’ for using povidone iodine mouthwash to prevent COVID-19 [313]. An interviewed gynecologist/obstetrician commented that ‘we use it before surgery to clean the vagina’ and that ‘it could result in iodine poisoning if taken orally’. Another physician who appeared unable to give statements without including profanities in his sentences commented that ‘drinking iodine’ had caused a patient a transient kidney failure and that povidone iodine definitely could not reducethe effects of COVID-19 or prevent its transmission. An ’Australian family physician’ stated that ‘there have been no human studies on the use of Betadine to treat COVID-19, just hypotheses and lab studies’.

On September 13, the Guardian wrote about ‘ivermectin frenzy’ being ‘a cottage industry of advocacy groups, anti-vaccine activists and telehealth companies’ despite stances of FDA, NIH and some US medical and pharmaceutical associations [314]. It noted that FLCCC had signed open letters in favor of ivermectin which had also been signed by ‘anti-vaxx’ organizations. Telehealth sites were said to have connections to a conservative doctor group America’s Frontline Doctors in favor of hydroxychloroquine treatments and whose opinions had been quoted by ‘Donald Trump, his son Donald Trump Jr and numerous QAnon conspiracists’.

On September 13, Mother Jones magazine wrote that people associated with Q-Anon had harassed a hospital where a Q-Anon member had been hospitalized with hundreds of calls and emails, in order to get ivermectin administered to her [315].

On September 14, in a Cochrane Collaboration author interview, Stephanie Weibel and Maria Popp described their ivermectin meta-analysis [316]. The authors said that because of a lack of good-quality evidence, it was unknown whether ivermectin reduces or increases mortality, caused adverse effects, improved or worsened patients’ condition, or increased or decreased viral load, led to more or fewer negative COVID-19 tests 7days after treatment. Likewise, they could not say whether ivermectin prevented COVID-19 infection or reduced the number of deaths after high-risk exposure to the SARS-CoV-2 virus.

On September 14, Menichella wrote about Peter McCullough’s influence in Italy and about a protocol developed in Italy by a group led by Giuseppe Remuzzi [317]. The Remuzzi protocol was mainly based on relatively selective COX-2 inhibitors [318]. In a retrospective observational matched-cohort study with 90outpatients and 90 controls with mild disease the proportions of patients who required hospitalization were2% vs 14% (p=0.01); cumulative days of hospitalization were 44 vs 481 days, and costs of hospitalization were EUR 28,000 vs EUR 296,000, respectively. Menichella wrote that the standard of care resulted in approximately 2% mortality; with a ’serious home treatment protocol’ mortality could be lowered to 0.05%.

On September 15, an article by Talwar et al. described a case of a successful management of ivermectinpoisoning [319]. A 6-year-old girl weighing 20.5 kg had accidentally consumed 600 mg of ivermectin (29.3mg/kg). Mechanical ventilation, ceftriaxone, clindamycin, intravenous midazolam, phenytoin and supportivemeasures were utilized. The girl was discharged after nine days of hospitalization.

On September 15, a news report in Willamette Week discussed US biologist Bret Weinstein’s role in the ivermectin controversy, including his influence on Joe Rogan [320].

On September 15, a letter to the editor by Boretti discussed quercetin, suggesting that quercetin might help to lower inflammation, as well as reduce the toxic effects of COVID-19 vaccines and the chances of being infected [321]. Quercetin had been included in the FLCCC protocols since early 2020.

On September 15, Fenton et al. discussed unreliability of current vaccine studies [322].

On September 16, Cheng et al. presented a meta-analysis about efficacy and safety of various medications for treating severe and non-severe COVID-19 patients [323].

On September 16, Malhotra discussed Indian Bar Association’s legal notice to WHO [324].

On September 16, an Australian medical newspaper wrote that a secretive organization called the COVID19 Antiviral Advisory Group had said it had been instructing 200 doctors to prescribe ivermectin and was planning on going public against TGA’s ivermectin ban [325].

On September 17, an article by Singh et al. suggested a positive correlation between European populations’zinc sufficiency status and COVID-19 mortality. The authors noted that the observed association was contrary to what would be expected if zinc sufficiency was protective in COVID-19, suggesting that controlled trials or retrospective analyses of the adverse event patients’ data should be undertaken to correctly guidethe practice of zinc supplementation in COVID-19 [326].

On September 17, an article by Gurung et al. described an in silico study which indicated that ivermectin demonstrated moderate binding to human serum albumin [327].

On September 17, a preprint by Karale et al. presented an updated systematic review and meta-analysis of mortality, need for ICU admission, use of mechanical ventilation, adverse effects and other clinical outcomes

[328]. 52 studies (n=17,561) were included in a qualitative analysis and 44 of those (n=14,019) were included in the meta-analysis. A mortality meta-analysis indicated lower odds of death (OR 0.54, 95% CI 0.34-0.86,p=0.009, 29 studies). As adjuvant therapy, the odds of viral clearance were higher (OR 3.52, 95%CI 1.816.86, p=0.0002, 22 studies), the duration to achieve viral clearance was shorter (p=0.02, 8 studies), andthe need for hospitalization was reduced (OR 0.34, p=0.008, 6 studies). The authors concluded that themortality benefit of ivermectin in COVID-19 is uncertain but as an adjuvant therapy ivermectin may improve viral clearance and reduce the need for hospitalization.

On September 17, a news report by Piper in Vox magazine questioned the validity of studies by Carvallo etal. [329,330], saying that experts on scientific fraud didn’t believe Carvallo conducted his study as described:the data appeared fabricated, key data was missing, study registration and published results didn’t match with each other, Carvallo could not explain these issues, and the hospital in which the study was said to have been conducted stated that it had not been conducted there, to which Carvallo replied that it had been but without the hospital administration knowing [331]. In another context, Lawrie of the BIRD group had been asked what evidence would persuade her that ivermectin didn’t work, to which she had replied thatthere could be nothing that would persuade her. Mills involved in the Together trial commented that themost culpable parties weren’t those who had believed in the apparently fraudulent studies but those whohad conducted, published, and boosted them.

On September 17, Business Insider wrote about FLCCC’s Kory and Marik, calling them ’fringe doctors whipping up false hope that could have deadly consequences’ [332]. According to Business Insider, Kory was’a once respected doctor whose hospital rejected his unsupported treatment ideas’ while Marik was ’a doctor who ostracized himself from mainstream medicine after his high-profile sepsis treatment was a dud’, adding that ’Marik’s failed sepsis protocol later became the backbone of the FLCCC’s first iterations of COVID-19treatment’ (the MATH+ inpatient protocol) [333]. Recently they had been ’sucked (willingly or not) into the embrace of the anti-vaccine far right .. . ivermectin is now a darling drug of QAnon’. A former FLCCCmember, Eric Osgood, had left the group in summer 2021. The editor in chief of Science Communication said that FLCCC’s communication style was objectionable but added that the existence of ’rogue opinions’was a necessary condition for scientific breakthroughs. However not everyone had the skills to assess claimsnor understood how science worked, which had led to ’a conflict between our commitment to freedom of speech and a clash with the nature of scientific truth and people’s right to say anything they want . . . the hype machine they’ve created is out of control’.

On September 17, Seheult on MedCram reviewed ivermectin, with comments from cell biologist Rhonda Patrick [334]. Seheult stressed the importance of taking all treatment options into account; Patrick said ivermectin had seemed to consistently reduce viral load but the hype around ivermectin was pushing researchers away from the subject.

On September 20, an Indian news agency reported that 31 of 75 districts of the state of Uttar Pradesh inIndia were COVID-19 free [335]. In total, the state reported 17 new cases in the last 24 hours out of 182,742samples tested.

On September 20, the Guardian worried about horses being deprived of a deworming agent [336].

On September 21, Brazil’s president Bolsonaro stated that Brazil had supported clinicians’ early treatment measures since the beginning of the pandemic, adding that he could not understand why some countries opposed early treatment measures [337].

On September 21, Ars Technica discussed the validity of Covid Analysis group’s ivmmeta.com meta-analysis[338].

On September 22, a letter to the editor by Lawrence et al. in Nature Medicine concluded that metaanalyses based on summary data alone were inherently unreliable [339]. The authors stated that most,if not all, of the flaws in recent ivermectin meta-analyses would have been immediately detected if metaanalyses were performed on an individual patient data (IPD) basis. They recommended that meta-analysts who study interventions for COVID-19 should request and personally review IPD in all cases, even if IPDsynthesis techniques were not used. They also recommended that all clinical trials published on COVID-19should immediately follow best-practice guidelines and upload anonymized IPD. They authors said that their proposal was a change to a nearly universally accepted practice over many decades and substantially more rigorous than current standards; regardless, the proposed change was imperative.

On September 22, in a FLCCC weekly update, Marik announced an upcoming publication of an article on the pathophysiology of COVID-19 [340].

On September 22, a video by John Campbell described the contents of ivermectin kits used in state of Goain India [341]. The kits in Goa contained pulse oximeter, a thermometer, paracetamol, vitamin C and D,multivitamin tablets containing zinc, ivermectin (10 x 12 mg), doxycycline (10 x 100 mg), and personal protective equipment. The cost of one kit was USD 2.65. The kits used in Uttar Pradesh contained ivermectin, doxycycline, vitamins B, C and D, zinc, paracetamol, thermometer and a pulse oximeter. Outpatients weremonitored by phone twice a day. Campbell said that the intervention had actually been organized under a WHO monitoring program. A WHO report described that since May 5, 2021, 141,610 government teams were moving across 97,941 villages in 75 districts over five days in Uttar Pradesh, a state with a population of 230 million [342]. WHO field officers monitored over 2,000 government teams and visited at least 10,000 households. WHO also said it was to support the Uttar Pradesh government on the compilation of the final reports; these reports had not yet been published.

On September 23, a preprint by Mayer et al. described an intervention program of high-dose ivermectin in COVID-19 carried out by the Ministry of Health of the Province of La Pampa, Argentina [343]. Within five days of symptoms onset, 0.6 mg/kg/day of ivermectin for five days was administered. Active pharmacosurveillance was performed for 21 days, with hepatic laboratory assessments performed in a subset of patients. From 21,232 subjects with COVID-19, 3,266 were offered and agreed to participate in the ivermectin program. 17,966 did not participate and were considered as controls. A total of 567 participantsreported 819 adverse events; 3.13% discontinued ivermectin due to adverse events. Mortality was lower in the ivermectin group in the full group analysis (1.5% vs 2.1%, OR 0.720, p=0.029), as well as in subjects over 40year-old (2.7% vs 4.1%, OR 0,655, p=0.005). ICU admission was significantly lower in the ivermectin groupcompared to controls among participants over 40 year-old (1.2% vs 2.0%, OR 0.608, p=0.024). According to Covid Analysis group [344], in a full group analysis the unadjusted risk of death was 27.6% lower (RR 0.72,p=0.03) and unadjusted risk of ICU admission was 26.0% lower (RR 0.74, p=0.13).

On September 23, several groups of clinicians in favor of early treatments announced a new organization,World Council for Health, an umbrella organization with over 45 affiliated organizations [345]. The council released a home treatment guide with a combination protocol consisting of vitamins C and D, zinc, quercetin, melatonin, ivermectin, mouthwash, ibuprofen, N-acetylcysteine, antihistamines, aspirin, and others [346].

The protocol was one of the first ones to tentatively include iodine (Lugol’s solution).

On September 23, the Indian Council of Medical Research (ICMR) dropped ivermectin and hydroxychloroquine from clinical guidelines for the management of adult COVID-19 patients [347,348,349,350].

On September 23, a fact-checking website discussed social media posts claiming that ’ivermectin apparently sterilizes the majority (85%) of men that take it’ and a news report claiming that ’ivermectin causes sterilization in 85 percent of men, study finds’ [351,352].

On September 24, the Guardian wrote about misinformation spreading globally [353].

On September 24, the Guardian wrote about fraudulent ivermectin studies [354].

On September 24, Mashable interviewed ex-FLCCC member Osgood who said that he had initially joined the FLCCC because they were ’forward thinking doctors who were able to get ahead of the profession’ on a few hospital treatments (e.g. the use of anticoagulants) but he had left the organization because of his view that FLCCC insisted on promoting ivermectin over vaccines [355]. He referred to povidone iodine prophylaxis of COVID-19 as misinformation.

On September 26, an article by Marik et al. presented a scoping review of the pathophysiology of COVID-19[356]. The article described severe COVID-19 as one of the most complex of medical conditions known to medical science, noting that an overarching and comprehensive understanding of its pathogenesis, a requirement for the formulation of effective prophylactic and treatment strategies, was still lacking. Threebasic pathologic processes were identified: a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thromboticmicroangiopathy, and platelet activation with the release of serotonin and the activation and degranulation of mast cells contributing to the hyper-inflammatory state (quercetin had been a part of FLCCC protocols sinceMarch 2020; in one study, it was found more effective than cromolyn in blocking mast cell cytokine release[357]). The article also mentioned the C-C chemokine receptor type 5 (CCR5) pathway which interacts with chemokine ligand 5 (CCL5 or RANTES).

On September 26, in a discussion with Robert Malone, Geert Vanden Bossche stated that the proper way would have been to vaccinate vulnerable groups only, and mentioned ivermectin chemoprophylaxis as a possible solution [358].

On September 26, the New York Times interviewed the acting head of the New Mexico (US) state health department who claimed that ivermectin ’had contributed to’ deaths of two hospitalized patients who had previously self-medicated with ivermectin ’instead of proven treatments like monoclonal antibodies’ [359].

On September 27, in a discussion with Anmol Ambani and Peter A. McCullough, Marik presented the contents of the new article in a video lecture [360].

On September 27, 5,200 doctors had signed a Global Covid Summit related ’Rome declaration’ [361].

On September 27, an article by Deng et al. presented a systematic review and meta-analysis about the efficacy and safety of ivermectin [362]. Based on an analysis of three observational studies and 14 RCTs representingvery low to moderate quality of evidence, the authors concluded that ivermectin was not efficacious atmanaging COVID-19.

On September 28, an article by Barkati et al. concluded that corticosteroid therapy was an important risk factor for Strongyloides hyperinfection but there were challenges associated with the performance, availability and quality of Strongyloides tests. The authors concluded that presumptive use of ivermectin was reasonablein selected situations [363].

On September 28, an article by Zhang et al. presented a Bayesian network meta-analysis of 222 randomized controlled trials with 102,950 patients, suggesting that imatinib, intravenous immunoglobulin andtocilizumab led to lower risk of death; baricitinib plus remdesivir, colchicine, dexamethasone, recombinanthuman granulocyte colony stimulating factor and tocilizumab indicated lower occurrence of mechanical ventilation; tofacitinib, sarilumab, remdesivir, tocilizumab and baricitinib plus remdesivir increased the hospital discharge rate; convalescent plasma, ivermectin, ivermectin plus doxycycline, hydroxychloroquine, nitazoxanide and proxalutamide resulted in better viral clearance [364]. On a treatment class level, the analysis found that the use of antineoplastic agents was associated with fewer mortality cases, immunostimulants could reduce the risk of mechanical ventilation and immunosuppressants led to higher discharge rates.

On September 28, the New York Times wrote that Facebooks groups promoting ivermectin continued to flourish [365].

On September 28, a rapid review by Cardwell et al. about pharmacological interventions to prevent COVID19 mentioned ivermectin prophylaxis trials [366].

On September 29, a preprint by Budhiraja et at. described secondary infections in hospitalized patients inNorth India, mentioning that 43.5% of the patients had been administered ivermectin [367].

On September 29, referring to FLCCC, BIRD and America’s Frontline Doctors (AFLDS), Scientific Americanwrote about fringe doctors’ groups promoting ivermectin for COVID despite a lack of evidence [368].

On September 29, Chemistry World wrote that ivermectin debacle had exposed flaws in meta-analysis methodology [369]. The report stated that ’the people who’ve done these meta-analyses haven’t stuffed up. . . they haven’t deviated from accepted standards or made big mistakes . . . instead, there is a fundamentalflaw in the approach’.

On September 29, the Hill, the largest independent political news site in the US, wrote that ivermectin disinformation had led to new kinds of chaos [370].

On September 30, a preprint by Schaffer et al. describing changes in dispensing of medicines proposed for re-purposing in the first year of the COVID-19 pandemic in Australia noted that there had a small but sustained increase in ivermectin dispensing between March 2020 and November 2020 [371].

On September 30, an introduction to Popp et al.’s Cochrane review by Jordan said that at this stage there were very few completed well conducted studies about either prevention or treatment but 31 trials were underway [372].

Discussion

On a closer look it appeared that the quality of some early ivermectin trials had been lower than assumed.

As individual patient data had not been generally available, most parties including various groups publishing meta-analyses had implicitly trusted the summary data and ignored slight inconsistencies. The current best practice guidelines did not require analysis of individual patient data. The proposal that meta-analyses should be performed on individual patient data appeared justified. An additional, likely necessary change to methodology would be adoption of the do-search method, assumedly the most general tool currently available for causal effect identification, and as such an improvement over Bayesian methods [179,373].

In 2014, Every-Palmer et al. noted that little ‘high quality’ (according to evidence-based medicine standards)empirical evidence existed that EBM should benefit the population, i.e. evidence about EBM’s superiority in improving patient outcomes [374]. In 2018, Anjum claimed that EBM relied on a flawed positivist methodology [375]. Recently, Martini claimed that the concept of evidence was insufficiently defined [376].

A fundamental error appeared to be the insistence on trialing single agents instead of combination protocols.

All of the currently utilized early treatment protocols were combination protocols and it was unlikely that the same results could have been obtained with a single agent. Thus, combination protocol trials would have been more likely to produce statistically significant effects. The insistence on large trials, instead of eliminating biases, possibly introduced them. For example, a lack of funding for repurposing may have introduced a severe funding-related bias.

It appeared that prolonged stress and continuing unpredictability of the situation had overwhelmed many,occasionally leading to actions whose consequences were perhaps badly thought out. The situation seemedto amplify preexisting tendencies and weaknesses within groups, leading to group-specific biases, formationof subcultures, or variants of ’groupthink’ [103]. Groups suspecting the pharmaceutical industry, authoritiesand ’the mainstream’ seemed to amplify these tendencies in-group, whereas groups suspecting anything’fringe’ but favoring mechanistic thinking and overreliance on specific methods or paradigms seemed toamplify these tendencies. Groups with a tendency to act out in panic or anger exhibited that behavior,while groups with a tendency to retreat into fearful inaction and silence did that. The central role of trustwas highlighted, yet trust seemed practically nonexistent.

Also strengths were exhibited, most prominently the capability of forming groups and alliances. However,these groups tended to become tribal in their nature, and the result resembled tribal warfare, a practice that the humanity should already have transcended. It seemed as if everyone was trying to take care of others in their own ways but these ways were incompatible with each other; someone once defined conflicts as ’failed attempts to love’.

It also seemed that journalists and the public had an idealized image of science and were trying to find solace in it as in a religion, with some scientists maybe trying to maintain these illusions. One commentator noted that ’society was not ready to watch science in real time’ [377]. Another added that ’science was not prepared to display itself to the public in real time’, while a third said that ’society was not ready to watch science in any other way either’.

In the news media, emotionally manipulative tactics seemed common. A prime example of arrogance and lack of due diligence was the case of Rolling Stone ridiculing povidone iodine use [313], claiming that there had been no human trials about it on COVID-19, despite the fact that there had been several, with promising results [10,378,379,380,381] (for observational studies, see e.g. [382,383]; for an updating list, see [384]).

Ways of reasoning appeared incompatible for example in the case of the Guardian’s critique of the BIRD group affiliating with organizations labeled as anti-vaccine for the purposes of promoting early treatment.

In the view of the BIRD group founder, vaccinations were unrelated to early treatments and, subsequently,the vaccination stances of the affiliates irrelevant. While technically correct, this view predictably appeared confusing.

In a similar manner it could be noted that, for example, the possible usefulness and validity of FLCCC’s protocols was unrelated to FLCCC members’ extra-medical opinions, and that ivermectin was only one component of the synergistic protocols consisting of more than ten components. Also, some news reports[332] severely misrepresented the sepsis protocol [333]. With regard to the social media communications of the FLCCC, it may have made a mistake in leaving these communications largely to a couple of ex-journalists whose communication style appeared unsuitable already in the first half of 2020.

With regard to conflicts of interest, the members of US National Institutes of Health’s (NIH) ivermectinworking group had disclosed several relationships to pharmaceutical companies working on COVID-19 treatments [385]. As mentioned, three of the nine members of the working group [305] had disclosed relationshipswith Merck & Co/MSD which, during the pandemic, had issued a statement against the use of ivermectinin COVID-19 [386], was working on a competing product molnupiravir [387,388,389], and had receivedsignificant US government funding for development of investigational pharmaceuticals for COVID-19 [390].

Adimora had received research support from Gilead Sciences and was a consultant and a member of an advisory board of Merck & Co/MSD; Bedimo was a member of advisory boards of Gilead Sciences, Merck &Co/MSD and ViiV Healthcare (a subsidiary of GlaxoSmithKline); Glidden was a consultant to Gilead Sciences and a member of an advisory board of Merck & Co/MSD [385]. A fourth member, Pavia, was a consultant to GlaxoSmithKline. A fifth member, Naggie, the head of US NIH’s ACTIV-6 trial (NCT04885530) [306]had received research support from AbbVie and Gilead Sciences, had a connection to Bristol Myers SquibbCompany, and was a stockholder and an advisory board member of Vir Biotechnology, the producer ofsotrovimab together with GlaxoSmithKline [391]. In summary, more than half of the members of the working group were associated with producers of molnupiravir, sotrovimab, remdesivir (Gilead Sciences),lopinavir/ritonavir (AbbVie), and investigational monoclonal antibodies (Bristol Myers Squibb Company).

However, NIH had specifically intended to involve the industry in its decision-making processes through the ACTIV public-private partnership [392]. Whereas this organizational structure likely appeared beneficialfrom the point of view of a swift development of investigational pharmaceuticals, with regard to repurposingit appeared to have included conflicts of interest by design.

For the pharmaceutical industry, incentives for unethical behavior may currently overpower those for ethical behavior. The current setting appeared designed for gambling [393], hardly the best method for optimizing public health, and it was difficult to see why societies considered it appropriate.

The event descriptions did not delve into details of the experiences of Honduras and the Dominican Republic; readers are encouraged to acquaintance themselves with the original sources [217,106,107,311,312].

These countries used relatively little clinical trial evidence to implement their protocols. Similarly, no RCT evidence on FLCCC protocols exists, yet they have been successfully used. These parties seemed to embrace uncertainty instead of requiring an unattainable level of certainty; high-income countries were probably less accustomed to radical uncertainty than developing countries.

Cameron described critical care archetypes on a two-axis model, with the first axis comparing interventionism(early, aggressive treatment) versus minimalism (’wait and see’) preferences, and the second axis measuring individualism versus collectivism [74]. In this model, the FLCCC appeared high on interventionism and individualism. The ’mainstream’, for example the World Health Organization and national authorities, appeared high on minimalism and collectivism.

During the whole pandemic (and before it), little to no attention was paid to the optimization of innate immunity. If the immune system is dysfunctional or in a suboptimal state, attempts at medicating symptoms including symptoms of SARS-CoV-2 infection are unlikely to be very effective, and the same likely applies to vaccines. While the role of zinc was acknowledged to some degree, the roles of, for example, copper, selenium and iodine were still mostly ignored. Conventionally, a long-term zinc supplementation without simultaneous copper supplementation is considered a risk for development of copper deficiency which would compromise immune function and host defence [394]; FLCCC recently lowered the dose of zinc supplementation. Astudy on European populations found a positive correlation between zinc sufficiency status and COVID-19mortality and incidence, contrary to what would be expected if zinc sufficiency was protective in COVID-19[326]; however, the result might also indicate lack of zinc ionophores.

Suggested solutions

In addition to the methodological issues there were other types of challenges to overcome. Considering that the nature of communication between parties involved in the ivermectin controversy was predominantly ofa rather violent nature, a method for improving communications would be needed. A suitable method forthe purpose may be the rather well known but rarely applied ’non-violent communication’ (NVC) method developed by Marshall Rosenberg [395,396]. The method presupposes a willingness to a certain degree ofvulnerability in order to express one’s real needs and feelings, and a willingness to actually listen to others without judging.

The method consists of two parts: expressing oneself, and empathically acknowledging others. NVC defines empathy as ’a process of connecting with another by guessing their feelings and needs’ [397]. Friesem describes the expressing part as a sequence of four steps: making observations (not evaluations) without blaming or criticizing, connecting feelings (bodily sensations instead of thoughts) to these observations, expressing the needs/values (not preferences) that caused the feelings, and making requests (concrete actions instead of vague wishes) without demanding [398]. The listening part consists of the same steps but the expressions use the pronoun ’you’ instead of ’I’. The four components are thus expressed as ’when I/you see/hear. . . ’(observation), ’I/you feel. . . ’ (feeling), ’. . . because I/you need/value. . . ’ (need), and ’would you be willing to/would you like. . . ’ (request).

The content must be as free from interpretations as possible, instead expressed in a neutral ’observation anguage’. Feelings, which are functions of the states of satisfaction of various needs, must be identified, named, connected with, and expressed without interpretation. Needs must be distinguished from strategies(strategies include objects and parameters while needs do not). Requests are aimed at assessing how likelyone is to get cooperation for particular strategies for meeting one’s needs; requests should be concrete and specific. Pandemic-specific examples are left as an exercise for the reader. With regard to therapeutics research, it might be worth a try to organize a conference whose participants would be required to find at least one detail they could agree on and then build on that foundation.

Considering that the communications at times appeared hopelessly dysfunctional, more potent methods are likely also needed. To a large extent, the damage associated with the pandemic was not caused by the virus itself but by a preexisting societal conditioning to fixed beliefs and subconscious biases which eventually led to disorganized and dissociative behavior. This ’inflexible disorganization’ subsequently created a massive amount of additional anxiety, burnout and depression.

Psychedelic therapy, currently maybe the second most trendy research subject after COVID-19 itself, wouldlend itself well for resolving these issues [399,400,401,402,403,404]. Psychedelics are likely the most effectivefacilitator of inspection of subconscious biases and fixed beliefs, and as such a valuable tool especially forscientists. Smaller doses may be preferable; this practice is called psycholytic therapy. It differs from the so-called ’microdosing’ in that doses are typically approximately a half or a third of a regular dose, and the effects of the substance are clearly perceived but different from those of high-dose psychedelic therapy.

Subconscious biases could be said to be a type of dissociative phenomena, in which a trigger related to a previous experience of overwhelming trauma triggers a slight dissociation, or a ’defence mechanism’. The mechanism of action of psychedelics in this case, in short, is to enable a person to relive the traumatic experience in order to neutralize the trigger. This must be done in an environment which provides thenecessary support so that the experience would not be experienced as overwhelming once again, as that would constitute a retraumatizing experience. Although various psychedelics produce slightly different effects, all of them would be useful for this kind of work. This includes also substances not always considered psychedelics,namely MDMA which is often called an ’empathogen’, and ketamine, often called a ’dissociative’.

Thus, an available pharmacological method would be off-label ketamine [405,406,407]. A trial by Federet al. compared treatment of post-traumatic stress disorder with either midazolam or ketamine (n=30)(NCT02397889) [408,409,410]. The mean score on the clinician-administered PTSD Scale for DSM-5(CAPS-5) was reduced from 40.1 to 33.2 in the midazolam group, and from 41.9 to 22.5 in the ketaminegroup. A similar reduction was observed for depressive symptoms.

A recent example of conflict resolution through altered states of consciousness, with promising results, was an attempt to alleviate the Israeli-Palestinian conflict by organizing ayahuasca group ceremonies [411].

The essence of psychedelic therapy, however, are not the molecules but the ’states of consciousness’, or states of mind, or emotional states, reached with the help of the molecules; change, progress or ’healing’ happens in or through these states. The same states may also be reached by other methods, although psychedelics provide a shortcut in situations in which there is a lack of time, skill or resources; the cost-effectiveness of psychedelic therapy is typically superior to other methods.

Non-pharmaceutical methods capable of inducing altered states include holotropic breathwork developed by Stanislav and Christina Grof [412]. Holotropic breathwork consists of continuous forceful circular breathing,combined with some bodywork and other techniques for guidance. The breathing technique leads to changes in oxygenation and typically to altered states of consciousness with the potential of resolving embodied traumatic experiences or opening new perspectives to overcome fixed beliefs. Grof developed the method as an alternative to LSD therapy sessions and has described the states and results as similar. A gentler approach from Buddhist traditions, also applicable to trauma therapy, is the Ch¨od method based on visualization[413,414].

The Wim Hof method is applicable for innate immune system enhancement [415]. In 2014, Kox et al.proved that sympathetic nervous system and immune system can be voluntarily influenced, and that itis possible to attenuate the innate immune response in humans [416,417]. Healthy volunteers practicing specific breathwork (hyperventilation), meditation and cold exposure techniques exhibited profound increases in the release of epinephrine, which in turn led to increased production of anti-inflammatory mediators and subsequent dampening of the proinflammatory cytokine response elicited by intravenous administration ofbacterial endotoxin. The Wim Hof method has numerous advantages: it is free, available to everyone,unlikely to produce adverse effects, and unconnected to health care systems and clinicians.

Conclusions

Similarly to SARS-CoV-2 virus emerging as a possibly inexhaustible source of ever more infectious variants,the issue of COVID-19 treatments emerged as a possibly inexhaustible source of increasingly complex epistemological challenges. Current best practices of clinical trial result meta-analysis were found to be unsound;methodological changes were proposed. More broadly, the whole approach based on sole reliance on single agent clinical trials that no-one really wanted to fund appeared fundamentally unsound. The pandemic also revealed various severe problems with mindsets and subconscious biases; methods to overcome these issues were also proposed. The impression of the ivermectin controversy as a whole was that what is ideally understood by science will remain out of reach if scientists are riddled with subconscious biases, methodologies are fundamentally unsound, commercial interests dominate, and the behavior more closely resembles tribal warfare than a silent meditation retreat.

Authors’ contributions

The author was responsible for all aspects of the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The author declares that he has no competing interests.

Author details

Independent researcher, Helsinki, Finland. ORCID iD: 0000-0002-8575-9838

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An extension to a previous timeline covering April 2020–March 2021. The new timeline covers the period from April 2021 to June 2021.

Read the timeline by going to the source link.

The final discussion and conclusion is copied below.

Topics:

WHO's role and its funding, Gavi, COVAX, Trusted News Initiative, International Fact-Checking Network, the role of private philanthropy, Frontiers issue, comparison to the H1N1 pandemic, new treatment protocols, causal modeling.

Introduction

Ivermectin is a multifaceted medication invented in collaboration between Japanese professor emeritus Satoshi ¯ Omura from Kitasato University and US researcher William Campbell from Merck & Co/MSD between 1973 and 1979 [1];[2]. Each of them received one quarter of the 2015 Nobel Prize in physiology or medicine for their discoveries [3]. Ivermectin is best known as an antiparasitic agent, with approximately four billion doses having been administered since 1981, predominantly in Africa. Merck &Co/MSD’s patent expired in most countries in 1996, and ivermectin preparations are currently available internationally from many sources, with the production cost of a single dose estimated to be less than0.1 US dollars [4].

This article extends the timeline of ivermectin related-events described in a previous preprint available in two versions, March 30, 2021 and April 3, 2021 [5];[6]. The latter preprint covered the period from April 1, 2020 to March 31, 2021. This preprint extends the timeline to cover April–June 2021, as well as adding a few earlier events. Some caveats of the review are described in the previous preprint. Due to resource limitations, details of many developments are not covered in detail but only mentioned briefly,and omissions have been unavoidable. The focus of this review entails the social, organizational, financial and legal aspects of the situation with ivermectin, with less emphasis placed on presenting clinical trial results and biomedical research.Some of the main events in the previously covered period from April 2020 to March 2021 were an Australian in vitro study which initiated the interest in ivermectin [7]. This was followed by adoption of ivermectin in several South and Central American countries, the state of Uttar Pradesh in India, and Bangladesh in the second and third quarter of 2020. In late October 2020, the Front Line COVID-19Critical Care Alliance (FLCCC) published its ivermectin-based outpatient protocol called I-MASK+ [8];[9];[10].

A month later, another group called CovidAnalysis begun publishing a meta-analysis of ivermectin trials [11] and a list of ivermectin studies [12]. A main event in December 2020 was the US Senate hearing of Pierre Kory of the FLCCC [13]. The hearing raised interest of Lawrie et al. and Bryant et al. who produced additional meta-analyses [14];[15]. In conjunction, another group called British Ivermectin Recommendation Development (BIRD) was founded.

Another main event was the introduction of a preprint of a Unitaid/WHO-funded meta-analysis by Hillet al. [16]. Yet another notable event was the publication of an extensive review by a Japanese group including the discoverer of avermectins, the Nobel prize winner Satoshi ¯ Omura [2];[17].

In the first quarter of 2021, ivermectin had been adopted in several additional countries including Slovakia as the first European Union member country. However, in March 2021 both the European Medicine Agency (EMA) and the World Health Organization (WHO) advised against the use of ivermectin except in clinical trials, ignoring the various meta-analyses and the results of 26 existing randomized clinical trials, in addition to a similar amount of observational trials and other studies.

The majority of indications and the safety of ivermectin have been described in the previous preprint [6].In addition, in April 2021 ivermectin was found to effectively inhibit hepatitis E virus replication [18]. There is also a relatively large amount of research about the treatment of cancers with ivermectin [19][20][21][22][23][24][25], including breast cancer [26][27][28][29][30][31][32], ovarian cancer [33][34][35][36][37][38][39], cervical cancer [40], oesophageal squamous cell carcinoma [41], renal cancer [42], glioma [43][44][45], nasopharyngeal carcinoma [46], melanoma [47][48], gastric cancer [49][50], liver cancer [51] and leukemia [52][53] (list from [54]).

Recently, mass distribution of ivermectin has been studied for prophylaxis of malaria [55];[56];[57]. Ivermectin has also been found to promote wound healing partly through modulation of the inflammatory process and the levels of transforming growth factor beta 1 (TGF-β1) and vascular endothelial growth factor (VEGF) [58]. Ivermectin has also been proposed for the treatment of autoimmune disorders [59].

Omura has characterized ivermectin as “a panacea for resource-poor communities” [60]. Ivermectin has also been said to “continue to surprise and excite scientists, offering more and more promise to help improve global public health by treating a diverse range of diseases, with its unexpected potential as an antibacterial, antiviral and anti-cancer agent being particularly extraordinary” [61]. Possible issues include environmental toxicity [62];[63] and the emergence of ivermectin resistance [64].

April 2021...

Read the timeline by going to the source link. The final discussion and conclusion is copied below.

Discussion

In the United States and the European Union, most of the year 2020 appeared to have been characterized by an attempt to collect ivermectin-related data. The period from the beginning of November 2020 tothe end of March 2021 appeared to be characterized by disputes about interpretation of this data. The change of administration in the United States did not appear to significantly change its ivermectin-related health policy, likely to the disappointment of ivermectin proponents. Beginning from the March 30 guideline decision by the WHO against ivermectin, a period of a kind of trench warfare appeared to emerge. Ivermectin proponents, especially the FLCCC, announced they had resigned their attempts to influence the US National Institutes of Health, the Food and Drugs Agency, the European Medicines Agency and the World Health Organization. Similarly, the BIRD group turned directly to clinicians and the public. Changes to existing treatment protocols were mostly minor. Fluvoxamine emerged as an option and was added to many protocols including the FLCCC’s. The FLCCC introduced two new protocols: the I-MASS protocol for mass prophylaxis and the I-RECOVER for long haul COVID-19syndrome (LHCS). An interesting new development was the recognition of the role of mast cell activation and histamine release in LHCS [456].

The US NIH announced a new trial, ACTIV-6, for repurposed medicines, estimated to finish in March2023, almost two years in the future, rendering the trial practically irrelevant for the purposes of handling the pandemic. Simultaneously, pharmaceutical companies continued their attempts to finish their trials of new outpatient treatment pharmaceuticals as swiftly as possible, and new projects for the development of such treatments were initiated in the US and the UK.

A third concurrent process was the slower-than-expected progress of vaccination programs. A fourth concurrent process was the adoption of ivermectin in countries outside the US and EU. The countries who had adopted ivermectin previously, including Slovakia, implicitly disregarded the March 2021 guideline set by the WHO [171];[457]. India adopted ivermectin nationally after the announcement of the WHO guideline, then mostly dropped it, with the current situation being somewhat unclear. Legal action against the WHO was initiated in India. At the end of the period, Indonesia adopted ivermectin.With regard to researchers and clinicians, medical professionals whose practices appeared to be predominantly based on following existing regulations and protocols appeared to feel criticism against them unjustified and unfair. Similarly, medical professionals whose interest was in the further development of the protocols felt criticism against them unjustified and unfair. The first group may have perceived the latter group as deviants, whereas the latter group may have perceived the first group as anti-innovative.Presumably, both groups saw each others’ practices as somewhat unethical and antisocial. The difference was possibly due to different perspectives on collegiality and the perception of the role of patients. The first group appeared to put more weight on collegial cohesion and rule-adherence, with less weight put on individual patient outcomes, assumedly perceiving that patient outcomes were predominantly the product of the inflexible regulations which lay beyond their responsibility. The second group appeared to put less weight on collegial cohesion and regulations, placing more weight on individual patient outcomes, assumedly perceiving that patient outcomes superseded the rules and that validation of rules was the responsibility of individual clinicians.

With regard to COVID-19, knowledge about the mechanisms and treatments was somewhat scarce especially in the early phase of the pandemic. A recent study described that in such a situation, it would be adaptive to seek further information to resolve uncertainty and obtain a more accurate worldview but biases in such information-seeking behavior could contribute to the maintenance of inaccurate views [458].

The study indicated that more dogmatic individuals were less likely to seek out new information to refine an initial perceptual decision, leading to a reduction in overall belief accuracy despite similar initial decision performance. In addition, dogmatic participants placed less reliance on internal signals of uncertainty, rendering them less likely to seek additional information to update beliefs derived from weak or uncertain initial evidence. Dogmatism is often defined as a viewpoint or system of ideas based on insufficiently examined premises. Thus, differences in openness to research evidence may have been due to differences in personalities and habits which, in turn, may be seen as products of the life experiences(environments) of the individuals, including their medical education.

At times, the views appeared to differ up to a point in which the existence of a shared reality could be questioned, and the practice of presenting opposite conclusions on the same, existing data was in effect making further research irrelevant.

Validity of statistics-based research

In the context of clinical trials, the fundamental validity of the statistics-based research in general is rarely discussed. In 2011, Penston said that the extent and depth of the criticisms of statistics-based research usually comes as a surprise to investigators, doctors and other health care professionals who use the data from large-scale RCTs and epidemiological studies, as they rarely have the time, inclination and skill to read the related literature [459]. He questioned the large size of a study as a sign of strength,saying that as the number of patients recruited to a study increases, statistical significance may be achieved but causal inference is weakened, adding that the source of the problem was the belief that causal relationships of value can be derived from extremely heterogeneous samples. He also said that the methodology of statistics-based research cannot be tested independently of statistics; therefore it is unknown whether the causal inferences drawn from the data of large-scale RCTs and epidemiological studies are valid. According to him, lack of understanding of diseases and the properties of drugs, i.e.ignorance, were driving up the size of studies, and we had witnessed “an inexorable increase in the size of epidemiological studies and RCTs over the past 50 years without any concern for the consequences”.

Saint-Mont discussed the effect of randomization, detailing various false assumptions related to it, concluding that randomization does not lift experimental procedures in the medical and social sciences to the level of classical experiments in the natural sciences but may lull researchers into a false sense of security instead [460]. Both Saint-Mont and Penston stressed the importance of the existence of sound background theory as crucial for the success of science. Theory allows for stricter definitions of concepts and the identification of homogeneous reference classes that ensure regularity and, hence, reliable causal inference. In the context of COVID-19, the FLCCC appeared to present their conclusions more in the context of background theory (especially the MATH+ protocol [77]), while most others appeared to relymore on statistics.

An alternative or adjunct to RCTs to investigate could be causal modeling [461];[462];[463];[464]. According to Sgaier et al., causal modeling allows testing for causality in individuals and population groups faster and more efficiently, along with the ability to unravel the underlying complexity, and allows researchers and program designers to simulate an intervention and infer causality by relying on already available data [461]. Karvanen has provided examples of causal models for a case-control study,a nested case-control study, a clinical trial and a two-stage case-cohort study [463].

Journalistic ethics

With regard to journalistic ethics, the censorship discussion of April 11 appeared to indicate that journalistic principles that should have been self-evident no longer were, such as the responsibility of the media “to tell the truth” [165]. As described already for the period preceding April 2021, the financial press (e.g. the Wall Street Journal [163] and the Financial Express [171]) seemed to be more in favor of repurposed medicines, whereas the generalist press mostly continued to ignore or oppose them [217]. MacLeod has written about practices of the mass media in the United States, stating that corporate shareholders have no interest in the veracity of the news, only in short-term profits, and that reporting that challenges corporate profits is strongly discouraged [465]. A key factor shaping the content of the media is its reliance on advertising from large businesses for revenue. Advertisers wish to appeal to the groups and individuals with a greater spending power and to avoid controversial and critical content. Also, the collapse in advertising revenue in the traditional media has led to an increasing dependence on official sources, government and corporations which effectively subsidize the media by providing free content but expect something in return. In addition, in many cases, journalists are preselected based on their obedience to authority and their credulousness, and they increasingly come from the elite themselves [466]. The media houses also depend on social media for visibility which may be easily denied of them. Yet another factor are ideologies which in the United States were traditionally anti-communist but more recently anti-Trump and anti-Russian, for example. In the US media, ivermectin was often associated with hydroxychloroquine, and hydroxychloroquine with president Trump [467].

The dismissal of ivermectin in the press appeared to be related to the Trusted News Initiative (TNI) founded by Associated Press (AP), Agence France-Presse (AFP), British Broadcasting Corporation(BBC), Canadian Broadcasting Corporation (CBC), European Broadcast Union (EBU), Facebook, Financial Times, First Draft, Google, YouTube, The Hindu, Microsoft, Reuters, Twitter and Washington Post [321]. TNI appeared to function as some kind of peer-to-peer structured censorship mechanism.

Social media fact-checkers

In its COVID-19 medical misinformation policy, YouTube explicitly forbade treatment misinformation including “content that recommends use of ivermectin or hydroxychloroquine for the treatment of COVID-19” and “claims that ivermectin or hydroxychloroquine are effective treatments for COVID-19” [468]. The policy forbade also a large amount of peer-reviewed medical publications, in effect making YouTube an anti-science organization.

In a similar manner the policy forbade “prevention misinformation”, explicitly defined as “content that promotes prevention methods that contradict local health authorities or WHO”, specifically mentioning“content that recommends use of ivermectin or hydroxychloroquine for the prevention of COVID-19”. It also explicitly disallowed discussions of efficacy and possible adverse effects of vaccines which “contradict expert consensus from local health authorities or WHO”. Also diagnostic, transmission, social distancing and self-isolation information contradicting local health authorities or WHO were banned. The definitions of “expert” and “consensus” remained undefined, making the policy arbitrary, subsequently making YouTube an unpredictable promoter and enforcer of possibly arbitrary or authoritarian practices. In addition, technically, where local health authorities and WHO disagreed, application of the “or” operator banned content contradicting with either of them. Therefore in countries such as Slovakia and India,YouTube could not be used for content that recommended either for or against ivermectin for prophylaxis of COVID-19.

Clarke mentioned that YouTube and Facebook were relying on third party fact checkers funded partly by Charles Koch Institute [373];[374];[372]. Koch was listed as one of the 18 major funders of Poynter Institute, each with an undisclosed sum of at least USD 50,000, making it impossible to compare funders’ contributions [469];[470]. The International Fact-Checking Network (IFCN) is a unit of the Poynter Institute [471]. In May 2020, Facebook stated that all of its fact-checking partners were certified byIFCN [472]. IFCN stated it led an alliance of over 100 fact-checkers [473]. Poynter Institute described that the alliance was launched in January in response to “rampant misinformation globally” which the WHO classified as an “infodemic”, with the alliance “on the front lines in the fight against it”.

IFCN and the alliance also maintained a database of checked facts [474]. The database was updated daily, with members collaborating on the “massive crowdsourcing project” by using a shared spreadsheet and instant messaging apps. Poynter said the international collaboration had allowed the members to respond faster and reach larger audiences. All of the over 80 items found in the database with search term “ivermectin” dated between April 2020 and May 2021 were labeled either as no evidence, unproven, exaggerated, misleading, missing context, partly false, or false (the most common label), with two items labeled as explanatory [474]. Most of the items originated from South American partners such as Estadão Verifica in Brazil.

Some of the other major funders of Poynter included Facebook, Google News Initiative [475], Foundationto Promote Open Society (FPOS) of George Soros, a primarily US government funded agency National Endowment for Democracy (NED) [476], Democracy Fund created by eBay founder Pierre Omidyar, funding especially PolitiFact [477], and the Omidyar Network/Luminate also of Omidyar, Craig New-mark Foundation of Craigslist founder Craig Newmark, with at least USD 6 million donated to PoynterInstitute [478], and Rita Allen foundation involved in medical research, with its stated goal of “investing in transformative ideas in their earliest stages to promote breakthrough solutions to significant problems” [479].

It was of note that the major funders of Poynter included several individuals who were billionaires. Assumedly, they may have possessed influence over guidelines for what qualified as “facts”. While there was not enough information to ascertain whether the observed patterns of social media censorship were related to the values and previously observed practices of the any of the funders specifically, it was also not possible to rule out such influences.

An example may illustrate what kind of issues may arise from the use of donations as a tool for gaining political influence. With regard to funding by Koch, a report by Mayer in the New Yorker described the Koch brothers as “longtime libertarians who believe in drastically lower personal and corporate taxes,minimal social services for the needy, and much less oversight of industry .. . their combined fortune of thirty-five billion dollars is exceeded only by those of Bill Gates and Warren Buffett . . . many of the organizations funded by the Kochs employ specialists who write position papers that are subsequently quoted by politicians and pundits. David Koch has acknowledged that the family exerts tight ideological control. ‘If we’re going to give a lot of money, we’ll make darn sure they spend it in a way that goes along with our intent .. . and if they make a wrong turn and start doing things we don’t agree with, we withdraw funding’ ” [480];[481].

A republican political consultant commenting Kochs’ strategies for opposing climate change related oil industry reforms said that “the key .. . was to question the science – a public-relations strategy that the tobacco industry used effectively for years to forestall regulation”. As an example of health related interests, David Koch had served on the US National Cancer Advisory Board without disclosing his conflicts of interests as a major producer of formaldehyde, while simultaneously lobbying to prevent theUS Environmental Protection Agency (EPA) from classifying formaldehyde as a carcinogen, and funding members of Congress who had stymied the EPA, requiring it to defer new regulations until more studies would be completed.

Mayer’s article described Kochs’ operations as “covert”, referring to David Koch’s description of their businesses as “the largest company that you’ve never heard of”. According to Source Watch, in addition to denying climate change, other issues on the Kochs’ agenda included repealing health reform Obamacare), dismantling collective bargaining rights, fighting reductions in carbon emissions, keeping corporate money in elections and fighting internet neutrality [482];[483]. With regard to COVID-19, Koch Industries were producing test kit materials, sanitizers, alerting systems, healthcare IT systems related to COVID-19diagnostic testing, ventilators, and personal protective equipment [484].

Poynter’s largest custom training partners in 2019-2021 included Facebook, Huffington Post, Market-place, MRC Media, Middle East Broadcasting Networks, National Public Radio (NPR), Newsweek, New York Times, Southern Newspapers Publishers Association, Washington Post, TikTok, USA Today Network, Vice and Voice of America [469].

Academic journals

Regarding the academic journal publisher Frontiers Media SA’s, one of the members of its board of directors responsible for the financial and governance oversight of the company was Steve Koltes, founder and co-chairman of CVC Capital Partners Ltd [485]. In 2019, CVC Capital Partners, one of the world’s largest private equity and investment advisory firms, was said to have USD 75 billion of assets under management [486]. CVC announced that a group of its executives had helped fund University of Oxford’s vaccine research [487];[488]. CVC had also invested in System C, a company providing key software being used for planning and managing the UK’s COVID-19 vaccination programme [489]. The Times described CVC as “powerful, successful and extremely low profile” [490].

In 2015, Frontiers had removed 31 editors after the editors had complained that company staff were interfering with editorial decisions and violating core principles of medical publishing [491].

The WHO

During the period, an intensifying critique of the WHO emerged as a result of the March 2021 ivermectin guideline lacking transparency and breaking established practices of meta-analysis and research.Presenting criticism towards the feasibility of the vaccines-only approach and its possible relationship to financial interests of the pharmaceutical industry, or possible failures of entities such as WHO, FDA,NIH and EMA, has been difficult during the pandemic. Regardless, it is necessary to consider whether funding-related biases might exist with regard to the current practices of these agencies, especially the WHO.

First we may note that the main funders of the WHO for the 2018/2019 biennium were United States(USD 893 million), Bill and Melinda Gates Foundation (USD 531 million), United Kingdom (USD435 million), Gavi The Vaccine Alliance (USD 371 million), Germany (USD 292 million), Japan (USD214 million), UN Office for the Coordination of Humanitarian Affairs (UNOCHA) (USD 192 million),Rotary International (USD 143 million), World Bank (USD 133 million), European Commission (USD131 million), National Philanthropic Trust (USD 108 million), Canada (USD 101 million), China (USD86 million), Norway (USD 86 million), UN Central Emergency Response (USD 86 million), Sweden (USD77 million), France (USD 76 million), Kuwait (USD 70 million), Republic of Korea (USD 70 million) and Australia (USD 67 million) [492];[493];[494].

The Bill and Melinda Gates Foundation stated that its focus was on vaccine equity [307]. Also Gavi The Vaccine Alliance had been founded by the Bill and Melinda Gates Foundation in 1999, and the Gates foundation had invested a total of USD 4 billion in Gavi [495]. Gavi described the Gates foundation as“a key Gavi partner in vaccine market shaping”. The Gates Foundation also had long-term partnerships with Rotary International (polio vaccinations), National Philanthropic Trust, and the World Bank. Together, the USD 902 million contributions of the Gates Foundation and Gavi exceeded the United States contributions of USD 893 million, making the Gates-Gavi cluster the largest funder of the WHO in the2018/2019 biennium (in April 2020, president Trump announced that US halted funding to the WHO; the effects of this remained unclear [496];[497]). In addition, the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) contributed 33 million. Co-founded by the Bill and Melinda Gates Foundation in 2002, the foundation has contributed a total of USD 2.49 billion to GFATM [498]. Considering the recent USD 4 billion donation by the United States government to Gavi [89], one interpretation of the situation might be that the US outsourced a large part of its public health policy setting to Gavi and, subsequently, to Gates.

Yet another member of the Gates cluster was the Seattle-based PATH (Program for Appropriate Tech-nology in Health), one of the largest nonprofit organizations in global health [499]. In 2021, its website presented with a banner saying “600 million people are vaccinated. 7 billion haven’t had a shot. Help PATH today”. PATH’s CEO Nikolaj Gilbert, previously the global partnerships director for the United Nations Office for Project Services (UNOPS) and an employee of Novo Nordisk, described PATH’s priorities: “the partnership with the Bill and Melinda Gates Foundation and the U.S. government has shaped what this organization is all about today .. . so one of my key priorities will be to see: how can we sustain and grow those relationships that we have, how can we continue to be the preferred partner for those donors, and how can we also help them with their priorities?” [499].

A 2017 Politico article described Gates as “the world’s most powerful doctor”, saying his sway over the WHO spurred criticism about misplaced priorities and undue influence [500];[501]. The article quoted Gates’ critics saying that “Gates’ priorities have become the WHO’s . .. he is treated liked a head of state,not only at the WHO, but also at the G20”. Top WHO officials were said to have raised concerns that the foundation was distorting research priorities. Over three quarters of the WHO’s budget was coming from voluntary contributions which were usually earmarked for specific projects or diseases so that the WHO could not freely decide how to use them. The article stated that the Gates foundation’s focus on delivering vaccines and medicines, rather than on building resilient health systems, had drawn criticism.Changes had been made to the WHO’s budget approval process to in order to decrease the foundation’s influence. Yet a senior fellow for global health at the Council on Foreign Relations commented that “the foundation’s impact on the WHO is enormous . . . if they weren’t there, if they walked away with their money, the deleterious impact would be profound, and everyone is all too aware of that”.

Importantly, it should also be noted that the other top 20 funders predominantly represent high-income countries of the North America and Europe. None of the countries that had officially adopted ivermectin country-wide for COVID-19 up to April 2021 were represented [502]. Similarly, Coalition for Epidemic Preparedness Innovations (CEPI), an organization aiming to accelerate the development of vaccines against emerging infectious diseases and enable equitable access to these vaccines for people during outbreaks was founded by the governments of Norway and India, Bill and Melinda Gates Foundation, UK Wellcome Trust, and the World Economic Forum [503]. It had later secured financial support from Australia, Austria, Belgium, the Bill and Melinda Gates Foundation, Canada, Denmark, the European Commission, Ethiopia, Finland, Germany, Hungary, Iceland, Indonesia, Italy, Japan, Kuwait, Lithuania, Luxembourg, Malaysia, Mexico, Netherlands, New Zealand, Norway, Panama, Romania, Saudi Arabia,Serbia, Singapore, Switzerland, The Republic of Korea, United Kingdom, USAID, and UK Wellcome Trust. Of these countries, as of June 2021, ivermectin had been officially adopted in Mexico, Panama and Indonesia, as well as mixed use or occasional off-label use in some other countries [502].

Additionally, CEPI had received support from undeclared private sector entities as well as public contributions through the UN Foundation COVID-19 Solidarity Response Fund [503]. Each investor was to get one representative to an Investors Council providing guidance and oversight of CEPI activities, with four members serving on the CEPI board. Another entity, a Joint Coordination Group, was intended to discuss how to best enhance CEPI’s efforts to deliver and deploy vaccines, and had a role in planning for rapid response to a priority pathogen or an unknown pathogen. The Joint Coordination Group included the WHO, Gavi, European Medicine Agency (EMA), United States Food and Drug Administration Agency (FDA), Médecins Sans Frontières (MSF), UNICEF, International Federation of Red Cross and Red Crescent Societies (IFRC), African Vaccine Regulatory Forum (AVAREF), UK National Institute for Biological Standards and Control (NIBSC) and UK Wellcome Trust.

The Wellcome trust had been previously found out to secretly invest in companies that contributed to the same problems the trust said it wanted to solve [504]. The trust’s known investments through offshore companies in the Cayman Islands amounted to USD 891 million in 2018.

In 2010, the Bill and Melinda Gates Foundation, Gavi, WHO, US NIH/NIAID, CDC, UNICEF, PAHO and several research organizations launched a Decade of Vaccines collaboration, initiated by the Gates Foundation [505]. The intention was to enable greater coordination across all stakeholder groups – national governments, multilateral organizations, civil society, the private sector and philanthropic organizations. The five-member leadership council included the director general of WHO, Anthony S. Fauci of the National Institute of Allergy and Infectious Diseases (NIAID), executive director of UNICEF, an representative of African Leaders Malaria Alliance, and the president of global health at the Bill and Melinda Gates Foundation. All the relevant organizations had thus intimately and for the long term participated in the vaccine-centric collaboration initiated by Gates.

According to a recent study, in 2020, governments had spent a total of EUR 93 billion on COVID-19 vaccine and therapeutics development projects, with 95% allocated to vaccines and 5% on therapeutics [506]. 32% of the funds came from the US, 24% from the EU, and 13% from Japan and SouthKorea (a total of 69%). Only 7% of funds were preferred loans or conventional grants. 93% were advance market commitments (AMCs), i.e. binding agreements to subsidize purchases of vaccine doses prior to availability. Interestingly, 71% of the vaccine funding was allocated to Small and Medium Enterprises(SMEs) and MidCaps, with only 18% allocated to large pharmaceutical manufacturers. The figures did not include private sector investments.

The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership program initiated by the US National Institutes of Health aimed at developing a coordinated research strategy for prioritizing and speeding development of the most promising treatments and vaccines [228]. Its public partners included Biomedical Advanced Research and Development Authority (BARPA), Centers for Disease Control and Prevention (CDC), Department of Defense, Department of Veterans Affairs,European Medicines Agency (EMA), National Institutes of Health (NIH), The Operation (formerly known as Operation Warp Speed), and US Food and Drug Administration (FDA). Industry partners included AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Dewpoint Therapeutics, Eisai, Eli Lillyand Company, Gilead, GlaxoSmithKline, Johnson & Johnson, Merck & Co/MSD, Moderna, Novartis,Novavax, Pfizer, Rhythm Therapeutics, Roche-Genentech, Sanofi, Takeda, and Vir Biotechnology. Nonprofit partners included Bill and Melinda Gates Foundation, Fred Hutchinson Cancer Research Center,Foundation for the National Institutes of Health, and RTI International.

According to the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), as of February 2021, there were approximately 382 vaccine candidates in development, of which 24 in Phase I, 34 in Phase II and 23 in Phase III [507]. In addition to vaccines, there were over 1,000 clinical trials for therapeutics, of which 190 in Phase III. For example, Eli Lilly and Company and the Bill and Melinda Gates Foundation had entered into an agreement to facilitate access to future Lilly therapeutic antibodies under development, to benefit low- and middle-income countries.

Bill and Melinda Gates Foundation

According to Schwab, in five years up to 2020 the Gates Foundation had invested at least USD 250 million in companies that were currently working on COVID-19 vaccines, therapeutics, diagnostics or manufacturing [508];[509]. He also noted that Wellcome Trust had invested at least USD 1.25 billion to COVID-19 related industries [510]. Both funders were thus positioned to potentially gain from the pandemic financially. Wellcome’s director had a position on the Scientific Advisory Group for Emergencies advising the UK government on COVID-19, as well as a board seat on the Coalition for Epidemic Preparedness Innovations (CEPI). Earlier, the UK’s Scientific Advisory Group for Emergencies had failed to publicly disclose competing interests related to COVID-19. A Canadian professor emeritus of health policy and management commented that the funders were assumedly “acting the way they always have .. . looking after their own financial interests [and] pursuing their own privately developed objectives without being responsible to anybody but their own boards of directors”. Schwab said that despite the outsize role of the private charities in the pandemic response their financial interests had been little scrutinized, likely because foundations were not subject to the same oversight mechanisms as public institutions. A professor of sociology in the UK commented that the foundations were giving a false ideological impression that they are solving the problem even when they’re not.

The Gates foundation had also donated almost USD 2 billion to for-profit businesses, including USD 89 million to Novavax Inc., USD 65 million to GlaxoSmithKline Biologicals, USD 63 million to Evotec and Just Biotherapeutics, USD 61 million to Biologial E. Limited, USD 53 million to LG Chem Ltd., USD43 million to Dimagi Inc, USD 40 million to Inventprise, USD 38 million to Bharat Biotech International Ltd., USD 37 million to Janssen Vaccines and Prevention BV, and USD 35 million to AJ VaccinesAS [510]. Schwab claimed the foundation was subsidizing private companies’ research costs, opening up markets for their products, and bankrolling their bottom lines. He also claimed the foundation had funded groups pushing for industry-friendly government policies and regulation, including the Drug Information Association. He was also said to have funded nonprofit think tanks and advocacy groups that wanted to limit the role of government or direct its resources toward helping business interests. Schwab also noted that despite having given away USD 23.5 billion in the last five years up to 2020, Bill and Melinda Gates Foundation’s income from its investments had exceeded USD 28.5 billion in the same period [510].

Other commentators asked whether the Gates Foundation was addressing or reinforcing systemic problems raised by COVID-19, citing lack of transparency, dogmatic defence of intellectual property rights and monopolies, and intimate involvement with large pharmaceutical corporations as the main issues [511]. A 2016 report by Curtis gave details about Microsoft’s tax avoidance practices and its monopolistic nature, the foundation’s excessive global influence and support to various questionable practices including industrial agriculture with patented genetically modified seeds, Gates family’s “considerable personal access to senior levels of the WHO”, Gavi’s alleged overpaying for vaccines leading to excessive increases in vaccine prices, Gates’ dismissal of the issue, and the foundation’s agenda skewing health priorities and distorting health programmes [512]. Curtis wrote that one problem with the foundation’s heavy focus on developing new vaccines was that it detracted from other, more vital health priorities such as building resilient public health systems. As a rationale, Gates was said to have provided the following: “Vaccines are an extremely elegant technology. They are inexpensive, they are easy to deliver, and they are proven to protect children from disease. At Microsoft, we dreamed about technologies that were so powerful and yet so simple.. . all 193 member states, you must make vaccines a central focus of your health systems”. Curtis commented that Gates had “a fixation on vaccines”. He also claimed the foundation was stifling criticism through its media and NGO influence built on donations. An US professor of media, culture and communications was quoted saying the foundation “wielded enormous propaganda power”. A 2009 editorial in the Lancet, describing the foundation’s governance principle of being “driven by the interests and passions of the Gates family” as “whimsical”, proposed that the foundation should be more transparent and accountable and listen to opinions of external parties [513];[514].

In April 2020, the Bill and Melinda Gates Foundation awarded a five-year grant of USD 50 million to Unitaid to fight against HIV, tuberculosis and malaria, in addition to previous contributions of USD 100 million since 2006. Unitaid’s budget for the year 2021 was approximately USD 32 million [515]. In late 2020, Unitaid partially funded the ivermectin meta-analysis by Hill et al. published as a preprint [16].This meta-analysis was later ignored by the WHO in its March 2021 decision against the use of ivermectin except in clinical trials [6]. On April 22, the chief of Unitaid stressed the need to increase commercialresearch and development of new pharmaceuticals for the treatment of COVID-19 [242]. A core function of Unitaid is Medicines Patent Pool, a tool or practice to negotiate patents for low-income countries; this emphasis may have made unpatentable products seem foreign to the organization [516];[517]. Gates foundation was the chair of Unitaid’s Finance and accountability committee and a member of its policy and strategy committee [518].

Comparing the countries most heavily involved in the development and funding of vaccines to the countries with interest in ivermectin it can be noted that the two sets of countries have little overlap. Also, it can be noted that if influence is related to the amount of funding given, the first set of countries likely had more influence in the WHO in comparison to the rest of the countries.

The WHO, the philanthropic entity Bill and Melinda Gates Foundation, the public-private partnership Gavi, The Vaccine Alliance, and the philanthropic-commercial entity CEPI appeared to be strongly interconnected with each other and with high-income nation states. Major financial investments and commitments likely created propensities for various biases and a vulnerability to the sunk cost fallacy [519]. A haphazard or ideological commitment solely to vaccines (95% of government spending) may have overlooked considerations of cost-effectiveness and feasibility, such as vaccines likely being more expensive and more vulnerable to viral variants than repurposed medicines, their long-term safety being unclear, and vaccines likely requiring constant redevelopment and revaccinations, in addition to not being suitable for self-administration and requiring refrigerated delivery systems. With regard to the sunk cost fallacy, it would be more economical for the governments to reconsider the vaccine and investigative pharmaceuticals dominated pandemic policy and at least adjunct it with broad-spectrum repurposed medicines.

Comparisons to the H1N1 pandemic

After the H1N1 ‘swine flu’ pandemic of 2009-2010, the WHO was accused of malpractice when conflicts of interests of key WHO scientists led to unfeasible WHO recommendations which in turn led to billions of public money spent on inefficacious antivirals for H1N1 influenza [520];[521];[522];[523]. In her book, Abeysinghe has written about the role of the WHO [524]. A review by Andres summarizes keypoints, including the monopoly of the WHO to declare a pandemic [525]. In the case of H1N1, WHO was retrospectively criticized for unnecessarily declaring a pandemic, as for example the European Centre for Disease Control (ECDC) did not agree that the disease should be qualified as severe (measured by mortality), which at the time was considered a requirement for a pandemic but is no longer mentioned. At the time, an epidemiologist commented that the WHO, public health officials, virologists and pharmaceutical companies had “built this machine around the impending pandemic . . . there’s a lot of money involved, and influence, and careers, and entire institutions .. . all it took was one of these influenza viruses to mutate to start the machine grinding” [526].

WHO was later criticized by the Council of Europe for giving too much importance to vaccination and for not sufficiently emphasizing other measures such as the use of antivirals even though some arguments suggested that other measures, such as taking antivirals preventively, could be at least as efficacious as vaccines [525];[521];[522]. WHO emphasized mass vaccination as the most effective strategy against H1N1 [524]. According to Abeysinghe, this emphasis was a result of the path-dependent institutional reaction of the organization, where prior experience with infectious disease (including notable victories using mass vaccination strategies) resulted in the favoring of this reaction, whereas other potential actions were disregarded or underemphasized.

In June 2010, the rapporteur of Council of Europe Parliamentary Assembly described the acts of the WHO as foolish, saying “this is not going to go away” [524]. The rapporteur assumedly meant the criticism was not going to go away; yet it appears instead that the organizational patterns did not go away, leading the WHO and the national governments to repeat the same issues a decade later in theCOVID-19 pandemic.

Legal responsibility of public-private partnerships and the WHO

Clarke has noted that the regulation of global health has partially shifted from the hands of states and international organizations into the hands of public-private partnerships such as Gavi, The Vaccine Alliance and the Global Fund [527];[528]. These partnerships then become capable of also adversely impacting the rights of individuals, leading to concerns of responsibility under international law. However, the private entities in public-private partnerships typically fall outside the framework of responsibility under international law, and thus cannot be held responsible under it. In addition, in certain instances the partnerships have been granted immunity from the jurisdiction of domestic courts. This immunity applies to the staff, funds, properties and assets of these partnerships. The situation regarding Gavi andthe Global Fund appeared especially complicated and the legal details were therefore considered out of the scope of this review.

With regard to the WHO, Gostin has described WHO’s regulatory powers as extraordinary, noting that it may set regulations on a broad range of health topics including the safety, potency, and advertising of biologicals and pharmaceuticals, and a nomenclature for diseases, causes of death, and public health practices [529];[530]. These regulations, unlike most international law, are binding on member states unless they proactively “opt out”. In addition, also the WHO enjoys several privileges and legal immunities. Regardless of the original purpose of these privileges, the possibility of abuse of these privileges by the WHO also exists. Also here the details were considered out of the scope of this review.

Private philanthropy, society and science

In his recent book, Callahan discussed the role of private philanthropy, noting the rising influence and political significance of elite philanthropy, asking who is making choices over public life and who actually benefits from those choices [531]. Callahan described “today’s era of austerity” as a result of an orchestration of the upper class to reduce its taxes and the size of government, even so that in some US states, cuts to higher education specifically helped finance tax reductions for the wealthy and corporations. He noted that in a decade, Bill Gates and Warren Buffett, the main funders of the Bill and Melinda Gates Foundation, had added USD 25 billion and USD 80 billion, respectively, to their wealth, and that the Koch brothers had increased their wealth from USD 9 billion in 2005 to USD 85 billion in 2015.In a book review, Saunders-Hastings asked whether elite philanthropists are a counterweight to other, self-interested elites or to democracy itself, and noted that the distance between elite “charity” and elite political influence is small and shrinking, and that donors’ motivations matter less than the results of their actions [532].

Broad wrote that due to cuts to public funding and increase in private donations, “American science, long a source of national power and pride, is increasingly becoming a private enterprise” and quoted a policy analyst commenting that “the practice of science in the 21st century is becoming shaped less by national priorities or by peer-review groups and more by the particular preferences of individuals with huge amounts of money” [533].

Callahan proposed putting some curbs in place against the private philanthropy, yet noted that foundations and nonprofit trade groups are strongly against any new restrictions, partly due to their dependency on philanthropy. He noted that “rethinking philanthropic freedom is a Pandora’s box that almost nobody wants to open”, saying the current situation was a result of “yesterday’s mantras about philanthropic freedom and the dated regulation upholding it”.

Vaccines vs repurposed medicines

In Finland, a team led by two leading Finnish professors, Kari Alitalo and Seppo Ylä-Herttuala, had a patent and intellectual property free adenovirus-based nasal spray COVID-19 vaccine ready in May 2020. Despite taking approximately EUR 18 billion of public debt to mitigate damages caused by societal lockdowns and using hundreds of millions of Euros on diagnostic tests only, the Finnish government refused the approximately EUR 50 million needed to fund a phase III patient trial for the vaccine [534];[535].

The above case illustrates that the issue at hand is fundamentally not even about vaccines versus repurposed medicines or new pharmaceuticals versus repurposed medicines. Based on this data it is difficult to say whether it is about excessive adherence to inflexible regulations, subconscious biases present in corporate cultures and individuals, intellectual property enforcement, or intentional misleading for profit; likely, it is a mixture of all these factors. Personal biases, organizational cultures and commercial incentives of the vaccine cluster may have lead to attempts to build near-monopolies mass-producing proprietary but inferior products that outcompete more feasible alternatives. In Finland, significantly less interest has been present for any repurposed medicine than for the patent-free vaccine, with the sole exception of the company which developed the ivermectin-containing nasal spray not yet on the market [356].

More generally, the situation may partly be a result of the unprepared and rushed way in which the pandemic has been handled by the governments. Assumedly, from the perspective of governments with 95% of their funding committed to vaccines and international co-operation led by the WHO, paradigm change inducing innovations from outsiders may be perceived as unwanted disturbances. Considering these paradigms, the dismissal of ivermectin might be perceived as cultural discrimination, an instinctive reaction to avoid unfamiliar ideas. As a result of the chosen policy of vaccines and new pharmaceuticals only, in order to avoid losing the sunk costs and credibility, the interests of the governments and the pharmaceutical industry appeared to align with each other but likely not with the public health interest.

The concept of “regulatory capture” may be described as the agencies tasked with protecting the public interest coming to identify with the regulated industry and protecting its interests against those of the public, with the result of government failing to protect the public [536]. Whether rejection of ivermectin may be seen as an example of “regulatory capture” depends on how the vaccines-only policy was selected: primarily to align with the interests of the pharmaceutical industry, or because a better option could not be imagined. Curiously, options could be imagined early on in many low-income countries, but not in the high-income countries, possibly as a result of “technological capture”: when access to advanced technology exists, every problem looks like a problem to be solved with advanced technology, even though such solutions would be suboptimal due to being overly complex and unnecessarily expensive. For example, the idea of spending tens of billions of dollars per year for testing 20 percent of the global population every week assumedly for a single pathogen (SARS-CoV-2) appeared irrational at best [89]. Gates’s speeches repeated terms such as “war and “battle plan” [537]; these talks may easily be interpreted as priming fear in the public. Gates is also famous for regularly predicting the next pandemics [538].

Since the beginning of 2021 at the latest it should have been obvious that the continuing denial of early treatments could not be characterized either as accidental or as a rational choice with respect to public health interest. During the pandemic, a large part of the medical community seemed incapacitated like an old-fashioned military unit lacking leadership. The model based on the fear of losing medical license and an inflexible hierarchical chain of command appeared unsuitable for ensuring proper care of populations.While denial of treatments for certain illnesses such as drug addictions, post-traumatic stress disorder or “treatment-resistant” depression for years or decades for example by denying funding for the research of psychedelic therapies has become normalized, it was unexpected that in the case of COVID-19 this antisocial behavior on behalf of governments and the pharmaceutical industry would be extended to literally everyone in the world. In a comment suggesting adoption of ivermectin, a patent attorney and a former director of a pharmaceutical company referred to “potential civil/criminal liability for censorship, scientific misconduct for misrepresenting ivermectin and other generics” [387].

The exact causes of the situation remained unclear. Regardless, the consequences remain to be seenand felt. One way forward might entail the majority of governments halting their funding to the WHOin order to dissolve the whole organization which appeared beyond repair. Another necessary changemight be the eviction of the so-called philanthropic entities from healthcare contexts. In the long term,another beneficial action might be a worldwide conversion of the pharmaceutical industry into a nonprofit operation. Continuing on the current path may result in a further polarization or destabilization of societies.

Near-future objections to adoption of ivermectin will undoubtedly include the possible environmental impacts. In the mid-to-long term, due to the need to reduce water usage and enable better retention of nitrogen, phosphorus and ammonia [539], transition from water based sewer systems to toilet systems not using water and not requiring wastewater processing but utilizing for example composting and new kind of treatments to degrade pharmaceuticals will become inevitable in many areas in any case.

Conclusions

During this period, ivermectin was officially adopted in South Africa but not widely used, adopted but later dropped in most of India, and adopted in Indonesia. In the United States and the United Kingdom, projects with involvement of both the governments and commercial companies were announced for development of new pharmaceuticals for early outpatient treatment of COVID-19, indicating unclear boundaries between these entities. The dismissal of repurposed medicines including ivermectin continued in high-income countries due to very differing views on what constituted evidence of efficacy. The divide between ivermectin proponents and opposers remained mostly unchanged during the period, indicating a stagnated situation.

There was a noticeable centralization of power, with pandemic response and public discussions largely directed by a few organizations that were largely funded by a few billionaires which, in turn, were affectedby their own personal preferences and biases such as obsessive-compulsive attachment to testing and new technologies, primarily vaccines. Legal responsibilities of these organizations appeared, in the words of one researcher, “obscure”.

Commercial interests appeared to override public health interests during this period. As a result, several low-and-middle-income countries and regions either implicitly or explicitly disregarded the WHO guidance, accelerating an erosion of WHO’s credibility.

Introduction

This article aims at giving an overview of the ivermectin controversy, including current practices of research, publishing and governmental policy formation, by presenting a timeline of relevant events, compiled from peer-reviewed academic journals indexed in PubMed, preprint servers such as medRxiv, chemRxiv, SSRN, Research Square and ResearchGate, international clinical trials registers, international newspapers and medical news service providers as well as websites. As there have been a lot of sparsely documented events internationally, the search has not been systematic, the timeline is unavoidably incomplete, and there may naturally be some personal bias with regard to what has been selected. Also, the main focus of the article is on the last quarter of the 2020s and the first quarter of 2021. Despite these limitations the timeline may serve as a template for more detailed inquiries.

Due to the large number of studies and limited space, each study is mentioned only briefly, without a possibility to analyze methodologies or results in depth. Statistically significant endpoints are reported, with nonsignificant endpoints mostly left out. For consistency, results are in most cases formatted as they appear in a meta-analysis by the Covid Analysis research group, possibly reformulated in comparison to the original sources (e.g. odds ratios converted to relative risk or methodological errors corrected) [1];[2];[3].

Ivermectin was invented in Japan in 1975 by Kitasato University professor emeritus Satoshi ¯ Omura, for which he won the 2015 Nobel Prize in physiology or medicine [4]. The drug has proven effective in eradicating parasitic infections and it is therefore best known as an antiparasitic agent, with several billion doses having been administered since 1981. The patent for the product was owned by Merck & Co/MSD. In most countries the patent expired in 1996. Currently, ivermectin preparations are available internationally from many sources, with the production cost of a single dose estimated to be less than 0.1 US dollars [5].

For prophylaxis of onchocerciasis (river blindness) and strongyloidiasis ivermectin is administered as a single oral yearly dose of 0.15-0.20 mg/kg [6];[7]. For lymphatic filariasis, a once-yearly dose of 0.3-0.4 mg/kg or bi-yearly dose of 0.15–0.2 mg/kg is administered [6]. For classic scabies, two doses of 0.2 mg/kg approximately one week apart are recommended, and for crusted scabies three to seven doses of 0.2 mg/kg depending on the infection severity [8];[9]. With regard to malaria, repurposing ivermectin as a complement to current malaria vector control tools is currently being investigated, with a proposed dosing regime of 0.4 mg/kg repeated three times during the malaria season, and another proposed dosing regime of 0.3 mg/kg on three consecutive days in combination with two other pharmaceuticals also repeated three times during the season [10].

With regard to its in vitro antiviral action, ivermectin has shown robust antiviral action towards a range of RNA and DNA viruses, including HIV-1, dengue, Zika and West Nile Virus, Venezuelan equine encephalitis virus, Chikungunya, pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19) [11]. For dengue virus, a combined phase II/III patient randomized controlled trial (RCT) has been completed[12].

Another recent line of research has been an investigation into ivermectin’s efficacy in cancer. A study found out that ivermectin at a very low dose drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo [13]. Ivermectin could thus be used in combination with chemotherapeutic agents to treat drug-resistant cancers.

With regard to the mechanism of action of ivermectin as an antiparasitic medication, Chung et al. describe that ivermectin interacts with vertebrate and invertebrate γ-aminobutyric acid (GABA) receptor and invertebrate glutamate-gated chloride channels, increasing chloride ion influx with subsequent paralysis and death in the target organism [14]. Ivermectin is effective in killing nematodes and arthropods with a single dose of 0.1-0.3 mg/kg but has has a very wide margin of safety in mammals because in mammals GABA-mediated nerves occur only in the central nervous system and ivermectin does not readily cross the blood-brain barrier [14].

With regard to safety of overdosing, in chickens and most dogs subcutaneous doses of approximately 5 mg/kg have been shown to cause mild symptoms and doses of approximately 15 mg/kg severe symptoms up to coma and death. In two described cases on humans, a 16-month-old child ingesting 6.7 to 8.72 mg/kg ivermectin resulted in frequent vomiting, somnolence, mild tachycardia, and hypotension, and a 61-year old woman became comatose three hours after ingesting 15.4 mg/kg agricultural ivermectin, requiring supportive intensive care but was discharged uneventfully on day 9 [14].

A double-blind, placebo-controlled dose escalation study with 68 healthy volunteers found no indication of central nervous system or general toxicity, or a difference in adverse effects between ivermectin and placebo groups for doses up to 2 mg/kg (ten times the highest FDA-approved dose of 0.2 mg/kg), in either single doses of 90 mg (1.0-1.5 mg/kg) or 120 mg (1.4-2.0 mg/kg), or in a repeated dosing regime with 30 mg (0.35-0.54 mg/kg) or 60 mg (0.71-1.1 mg/kg) on days 1, 4 and 7 (a total of three doses) [15]. Mean plasma concentrations were 2.6 times higher when administered with food.

The FDA-approved dosing for treatment of parasitic diseases is 0.2 mg/kg. The doses used in COVID-19 related clinical trials described in this article varied between 0.2-0.6 mg/kg. With regard to safety of ivermectin in general, a current World Health Organization (WHO) document on the treatment of onchocerciasis states that “ivermectin is safe and can be used on a wide scale” [16]. With regard to safety for children, a recent systematic review and and an individual patient data meta-analysis of ivermectin use in children weighing less than 15 kg concluded that existing limited data between January 1980 and October 2019 suggest that oral ivermectin in children weighing less than 15 kilograms is safe [17]. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported.

With regard to safety of ivermectin during pregnancy, a document from 2004 published by the WHO titled “Mass treatment with ivermectin: an underutilized public health strategy” describes safety during pregnancy, noting that “a number of follow-up studies have found that inadvertent filariasis mass campaign use of ivermectin during pregnancy has not been associated with adverse pregnancy outcomes or negative effects on pregnant women or their offspring”, referring to a study by Gyapong et al. who concluded “there is no evidence of a higher risk of congenital malformation or abortions in those who are inadvertently exposed” [18];[19].

April 2020

On April 3, a Monash University of Australia in vitro ivermectin study by Caly et al. reported that ivermectin is an inhibitor of SARS-CoV-2 virus in vitro, that a single treatment effected approximately 5000-fold reduction in virus at 48 h in cell culture, and that ivermectin is FDA-approved for parasitic infections and included on the WHO model list of essential medicines, thus being widely available [20];[21];[22];[23].

On April 6, a French biotechnology company MedinCell which had been studying ivermectin for malaria announced an initiative to develop an injectable form of ivermectin for prophylaxis of COVID-19 [24];[25];[26].

On April 10, mentioning increased interest in ivermectin after the Australian in vitro study, US FDA issued a warning against using veterinary ivermectin as treatment for COVID-19 in humans, citing safety concerns [27]. It noted additional testing is needed to determine whether ivermectin might be safe or effective in COVID-19 in humans.

On April 13, two Florida, US pulmonologists Rajter and Cepelowicz-Rajter were said to be pioneering early treatments with ivermectin, reporting a nearly 100% response rate with early administration, adding that they were initiating clinical studies [28].

On April 13, a preprint by Patel et al. described an observational registry-based study from 169 hospitals claiming that a single dose of 0.15 mg/kg of ivermectin produced a significant mortality reduction (7.7% vs. 18.6%) in 1,970 patients requiring mechanical ventilation [29];[30].

On April 14, two medical doctors, Gustavo Elera Arévalo and Fernando Polanco Hinostroza in La Merced (Chanchamayo) in Peru, begun treating a COVID-19 outbreak in a prison with ivermectin, later also treating the local police [31].

... and hundreds more events to April 3 2021. Go to the source to read the full chronology.

Discussion

A central question in the communications was whether more studies were needed. In October 2020, when the FLCCC Alliance recommendation on ivermectin was published, the decision to recommend it was assumedly largely based on the perceived consistent positivity of the effects: “seeing a ‘signal’ in the data”. This method could also be called reliance on “clinical experience” or even “intuition”. Comparing five Covid Analysis group’s meta-analyses from November 26 (n=21), December 29 (n=28),January 26 (n=35), February 27 (n=42), and March 31 (n=49) [438], calculated improvements in clinical indicators, with probabilities of an equal or greater percentage of positive results from an ineffective treatment, were as follows: improvements in prophylaxis (pre-exposure/post-exposure or total) we-re 98%/87% (p=0.063/0.25), 91%/90% (p=0.0078/0.25), 90% (p=0.00098), 89% (p=0.00049), and 89%(p=0.00024), respectively. In early treatment, the improvements were 91% (p=0.13), 87% (p=0.016), 84%(p=0.00098), 83% (p=0.00012), and 80% (p=0.0000076). In late treatment, the improvements were 60%(p=0.00024), 48% (p=0.00012), 39% (p=0.000031), 51% (p=0.0000038), and 50% (p=0.00000095). All together, the improvements were 75% (p=0.00000048), 78% (p=0.0000000037), 74% (p=0.000000000029),75% (p=0.00000000000023), and 72% (p=0.000000000000002). It appears that in 2021 the variation in estimated efficacy due to addition of more studies to the meta-analysis was too small to be clinically meaningful. Therefore, more studies provided little additional clinically relevant information, and the argument against the treatment was solely based on the assumed unreliability of all the existing data.The panel which prepared the WHO guideline of March 30, 2021 included in its meta-analysis only five studies that directly compared ivermectin with standard of care and reported mortality [428]. The result indicated 64% reduction in mortality (RR 0.36, 95% CI 0.17-0.75, no p value given, n=915,very low certainty evidence). The meta-analysis of six studies by Hill et al. indicated 75% reduction in mortality (RR 0.25, CI 0.12-0.52, p=0.0002, n=1,255) [275]. The March 31, 2021 meta-analysis of eight randomized controlled trials by the Covid Analysis group indicated 70% reduction in mortality (RR 0.31,95% CI 0.16-0.61, n=1,729, p<0.00032) [437]. The meta-analysis of thirteen trials by Bryant et al. devised using Cochrane standards indicated 68% reduction in mortality (RR 0.32, 95% CI 0.14-0.72, n=1,892,low to moderate-certainty evidence) [387]. The FLCCC group’s meta-analysis of four observational and six randomized controlled trials indicated an overall 69% reduction in mortality (RR 0.31, n=3,508,p<0.0001) [168];[214].

In addition to presenting the new meta-analysis, the guideline presented data from the WHO living guideline [439]. The living guideline analysis indicated 70 deaths per 1,000 patients (7%) for standard of care, and 14 (1.4%) for ivermectin, respectively, i.e. an absolute difference of 56 patients (5.6%) with a 95% confidence interval of 64 to 44 fewer deaths, and a relative mortality reduction of 80%. The odds ratio for mortality was 0.19 (OR 0.19, 95% CI 0.09-0.36) based on 1,419 patients in seven studies. The certainty of evidence was estimated to be very low due to serious risk of bias and very serious imprecision.

This imprecision was explained as follows: “for mortality there were only 31 deaths across all 915 patients randomised - an extremely small number of events on which to base conclusions” (referring to five studies instead of seven), suggesting unsuitability of the chosen methodology for evaluation of medicines that might significantly reduce mortality, as conclusions could then not be made.

As a reference for the above data the guideline cited Siemieniuk et al. [440] which did not contain theabove results but instead presented a third set of mortality results, indicating a mortality of 130 per1000 patients (13%) for stardard of care. For a combination of doxycycline and ivermectin, the estimated reduction in deaths was 130 (95% CI 130-123). For ivermectin alone, the reduction was 103 (95% CI117-78). For proxalutamide, the values were 130 (95% CI 130-118), for colchicine 78 (95% CI 110-9), and significantly less for other included options.

These two additional sets of results indicated larger reductions in mortality (approximately 80%) than the meta-analysis. With regard to the earlier meta-analysis by Hill et al. [275], Siemieniuk et al. stated that “several of these trials could not be included in the analysis . . . ten trials that reported no outcomesof interest”, citing the Hill et al. meta-analysis among the trials reporting no outcomes of interest. Thenew meta-analysis was presented in Rochwerg et al. [441]. This article mentioned neither the meta-analysis by Hill et al. nor the mortality results of Siemieniuk et al. Rochwerg et al. also noted that “we currently lack persuasive evidence of a mechanism of action for ivermectin in covid-19; any observed clinical benefit would be unexplained”, possibly suggesting that not even an effective intervention could be utilized unless the mechanism of action was “explainable”.

Based on their meta-analyses the other groups (FLCCC, CovidAnalysis, BIRD) recommended treatment, the WHO panel did not, referring to “the strong likelihood that chance may be playing a role in the observed findings” [441]. None of the authors of the WHO-funded meta-analysis by Hill et al. were included in the panel. The low cost and wide availability of ivermectin did not, in the panel’s view, mandate the use of a drug with uncertain benefits and possible harms. Resource considerations, accessibility,feasibility and impact on health equity “did not alter the recommendation”. The panel worried about drug shortages in helminth control and elimination programmes [441];[428]. The panel listed the risk of severe adverse events leading to drug discontinuation as a reason for non-adoption, apparently suggesting that a pharmaceutical should not be adopted at all if a small subset of patients might stop using it. For some reason the panel “inferred that almost all well-informed patients would want to receive ivermectin only in the context of a randomized trial, given that the evidence left a very high degree of uncertainty . . . the panel anticipated little variation in values and preferences between patients when it came to this intervention”, giving an impression of dictating patients’ preferences without asking them or giving them a choice.

The panel “raised concerns about diverting attention and resources away from care likely to provide a benefit such as corticosteroids in patients with severe COVID-19 and other supportive care interventions”. Considering that in the majority of countries, no prophylaxis or early treatment method was officiallyavailable, that corticosteroids were to be avoided in prophylaxis and early treatment, and that the useof corticosteroids in late treatment practically necessitated use of ivermectin to prevent strongyloidiasis-related hyperinflammation, this rationale appeared particularly illogical. The panel did note, however,that “ivermectin may still be considered in strongyloidiasis endemic areas, at the discretion of clinicians overseeing treatment, albeit not for treatment of COVID-19 itself”.

Considering the attitudes towards ivermectin in the industrialized countries in general, one of the main obstacles for reception of the idea of repurposed medicines may have been the Surgisphere scandal and the widespread controversy regarding hydroxychloroquine in early 2020, leading to a generalized distrust of research among the politicians, governmental administrative personnel and the public, especially in the more developed countries which appeared to put more importance on the research. This distrust, in turn, possibly opened new avenues for various kinds of societal manipulation.

The distrust appeared to have also lead to, for example, social media and video streaming platforms actively but inconsistently and indiscriminately censoring many subjects and groups, including ivermectin research groups and their results, regardless of their level of academic merit. These practices often appeared similar to censorship practices in authoritarian countries. Mainstream media appeared to maintain an inverted understanding on the process of science in which scientific knowledge was apparently assumed to flow down from the NIH and WHO to the researchers, not the other way around. Financial newspapers (Wall Street Journal, Financial Times) may have possessed a more realistic view on medical research and ivermectin than generalist press conventionally considered high quality (e.g. The New York Times, Associated Press, The Guardian), with some practically accusing researchers of not adhering to the guidelines given by the NIH, for example. The open encyclopedia Wikipedia took pains to only mention negative studies about ivermectin, listing it among the COVID-19 misinformation, even citing a commentator saying that “the narrative of ivermectin as a ‘miracle cure’ for COVID-19 is a ‘metastasized’ version of a similar conspiracy theory around the drug hydroxychloroquine, in which unspecified powers are thought to be suppressing news of the drug’s effectiveness for their own malign purposes” [442];[443];[444].

As noted by Wall Street Journal quite early on in the ivermectin saga, the majority of the medical establishment appeared to require almost absolute certainty, resulting in “too much caution killing patients”, both health-wise and financially [183]. This approach seemed to only take into account quite theoretical health risks, disregarding not only the very probable societal harms of not taking any action but also the possible health benefits of taking an action under uncertainty. Thus, the process appeared largely a failure of a relatively simple risk-benefit analysis.

The more medically oriented arguments against the adoption of ivermectin were usually based on the hypothesis that the required (as indicated by the Caly et al. in vitro study [22]) plasma and lung tissue concentrations for an antiviral effect would likely not be achievable. Another argument was based on the host-directedness and the assumed toxicity of larger doses.

An additional disagreement concerned the use of placebo in clinical trials. This disagreement may havebeen at least partly related to a long-standing divide of the research community into active-control and placebo orthodox proponents [445]. Vagueness of the Helsinki Declaration of 2013 may easily lead into opposite interpretations of what should be done [446]. For example, the sentence to allow the use of placebo “where no proven intervention exists” left open who should decide what is a “proven intervention”, easily leading to a circular reasoning according to which a proven intervention cannot exist without a placebo-controlled randomized trial, thus the use of placebo must be allowed to prove the efficacy of the intervention. Similar vagueness plagues the whole section about placebo controls. The parties involved in the ivermectin trial controversies appeared unable to find any common ground with regard to this issue.During the period there appeared to be somewhat scarce interest in treatments research, with the wealthy societies’ focus on vaccinations and lockdowns, despite vaccinations being largely unavailable and lockdowns harmful for the economy. These countries appeared to pursue expensive, narrow-spectrum vaccination and new pharmaceuticals based strategies, ignoring cheaper options, whereas developing countries put more emphasis on affordable, broad-spectrum antivirals. One factor may have been the developing nations’ clinicians’ familiarity with ivermectin and its easy availability, whereas it has been a rarely prescribed medicine in most industrialized countries. In addition, prejudices and a bias against ideas originating outside of familiar organizations or one’s own country may have played a part in the industrialized countries ignoring ivermectin research carried out in the developing countries [447]. Cost-effectiveness of government funding for development of new medications and vaccines is an important issue. The US government invested USD 356 million in 60,000-100,000 doses of MK-7110, indicating aunit price between USD 5,933.00 and USD 3,560.00, with the initial results of efficacy indicating the same or slightly smaller efficacy as that of ivermectin. A 2015 article about mass treatment of onchocerciasisin Africa stated that Merck & Co/MSD had offered ivermectin at USD 1.51 per treatment, indicating a2300 to 3900-fold difference between the prices of ivermectin and MK-7110 [448];[222]. In this example,allocation of US government funding appeared inefficient with respect to investment in an experimental product with the unit costs in thousands of dollars, versus the option to use an existing medication with similar efficacy proven at least on a similar level of evidence and the unit costs in single digits.

There was a widespread disagreement on the fundamentals: which methods were appropriate as a basis for decision making, what counted as evidence, and what was ethical. In a broader view, the appropriateness and usefulness of the evidence based medicine paradigm as it was understood and applied during the period appeared questionable. US and European governmental bodies appeared to reject or ignore most of the ivermectin-related data, referring to insufficient evidence. In the US, the paradigm appeared inconsistently applied; more specifically, not applied to US Food and Drug Administration Emergency Use Authorization of remdesivir, whereas strictly applied to other medications including ivermectin. In addition, a strict requirement to compare a significantly more effective treatment to placebo may be considered unethical with regard to high mortality of patients in control groups. These indicate a clear need for a new methodology better than the current understanding and application of evidence-based medicine.

With regard to conflicts of interest, the US Food and Drug Administration (FDA) issued an EmergencyUse Authorization (EUA) for the use of remdesivir in patients with severe disease on May 1, even before the initial results of an ongoing trial were published and despite remdesivir being an investigational drug not approved for any indication. The 1,063-patient randomized controlled trial of remdesivir publishedon May 22 only indicated that remdesivir shortened the time to recovery (11 days vs 15 days, p<0.001)[449]. There wasn’t an obvious difference in mortality rates (8% vs. 11.6%, p=0.059) and the endpoints were changed mid-study which was deemed a questionable practice [450]. The final results were published on October 8. On August 28 the EUA was extended to “no longer require a severe disease”.

The adoption of corticosteroids as a consequence of the WHO-initiated 2,000-patient RECOVERY trial results was relatively swift. Also the emergency use authorization of remdesivir in the US was swift,based on initial and conflicting evidence. Twenty randomized clinical trial results on ivermectin’s efficacy for COVID-19 were available in February 2021. These trials were predominantly carried out outside the US and the EU, and did not lead to emergency use authorizations in the US or the EU. US FDA document “Emergency Use Authorization of Medical Products and Related Authorities – Gui-dance for Industry and Other Stakeholders” section “1. Criteria for Issuance” subsection “d. No Alternatives” states that “For FDA to issue an EUA, there must be no adequate, approved, and available alternative to the candidate product for diagnosing, preventing, or treating the disease or condition. A potential alternative product may be considered ‘unavailable’ if there are insufficient supplies of the approved alternative to fully meet the emergency need. A potential alternative product may be considered ‘inadequate’ if, for example, there are contraindicating data for special circumstances or populations (e.g., children, immunocompromised individuals, or individuals with a drug allergy), if a dosage form of an approved product is inappropriate for use in a special population (e.g., a tablet for individuals who cannot swallow pills), or if the agent is or may be resistant to approved and available alternative products” [451].

It may thus be derived that licensing of repurposed medicines such as ivermectin for outpatient treatment and prophylaxis of COVID-19 would have prevented emergency use authorizations of new pharmaceuticals in development. In the case of prophylaxis, such licensing might even have affected vaccines. Thus,there appeared to exist substantial financial conflicts of interest against licensing of repurposed medicines.

Considering the total net utility of a society it is unlikely that unilateral support to only the investments of the pharmaceutical industry could ever offset the harms to other industries and the population. The society thus has a strong incentive to abolish the financial incentive structures of the pharmaceutical industry and the government that led to the current situation, in order to prevent a similar outcome in the future.

Considering the estimated efficacy of ivermectin around 90% in prophylaxis and the option of an early outpatient treatment with an estimated efficacy around 75%, an early introduction of ivermectin might have prevented a large part of COVID-19 infections post first wave in many European Union countries and in the United States.

Administrative issues, inconsistent requirements of evidence related to the evidence-based medicine paradigm, and possibly conflicts of interest with patentable, commercial products in development prevented introduction of early outpatient ivermectin treatments in the last quarter of 2020 and the first quarter of 2021. This lack of response is likely to have caused unnecessary deaths and difficult-to-repair financial and health consequences in the affected societies.

The culture of medical litigation prevalent in the United States may have created patterns of behavior that have also spread to countries with less actual litigation, yet leading to mental paradigms favoring extreme caution and non-action, in turn leading to stagnation. One of the features of a paradigm is an inability of the involved people to transcend it or even see that it is just one possible paradigm out of many options, some of which may be more optimal in a given situation.

Conclusion

The period appeared conflicted, with researchers, clinicians, governmental agencies and commercial entities holding deeply conflicting views on fundamental issues, including which methods were considered appropriate as a basis for decision making, what could be considered as sufficient evidence, and what was ethical. In a broader historical perspective, the timeline of events depicts rather dysfunctional societies unable to properly communicate and organize themselves, leading to misallocation of resources and decisions that may have conflicted with elementary ethical considerations, with this behavior rationalized by claiming adherence to mental paradigms that may have poorly matched the situation. In summary, the pandemic response especially in the United States and the European union appeared severely lacking.Further research on the details of these processes is warranted.