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A Timeline of Ivermectin-Related Events in the COVID-19 Pandemic [April 3, 2021]

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A Timeline of Ivermectin-Related Events in the COVID-19 Pandemic [April 3, 2021]

Abstract

First part part of the timeline covering a period from April 2020 to March 2021 (this is an extended version of an earlier preprint written on March 24, 2021. Changes: Abstract, Introduction, April 26, September 25, December 7, February 9, March 15, from March 22 to March 31, Discussion) *** Other parts: Part 0: https://www.researchgate.net/publication/348077948 *** *** Part 2: https://doi.org/10.13140/RG.2.2.16973.36326 *** Part 3: https://doi.org/10.13140/RG.2.2.23081.72805 *** Part 4: https://doi.org/10.13140/RG.2.2.26000.53767 *** Part 5: https://doi.org/10.13140/RG.2.2.35015.16807 *** Additional notes (Feb-Apr 2022): https://doi.org/10.13140/RG.2.2.24356.55682 ***
A timeline of ivermectin-related events in the COVID-19
pandemic
Mika Turkia
M.Sc., mika.turkia@alumni.helsinki.fi, April 3, 2021
Abstract
Background
Ivermectin is a multifaceted medication invented in Japan in 1975 by professor Satoshi ¯
Omura, for which
he won the 2015 Nobel Prize in medicine. Several billion doses of ivermectin have been administered
since 1981. Currently, ivermectin preparations are available off-patent from many sources, with the
production cost of a single dose estimated to be less than 0.1 US dollars.
Review
The interest in ivermectin with regard to COVID-19 was initiated by an Australian in vitro study
published on April 3, 2020, indicating that a single treatment with ivermectin effectively eliminated the
SARS-CoV-2 virus in cell culture. A few days later, two doctors in Peru begun treating a COVID-19
outbreak in a prison with ivermectin, later also treating the local police.
In the second and third quarter of 2020 the use of ivermectin spread to other South and Central American
countries, Egypt, India and Bangladesh, and later to Lebanon, Southern Africa and Southeastern Europe,
with Slovakia being the first European Union country to adopt it.
Ivermectin treatments raised controversy in many European Union countries and the United States which
ignored ivermectin, referring to a lack of evidence of its efficacy and safety and demanding large-scale
clinical trials. The World Health Organization (WHO) and the European Medicine Agency (EMA)
advised against using ivermectin even after results of 26 randomized clinical trials were available in
March 2021. In contrast, many developing countries adopted ivermectin with little evidence.
In the United States, government funding was allocated to the development of a novel pharmaceutical
estimated to possess an efficacy comparable to ivermectin but priced several magnitudes higher. Social
media companies censored ivermectin researchers and research, with for example YouTube censoring
results of a meta-analysis commissioned by the WHO. Traditional media appeared to either ignore
ivermectin or publish negative commentaries only.
Conclusion
There was widespread disagreement on the fundamentals: which methods were appropriate as a basis
for decision making, what counted as evidence, and what was ethical. Societies appeared disorganized,
unable to transcend their current practices, financial structures and mindsets even when facing an obvious
failure.
Keywords: COVID-19, SARS-CoV-2, ivermectin
1
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 CovidAnalysis 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. de-
scribe that ivermectin interacts with vertebrate and invertebrate γ-aminobutyric acid (GABA) receptor
and invertebrate glutamate-gated chloride channels, increasing chloride ion influx with subsequent paral-
ysis 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 8.7
2
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 dur-
ing 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].
On April 19, a second preprint by Patel et al. described an observational propensity-matched case-
controlled study in 1,408 patients (of which 704 received ivermectin) which claimed to demonstrate an
3
association of ivermectin use with lower in-hospital mortality 1.4% vs 8.5%, concluding that ivermec-
tin was associated with a potential survival benefit in COVID-19 and should be investigated urgently
in randomized controlled trials [32];[33]. The data was said to originate from an international multi-
institutional deidentified healthcare outcomes database compiled by Surgisphere Corporation, Chicago,
IL, using data from hospitals located throughout the world. The registry was said to ensure compliance
with the FDA’s guidance on real-world evidence. Data was said to have been collected through “automa-
ted data transfers that capture 100% of the data from each healthcare entity at regular, predetermined
intervals, thus reducing the impact of selection bias”.
On April 19, Chaccour criticized the methods and the analysis of the Patel et al. study on Twitter,
subsequently contacting the authors about inconsistencies in the data [34].
On April 21, Antiviral Research journal published letters to the editors commenting the Caly et al. study,
with Rayner et al. commenting that “a small window exists for the current data to have relevance for
humans”, and Noël commenting that the higher than usual doses that would be necessary could be toxic
and thus a phase I study is absolutely needed. Jans and Wagstaff commented that a vitally important
reason to be very cautious is that ivermectin’s key direct target in mammalian cells is a not a viral
component but a host protein important in intracellular transport. They also commented that the basis
of ivermectin’s broad-spectrum activity against a number of different RNA viruses in vitro is the fact
that it is a host-directed agent (HDA), and the way a HDA can reduce viral load is by inhibiting a key
cellular process that the virus hijacks to enhance infection by suppressing the host antiviral response.
Reducing viral load by even a modest amount by using a HDA at low dose early in infection can be
the key to enabling the body’s immune system to begin to mount the full antiviral response before the
infection takes control. However, it cannot be assumed that even low doses are safe in the context of a
burgeoning viral infection, where a measured immune response is key to recovery [35].
On April 23, Honduras adopted ivermectin country-wide [3].
On April 26, a rapid response by Hoy suggested a trial of ivermectin for treatment and prophylaxis of
COVID-19 [36];[37];[38].
On April 26, a preprint by Schmith et al. described pharmacokinetic model simulations to predict plas-
ma concentration-time profiles after a single and repeat fasted administration of the approved dose of
ivermectin (200 μg/kg), noting that plasma or lung ivermectin concentrations do not reach the IC50
indicated by the Caly et al. in vitro study, even for a dose level ten times higher than the approved dose,
thus concluding that a “likelihood of a successful clinical trial using the approved dose of ivermectin is
low. Combination therapy should be evaluated in vitro. Re-purposing drugs [. . . ] is an ideal strategy
but is only feasible when product safety has been established and experiments of re-purposed drugs are
conducted at clinically relevant concentrations” [39].
May 2020
On May 2, Aguirre Chang published a preprint of an observational case study of seven patients, showing
improvement and resolution of fever within 48 hours and a 100% recovery [40].
On May 6, a randomized clinical trial of ivermectin for treatment and prophylaxis of COVID-19 (ECIT-
PRO19) was started Spain (EudraCT 2020-001994-66) [41].
On May 7, a peer-reviewed version of the Schmith et al. pharmacokinetic model simulations study was
published [39]. On the same day, a pilot study to evaluate the potential of ivermectin to reduce COVID-
19 transmission (SAINT) by Chaccour et al. was started by University of Navarra in Pamplona, Spain
(EudraCT 2020-001474-29) [42].
On May 8, Peru adopted ivermectin country-wide [3].
On May 11, in an editorially independent blog from the publishers of Science Translational Medicine,
Lowe discussed organic chemistry aspects of ivermectin [43].
4
On May 15, a multi-center, randomized, double-blind, placebo-controlled study investigating efficacy,
safety and tolerability of ivermectin in patients with a proven SARS-CoV-2 infection (HUVE-19-CT-
001) by Huvepharma EOOD (Petkov) was started in Sofia, Bulgaria (EudraCT 2020-002091-12) [44].
On May 19, an Indian newspaper wrote about an observational trial by Alam et al. in Bangladesh, with
60 patients treated with a combination of ivermectin and doxycycline recovering within four days [45].
Alam, who was referred to as “a reputed clinician in Bangladesh”, said the combination “yielded virtually
the near-miraculous result in curing the patients” with no side effects. He mentioned being “a hundred
per cent hopeful about the effectiveness” and that they had contacted government regulators to prepare
for national and international adoption of the treatment.
On May 20, an observational early treatment outpatient study in Peru by Mogrovejo Ramos et al. with 63
symptomatic patients diagnosed through teleconsultations and prescribed 0.2 mg/kg ivermectin reported
that symptoms such as fever had significantly decreased at 24 hours, with sense of smell recovered and
discomfort overcome at 48 hours, while the cough and muscle aches remained on day 5 [46]. The authors
concluded that “a massive distribution of this drug with a prescription should be considered as a public
health strategy to be applied by the first-line establishments, in order to avoid overcrowding and collapse
of the national health system”.
On May 27, Rizzo suggested that ivermectin may have an ionophore role, thus introducing a possible
new mechanism of action [47].
On May 31, another Indian newspaper referred to the results of the study by Alam et al. in Bangladesh,
saying that the Indian Council of Medical Research (ICMR), the country’s apex medical research body,
is reviewing the benefits of the combination. A senior ICMR researcher said the agency had reviewed
ivermectin multiple times and continued to study it, adding that “however, to conclude anything we would
need solid evidence or a published study, backed by statistically significant data on a bigger sample size”.
The article mentioned ivermectin being a part of at least five ongoing trials in India [48].
June 2020
On June 1, to prevent outpatient deterioration and hospital congestion, the government of Peru launched
a ‘Territorial Aid Operation for Treatment and Isolation in Response to COVID-19’ (Tayta), consisting
of early outpatient treatment with individually prescribed combinations of paracetamol, azithromycin,
hydroxychloroquine and ivermectin [49].
On June 2, a study about ivermectin as an antiviral treatment for patients infected by SARS-COV2
(CORIVER) was started by Hospital Universitario Virgen de las Nieves (Sergio Sequera) in Granada,
Spain (EudraCT 2020-001971-33) [50].
On June 2, Science wrote about Expressions of Concern (EOCs) posted by the Lancet and the New
England Journal of Medicine about two non-ivermectin studies based on the Surgisphere database [51].
The two EOCs led to temporary halting of many hydroxychloroquine studies unrelated to Surgisphere
database. A researcher involved in one of the halted studies commented that “the problem is, we are left
with all the damage that has been done . . . the whole world thinks now that these drugs are poisonous”.
On June 3, The Guardian (UK) wrote about “flawed data” from Surgisphere Corporation having
prompted the Peruvian government to add ivermectin to its national COVID-19 therapeutic guidelines
[52];[53]. The story described Surgisphere employees having little or no scientific background, saying a
science editor appeared to be a science fiction author and fantasy artist, and a marketing executive being
an adult model and events hostess. The article referred to a peer-reviewed hydroxychloroquine study
published in The Lancet, based on the same database, stating that seven hospitals “whose cooperation
would have been essential for the Australian patient numbers in the database to be reached .. . denied
any role in such a database, and said they had never heard of Surgisphere”. The ivermectin preprint
based on the database was available on June 2 but no longer on June 3 [33].
On June 4, Science wrote about retractions of two peer-reviewed articles by Patel et al. published by
The Lancet and The New England Journal of Medicine that were not about ivermectin but based on the
same database compiled by Surgisphere Corporation [54]. The Science article noted that the ivermectin
5
study was only posted online as a preprint and was no longer available but it was said to have prompted
increased use and government authorization of the drug in several Latin American countries. On June
8, Science wrote about the backgrounds of the researchers involved in the Surgisphere scandal [55].
On June 4, a Brazilian clinician Lucy Kerr described her ivermectin treatments, stating that “I decided
to use it on patients because the side effects are almost nonexistent and if it worked I would save a lot
of lives. Now I have more than 30 cases that I treated and cured. Many more were cured by doctors in
the group of 570 doctors that I administer in WhatsApp and Telegram” [56];[57].
On June 7, a news report from Peru wrote that Arévalo and Hinostroza had treated 1,200 patients with
ivermectin “with excellent results” since April 14 [31]. Arévalo had initially treated prisoners, then the
police and later the residents in the community. The report said that the government had announced
a plan to acquire 490 000 doses. About the role of the WHO, Arévalo commented that “the WHO has
made serious mistakes that resulted in thousands of human deaths at the beginning of the pandemic,
such as not replying to the October 2020 letter from South Korea reporting atypical pneumonia in that
region, the advice against masks, the banning of ivermectin after promising results from two Australian
researchers, as well as ten more mistakes. After this pandemic we have to look back and restructure
that organization”. About the lack of evidence from large trials he said that “in this disease the only
evidence we had was about the mechanisms by which the patients died and trials of drugs that had
little or no effect in the late phase of the disease . . . the great discoveries in medicine have been based
on observations, accidents and coincidences”. The report also mentioned ivermectin treatments having
been carried out in neighboring countries including Bolivia commencing several weeks earlier, with good
results.
On June 10, initial results of an observational controlled 280-patient ICON ivermectin trial were made
available as a preprint on medRxiv [58]. The trial used propensity matching. Mortality was significantly
lower among ivermectin-treated patients with severe pulmonary involvement (38.8% vs 80.7%, OR 0.15,
95% CI 0.05-0.47, p=0.001). Among all ivermectin-treated patients, mortality was also lower in the
ivermectin group (13.3% vs 24.5%, OR 0.47, 95% CI 0.22-0.99, p<0.05) [59].
On June 12, Heidary et al. published a systematic peer-reviewed review of the antimicrobial, antiviral, and
anti-cancer properties of ivermectin [60]. On the same day, TrialSite News wrote about early grassroots
experimentation with ivermectin in Peru [61].
On June 12, a peer-reviewed article about case series of 100 patients treated with a combination of
ivermectin and doxycycline in Bangladesh by Alam et al. found the combination very effective in viral
clearance in mild and moderately sick patients, with all of them testing negative and symptoms improving
within 72 hours [62].
On June 12, a randomized double-blind multi-centre phase II proof of concept dose finding clinical trial
on ivermectin for the early treatment of COVID-19 (COVER) was started in Negrar di Valpolicella, Italy
(EudraCT 2020-002283-32) [63];[64];[65].
On June 13, a news article described “an avalanche of cases” in May 2020 in Iquitos, Peru, a lack of
response from the officials, and a successful containment of the initial epidemic by local doctors utilizing
ivermectin for early outpatient treatments [66]. One of the doctors, Sergio Bardon, a neurosurgeon, oc-
cupational physician and specialist in community and rural health trained at the University of Buenos
Aires and the University of Sheffield in the United Kingdom, described that ivermectin reduced viral
loads, causing a drastic improvement in the clinical representation of the patients. Bardon mentioned
chaotic changes in the WHO and national regulations, saying a ministerial resolution prohibiting the use
of antibiotics and corticosteroids but allowing ivermectin had just been issued. Bardon stressed the need
for early treatment to prevent the patient going into an inflammationary phase in which the viral load
was not relevant any longer and in which “ivermectin no longer makes much sense”. Bardon described
the phase-specificity of COVID-19, including the stopping of viral replication in a few days after the
beginning of the symptoms, and the lack of efficacy of antivirals in the inflammatory phase. Bardon said
he had only needed to hospitalize his first COVID-19 patient, after which he had been able to treat all
the others as outpatients. He said he had also treated patients in Loreto, Amazonas where there were
no hospitals but all patients had been successfully treated as outpatients with a combination of iver-
mectin and azithromycin. With regard to the hospital in Iquitos, Bardon added that the internationally
6
publicized immediate crisis with people dying outside the hospital had been solved a few days later by
administering single-dose injectable ivermectin, with Bardon participating in the process. The problem
was that pharmacies were becoming out of stock and the prices had multiplied by approximately seven,
from USD 4 to USD 30. Bardon stressed the importance of ensuring the supply. Many patients had been
unable to obtain the drug even though Brazil produced it nationally and it had initially been relatively
affordable. Even if the production had been sufficient the drug had not been properly distributed in the
areas in need. Also, the situation was worsening, with too many infected patients leading to a chaos in
the underresourced health care system.
On June 14, Sparavigna published an initial version of an ongoing review of the history of ivermectin
in COVID-19, describing, among other issues, the case of Iquitos, Peru. The review was continuously
updated up to July 29, then again updated on September 8 and September 20 [67]. On the same day,
German weekly magazine Der Spiegel wrote about the Surgisphere scandal [68].
On June 15, a preprint discussed the role of CD147 transmembrane receptor in the binding of SARS-
CoV-2 and mentioned treatments of 71 patients by Rajter in Florida had yielded a statistically significant
reduction in mortality, with fast reversals of rapidly deteriorating oxygen status [69];[70];[71].
On June 17, a Japanese treatment manual listed ivermectin as one of the treatment options [72].
On June 19, an in-silico analysis indicated ivermectin may interfere with SARS-CoV-2 spike attachment
to cell membrane [73].
On June 21, an in vitro study by Zhang et al. concluded that ivermectin produces genotoxicity and cyto-
toxicity by inducing DNA damage and AMPK/mTOR-mediated autophagy, thereby posing a potential
risk to human health [74]. The authors also warned that accumulation of ivermectin in animal tissues
and the excretion of urine and feces in the environment is a major source of potential toxicity.
On June 23, the Ministry of Health of Peru published instructions for making 6 mg/ml oral solution of
ivermectin [75].
On June 24, Molento et al. published “a word of caution” against self-medication [76].
On June 30, a peer-reviewed version of Caly et al’s in vitro study was published [22]. On the same day,
the president of a company operating three hospitals and several outpatient clinics and other facilities in
the Dominican Republic, José Natalio Redondo, described their experience with off-label treatment of
1,300 patients with 0.1-0.4 mg/kg of ivermectin in conjunction with azithromycin, stating that 99% of
them had been cured within 8-10 days, the average duration of the full infection was reduced from 21 days
to 10 days, and the only side effects had been mild heart burn and diarrhea [77]. Doctors from Mexico,
Ecuador, Peru, Bolivia, Brazil and a few other countries had formed a network for sharing protocols.
Redondo mentioned that the public healthcare has less flexibility and followed WHO, the US and other
guidance based on funding. He mentioned companies cannot profit off of a generic drug, adding that
the priorities are wrong: early treatment should have been prioritized. Redondo mentioned that Merck
&Co/MSD had been in touch with them at one point but the medicine used in the Dominican Republic
had been produced by a local company. Redondo stressed the importance of harm reduction by saying
that “the health, economic and social benefit of cutting 10 days out of the sickness and reducing the
amount of time a person is contagious .. . [it has had] a huge impact. A huge value to society. Look at
what this pandemic has done to the global economy! Look at New York City – the greatest city with
per capital perhaps the greatest doctors and health systems yet look at the amount of death and the
impact. It is horrific; a tragedy”. With regard to trials, Redondo commented that “it is very expensive to
conduct clinical trials. In developed nations in the Caribbean, Central and South America, countries in
Africa and some in Asia we must act now to stop the disease from progressing and spreading. We have
an investigation we are in fact undertaking and there are other good studies in the works from Johns
Hopkins University to Sheba Medical Center in Israel. But those will take some time. The network in
Latin America and the Caribbean has acted on observational, off-label data, and it is working. After all,
over a trillion doses of ivermectin are given annually for fighting parasites. It is an incredibly safe drug
. . . The results speak for themselves”.
In June, country-wide ivermectin use begun in Bangladesh [3].
7
July2020
On July 1, a preprint by Scheim hypothesized about alleviation of CD147 transmembrane receptor
mediated vascular occlusion with ivermectin [78].
On July 2, Syed discussed studies by Caly et al. and Rajter et al. and the Dominican Republic experi-
ences, commenting that ivermectin appears useful in all stages of COVID-19 but should not be used in
individuals with a compromised blood-brain barrier [22];[58];[79].
On July 7, the deputy director of the Bulgarian Center for Parasitic and Infectious Diseases described
ivermectin as “the most promising”, citing the long experience (1975 onwards) about it as a benefit,
however noting that there is a need to wait for results of its possible clinical efficacy in COVID-19 [80].
She also expressed satisfaction that there was a company in Bulgaria that was ready to produce it.
On July 8, a small open-label pilot trial by Gorial et al. with 87 inpatients of which 16 treated with
ivermectin indicated a 42% lower mean hospital stay with a 0.2mg/kg single dose of ivermectin ad-
ded to a standard regime of hydroxychloroquine and azithromycin (7.62 vs 13.22 days, p=0.00005)
(NCT04343092) [81].
On July 9, an in-silico docking and simulation study indicated that a combination of ivermectin and
doxycycline might inhibit viral entry and enhance viral load clearance by targeting various viral functional
proteins [82].
On July 11, Aguirre-Chang et al. reported a high rate of clinical improvement in 33 patients with
persistent or post-acute symptoms treated with ivermectin [83]. A complete remission of symptoms was
observed in 87.9% of the patients after two daily doses of ivermectin. An additional dose of ivermectin
for the rest of the patients resulted in a compete remission in 94% of cases.
On July 12, the BBC wrote about fake cures in Latin America, citing Pan American Health Organization
(PAHO), a regional office for the Americas under the World Health Organization (WHO) [84]. PAHO
stated ivermectin was being used “incorrectly .. . without any scientific evidence of its efficacy and
safety”.
On July 14, a randomized controlled trial by Chowdhury et al. about early treatment of 116 patients
compared ivermectin-doxycycline and hydroxychloroquine-azithromycin. Times to symptomatic recovery
were 5.93 days vs 6.99 days, respectively, not indicating a significant difference [85].
On July 15, Rajter and Cepelowicz-Rajter discuss their ivermectin experiences in Florida [86];[87].
On July 17, a letter to the editor by Peña-Silva et al. stated that there was no evidence that the 5 μM
concentration used in the Caly et al. in vitro study could be achieved in vivo [88]. The authors stated that
even with the highest reported dose of approximately 1.7 mg/kg (8.5 times the FDA-approved dose of 0.2
mg/kg) the maximum plasma concentration was only 0.28 μM. They also stated that 93% of ivermectin
is bound to plasma proteins which limits its cellular uptake by endothelial cells, thus the free plasma
concentration of ivermectin would be 250 times lower than the required concentration. In addition, it
was suggested to be unlikely that lung accumulation would be sufficient to achieve the antiviral effect
with conventional doses. Also the clinical effects of ivermectin at a concentration of 5 μM range were said
to be unknown and possibly associated with toxicity. In summary the authors suggested that ivermectin
has in vitro activity against SARS-CoV-2 but the effect is unlikely to be observed in vivo using current
dosing. On the same day, Arpornsuwan et al. presented a proposal for early diagnosis and management
of COVID-19 with ivermectin [89].
On July 18 in India, a panel of senior doctors including Behera evaluated ivermectin and concluded it can
be a potential agent for prophylaxis and treatment of COVID-19, due to its antiviral properties, afford-
ability, availability and safety [90]. The suggested dose was 12 mg twice a day. The panel recommended
randomized controlled trials.
On July 30, Aguirre-Chang et al. published a proposal on post-exposure prophylaxis with ivermectin
[91].
On July 30, Stauffer et al. presented a potential strategy to avoid potentially fatal steroid-related
strongyloides hyperinfection [92]. They reported that 10% to 40% of populations in tropical and sub-
8
tropical regions may be infected with a nematode causing strongyloidiasis. The estimated prevalences
among immigrants varied between 11% and 50%. The authors suggested either screening or presumptive
treatment with ivermectin.
On July 31, a comparative study by Rahman et al. of 400 patients in Bangladesh compared ivermectin-
doxycycline and hydroxychloroquine-azithromycin, concluding that ivermectin-doxycycline was a safe
and effective combination for obtaining early viral clearance in mild to moderate COVID-19 patients
[93].
In July, the city of Cali in Colombia adopted ivermectin, with an initial distribution of 10,000 doses [94].
The decision was based on good results achieved in Guayaquil, Ecuador. Ivermectin was used in the
early phase to prevent progression of disease and subsequent hospitalization. It was distributed to all
COVID-19 positive patients and people suspected of exposure to the SARS-CoV-2 virus. The mayor of
Cali stated that “we are going to do it even if there is no consensus in the scientific community”.
August 2020
On August 1, state of Chiapas in Mexico adopted ivermectin [95].
On August 6, an expert panel in Uttar Pradesh, India gave a recommendation for ivermectin prophylaxis
of health-care workers and COVID-19 contacts, and for ivermectin treatment of symptomatic patients,
with the exception of pregnant and lactating women, and children below 12 years [96].
On August 11, interestingly, Pan American Health Organization’s (PAHO) update of potential thera-
peutics still included two retracted preprints by Patel et al., in addition to Caly et al. in vitro study,
and studies by Rajter et al. and Gorial et al., concluding that the evidence is unconvincing [97].
On August 13, The Guardian wrote that “world-leading parasite researcher Dr Carlos Chaccour says using
the drug in fight against the virus could be ‘very, very harmful’”, warning against Australia adopting
the drug without proper evidence [98].
On August 14, a peer-reviewed observational retrospective late treatment study by Battacharya et al.
in Kolkata, India indicated that a triple therapy with ivermectin, N-acetylcysteine and atorvastatin for
148 patients resulted in an in-hospital mortality rate of 1.35% which was well below the national average
[99].
On August 14, Lier et al. reported a complicated case of disseminated strongyloidiasis in a patient with
severe COVID-19 requiring ventilation [100].
On August 15, a peer-reviewed early treatment study by Espitia-Hernandez et al. in Mexico with 28
treated patients and 7 controls indicated that ivermectin, azithromycin and cholecalciferol reduced viral
positivity by 97% at day 10 and the mean duration of symptoms from ten days to three days [101].
On August 15, an Australian new article described a triple therapy with ivermectin, doxycycline and
zinc by Borody as effective, adding that “other than Borody, almost nobody in Australia is treating
patients with ivermectin .. . at first glance, it seems inexplicable . . . the safety profile is so well-known
that there is virtually no risk. There are already 33 clinical trials running around the world. The results
so far are uniformly positive” [102];[103]. The article concluded that “medical litigation has created an
ultra-cautious culture even when there is virtually no risk, and second, doctors are mostly imprisoned in
the prevailing paradigm which holds that there is no effective treatment to cure Covid-19 and that the
only way out of Australia’s pandemic penitentiary is a vaccine .. . a vaccine for a coronavirus should
never have been Plan A for anyone as a way out of a pandemic . . . it is extraordinary how little thought
has been given to an effective cure .. . in part that’s because the only drug, other than ivermectin,
that has shown promise as a prophylactic, an anti-viral and in dampening down Covid’s fearful cytokine
storm is hydroxychloroquine, which has been demonized both by Big Pharma and by US Democrats. It
is now an article of faith on the Left that it doesn’t work, despite remarkable results at some of America’s
leading hospitals and support from Ivy League academics” [102].
On August 21, a second preprint of the observational ICON study by Rajter et al. in Florida, USA
indicated mortality rates of 12.4% vs 25.8% (OR 0.41, CI 0.19-0.87, p=0.02) with and without iver-
9
mectin, respectively, in a propensity-matched cohort of 194 patients [104]. As stated earlier, mortality
was significantly lower among ivermectin-treated patients with severe pulmonary involvement (38.8% vs
80.7%), although this result had been observed before corticosteroid use became more widespread.
On August 22, capital city of Lucknow in Uttar Pradesh, India, adopted ivermectin [95].
On August 27, the National Institute for Health (NIH) of the United States gave a recommendation
on ivermectin, advising against using it except in clinical trials [105]. The FLCCC group noted the
recommendation was rated A III, i.e. a strong recommendation based on expert opinion only [95]. The
rating implied that there was no available evidence at the time to make an “evidence-based” grading (in
quality of evidence for recommendation classes I, IIa and IIb). However, the results of the ICON trial
were available, indicating a possibility for a class IIa or IIb recommendation [58].
On August 27, Shouman et al. posted results of a randomized clinical trial in Egypt about prophylactic
ivermectin treatment of family members of COVID-19 outpatients, indicating that 7% of treated were
infected vs 58% in the control group (NCT04422561) [106];[107].
On August 27, MedPage Today mentioned the Australian study, use of ivermectin in Peru and Bolivia,
commenting that “although the drug is relatively safe, some scientists are worried that clinicians are
putting the cart before the horse”, and quoted Chaccour emphasizing the need for scientific rigor and
the possibility of side effects [108]. The article mentioned the FDA warning cautioning against the use
of veterinary formulation of ivermectin, mentioning it was presumably intended “to protect the public
against misinformation, after a man died in March from consuming chloroquine phosphate, an aquarium
cleaner, when hydroxychloroquine (HCQ) was making headlines”, adding that “however, in doses used
off-label for scabies, for example, ivermectin has a low side-effect profile”. The article then mentioned
“positive signal in Florida” interviewing Rajter about his early experience in April 2020, who mentioned
that “the success story we had in early April has been duplicated in other smaller studies across the
world”. Two other researchers commented that the studies were difficult to interpret and saw parallels to
hydroxychloroquine studies. The article also referred to the Surgisphere scandal, positive findings from
India, and a triple therapy with ivermectin, doxycycline and zinc by Borody, ending with comments by
Chaccour that “the drug should not be written off, but neither is it ready for widespread clinical use” and
by Rajter that he is “frustrated by an intentionally slow review process . . . certain drugs are expedited
by the FDA, while other treatments which have been shown to be quite effective – like ivermectin –
have not seen the light of day”, and an Italian researcher commenting that “it’s a shame that so few
randomized controlled trials have been performed in the U.S. on potential treatments such as this one”.
On August 27, a news story described mass ivermectin distribution of 1.5 million pills in the city of Itajaí
in Brazil organized by the city’s mayor (who was also a medical doctor) as a “pseudo-health”, “a magic
potion to circumvent what scientific evidence is showing”, “irrational and reckless” and a “national joke”
[109]. An infectious diseases consultant commented that ivermectin had “sparked an ideological war .. .
no one speaks the same language anymore”.
September 2020
On September 3, an open-label randomized controlled study by Podder et al. in Bangladesh with 62 mild
to moderate patients did not produce statistically significant results [110].
On September 6, state of Alto Parana in Paraguay adopted ivermectin [95].
On September 10, Marchese et al. in Italy reported a case of strongyloidiasis after eleven-day treatment
with high-dose corticosteroids and tocilizumab for severe COVID-19, with a 4-day course of ivermectin
leading to full recovery [111].
On September 11, Elkholy et al. proposed that inhaled ivermectin could attain the desired lung concen-
tration rendering it effective against SARS-CoV-2 [112].
On September 14, Manikappa suggested a quadruple therapy involving ivermectin, doxycycline, zinc and
vitamin D3for both prophylaxis and treatment [113].
10
On September 15, an article by Jans et al. reviewed the existing data on broad-spectrum antiviral effects
of ivermectin, writing that “an instinctive response in developing antiviral agents is to strive for high
specificity since ideally they don’t impact host function. However, viral genomes of RNA viruses have
a high propensity to mutate. Host-directed agents that impact host cellular pathways utilized by many
viruses may largely circumvent the problem of development of viral resistance and have true potential
to be broad-spectrum antivirals” [6].
On September 15, a preprint by Carvallo et al. described an early treatment prospective trial of iver-
mectin, dexamethasone, enoxaparin and aspirin in Argentina with 167 patients, indicating a mortality
rate of 3% in hospitalized cases in study vs 25% cases in the same hospital not in the study (RR 0.12,
p=0.05) (IDEA, NCT04425863) [114];[115];[116];[117];[118].
On September 20, Sparavigna’s review was updated [67]. Among other issues it mentioned that the
reason for continuing high mortality in Peru was self-medication with corticosteroids in the early phase,
with these patients being hospitalized in worse condition than patients who had not self-medicated [119].
The review also suggested that it was not possible to separate the effect of ivermectin among widespread
self-medication with ivermectin, chloroquine, hydroxychloroquine, azithromycin and a “famous triple”
consisting of piperacillin-tazobactum, metamizole and intramuscular dexamethasone.
On September 22, a study by Li et al. was the first to provide ivermectin-regulated virus-related path-
ways by SILAC quantitative proteomics analysis, which revealed a broad-spectrum antiviral property
of ivermectin [120]. The 52 identified ivermectin-regulated proteins included some reported SARS-CoV-
2 related proteins, which the authors suggested could assist in exploiting potential ivermectin-related
biomarkers and the novel mechanisms in the treatment of SARS-CoV-2 infection.
On September 24, a retrospective late treatment study by Khan et al. with 115 ivermectin-treated
patients and 133 controls indicated a mortality rate of 0.9% vs 6.8% (RR 0.13, p<0.05) and 73.3% lower
time to viral clearance (relative time 0.27, p<0.001) [121].
On September 24, Tilli et al. warned that even low-dose corticosteroids may induce a strongyloidiasis
hyperinfection and dissemination with very high fatality rate, suggesting that immigrants and elderly
patients should be either screened for strongyloidiasis or presumptively treated with ivermectin when
treatment with steroids is imminent [122].
On September 25, a rapid response by Taylor to an interview of Dr. Anthony Fauci asked why Fauci’s
approach to the AIDS epidemic and the COVID-19 pandemic were so different with regard to his attitudes
to the importance of clinical trials, more specifically, why in the case of AIDS it was more important to
try even unproven, experimental treatments to save patients than rigidly follow formal rules, whereas in
the case of COVID-19 the rules could not be at all flexible [123];[124].
On September 30, a peer-reviewed randomized controlled late treatment study by Chachar et al. with
25 ivermectin-treated patients and 25 controls did not produce a statistically significant result [125]. On
the same day, the Dominican Republic adopted ivermectin country-wide [3].
October 2020
In the beginning of October, Chamie published a preprint reviewing the epidemiological “real-world” evi-
dence of the effect of ivermectin mass distribution in Peru on COVID-19 excess deaths in the population
older than 60 years [126].
The data was presented also on TrialSite News on October 5 [127]. The article commented that “the
Peruvian government approved the use of ivermectin by decree on May 8. Despite having received several
requests to suspend it in September . . . the new Minister of Health ratified it. These measures have
aroused much criticism among the scientific community. They do not understand why [Peru] continues
to distribute the antiparasitic drug without having a randomized blind study to prove its effectiveness
and overlook that the total death toll from COVID-19 in Peru is one of the world’s highest”.
On October 8, an in silico study by Frances-Monerris et al. indicated that a wide spectrum of actions
of ivermectin involving interference with cell infection, inhibition of viral replication and elusion of the
11
host immune system could point to an unprecedented synergy between host- and virus-directed effects
explaining the observed high anti-SARS-CoV-2 activity [128].
On October 8, a retrospective database study about late treatment by Soto-Becerra et al. in Peru
indicated no beneficial effect from ivermectin [129];[130]. The CovidAnalysis group and others criticized
the methodology of the study [131];[132].
On October 9, a preprint of a randomized controlled late treatment study by Mahmud et al.
(NCT04523831) with 183 patients in the treatment group and 183 controls indicated 49% lower risk
of no recovery (23% vs 37.2%, RR 0.51, p<0.004), 55% lower risk of disease progression (8.7% vs 17.8%,
RR 0.45, p<0.01) and 42.0% lower risk of no virological cure (7.7% vs 20.0%, RR 0.58, p<0.001) [133];
[134].
On October 10, states of Uttar Pradesh in Northern India with a population 210 million people and the
state of Goa on the Southwestern coast of India with a population of 1.5 million people adopted early
home treatment kits which include ivermectin [95];[135].
On October 11, Kant et al. from Uttar Pradesh published a review of ivermectin describing the Uttar
Pradesh treatment model of prophylaxis for contacts: 0.2 mg/kg on days 1 and 7, and prophylaxis for
healthcare workers: 0.2 mg/kg on days 1, 7 and 30, followed by monthly for six months. The total cost of
ivermectin treatment of COVID-19 patients was USD 15 for 12 mg twice daily for 3-7 days; it was used
in combination with doxycycline [136]. Earlier on September 20, Medtalks had published an interview
of the researchers [137].
On October 12, Scheim hypothesized that ivermectin may limit virulence of SARS-CoV-2 by steric inter-
ference with multivalent spike protein attachments to sialic acid binding sites, blocking hemagglutination,
an effect likely to target mutant viral strains [138].
On October 12, the Ministry of Health of Peru retracted the ivermectin recommendation for hospitalized
patients [139]. Distribution in many outpatient clinics continued.
On October 13, final results of the 280-patient retrospective late-treatment ICON study by Rajter et
al. were published in the journal Chest, indicating 13.3% vs 24.5% total mortality (OR 0.47, 95% CI
0.22-0.99, p=0.045) and 32% vs 81.8% mortality in severe disease (OR 0.27, 95% CI 0.08-0.92, p=0.002)
[58];[59].
On October 15, a Peruvian newspaper reported on a controversy about the Ministry of Health first
allowing treatment of hospitalized patients with hydroxychloroquine, azithromycin and ivermectin in
May, then disallowing them in October [140]. The news report pointed to a local study indicating no
benefit from ivermectin and harm from hydroxychloroquine-azithromycin combination in hospitalized
patients. Apparently, the change only concerned inpatients, not outpatients, for which self-treatment
kits had been distributed since May.
On October 18, a trial in Sofia, Bulgaria was completed (EudraCT 2020-002091-12) [44].
On October 19, a study about prophylaxis of healthcare workers with ivermectin and carrageenan by
Carvallo et al. (IVERCAR, NCT04425850) with 131 treated and 98 controls indicated a 96.3% reduction
in infections (0% vs 11.2%, RR 0.04, p<0.001) [141];[142];[117]. Carvallo later reported that carrageenan
is not necessary [143].
On October 22, a review of ivermectin use in Africa by Guerrero et al. estimated a 28% lower COVID-19
mortality in African countries using ivermectin for control of onchocerciasis vs African countries not
using it (RR 0.72, 95% CI 0.67-0.78) [144];[145].
On October 26, a randomized controlled late treatment study by Hashim et al. in Iraq (NCT04591600)
with 70 patients treated with ivermectin and doxycycline and 70 controls indicated mean times to recovery
of 6.3 vs 13.7 days in patients with mild or moderate disease (p<0.0001) and 10.6 vs 17.9 days for all
patients (p<0.0001) [146];[147].
On October 28, Gupta et al. published a study about the binding mechanism of ivermectin, identifying
RNA-dependent RNA polymerase (RdRp), an enzyme that catalyzes the replication of RNA from an
RNA template, as the most probable target for ivermectin [148].
12
On October 30, the Front Line COVID-19 Critical Care Alliance (FLCCC) published an ivermectin-based
I-MASK+ protocol for prophylaxis and early outpatient treatment of COVID-19 [149];[150]. According
to the authors, ivermectin was considered the first agent effective for both prophylaxis (prevention)
of COVID-19 and for treatment of all phases of COVID-19 including outpatient treatment of the early
symptomatic phase. Ivermectin was also upgraded from an optional component to an essential component
of the group’s MATH+ inpatient protocol which was later renamed to I-MATH+ protocol.
On October 31, a preprint by Chang et al. described ivermectin pre-exposure prophylaxis of 129 persons,
indicating a dose and dosing interval dependent prophylactic responses between 90% and 100% [151].
Off-label use of ivermectin for COVID-19 begun in some regions of the US by the end of October,
with the total prescription count of ivermectin multiplying approximately six-fold [3]. A Reddit channel
/r/covidlonghaulinfo was founded [152].
November 2020
On November 3, a matched case-control study by Behera et al. in India with 41 cases and 76 controls
about ivermectin prophylaxis of healthcare workers using two doses of 0.3 mg/kg on days 1 and 4 indicated
a 73% reduction in infections in the following month (p<0.001) [153];[154].
On November 3, a peer-reviewed article by Morgenstern et al. in the Dominican Republic described a
retrospective observational study about early treatment with ivermectin and azithromycin [155]. 2,706
outpatients with mild infection were treated with a single dose of 0.4 mg/kg ivermectin and 500 mg
of azithromycin for five days. The average delay between the onset of symptoms and the initiation of
treatment was 3.6 days. Sixteen (0.59%) later required hospitalization without ICU care. Two (0.08%)
required hospitalization with ICU care, of which one (0.04% of total) died.
On November 4, a preprint describing an open-label observational prospective study by Cadegiani et al.
about early outpatient treatment of 110 patients and 137 controls (a group of paired untreated patients
randomly obtained retrospectively from the COVID-19 patient population of the same community) with
0.2 mg/kg/day of ivermectin for three consecutive days 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) [156];
[157];[158].
On November 6, Carvallo said in an interview that after publication of the results (IVERCAR,
NCT04425850) in Argentina, the group met resistance from many doctors working in the pharmaceuti-
cal industry, likely due to the too low cost of treatment, approximately USD 2 per day [143]. He also
stated that at that time, half of Argentina’s states had adopted ivermectin protocols by decisions by
local governments, with the rest of the states working on adoption. According to Carvallo, the protocols
were also used in Chile, Paraguay, Bolivia, Southern Brazil, Peru, Venezuela, Colombia, Equador, Costa
Rica, the Dominican Republic and Honduras. He also commented that “for those who follow the WHO,
it’s like blind person following another blind person, because WHO has committed so many mistakes
that we sometimes wonder whether WHO has doctors in its staff, because the mistakes they have made
are really blunders, and it’s impossible to believe that experienced people working in an international
organization like WHO could commit so many mistakes”.
On November 6, in France, a criminal lawyer representing the Association of COVID-19 Coronavirus
Victims in France pleaded in favor of ivermectin before an administrative tribunal, asking for temporary
permit. Neither a representative of the Ministry of Health nor the national drug agency was present at
the hearing. The request was rejected by the judge [159].
On November 10, a preprint by Turkia briefly reviewed the early history of the FLCCC Alliance protocols,
suggesting that ivermectin should be used based on existing data suggesting significant benefits, and that
waiting for additional data may result in significant harm [160];[161].
On November 11, a preprint indicated that 0.6 mg/kg/day for five days was well tolerated
(NCT004381884) [162]. A significant difference in reduction in viral load was found in patients with
higher median plasma ivermectin levels (72% IQR 59–77) versus untreated controls (42% IQR 31–3)
13
(p=0.004). The mean ivermectin plasma concentration levels also showed a positive correlation with
viral decay rate (r=0.47, p=0.02).
On November 11, a peer-reviewed retrospective study by Camprubi et al. with 13 treated patients and
13 controls about late treatment of severe disease with 0.2 mg/kg ivermectin plus hydroxychloroquine
initiated a median of 12 days after symptoms did not indicate a statistically significant result, leading
the authors to suggest a trial with a larger dose [163];[164]. On the same day, a podcast described
Brazilian distribution of ivermectin [165].
On November 13, a preprint by Elgazzar et al. of a randomized controlled prophylaxis trial with a group
including healthcare workers (pre-exposure) and outpatients’ family members (post-exposure) with 100
members in total, compared to 100 healthcare workers and family members using only standard personal
protective measures (hand hygiene, social distancing measures, avoiding touching the eyes or nose, and
face masks, gloves, respiratory etiquette and self-isolation). The prophylaxis group received a single dose
of 0.4 mg/kg ivermectin at days 1 and 8. The results indicated infection rates of 2% vs 10%, i.e. 80% lower
risk of infection (RR 0.20, p=0.03) [166];[167]. The same preprint included results of a late treatment
randomized controlled trial comparing ivermectin and relatively low dose of hydroxychloroquine indicated
a 50% reduction in time to viral clearance and a substantially lower risk of death, although the effect of
hydroxychloroquine in late treatment is inconsistent and it may increase mortality.
On November 13, an initial version of a preprint by the FLCCC group was posted on osf.io [168].
The preprint included a brief meta-analysis of mortality data from three observational studies (Rajter
et al, Khan et al, Gorial et al; OR 0.48, 95% CI 0.27-0.84, p=0.011) and two randomized controlled
studies (Mahmud et al, Hashim et al; OR 0.26, 95% CI 0.06-1.09, p=0.065), indicating a statistically
significant overall mortality benefit (OR 0.44, 95% CI 0.26-0.75, p=0.002). The report also cited a study
by Chamie that compared one state in Paraguay with mass distribution of ivermectin to three states
without distribution, showing a reduction in case counts and deaths, and Chamie’s similar study about
reduction of excess deaths of over 60 year olds in Peru.
On November 14, a peer-reviewed late-treatment prospective trial in India by Spoorthi et al. with 50
treated patients and 50 controls using ivermectin (a single dose of 0.2 mg/kg) and doxycycline combina-
tion indicated a 15.5% lower hospitalization time (relative time 0.84, p=0.01) and 21.1% lower recovery
time (relative time 0.79, p=0.03) [169];[170].
On November 17, a peer-reviewed report of a prophylaxis study (IVERCAR, NCT04425850) in Argentina
by Carvallo et al. with 788 healthcare workers and 407 controls indicated 0 (0%) vs 237 (58.2%) cases
of COVID-19, respectively (99.9% lower risk of infection, RR 0.001, p<0.001) [171];[172];[117]. The
reported dosing regime was one drop of ivermectin-containing liquid orally five times a day (every four
hours) for 14 days, with food and liquids avoided for one hour before and after treatment. The dosing
regime amounted to 12 mg per week. Hirsch and Carvallo also published an updated prophylaxis protocol
[173].
On November 17, Facebook begun removing ivermectin-related posts by the FLCCC Alliance, stating
that they did not follow Facebook’s community standards [174].
On November 18, an updated version of a preprint by the FLCCC group added a randomized controlled
trial by Elgazzar et al. to the meta-analysis, with three randomized controlled studies indicating a
statistically significant overall mortality benefit (OR 0.14, 95% CI 0.05-0.39, p<0.001), larger than the
observational studies or the overall result (OR 0.36, 95% CI 0.21-0.59, p<0.001) [168].
On November 18, a retrospective late treatment study in India by Budhiraja et al. of 34 ivermectin-
treated patients and 942 controls indicated a 99.1% lower risk of death (0% vs 10.9%, RR 0.009, p=0.04)
[175];[176].
On November 19, in an US Senate hearing, George C. Fareed, a Harvard professor with a background
in virology research at NIH, witnessed about usefulness of an early outpatient treatment with hydrox-
ychloroquine, zinc and ivermectin [177];[178]. A group called CovidAnalysis had earlier published
a meta-analysis of nine randomized controlled trials about early, pre-exposure prophylaxis, or post-
exposure prophylaxis treatment with hydroxychloroquine, stating that all trials reported positive effects
with an average of 30% risk reduction (RR 0.70, 95% CI 0.53-0.93, p=0.002) [179].
14
On November 24, the New York Times published an opinion by Brown University dean Jha, another
witness at the November 19 US Senate hearing. In the opinion, Jha called other witnesses including
Fareed “snake oil salesmen” and the hearing a “misinformation super-spreader event” [180].
On November 24, a preprint about a late treatment randomized controlled trial by Niaee et al. with 180
hospitalized patients with ivermectin but all patients receiving also a low dose of hydroxychloroquine
indicated dosing-dependent reductions in risk of death between 45.5% and 94.3% [181];[182].
On November 25, the Wall Street Journal published an article about too much caution killing COVID-19
patients, saying doctors should follow the evidence for promising therapies but “instead they demand
certainty” [183]. The article stated that “fear and panic are central impediments to competent decision-
making during a crisis . . . [creating] an air of inevitability, as if politicians have no choice but again to
restrict civil liberties, limit social gatherings, and cripple businesses that survived the initial lockdowns.
But there’s a better way: following the evidence for early treatment of Covid-19 . . . The health system
would be less burdened if more patients were treated before they require hospitalization, and there are
promising therapeutic options that patients can administer themselves at home. This was the subject of a
Nov. 19 hearing before the Senate Homeland Security and Governmental Affairs Committee. Testimony
from the hearing underscored an important issue: Too many doctors have interpreted the term ‘evidence-
based medicine’ to mean that the evidence for a treatment must be certain and definitive before it can be
given to patients. Because accusing a physician of not being ‘evidence based’ can be a career-damaging
allegation, fear of straying from the pack has prevailed, favoring inertia and inaction amid uncertainty
about Covid-19 treatments .. . when options are limited and there are safe treatments with evidence for
effectiveness, holding out for certainty can be catastrophic”.
On November 26, the CovidAnalysis group published a random-effects meta-analysis of 21 existing
ivermectin studies at the website ivmmeta.com, indicating an overall 75% reduction in the effect measured
(death, hospitalization, etc.) (RR 0.25, 95% CI 0.16-0.40, p=0.00000048), and 60% reduction in twelve
late treatment studies (RR 0.40, 95% CI 0.24-0.66, p=0.00024) [184]. Eight randomized controlled trials
indicated a 72% risk reduction (RR 0.28, 95% CI 0.13-0.59, p=0.0039). All 21 studies reported positive
effects, indicating a consistent effect in all stages of COVID-19.
On November 26, Syed discussed the mechanisms behind ivermectin’s action against SARS-CoV-2, also
introducing the I-MASK+ protocol [185];[186];[187];[188];[189];[190].
On November 28, a peer-reviewed statistical analysis of ivermectin prophylaxis by Hellwig et al. compared
African states with ivermectin mass distribution to African states without distribution, concluding that
mass distribution is associated with lower COVID-19 incidence and that prophylaxis could help bridge
the time until a vaccine becomes widely available [191].
On November 28, a peer-reviewed retrospective study in France by Bernigaud et al. described a case of
69 residents of a care home with a median age of 90, treated with ivermectin for scabies outbreak, with
seven (10.1%) later diagnosed with probable or certain COVID-19, with no serious cases and no deaths
[192];[193]. In residents in comparable care homes there were 22.6% infections and 5% deaths. The
CovidAnalysis group calculated 99.4% lower risk of death (0% vs 4.9%, RR 0.006, p=0.08) and 55.1%
lower risk of infection (10.1% vs 22.6%, RR 0.45, p=0.01).
On November 30, Egypt adopted ivermectin country-wide [3].
December 2020
On December 1, preliminary results of an early treatment observational study in Argentina by Alonso et
al. with 311 patients treated with ivermectin and 128 controls indicated 91.8% lower risk of death with
one (0.3%) deaths in the treatment group vs five (3.9%) in the controls (RR 0.08, p=0.009) [194].
On December 2, a peer-reviewed randomized controlled trial by Ahmed et al. with 72 patients treated
with 5-day course of ivermectin indicated a 42.5% lower risk of no virological cure at day 7 (50% vs 87%,
RR 0.58, p=0.01) and a 62.7% lower risk at day 14 (22.7% vs 60.9%, RR 0.37, p=0.02) [195];[196].
15
On December 3, Chamie posted a diagram of an analysis on Twitter, suggesting that distribution of
ivermectin home treatment kits since July 2020 in the state of Chiapas had resulted in lower mortality
in that state, compared to states without home treatment kits [197];[198];[199].
On December 4, the FLCCC Alliance organized a press conference, urging the NIH and CDC to imme-
diately review the research evidence that had appeared after the NIH’s September guideline, to allow
early outpatient treatment. The alliance suggested that widespread, immediate use of ivermectin “would
allow for a rapid and safe reopening of businesses and schools across the nation and quickly reduce the
strain on overwhelmed hospitals and ICUs” [200].
On December 7, a preprint of an early treatment double-blind randomized controlled trial (SAINT) in
Spain by Chaccour et al. with 12 patients treated with a single dose of 0.4 mg/kg ivermectin and 12
controls indicated 52.9% lower risk of unresolved symptoms at day 28 (RR 0.47, p<0.05) but no difference
in the primary outcome (the proportion of PCR positives), for which the trial was labeled negative by
many commentators [201];[202].
On December 7, the New York Times wrote that an upcoming December 8 US Senate panel had been
transformed into “a forum amplifying dubious theories and questionable treatments pushed by President
Trump”, adding that two witnesses “promote the use of ivermectin, a drug often used to fight lice and
pinworms, to treat coronavirus patients, despite the National Institutes of Health’s recommendation
against its use outside clinical trials” [203]. A democrat senator feared that the witnesses would “amplify
theories that are at odds with the broader scientific community and, according to experts, could cause
harm” and that “these fringe views run counter to what the Senate should be doing — working on a
bipartisan basis to protect the American people and tackle this deadly pandemic”.
On December 7, a rapid response by Hoy et al. stated vaccines alone are not enough and treatments will
still be needed for people with a vaccine-breakthrough disease and for those who refuse or otherwise do
not receive the vaccine [204].
On December 8, the Front Line COVID-19 Critical Care Alliance (FLCCC) president Pierre Kory gave
a testimony to US Senate Committee on Homeland Security and Governmental Affairs about the state
of ivermectin research [205].
On December 9, a post on FLCCC Alliance Facebook page commented that “we are thrilled to be back
with you after a three-day stint in Facebook jail for writing the name of a component of our I-Mask+
Prophylaxis and Early Outpatient Treatment Protocol on our Sunday post”. The post also gave a link
to YouTube video of Pierre Kory’s testimony on December 8. Facebook issued a warning that further
mentions of ‘ivermectin’ would result in a permanent deletion of the FLCCC page. Later posts on
the page referred to the ‘i-word’ and referred readers to the group’s website and Twitter for further
information.
On December 11, a peer-reviewed early treatment case series study in Bangladesh by Hussain et al. with
8 patients resulted in all patients testing negative by day six [206];[207].
On December 11, an article by Associated Press, “a part of The Associated Press’ ongoing effort to
fact-check misinformation that is shared widely online, including work with Facebook to identify and
reduce the circulation of false stories on the platform”, discussed Kory’s Senate Committee testimony
mentioning it had received one million views on YouTube, and referring to comments by two infectious
disease experts it concluded that “there’s no evidence ivermectin has been proven a safe or effective
treatment against COVID-19” [208].
On December 12, a post on FLCCC Alliance Facebook page noted that YouTube had taken down the
video of Kory’s US Senate Committee testimony. On December 14, another post commented that the
group’s repeated attempts to reach out to US health authorities including NIH, CDC and FDA in order
to discuss the information given in the Senate Committee testimony had failed.
On December 15, a preprint of an 95-patient early treatment study in Pakistan by Afsar et al. with
all patients receiving a low dose of hydroxychloroquine an azithromycin and the treatment group also
receiving ivermectin indicated 92.2% lower risk of fever at day 14 (0% vs 13.2%, RR 0.08. p=0.04) [209];
[210].
16
On December 15, a peer-reviewed observational prophylaxis study in Bangladesh by Alam et al. with
118 healthcare workers, of which 58 received 12 mg ivermectin monthly, indicated 90.6% lower risk of
infection (6.9% vs 73.3%, RR 0.09, p<0.001) [211];[212].
On December 17, the National Institutes of Health published an update to their guideline on prevention
and prophylaxis of SARS-CoV-2 infection [213]. The panel gave a strong recommendation based on expert
opinion only (class A III), recommending against the use of any agents in either pre-exposure or post-
exposure prophylaxis, except in clinical trials. Ivermectin was not mentioned in the recommendation.
On December 18, a preprint by Kory et al. presented a meta-analysis of one observational prophylaxis
studies (OR 0.06, 95% CI 0.03-0.11) and three randomized controlled prophylaxis studies (OR 0.13, 95%
CI 0.07-0.22) [214].
On December 18, Belize adopted ivermectin country-wide for serious cases [215];[3];[95].
On December 18, MedinCell announced that a continuous administration over a one-month period to
healthy volunteers confirmed ivermectin’s safety up to a daily dose of 75 μg/kg (NCT04632706) [216];
[217]. A news report commented that “as the vaccines won’t solve all of the short -term potential problems
with COVID-19 the challenge is that at least thus far government agencies in wealthy GPD nations show
little to no interest in such repurposed, generic drug responses” [218].
On December 20, a preprint of a prophylaxis study in Argentina by Vallejos et al. with 389 treated
patients and 486 controls indicated 73.4% lower risk of COVID-19 case (3.3% vs 12.6%, RR 0.27, p<0.001)
[219];[220].
On December 21, a news report described a late stage treatment experiment just initiated by professor
Cacopardo in Sicily, Italy, with results not yet available [221].
On December 23, Macedonia adopted ivermectin country-wide [3].
On December 23, Merck & Co/MSD announced it had entered into agreement with the United States
Government to develop, manufacture and distribute a biological therapeutic MK-7110 upon approval
or emergency use authorization from the FDA [222]. The company was to receive USD 356 million
for supply of 60,000-100,000 doses of MK-7110 for US Government through June 30, 2021 (apparently
indicating a price of USD 3,560.00-5,933.00 per dose). An interim analysis of 203 participants (75% of
planned enrollment) of a phase 3 study evaluating MK-7110 for severe and critical COVID-19 indicated
that a single dose showed a 60% higher probability of improvement and a more than 50% reduction in
risk of death or respiratory failure.
On December 24, a Macedonian newspaper wrote that the drug agency MALMED is going to approve
ivermectin for COVID-19 in Macedonia [223]. The price was said to be 12 euros (USD 14) per 12
mg. Ivermectin was said to be an integral part of hospital protocols in Bulgaria already, utilized by
for example professor Ivo Petrov at Acibadem City Clinic in Sofia, Bulgaria. Petrov commented when
ivermectin is applied in the first few days after the onset of symptoms they resolve significantly faster
and oxygenation is required less often. Petrov was also taking ivermectin for personal prophylaxis.
On December 24, a Facebook post by the FLCCC group commented that “the Associated Press refuses
to retract its article saying there is no evidence that the medicine we cannot name on FB can prevent
or treat COVID-19. To suppress this information is to bless a massacre that can be stopped.”
On December 24, a South African newspaper wrote that import ivermectin into South Africa had been
declared illegal by the South African Health Products Regulatory Authority (SAHPRA). Its chief exec-
utive stated that “our stance is unambiguous. This drug is not approved by SAHPRA and any attempt
to import it into the country will be dealt with by SAHPRA’s regulatory compliance unit in conjunction
with law enforcement agencies .. . SAHPRA is focused on quality, safety and efficacy and its ultimate
goal is to protect the health and well-being of all those who live in South Africa” [224].
On December 25, a Facebook post by the FLCCC group commenting NIH’s December 17 guideline
update stated that “the refusal of the NIH to cite or even acknowledge the irrefutable evidence in our
scientific manuscript means that tens of thousands of Americans will now go to their early graves. This
is an unconscionable and murderous declaration not based in science or the medical facts .. . When
17
history is written about how the NIH inexplicably placed the citizens it was impaneled to protect in
harm’s way, we will weep bitter tears at the words on the page”.
On December 27, Hill et al. published a YouTube video “Ivermectin meta-analysis by Dr. Andrew Hill”
giving out initial results of a WHO-funded meta-analysis [225]. The presented conclusions were as follows:
“In this meta-analysis of 11 randomized trials in 1452 patients, ivermectin treatment was associated with:
faster time to viral clearance, shorter duration of hospitalization, 43% higher rates of clinical recovery
(95% C.I. 21-67%), 83% improvement in survival rates (95% C.I. 65-92%)”. The video was branded
with University of Liverpool, Access to COVID Tools Accelerator and Unitaid logos. Unitaid is a global
health agency hosted by the World Health Organization [226]. The Access to COVID Tools Accelerator
is a partnership of the Bill & Melinda Gates Foundation, CEPI, FIND, Gavi [227], The Global Fund,
Unitaid, Wellcome, WHO and the World Bank [228]. From February to the end of March 2021, the link
lead to a notice “This video has been removed for violating YouTube’s Community Guidelines”.
On December 27, without warning or explanation, Twitter deleted the account of the CovidAnalysis
group which had provided meta-analyses of randomized controlled trials on various proposed treatment
agents for COVID-19, including ivermectin, vitamin D, hydroxychloroquine and zinc [229]. However,
the FLCCC Alliance was allowed to tweet about ivermectin, and in December 2020 it routinely referred
people from its Facebook page to its Covid19Critical Twitter account for news and updates about its
ivermectin protocols.
On December 28, in France, a preliminary filing was forwarded to the minister of health and to the
national medicines agency, requesting a temporary recommendation [159].
On December 30, a review by McCullough et al. stressing the need for early outpatient treatment with a
sequential multi-drug treatment algorithm mentioned home-based treatment kits with ivermectin having
been distributed in Argentina, Bangladesh, Colombia, India, Mexico and Peru [230].
On December 31, a peer-reviewed version of the brief review of the early history of the FLCCC Alliance
was published [149].
On December 31, a peer-reviewed study by Madrid et al. investigating safety of ivermectin in a fish
model stated that high doses of 0.22 and 0.86 mg/kg were not harmful to the intestinal tissues of the
animal model neither affected the blood cells counting in general [231]. An overdose of 170 mg/kg (10.2
g for a 60 kg person) in increased expression of the Myosin-Vb which may have implications in the
intestinal epidermal integrity [232].
On December 31, a report of three late-stage cases by Wijaya et al. reported significant clinical and
radiological improvement after a single dose of ivermectin [233].
January 2021
On January 3, Lawrie et al. published a preprint of a rapid review and meta-analysis of seven ivermectin
trials, indicating a mortality relative risk RR 0.17 (0.18-0.35) and prophylaxis cases RR 0.12 (0.08-0.18)
[234];[235]. Also on January 3, Kaur et al. published a review including results of molecular dynamics
simulations [236].
On January 4, Lawrie submitted an initial report to the UK government, including results of RCT trial
and basic quality observational controlled trials, showing 83% reduction in mortality [237]. On March 6,
she mentioned not getting any response from the government.
On January 4, Arab News published in Saudi Arabia with a target audience of businessmen, executives
and diplomats wrote about the meta-analysis by Hill et al., describing it as possibly transformative, with
a cost of USD 1-2 for a treatment course [238];[239].
On January 6, an uncontrolled retrospective study about ivermectin prophylaxis (0.2mg/kg weekly for
eight weeks, followed by 4 months rest) for healthcare workers in in Argentina by Hirsch and Carvallo
reported no infections among the 162 participants [240].
On January 6, a randomized controlled clinical trial in Nigeria by Babalola et al. indicated a 58% lower
risk of no virological cure with 12 mg of ivermectin (n=40, p=0.01) [241].
18
On January 6, Marik and Kory from the FLCCC Alliance appeared before the NIH’s COVID-19 Treat-
ment Guidelines Panel to urge review of current data and an updated NIH guidance [242].
On January 6, MedPage Today wrote about “maverick physicians spurning randomized trials”, reviewing
the views of the FLCCC and its critics, writing that “[FLCCC members] don’t see a need for more data
and argue it would be unethical to give placebo to patients given the established safety of ivermectin.
But that’s raising more than a few eyebrows among others in the field” [243]. The article reviewed
Marik’s invention of the hydrocortisone, ascorbic acid and thiamine protocol for sepsis, the FLCCC’s
early adoption of corticosteroids and the resulting 75% reduction in mortality in comparison to average
hospital mortality, and the introduction of the FLCCC’s I-MASK+ ivermectin protocol in October 2020.
The article then continued on to “what the science says”, mentioning four RCTs and South American
experiences about prophylaxis, five RCTs about early treatment, and four RCTs for late treatment,
plus “a host of observational studies and case series”. The article notes that only one of the studies, a
retrospective study, was done in the US.
FLCCC’s Kory was quoted commenting that “if someone wants to discount those studies . . . and says
they want to do an RCT with placebo, that’s problematic for me . .. I could not have a patient admitted
to my care and give placebo knowing what I know about ivermectin . . . [FLCCC members] are firm
believers in evidence-based medicine. But we disagree with how most practice evidence-based medicine.
We think they are way too biased toward randomized controlled trials and completely dismiss evidence
from anything but RCTs. We think that’s harmful and loses a lot of valuable data”. In contrast, an US
medical ethicist was quoted saying that he “doesn’t believe clinicians should be lowering our standards
of evidence because we’re in a pandemic . . . this group should be advocating strongly for a large,
generalizable randomized trial if they believe so strongly in the efficacy of ivermectin .. . If in fact it is
effective, the only way to convince the clinical and scientific community and allow patients all over the
world to benefit is to prove the case in such a trial . . . with good data and safety monitoring, if the
benefits are as overwhelming as they claim, the trial could be stopped early on the basis of interim data
and the treatment rapidly instituted”.
MedPage Today mentioned the meta-analysis by Hill et al. supporting the conclusions of the FLCCC,
said MedPage Today had been unable to confirm whether Hill had been contracted by the WHO, then
quoted an infectious diseases physician who called Hill et al’s overall evidence “very low grade”, adding
that “this whole thing feels like déjà vu of the first two months of the pandemic when we weren’t decided
about hydroxychloroquine .. . we don’t want to come around a year later saying it didn’t help and it
may have hurt”. The rest of the article surveyed whether the FLCCC might have financial connections
to pharmaceutical companies with an interest in ivermectin, the politicization of the issue in the US,
whether the intention of the FLCCC was to undermine vaccinations, and ended with a demand for
“proper studies”.
On January 8, a social media post about an epidemiological analysis by data analyst Juan Chamie
compared the state of Chiapas, Mexico which had adopted ivermectin, to other states which had not
adopted it, indicating a stabilization of cumulative case count in Chiapas but increasing case counts in
other states [244].
On January 8, the Ministry of Health of Peru reinstated ivermectin-containing home-treatment kits after
retracting them in late 2020 [245].
On January 8, South African Health Products Regulatory Authority (SAHPRA) raided a hospital in
search of ivermectin, not finding any [246];[247].
On January 9, a preprint about a double blind randomized placebo-controlled trial (n=112) about iver-
mectin for mild to moderate disease in India by Kirti et al. did not achieve a statistically significant result
but suggested a trend to benefits with regard to mortality, ventilation and ICU admission, for example
a 79% lower risk of ventilation (p=0.09) and 89% lower risk of death (p=0.12) (CTRI/2020/08/027225)
[248];[249].
On January 9, Lawrie posted an open video letter to Prime Minister of the United Kingdom Boris
Johnson, stating her company’s biggest clients are the National Health Service of the United Kingdom
(NHS) and the WHO, for whom the company produces industry-independent medical evidence synthesis
to support international clinical practice guidelines [250];[251];[252];[253];[254];[255]. Lawrie urged
19
Johnson to look at the evidence of ivermectin’s effectiveness, stating her analysis solidly substantiated
the FLCCC’s recommendation to adopt ivermectin globally and systematically for COVID-19.
On January 11, a preprint about an animal dosing study by Mousquet-Melou et al. suggested that iver-
mectin maintenance doses should be based on lean body weight instead of the total body weight in obese
subjects, while the loading dose should be based on the total body weight [256].
On January 11, a randomized controlled trial (Ivercar-Tuc) about ivermectin and iota-carrageenan pro-
phylaxis of 234 healthcare workers in Tucumán, Argentina by Chahla et al. indicated 0% vs 8% severe
cases (p=0.003) and 3.4% vs 21.4% of all cases (p<0.001) (NCT04701710) [257].
On January 11, a Macedonian journal wrote the drug agency MALMED had confirmed ivermectin was
going to be available in pharmacies across the country in a few days [258].
On January 11, a German magazine for pharmacists introduced the Monash University in vitro study,
FLCCC protocols and their meta-analysis, experiences of Peru, Brazil and Paraguay, the ICON study
in the US, the NIH hearing on January 6 with a mention of Hill et al’s meta-analysis, and listed 18
observational or randomized controlled trials that were completed by December 2020 [259].
On January 12, a preprint about a randomized controlled trial (n=60) about late treatment (severe illness)
in Turkey by Okumuş et al. compared low dose hydroxychloroquine, azithromycin and favipiravir with
and without ivermectin, indicating 80% lower risk of no virological cure (12% vs 63%, p=0.02) on day
10 (NCT04646109) [260].
On January 12, a post on the FLCCC group’s Facebook page commented that a post by a group member
“had been taken down for using the full name of the the medicine—and then restored one day later upon
appeal” which was interpreted as Facebook “beginning to recognize the growing body of irrefutable
scientific medical evidence”.
On January 13, a review by Kory et al. (the FLCCC group) was provisionally accepted by Frontiers of
Pharmacology [261]. On the same day, Martin et al. published a review about antivirals that target the
host importin α/β1-virus inferface [262].
On January 14, the US NIH updated its guideline on ivermectin, stating that there are insufficient data to
recommend either for or against the use of ivermectin [263]. The NIH COVID-19 Treatment Guidelines
Panel Financial Disclosure for Companies Related to COVID-19 Treatment or Diagnostics (updated on
February 11, 2021 but covering a period from October 1, 2019 to September 30, 2020, thus not indicating
up-to-date situation), indicated that the panel had 59 members, of which 35 (59%) reported no disclosures
[264]. Eight (14%) reported a connection to Merck & Co/MSD, of which one advisory board/consultant
role, three advisory board roles, two research support roles, one consultant/research support role and
one honoraria role. The updated guideline opened up the possibility of treating COVID-19 patients with
ivermectin.
On January 15, the Association of American Physicians and Surgeons (AAPS) applauded the NIH guide-
line change [265]. AAPS executive director Jane M. Orient referred to 49 ivermectin studies summarized
on c19study.com, 100 percent of which showing favorable results. Orient noted that many medical facili-
ties and many physicians refuse to prescribe it for COVID-19, citing NIH guidance, adding that “Perhaps
with this change, patients won’t need a court order to get a lifesaving drug . . . To have a doctor withdraw
a drug that appears to be saving a patient’s life, because a federal bureaucracy thinks it hasn’t been
studied enough for that use, is shocking to those who believe in the traditional ethic of Hippocrates”.
On January 15, a news report described a case in the US, in which family members of a 80-year ventilated
patient in a severe condition had asked the ICU doctors to administer her ivermectin [266]. A doctor had
administered one dose, with the patient then taken off the ventilator and transferred out of the ICU in less
than 48 hours. Her condition had then deteriorated but the hospital had refused to administer further
doses. The family members had subsequently acquired a court order for the hospital to immediately
administer the patient more ivermectin, which the judge had agreed to.
On January 15, a newspaper reported that El Salvador had classified ivermectin as an over-the-counter
product to boost self-medication in order to combat a second wave of COVID-19 [267]. A television
channel in Honduras was said to have promoted ivermectin as a prophylaxis against COVID-19 “for
20
months”. The government of Honduras, Guatemala, El Salvador and others in South America were
said to have begun distributing home kits with vitamins, acetaminophen, antibiotics and ivermectin
in mid-2020 for patients with mild symptoms. By the end of 2020, 18,000 kits had been distributed
in El Salvador. In Honduras, packages with azithromycin, ivermectin and zinc were distributed. A
Honduran scientist commented that “developed countries make adequate studies to make decisions and
our countries are based on anecdotal information and, practically, anything they hear they set it in
motion”. The government was accused of overpaying and corruption after having purchased 6 mg tables
for 1.08 dollars instead of 0.19 cents per tablet.
On January 15, Bulgarian Drug Agency issued a marketing authorization for 3 mg ivermectin tablets by
prescription [268].
On January 16, a preprint about a randomized controlled trial (n=103) in Pakistan by Asghar et
al. indicated a 90% viral clearance with 0.2mg/kg ivermectin vs 44% in controls (p<0.001) on day
7 (NCT04392713) [269];[270].
On January 16, a preprint about a randomized controlled trial (n=100) about early treatment in Beirut,
Lebanon by Raad et al. indicated a 59% lower risk of viral load (p=0.01) at day 3 (ChiCTR2000033627)
[271].
On January 16, a research letter by Bernigaud et al. described a case of oral ivermectin administration
for controlling a concomitant COVID-19 and ivermectin-treated scabies outbreak in a French long-term
care facility [272].
On January 17, the FLCCC Alliance commented the updated NIH guideline, stating that it “considers the
Panel’s unwillingness to provide more specific guidance in support of the use of ivermectin in COVID-19
to be severely out of alignment with the known clinical, epidemiological, and observational data” [273].
On January 18, a preprint asked whether a part of the mortality assigned to COVID-19 may be due to
an undiagnosed concomitant strongyloidiasis hyperinflammation [274].
On January 19, a WHO-funded meta-analysis with 40 authors including Andrew Hill analyzed 18 ran-
domized controlled trials with a total of 2,282 patients. The results indicated improved clinical recovery,
and lower hospitalization and mortality. Six RCTs of moderate or severe infection indicated a 75% re-
duction in mortality (RR 0.25, CI 0.12-0.52, p=0.0002) [275]. The report stated that “this meta-analysis
investigated ivermectin in 18 randomized clinical trials (2,282 patients) identified through systematic
searches of PubMed, EMBASE, medRxiv and trial registries. Ivermectin was associated with reduced
inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral
clearance was treatment dose- and duration-dependent. In six randomized trials of moderate or severe
infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95% CI 0.12-0.52]; p=0.0002);
14/650 (2.1%) deaths on ivermectin; 57/597 (9.5%) deaths in controls) with favorable clinical recovery
and reduced hospitalization. Many studies included were not peer reviewed and meta-analyses are prone
to confounding issues. Ivermectin should be validated in larger, appropriately controlled randomized
trials before the results are sufficient for review by regulatory authorities.”
On January 19, a randomized controlled trial on hospitalized patients (n=103) in Iran by Rezai et al.
indicated a 21% lower recovery time (p=0.02) and 18% lower hospitalization time (p=0.01) [276];[275].
On the same day, Tehran Times wrote that Iran was starting its own production of ivermectin [277].
On January 20, MedPage Today interviewed an US chief of hospital medicine who warned against para-
sitic “hyperinfection” in foreign patients, saying they “will need to be treated prophylactically for strongy-
loides, a parasitic infection that can emerge after corticosteroids are administered. The regimen is two
doses of ivermectin, one day apart, with the first dose preferably given before steroids are administered”
[278].
On January 20, a peer-reviewed in vitro study by Mody et al. indicated that ivermectin blocked more
than 85% of 3CLpro activity of SARS-CoV-2, thus suggesting an additional antiviral mechanism via
inhibitory effects on 3CLpro, in addition to the previously identified blocking of α/β1 importin [279].
On January 20, the Financial Times wrote that a cheap antiparasitic could cut chance of Covid-19 deaths
by up to 75%, citing the WHO-funded meta-analysis carried out by Hill et al. [280]. Hill stated that the
21
drug costs USD 3 in India and USD 960 in the US. Hill also noted that the purpose of his group’s meta-
analysis was “to forewarn people that this is coming: get prepared, get supplies, get ready to approve it
. . . we need to be ready”.
On January 21, a second, more polished preprint by Chamie-Quintero et al. analyzed the effects of
distribution of ivermectin in Peru, spanning an area equivalent to that from Denmark to Italy and
Greece in Europe or from north to south along the US, with a total population of 33 million [281]. In 24
Peruvian states vs one state without distribution, excess deaths for ages >=60 dropped by 59% vs 25%
at 30 days, and by 75% vs 25% at 45 days after the day of peak deaths, even though indices of community
mobility rose over the same period. For nine states that carried out mass distributions of IVM in a short
timeframe through a national program, excess deaths at 30 days dropped by a population-weighted mean
of 74%, each drop beginning within 11 days after the program start.
On January 23, the Times (UK) wrote that researchers at Oxford University are planning “the first, large
high-quality trial of a cheap drug that has been credited with dramatically reducing Covid-19 deaths in
the developing world” [282]. The trial was named ‘Principle’, aimed at identifying an early treatment
method that would prevent severe illness. On the same day, Errecalde et al. published results of an
animal study about a novel ivermectin nasal spray formulation [283].
On January 24, the FLCCC Alliance posted an open letter to the investigators of the Principle trial,
urging the investigators to properly inform enrolling patients about the efficacy of ivermectin, stating
that “inadequately communicating this information to potential participants would be a violation of
the primary responsibilities of clinical researchers as directed by the Belmont report to protect human
subjects of biomedical research” [284].
On January 25, a third attempt to allow emergency use of ivermectin in France was addressed to the
Council of State. Among the plaintiffs were 18 doctors and three associations: Syndicat des Médecins
d’Aix et Région, International Association for Scientific, Independent and Benevolent Medicine, and Bon
Sens [159];[285].
On January 25, Merck & Co/MSD announced that it discontinues development of COVID-19 vaccine
candidates but continues development of two investigational therapeutic candidates, MK-4482 (molnu-
piravir) and MK-7110 [286]. Molnupiravir was described as an oral novel antiviral agent for both in- and
outpatients, with initial efficacy data expected to be available in the first quarter of 2021.
On January 25, a news report described professor Cacopardo’s experiment in treating patients with
severe disease in Sicily, Italy a success, with Cacopardo commenting that “the patients who were given
ivermectin did very well . . . I have the impression that ivermectin combined with traditional therapies
is able to effect a dramatic improvement in clinical picture . . . we have used it in four serious cases of
bilateral pneumonia . . . after the administration of ivermectin, an impressive improvement of the clinical
picture was observed in the next 48 hours” [287]. The medicine was said to cost 12 cents per dose to
produce.
On January 26, a news report about the trial in Sofia, Bulgaria (EudraCT 2020-002091-12) said the
double-blinded, placebo-controlled ivermectin study had been conducted with 100 patients in 12 centers,
with 0.4 mg/kg of ivermectin on three consecutive days [288];[289];[290]. The results were said to
be positive, with a mention about reporting them to the WHO in order to include ivermectin in the
COVID-19 treatment options.
On January 27, the CovidAnalysis group claimed that the retrospective database analysis of 5,683 pati-
ents in Peru by Soto-Becerra exhibited “clear evidence of extreme bias” [129];[132].
On January 27, in a parliament session, an UK member of parliament David Davis asked Prime Minister
Boris Johnson about enhancing primary care to reduce the need for hospitalization, mentioning ivermec-
tin has been observed to reduce mortality by 75%. Johnson replied that he is aware of the results and
that therapeutics task-forces are currently reviewing ivermectin [291].
On January 27, a preprint of a meta-analysis by Castañeda-Sabogal et al. including twelve studies (five
retrospective cohort studies, six RCTs and one case series) with a total of 7,412 participants stated
that all studies had a high risk of bias and showed a very low certainty of the evidence. Ivermectin was
not associated with reduced mortality (logRR 0.89, 95% CI 0.09-1.70, p=0.04, I2=84.7%), or reduced
22
patient recovery (logRR 5.52, 95% CI -24.36-35.4, p=0.51, I2=92.6%). The meta-analysis concluded that
there was insufficient certainty and quality of evidence to recommend the use of ivermectin to neither
outpatients, inpatients nor prophylaxis [292]. The CovidAnalysis group described the meta-analysis as
“student-written meta analysis of a very small subset of studies exhibiting very high bias and significant
flaws .. . [having] no logic in the exclusion reasons . . . we checked the reported results for the mortality
outcome and found they do not appear to match the actual papers” [293].
On January 27, a news report stated that the South African Health Products Regulatory Authority
(SAHPRA) will consider ivermectin on a case-by-case basis, requiring practitioners to apply for approval
before use [294].
On January 29, a final peer-reviewed version of an article by Jans and Wagstaff was published [11].
On January 29, the French national institute of health and medical research (Institut national de la santé
et de la recherche médicale) issued a press release warning against the use of ivermectin outside clinical
trials, criticizing the first in vitro study and studies by Rajter et al. and Bernigaud et al. [295];[296].
On January 30, Tokyo metropolitan government announced plans to conduct clinical trials for patients
with mild symptoms at hospitals. The plan was to eventually apply the method for outpatient treatment
[297]. The article also mentioned that a 240-patient clinical ivermectin trial had begun at Kitasato
University Hospital in September 2020 for 240 patients.
Slovakia adopted ivermectin country-wide in January, with reports indicating limited availability and late
treatment only [3]. It had been used since early January by professor Pavol Török who later convinced
the Ministry of Health to adopt it [298].
Country-wide adoptions of ivermectin happened in Guatemala on January 23, in Nicaragua on January
25, in Lebanon on January 27, and in Zimbabwe on January 28 [3];[299].
February 2021
On February 1, a news report was published by an UK and Australia based medical news site describing
itself as “one of the world’s leading open-access medical and life science hubs .. . with 374,000 members,
12,000 Twitter followers and 268,000 likes on Facebook . . . [and] a trusted source of all your medical
and life science needs”, compliant with a Switzerland-based Health on the Net Foundation’s HONCODE
certificate of compliance. The news report reviewed the meta-analysis by Castañeda-Sabogal et al.,
concluding that there was no evidence that ivermectin changed the clinical outcome of inpatients or
outpatients [300].
On February 2, the Wall Street Journal published an opinion piece by US senate representative Ron
Johnson, stating that YouTube had censored Dr. Pierre Kory’s testimony to US Senate Committee in
which he asked the National Institutes of Health to review the current data on ivermectin [301].
On February 2, a preprint about a randomized controlled trial about early ivermectin treatment in mild
and moderate COVID-19 (RIVET-COV) in India by Mohan et al. comparing 24 mg (n=40), 12 mg
(n=40) and placebo (n=45) did not indicate a statistically significant result [302].
On February 3, Al Jazeera briefly covered India’s experiences of ivermectin, interviewed Wasif Ali Khan
from Bangladesh and Kory of the FLCCC, and mentioned Slovakia [303]. On the same day, a news report
from Peru described some details of the conflicts in the country, saying attempts to talk about ivermectin
“lead to stoning . . . it’s like trying to discuss abortion with ultraconservatives” [304].
On February 4, Ramírez et al. published a commentary in the Lancet, stating that “in the face of a
virus with a high mutation rate that could lead to loss of effectiveness of vaccines, worldwide research of
therapies for COVID-19 such as ivermectin should not be idled” [305].
On February 4, Merck & Co/MSD gave a statement on the use of ivermectin on COVID-19 [306]. They
noted that their analysis identified “no scientific basis for a potential therapeutic effect against COVID-19
from pre-clinical studies; no meaningful evidence for clinical activity or clinical efficacy in patients with
COVID-19 disease, and; a concerning lack of safety data in the majority of studies”, concluding that they
23
“do not believe that the data available support the safety and efficacy of ivermectin beyond the doses
and populations indicated in the regulatory agency-approved prescribing information”.
On February 4, a Belgian virologist Wathelet proposed a plan to eradicate SARS-CoV-2 in Belgium in
six weeks using ivermectin, calling for prophylaxis with two doses of 0.3 mg/kg 72 hours apart every
month, early treatment of outpatients, and treatment of hospitalized patients [307]. The author of the
news report concludes that “a failure to act swiftly on [the existing research] evidence might begin to
look like dereliction of moral responsibility”.
On February 5, a Brazilian manufacturer of ivermectin issued a declaration, stating that in Brazil,
ivermectin has been an option for early treatment since the beginning of the pandemic but especially
after publication of the Monash University study [308]. It mentioned that due to existing widespread
use in other diseases and low impact in terms of side effects, a large part of the medical community had
adhered to treatment protocols based on ivermectin, among other options. The statement mentioned
proven safety due to previous use, and dozens of international studies. It also stated that “the growth
of market for ivermectin, a low-cost and therapeutically low-risk product, naturally bothers especially
companies that are interested in launching high-cost patented products for the same disease, and this
can motivate campaigns against it in the media”.
On February 5, a preprint of a randomized controlled trial of relatively low risk hospitalized patients
(n=100) by Bukhari et al. indicated a significantly lower risk of no virological cure (10% vs 56%, p<0.001)
at day 7 (NCT04392713) [309].
On February 5, the FLCCC Alliance responded to YouTube’s removal of the video of Kory’s senate
hearing, stating that “YouTube unilaterally decided that [Kory] citing extensive scientific evidence, was
giving ‘dangerous and misleading’ information . . . while he was attempting to inform the government
that there was a safe, proven and inexpensive way to immediately begin to save lives, dramatically lower
case counts and significantly slow the pandemic itself . . . [it is] dangerous for social media giants like
YouTube to indiscriminately discredit and summarily remove official government information given under
oath” [310].
On February 7, the FLCCC Alliance published a response to Merck & Co/MSD’s statement, citing
FLCCC’s provisionally accepted review, the CovidAnalysis group’s meta-analysis and other published
studies and preprints on ivermectin’s efficacy and safety [311].
On February 9, a new ‘Together’ trial led by McMaster University and partly funded by the Bill and
Melinda Gates Foundation was announced (NCT04727424) [312];[313];[314];[315]. The ivermectin arm
was apparently planned to be carried out in Brazil, with a single dose of 18 mg for participants weighing
40-60 kg and 24 mg for participants over 60 kg. The number of participants was expected to be up to
3,200, with results available within three to six months. On the same day, the chairman of Tokyo Medical
Association in Japan stated that family doctors should administer ivermectin to infected outpatients
[316];[72].
On February 9, a rapid response by Taylor and Hoy suggested that there exists a legal requirement to
take all reasonably practicable steps to mitigate the risk from a hazard by using best endeavours, and
a lack of absolute scientific certainty about the effect of the intervention should not preclude taking
preventive steps. They stated that the failure to immediately approve and deploy the cheap and safe
drug ivermectin is against these principles [317].
On February 10, a peer-reviewed report of a prospective trial of outpatients (n=768) by Lima-Morales
et al. indicated that 481 patients treated with ivermectin, azithromycin, montelukast and aspirin showed
significantly lower mortality (3% vs 18%, p<0.001) and hospitalization (9% vs 31%, p<0.001), and lower
risk of no recovery at 14 days (16% vs 41%, p<0.001) in comparison to 287 controls [318].
On February 11, the NIH declined a Freedom of Information Act request about details on the process
that lead to its most recent ivermectin recommendation [319].
On February 11, ivermectin had become available without prescription in Bulgaria, with people later
queueing to buy it at pharmacies across the country [320];[321];[322].
24
On February 12, preliminary results of a double blind randomized controlled trial about early ivermec-
tin treatment of mild-moderate outpatients by Schwartz et al. in Israel indicated a significantly faster
reduction in viral load (NCT04429711) [323];[324].
On February 15, a Japanese magazine noted that ivermectin was a Japanese invention by Satoshi ¯
Omura
and referred to a FLCCC Alliance report and promising studies from Egypt, Iraq, India and Bangladesh
[325].
On February 15, a preprint of a second, larger study on prophylactic role of ivermectin in SARS-CoV-2
infection among healthcare workers (n=3,532) by Behera et al. indicated a 83% lower risk of infection
(p<0.001) in 2,199 workers who had received a two-dose ivermectin prophylaxis [326].
On February 16, a peer-reviewed version of Behera et al. study about ivermectin prophylaxis of healthcare
workers (n=117) indicated a 73% lower risk of in infection (p<0.001) [153];[154].
On February 16, a peer-reviewed non-randomized controlled trial (n=113) on the effect of a combination
of nitazoxanide, ribavirin and ivermectin plus zinc supplement (MANS.NRIZ) on the clearance of mild
COVID-19 by Elalfy et al. indicated a significantly faster viral clearance: 58% vs 0% on day seven, and
89% vs 7% on day 15 (p<=0.001) [327].
On February 16, the Guardian wrote that a member of parliament of Australia had been banned from
Facebook for a week for posting three pieces of misinformation, one of which was claiming ivermectin’s
usefulness for COVID-19 [328].
On February 17, Africa CDC issued a statement on using ivermectin for COVID-19, citing “no scientific
evidence”, “no safety data”, limitations of the existing studies, that “the doses used in the in laboratory to
produce those results are 100-fold higher than those approved for use in humans”, concluding that “data
from well-designed, randomized, controlled clinical trials are needed to provide evidence for decision”
[329].
On February 18, version 34 of the CovidAnalysis group’s meta-analysis covered 41 studies including
14,833 patients, with 100% of the studies reporting positive effects [330]. 20 of the studies were random-
ized controlled trials with a total of 2,796 patients, indicating an estimated risk reduction of 72% (RR
0.28, CI 0.17-0.47, n=2,796, p<0.000001). Of these, improvement in early treatment was 70% (RR 0.30,
CI 0.17-0.51, n=611), in late treatment 57% (RR 0.43, CI 0.25-0.72, n=1,447), and in prophylaxis 91%
(RR 0.09, CI 0.06-0.15, n=738). Six RCTs investigating mortality indicated a 75% reduction (RR 0.25,
CI 0.12-0.52, n=1,258, p=0.00012). Considering all 41 studies, prospective studies indicated a slightly
larger improvement than retrospective studies.
On February 20, Lawrie and a British company, Evidence-based Medicine Consultancy Limited (E-BMC
Ltd) organized a meeting under the name of British Ivermectin Recommendation Development (BIRD),
a recording of which was put available on YouTube [331]. The recording was apparently censored from
YouTube but later reinstated there and advertised on Twitter. The meeting panel of 75 participants
issued issued a recommendation for immediate global use of ivermectin. The summary described desirable
effects as large, undesirable effects as trivial, the certainty of evidence as high, and indicated large savings
of resources and a favorable cost-effectiveness, acceptability and feasibility.
On February 20, a Czech Republic newspaper reported that the head of the department of anesthesiology
and intensive care at the Bratislava National Oncology Institute had administered ivermectin to her
patients for two weeks, since they became aware of the possibility [298]. She stated its safety had been
demonstrated and when started early it appeared to eliminate the virus. The article also noted there
had been resistance towards its use in the country, however there had been a promising trial by Schwartz
et al. in Israel, and the Slovakian experience had been good. The article referred to a statement by the
mayor of Bratislava, the capital of Slovakia, stating that local real-life results suggest a benefit especially
in the outpatient setting, preventing deterioration and hospitalization. The mayor stressed the need to
obtain ivermectin in large quantities.
On February 22, the Brazilian manufacturer of ivermectin, Vitamedic, reportedly commented further on
Merck/MSD’s statement on February 4, saying Merck’s stance on effectiveness of ivermectin “reflects its
isolated opinion on the matter”, adding that “contrary to what Merck says, there is medical and scientific
evidence around the world demonstrating the antiviral action of the drug. Dozens of studies carried out
25
in several countries demonstrate the benefits of the drug, especially in the early stages of the disease
and, for this reason, the international medical community and also in Brazil started to include it in the
treatment protocols of COVID-19. It is a low-cost drug with low impact in terms of adverse effects”
[332].
On February 23, a small study (n=106) by Beltran-Gonzalez et al. about hydroxychloroquine (n=33),
ivermectin (n=36) and placebo (n=37) did not produce statistically significant results (NCT04391127)
[333].
On February 23, a report on TrialSite News accused Soto-Becerra et al. study about unreported protocol
violations causing it to show a negative result which was later quoted in the NIH recommendation and
was claimed to have negatively influenced it [131].
On February 23, a hospital in the Czech Republic was reported to have tested ivermectin in 30 severe
patients with COVID-19 since November 2020, with all patients recovering. Doctors intended to continue
ivermectin treatments, commenting its affordability and the good results, despite comments by the
director of the State Institute for Drug Control saying studies were incomplete and the Prime Minister
saying ivermectin was not suitable or effective [334].
On February 24, CovidAnalysis group wrote that WHO approved ivermectin for scabies after six studies
with a total of 613 patients indicating that ivermectin provided 35% improvement, yet WHO had not
approved ivermectin for COVID-19 after 21 randomized controlled trials with 2,869 patients indicating
70% improvement and a total of 42 studies with 14,906 patients indicating 75% improvement [330].
On February 25, UK newspapers reported ivermectin could cut deaths by 75%, referring to Paul E.
Marik and Pierre Kory of the FLCCC group, and to Lawrie’s and E-BMC Ltd’s 97-page report that was
said to have been sent to the WHO [335];[336]. On the same day, the Medical Association of Jamaica
requested adoption of ivermectin [337].
On February 25, the Scottish government responded to a January 14 information request about adoption
of ivermectin, stating it is aware of the ongoing trials, that prescribers should pay particular attention
to the risks associated with using a licensed medicine off-label, and that granting a license for use
in COVID-19 would require an application for a marketing authorization be made to the Medicines
and Healthcare products Regulatory Agency (MHRA), which has not received such an application but
would have processes in place to expedite such an application, as required [338]. It further explained
that compassionate access authorization for unlicensed medicines in individual extreme medical cases
is initiated by the patient’s doctor “who will have decided that the medicine is the best and the only
available treatment option” but that “it is for a pharmaceutical company to determine whether they will
offer a medicine though a compassionate use process . . . the decision to grant an individual patient
compassionate access is one that the pharmaceutical company makes”.
On February 25, a mayor in Slovakia denounced obedience to the government and provided ivermectin
for the inhabitants of his village, stating that “waiting for the government does not make sense. We
start not only with treatment, but also with prevention. All under the strict supervision of a doctor”
[339]. The article reported that Ministry of Health had granted an exception for ivermectin and it was
available at hospitals but not yet available at pharmacies. The mayor said he was convinced it should
be used also at outpatient clinics for early intervention, and after weeks of searching he had been able to
acquire 500 doses, to be delivered by the local doctor. The mayor had discontinued COVID-19 testing
in favor of ivermectin prophylaxis, saying “testing is not a cure”.
On February 25, a South African civil rights organization claimed that due to a failure by the regulatory
authority SAHPRA to properly register ivermectin as a medicine, and due to unregistered medicines not
automatically being illegal, ivermectin for COVID-19 had been legal all along [340].
On February 26, Syed and Kory discussed prevailing basic misunderstandings about COVID-19, such as
it still being characterized as viral pneumonia instead of organizing pneumonia, and varying clinical prac-
tices with regard to timing of corticosteroid administration [341]. Kory also described Aguirre-Chang’s
“therapeutic test” for post-COVID-19 syndrome, consisting of 0.2-0.3 mg/kg ivermectin twice daily for
five days, with aspirin 600 mg divided into 2-3 doses daily. If the patient responds to the treatment
26
after five days, both medicines were continued until symptoms had completely resolved. According to
Aguirre-Chang, 75%-85% of approximately 300 patients had responded.
On February 27, version 37 of the CovidAnalysis group’s meta-analysis added an analysis including only
peer-reviewed studies, of which there were 18 [330]. In these studies, improvement in early treatment
was 84% (RR 0.16, CI 0.06-0.44, n=268), in late treatment 39% (RR 0.61, CI 0.39-0.94, n=1,275), and in
prophylaxis 92% (RR 0.08, CI 0.02-0.25, n=2,127). All in all the 18 studies indicated a 75% improvement
(RR 0.25, CI 0.16-0.41, n=3,670, p<0.0001).
On February 28, a preprint by Bartoszko et al. presented a meta-analysis in which only three ivermectin
trials fulfilled the eligibility criteria (Shouman et al. (NCT04422561) [106], Chahla et al. (NCT04701710)
[257], and Elgazzar et al. [166]), concluding that there was a “very low certainty evidence” of the efficacy
of ivermectin [342].
On February 28, an Irish newspaper reported that critical patients would start receiving ivermectin as
part of an international REMAP-CAP clinical trial (NCT02735707) [343];[344]. Some hospitals had
reportedly already begun using ivermectin off-label.
March 2021
On March 1, the abstract of the already peer-reviewed and provisionally accepted ivermectin review
by Kory et al. with over 86,000 views was removed from Frontiers of Pharmacology [261]. A media
statement published the next day by the chief executive editor stated that the article made “a series
of strong, unsupported claims based on studies with insufficient statistical significance, and at times,
without the use of control groups. Further, the authors promoted their own specific ivermectin-based
treatment which is inappropriate for a review article and against our editorial policies .. . this paper
does not offer an objective nor balanced scientific contribution” [345]. A news article noted that there
was no explanation as to why such concerns were not taken into account earlier in the process [346].
On March 1, a preprint of an in-silico analysis predicted that ivermectin has a large binding affinity for
the SARS-CoV-2 spike protein [347].
On March 2, a Canadian broadcast station posted a video interview of Ondrej Halgas at the University
of Toronto [348]. The interview host referred to the unsatisfactory results of lockdowns and delays with
vaccinations. The interview reviewed the cost, availability and status of the research on ivermectin.
On March 3, ivermectin was provisionally authorized by the Ministry of Health of the Czech Republic
[349]. The decision cited FLCCC protocols and the CovidAnalysis group’s meta-analysis [350]. A Czech
Republic newspaper reported the head of a university hospital in Brno saying a large scale distribution
to hospitals and outpatients was beginning, with an initial inventory of 20,000 packages [351]. The prime
minister was quoted saying that “we cannot wait for results of clinical trials, let’s just try this” [352]. On
the same day, a German MD criticized German health politicians for ignoring ivermectin, demanding
that every possibility for the pharmaceutical industry to influence political decisions to be abolished
[353].
On March 3, a double-blind randomized trial to assess the safety and efficacy of ivermectin in asymp-
tomatic and mild severity COVID-19 patients started in Budapest, Hungary (EudraCT 2021-000166-15)
[354].
On March 3, Yang et al. published an article showing that ivermectin’s broad spectrum antiviral activity
relates to its ability to target the host importin α/β1 nuclear transport proteins responsible for nuclear
entry of cargoes, and that ivermectin can limit infection by the West Nile virus at low (μM) concentrations
[355].
On March 3, Syed discussed whether ivermectin interferes with efficacy of the vaccines, concluding that
it does not [356]. On the same day, an US clinic announced they are offering telemedicine-based early
outpatient treatment for patients with active infection and for patients experiencing post-COVID long-
hauler symptoms [357].
27
On March 4, a randomized clinical trial of low risk patients (n=398) in Colombia by López-Medina
et al. did not reach statistical significance (NCT04405843) [358]. The CovidAnalysis group claimed
that endpoints had been changed mid-study, the authors had received grants and personal fees from
five pharmaceutical companies including Merck/MSD also during the study period, a large part of the
control group was excluded due to receiving ivermectin, and it was suspected that even more controls
had received ivermectin instead of placebo [359];[237].
On March 4, the New York Times wrote that “a controversial anti-parasitic drug that has been touted
as a potential Covid-19 treatment, does not speed recovery in people with mild cases of the disease,
according to a randomized controlled trial published on Thursday in the journal JAMA . . . scientific
evidence for its efficacy against the coronavirus is thin .. . the trial was relatively small and did not
answer the most pressing clinical question, whether ivermectin can prevent severe disease or death .. .
bigger trials, which are currently underway, could provide more definitive answers . . . there’s such chaos
in the field” [360].
On March 4, MedPage Today wrote about “a Colombian trial flop”, mentioning a change of the primary
outcome and a labeling error resulting in all patients receiving ivermectin for two weeks, these patients
being excluded from the primary analysis and additional patients being recruited", adding that the
authors had described the study as possibly underpowered [361].
On March 4, the Kory et al. preprint previously provisionally accepted to Frontiers of Pharmacology
was posted at ResearchGate with explanations stating that the the manuscript had passed through
three rounds of peer-review by four different peer reviewers, two of them being career FDA scientists
[362]. After these reviews it was accepted for publication on January 13. After a long delay without
online publication of the full paper, the abstract was suddenly taken down on March 1, with the authors
receiving a rejection letter based on an anonymous external reviewer’s opinion that conflicted with the
previous four peer reviewers and found the manuscript to contain “unsupported conclusions”. The authors
noted that the rejection occurred despite the journal’s documented knowledge of identical conclusions
by the 75-member international consortium on February 20, the British Ivermectin Recommendation
Guideline (BIRD) panel.
On March 4, a news article reported Portuguese MDs using ivermectin prophylaxis for themselves for
a cost of EUR 5 per month, and one doctor using it to contain an outbreak at a senior home with 63
residents [363]. The ivermectin was produced by a Portuguese pharmaceutical company.
On March 4, Syed discussed whether ivermectin can fight all SARS-CoV-2 variants [364]. According
to him, the only area in which ivermectin’s efficacy may be compromised is in preventing the spike
protein binding to receptors. Ivermectin binds to the spike protein, and if the spike protein changes
significantly, ivermectin might not bind to it. However, this has not happened. The second phase is viral
fusion with the cell membrane and release of RNA. Ivermectin does not have a function in this phase.
The third phase is viral replication. Ivermectin affects RNA-dependent RNA polymerase (RdRp) and
3CLpro which are common for all variants [365];[148];[279]. Fourth phase is cellular defense reduction,
during which the virus enters the nucleus through the host importin α/β1 nuclear transport proteins
[355]. Ivermectin disrupts this process common for all variants. Another function of ivermectin is NF-
kB (nuclear factor kappa-light-chain-enhancer of activated B cells) blocking to prevent inflammation
[6]. This is also common for all variants. In summary, ivermectin is effective against all variants in
preventing replication, entrance of viral cargo to cell nucleus, and inflammation, but in theory, efficacy
against binding may vary.
On March 5, FDA issued a consumer update warning against use of ivermectin to treat or prevent
COVID-19, yet simultaneously stated that it had not reviewed data to support use of ivermectin in
COVID-19 [366].
On March 5, German medical magazine wrote about the Colombian trial, starting from the Caly et al. in
vitro study, moving on to the Surgisphere scandal, and finally the Colombian trial, ending by mentioning
that the authors of the trial “assumed that the treatment will probably not be of any (great) benefit”
[367]. Readers’ comments referring to the meta-analysis by Lawrie et al. objected with the conclusion.
On March 5, MedinCell published a preprint of an expert review on the safety of ivermectin by Descotes
who held shares to MedinCell but had no other relevant affiliations or financial involvement [368];[369];
28
[370]. MedinCell noted the review will be submitted for peer review to an acknowledged journal. The
report stated that “it is of note that neither deaths nor severe adverse events attributable to ivermectin
have been reported . . . the safety profile of ivermectin has so far been excellent in the majority of treated
human patients so that ivermectin human toxicity cannot be claimed to be a serious cause for concern”.
On March 6, according to a news report, professor Cacopardo in Sicily, Italy had successfully healed all
of his 13 ivermectin-treated patients in just 3-5 days [371]. Also, a Milan pharmacy announced it had
begun shipping ivermectin throughout Italy.
On March 6, a news article described outpatient treatment practices in Uttarakhand, India, consisting
of a home-delivered kit with a thermometer, an oximeter, azithromycin, paracetamol, three tablets of
ivermectin, vitamin C, ten masks, a bag for biohazardous waste and precise instructions, follow-up calls
by a doctor every two days, an in-person visit by two doctors on day 9 to check for a need of medication
or oxygen, and a test on day 14, all free of charge [372].
On March 6, Lawrie stated that a two-week randomized controlled trial for the post-COVID-19 syn-
drome (“long Covid”) would be appropriate and interesting [373]. She mentioned the production cost of
ivermectin was USD 168 per kilogram, with a WHO document on treatment of scabies mentioning 100
tablets of 12 mg each being available for a total cost of USD 2.90, thus indicating that the cost of a
single treatment with 12-24 mg would be USD 0.03-0.06 [5].
On March 6, Merck & Co/MSD announced positive results of a 182-patient phase 2a RCT with MK-4482
(molnupiravir) [374];[375];[376].
On March 7, the FLCCC group issued a statement calling the FDA statement misleading, saying the
guidance may lead to avoidance of off-label prescribing and that the patients cannot wait for phase III
trial results [377].
On March 7, in a CBS News interview, the director of the NIH mentioned a need for an oral broad-
spectrum medication for early treatment to be given immediately after a positive test result, that would
also be effective against viral variants. The director added that the NIH is working “right now” on pro-
ducing evidence on repurposed medicines including “colcichine, fluvoxamine and potentially ivermectin”
[378];[379]. The text of the story, however, only mentioned fluvoxamine. The director also mentioned
that the hydroxychloroquine controversy had had “a detrimental impact on looking for existing drugs . . .
maybe it got in the way of trying other kinds of repurposed drugs .. . we had to get over that. I think
we’re over it now”.
On March 8, a preprint by Chamie-Quintero et al. suggested that mass treatments with ivermectin most
likely caused a 14-fold reduction in excess deaths in Peru, and a later reversal of ivermectin policy caused
a 13-fold increase [380];[381]. The preprint was reviewed by TrialSite News on March 3.
On March 8, an article in MedPage Today criticized Facebook third-party fact-checkers in a case of an
op-ed about epidemiology, stating that the fact-checkers appeared to be “disproportionately academics
on Twitter who have mega-follower counts. They mostly have similar worldviews, and advertise those
views on Twitter. In a different case, a reviewer already tweeted criticism of the article before being
selected as a ‘fact-checker’ . . . it is cherry picking criticism from Twitter celebrities in order to extinguish
dissenting opinions .. . it feels like a high school clique . . . it is antithetical to the spirit of the academy
. . . this process is not acceptable or fair” [382].
On March 9, a preprint by Scheim et al. accused the recent trial by López-Medina et al. (NCT04405843)
of several protocol violations, including a labeling error substituting ivermectin for placebo doses of 38
patients, in addition to a blinding failure and patients in the control group possibly self-medicating with
over-the-counter ivermectin [358];[383].
On March 9, a peer-reviewed report of a small late treatment trial with 32 patients by Pott-Junior et al.
did not produce statistically significant results (NCT04431466) [384].
On March 9, referring to FDA consumer update on March 5, a MedPage Today article titled “FDA pooh-
poohs ivermectin” mentioned that “FDA detailed a laundry list of reasons on why not to use ivermectin
for COVID-19, including that it’s ‘not an anti-viral’ and that overdose could cause ‘seizures, coma and
even death’ ” [385].
29
On March 10, a commentary by Kory stated that “doctors fighting COVID-19 should be supported
by their profession and their government, not suppressed. Yet today physicians are smothered under a
wave of censorship . . . many in positions of authority [are] stubbornly refusing to allow any repurposed
treatments. This departure from traditional medical practice risks catastrophe .. . when doctors on the
front lines try to bring awareness of and use such medicines, they get silenced .. . actually ‘following the
science’ means listening to practitioners and considering the entirety and diversity of clinical studies”
[386].
On March 11, a preprint by Bryant et al. (with Lawrie) presented a systematic review and meta-analysis
done using rigorous Cochrane methods [387]. The review included 21 RCTs with 2,741 patients. Meta-
analysis of 13 trials indicated 68% reduction in mortality (RR 0.32, 95% CI 0.14-0.72, n=1,892, low to
moderate-certainty evidence). Low-certainty evidence found ivermectin prophylaxis reduced infections by
86% (95% CI 79-91). Low-certainty evidence also indicated reduction in deterioration to severe disease,
and ‘improvement’ measured with various indicators, but no reduction in need for mechanical ventilation.
As implications of all the available evidence the authors stated that the apparent safety and low cost
suggested that “ivermectin could have an impact on the SARS-CoV-2 pandemic globally. Ivermectin is
not a new and experimental drug with safety concerns; it is a WHO ‘essential medicine’ usually used in
different indications. It may be useful for more health professionals to get access to this medicine for use
against covid-19 during the ongoing pandemic”.
On March 11, the discoverer of ivermectin Satoshi ¯
Omura stated that ivermectin should be used for
COVID-19 immediately without requiring any specific approval [388];[389]. According to ¯
Omura, iver-
mectin suppresses both replication of the virus and the inflammation, in addition to activating the
immune system.
On March 12, a preprint about an early treatment retrospective database analysis by Roy et al. with 56
patients with mild disease, all treated with zinc and vitamins C and D, compared placebo, ivermectin plus
doxycycline, azithromycin, and hydroxychloroquine, without finding statistically significant differences
[390];[391].
On March 12, the CovidAnalysis group presented a comparison of the mortality results across the five
existing meta-analyses, with Kory et al. indicating 72% reduction (RR 0.28, 95% CI 0.19-0.45), Hill et
al. indicating 75% reduction (RR 0.25, 95% CI 0.12-0.52), Bryant et al. indicating 68% reduction (RR
0.32, 95% CI 0.14-0.72), Lawrie et al. indicating 83% reduction (RR 0.17, 95% CI 0.08-0.35), and the
CovidAnalysis group’s analysis indicating 75% reduction (RR 0.25, 95% CI 0.15-0.44).
On March 12, an editorial by Nardelli et al. presented a yet another meta-analysis of randomized clinical
trials on the impact of ivermectin on mortality [392]. The meta-analysis utilized Mantel-Haenszel test
and a fixed-effects model, and included 1,323 hospitalized patients in seven RCTs performed in six
countries. The included studies were the early treatment trial by Ahmed et al. in Bangladesh and the
late treatment trials by Elgazzar et al. in Egypt, Hashim et al. in Iraq, Mahmud et al. in Bangladesh,
Niaee et al. in Iran, Okumus et al. in Turkey, and Kirti et al. in India [195];[166];[146];[181];
[260];[248];[133]. Mortality in patients treated with 12-24 mg ivermectin for 1-5 days was 2% vs 9%
in the controls (OR 0.19, 95% CI 0.10-0.34, p<0.01). The authors wrote that “ivermectin followed the
opposite pathway of hydroxychloroquine: use of hydroxychloroquine was supported at first by medical
agencies worldwide, and later proven ineffective by several RCTs including the RECOVERY Trial. On
the contrary, ivermectin was mostly neglected so far and only used in a few countries; nevertheless,
scientific community is progressively building a body of randomized evidence which points in favor of
its use. After the ruinous experience during the first wave, however, physicians became more ‘skeptical’
and less prone to use repurposed drugs in COVID-19 patients. Having cried wolf for too long may be
preventing the spread of ivermectin use all over the world. While modern medicine cannot do without
ironclad evidence, in an emergency situation the use of a cheap medication without major side effects
may be reasonable even if strong verification of its efficacy is still lacking. While there is an urge of
large high quality RCTs, results from the reported trials all point in the same direction, and cannot be
overlooked”.
On March 15, in a TrialSite News interview, Lawrie said that in the meta-analysis by Hill et al. she had
noticed a mismatch between the analysis and the conclusion. When she had contacted Hill asking him
to explain the mismatch, Hill had, according to Lawrie, replied that the conclusion of the meta-analysis
30
had not been his own: it had been changed by the sponsor of the study Unitaid [393];[275]. Lawrie
also explained difficulties in her attempts to get her group’s meta-analysis published by the Cochrane
or journals. TrialSite News commented that “there doesn’t seem to be any urgency here” with regard to
adoption of treatments.
On March 15, a peer-reviewed article by Ngo et al. called on public health authorities to authorize
treatments with known low risk and potential benefit for use in parallel with mass immunization, i.e. a
“parallel track” approach [394]. The article compared the current pandemic to the emergence of AIDS
in the 1980s, describing that the first treatment for AIDS was approved after only one hastily set up
300-patient trial, the design and results of which remain controversial to this day. The article stated Dr.
Anthony Fauci had publicly advanced the idea of a parallel track to make drugs widely available even
while studies are progressing, and quoted Fauci saying that “clearly, the standard approach to the design
of clinical trials – that is, rigid eligibility criteria as well as the strict regulatory aspects that attend
clinical trial investigations and drug approval – was not well-suited to a novel, largely fatal disease such
as this with no effective treatments, and we had many intense discussions about how to make that
approach more flexible and ethically sound. One example, which I and others worked closely with the
AIDS activists to develop, was called a parallel track for clinical trials. The parallel track concept, which
the FDA ultimately came to support, meant that there would be the standard type of highly controlled
admission criteria and data collection for the clinical trial of a particular drug. In parallel, however, the
drug also could be made available to those who did not meet the trial’s strict admission criteria but were
still in dire need of any potentially effective intervention, however unproven, for this deadly disease”. In
the case of AIDS, the parallel track approach proposed by Fauci was adopted. The article wondered why
the current approach taken by Fauci, FDA and others with regard to ivermectin was so very different.
On March 15, an article by Rendic discussed drug-drug and drug-toxic chemical interactions related to
ivermectin [395].
On March 16, the FLCCC announced on its Twitter account that their article rejected by Frontiers of
Pharmacology had been accepted by American Journal of Therapeutics [396].
On March 16, an online television channel Reform TV in the United Kingdom, launched by a prominent
Eurosceptic Nigel Farage’s Reform UK, stated it had been exactly a year since the enactment of “the
most draconian legislation” that had “decimated peoples’ lives”, asking whether this progression could
have been prevented [397];[398]. Reform UK Deputy Leader, MD David Bull compared ivermectin to
penicillin and aspirin, explaining recent research and data from Peru by Chamie-Quintero et al. sug-
gesting a decrease in excess deaths after mass distribution and increase in excess deaths after restriction
of distribution by the new president in December 2020 [380], with the interviewer describing it as ‘an
extraordinary coincidence’, asking why there had been very little discussion about ivermectin in the UK.
Journalist David Rose described international experiences (e.g. India, French care homes) and two “strik-
ing” meta-analyses by British scientists Hill and Lawrie. Commenting on Merck & Co/MSD’s negative
view of ivermectin Rose referred to economic incentives related to Merck’s new drug in development,
adding that with regard to ivermectin, “the Big Pharma is going to have to take a back seat on this one”.
Lawrie mentioned 14 RCTs consistently showing benefits in prophylaxis and treatment. She added she
believed the government had been informed about ivermectin by their foreign colleagues in 2020, but “for
some reason it has not been prioritized . . . the developed countries seem to be very highly influenced by
the pharmaceutical industry”, with most studies conducted in low-to-middle income countries familiar
with ivermectin. She suspected more interest in smaller European countries was due to being “last in line
for vaccines” or unable to afford them. She mentioned developing countries relying not only on RCTs
but also on case studies and clinical experience accumulated since May 2020. Lawrie said it was already
unethical to randomize people to a placebo group in an ivermectin trial, but that there were no obstacles
to an immediate rollout of ivermectin without further studies. According to her, an earlier rollout would
have saved hundreds, potentially thousands of lives of UK citizens.
On March 16, the Association of American Physicians and Surgeons (AAPS) executive director Jane M.
Orient wrote that the US pandemic response has failed at every level, likely causing 100,000 or more
preventable US deaths. Orient concluded that “the disastrous global response to COVID-19 has been
plagued by lack of preparedness, conflicts of interest, highly politicized ‘science’, suppression of open
discussion, disregard of the bedrock principle of informed consent, and willful neglect of what is likely
31
the most important pillar of response: early treatment. Risk/benefit assessment is fatally compromised
by inaccurate, distorted, or absent data concerning the incidence and mortality of disease and the safety
and efficacy of countermeasures” [399];[400].
On March 17, a systematic review and and an individual patient data meta-analysis of ivermectin use
in children weighing less than 15 kg by Jittamala et al. 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];[401]. 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.
On March 17, an interview of a Brazilian MD Adler Menezes described an ivermectin prophylaxis exper-
iment in a factory with 12,000 employees [402]. Ivermectin was administered weekly to workers of one of
two work shifts, with infections disappearing in the prophylaxis group. Ivermectin was then administered
also to workers in the other shift, with the same result.
On March 18, the Infectious Diseases Society of America (IDSA), citing very low certainty of evidence,
gave a conditional recommendation against the use of ivermectin in hospitalized patients with severe
COVID-19 and in outpatients with COVID-19, outside of the context of a clinical trial, adding that
“adding that well-designed, adequately powered, and well-executed clinical trials are needed to inform
decisions on treating COVID-19 with ivermectin” [403].
On March 18, a Yale professor Santin, referring to Kory and CovidAnalysis group, stated he initially
did not believe such efficacy was possible but witnessed firsthand very rapid responses in both post-
COVID-19 syndrome patients with months of breathing issues, and in extremely severe patients close to
intubation [404];[405];[406].
On March 18, Del Franco et al. published a retrospective follow-up of 856 patients, indicating that
ivermecting improved recovery from post-COVID-19 syndrome [407].
On March 19, a French magazine wrote about the French care home experience, the Hill et al. meta-
analysis and several other developments, and interviewed a French ivermectin proponent Maudrux who
stated “we are witnessing a drift in the analysis of scientific studies: we look at the methodology but we
do not look at the result” [408];[409].
On March 19, a news report claimed that the participants of the study by López-Medina et al. had not
been informed that they were receiving ivermectin and that they had only been informed that they were
receiving “D11AX22 molecule” [410].
On March 21, The Manila Times in Indonesia wrote about the ivermectin controversy [411].
On March 22, the CovidAnalysis group’s listing of all studies about ivermectin on COVID-19 included
72 studies, of which 35 were peer-reviewed and 46 with results comparing treatment and control groups
[412]. A March 17, 2021 version 47 of their meta-analysis of the 46 studies included eight randomized
controlled trials (of which six double-blind RCTs, one single-blind RCT, and one open-label RCT) on
COVID-19 mortality in early treatment (two RCTs) or late treatment (six RCTs) indicated a 69% lower
risk of death (RR 0.31, 95% CI 0.16-0.61, p=0.00032, n=1,729) [413].
24 randomized controlled trials (of which 12 double-blind RCTs, two single-blind RCTs, and 10 open-label
RCTs) with 3,414 patients indicated a 70% improvement on the various measured indicators including
death, viral clearance, hospitalization, ICU admission, recovery, resolution of symptoms and infection
(RR 0.30, 95% CI 0.19-0.47, p<0.0001, n=3,414). Improvement in early treatment was 71% (RR 0.29,
95% CI 0.17-0.50, n=1,125), in late treatment 55% (RR 0.45, CI 0.28-0.72, n=1,551), and in prophylaxis
91% (RR 0.09, CI 0.06-0.15, n=738).
21 peer reviewed trials (of which 11 observational trials, five double-blind RCTs, and five open-label
RCTs) with 4,215 patients indicated a 75% improvement on the same indicators (RR 0.25, 95% CI
0.16-0.40, p<0.0001, n=4,215). Improvement in early treatment was 83% (RR 0.17, 95% CI 0.07-0.40,
n=782), in late treatment 41% (RR 0.59, CI 0.38-0.90, n=1,306), and in prophylaxis 92% (RR 0.08, CI
0.02-0.25, n=2,127).
32
The probability that an ineffective treatment generated results as positive as the 46 studies was estimated
to be one in 70 trillion (p=0.000000000000014). A remarkable feature was the unusual consistency of
the results, with all studies indicating positive effects, regardless of the phase of the disease.
As mentioned above, Bryant et al. had reviewed 21 RCTs with 2,741 patients, of which a selection of
thirteen RCTs in the Cochrane-standard meta-analysis had indicated 68% reduction in mortality (RR
0.32, 95% CI 0.14-0.72, n=1,892, low to moderate-certainty evidence) [387].
On March 22, “after reviewing the latest evidence”, the European Medicine Agency (EMA) advised
against use of ivermectin for the prevention or treatment of COVID-19 outside randomized clinical trials
[414]. EMA stated that ivermectin medicines were not authorized for use in COVID-19 in the EU, and
EMA had not received any application for such use, however it noted that the Czech Republic and
Slovakia had allowed temporary use within the remit of their national legislation. EMA stated that
“although ivermectin is generally well tolerated at doses authorized for other indications, side effects
could increase with the much higher doses that would be needed to obtain concentrations of ivermectin
in the lungs that are effective against the virus. Toxicity when ivermectin is used at higher than approved
doses therefore cannot be excluded”. EMA added that “further well-designed, randomized studies are
needed to draw conclusions”.
On March 22, a coronavirus drug and treatment tracker of the New York Times listed ivermectin under
the label “tentative or mixed evidence” [415].
On March 23, Lopez-Medina wrote in a comment to their article that the ethics committee and the
national regulatory agency had approved the use of “D11AX22 molecule” to refer to ivermectin in the
informed consent form, explaining that “the need arose from the extensive use of ivermectin in the city
of Cali during the study period, extensive recommendations from some political and medical leaders to
use it against COVID-19, and the fact that the initial placebo had a different taste from ivermectin.
The only option to maintain the blind and prevent self-medication for participants in the placebo group
during the dextrose/saline-placebo period was to use ‘D11AX22 molecule’ in the consent form” [358].
On March 24, an extensive review of the recent history and properties of ivermectin by Yagisawa et al.,
a group including the discoverer of ivermectin Satoshi ¯
Omura, was published in the Japanese Journal
of Antibiotics [4]. The article stated, for example, that early in the pandemic, Merck & Co/MSD had
declined Kitasato University’s request to conduct clinical trials with ivermectin in Japan. The university
had later initiated its own trial which was still ongoing but there was a concern that due to lack of
resources the clinical trial would be concluded only after the pandemic would be practically over.
On March 25, a press release by Huvemec described initial phase II trial results of a late-stage RCT in
Bulgaria with 0.4 mg/kg ivermectin for three consecutive days, indicating normalization of biomarkers
of inflammation (D-dimer and CRP) and 34.5% lower risk of no improvement (RR 0.66, p=0.07, n=100)
on day 4 (EudraCT 2020-002091-12) [416];[417].
On March 25, a peer-reviewed article by Choudhury et al. describing an in-silico analysis indicated that
ivermectin had a high binding affinity for the SARS-CoV-2 viral spike protein, main protease, replicase,
and human TMPRSS2 receptors [418];[419].
On March 25, a peer-reviewed article by Udofia et al. describing an in-silico analysis indicated that
ivermectin had the highest binding energy against the 3CLpro and RdRps of SARS-CoV-2 [420];[421].
On March 25, Bloomberg Businessweek wrote about Merck & Co/MSD’s molnupiravir (MK-4482), saying
it could “transform the fight against Covid” [422]. An analyst estimated that “it could be a $1 billion
or $10 billion product, depending on how the data turns out”. The article stated molnupiravir was also
considered for prophylaxis, possibly allowing an even more broad deployment.
On March 26, a preprint by Tanioka et al. describing a retrospective study of 31 onchocerciasis-endemic
countries using community-directed treatment with ivermectin and the 22 non-endemic countries in
Africa indicated 88.2% lower mortality per capita in the countries using ivermectin (RR 0.12, p = 0.002)
[423];[424].
33
On March 26, the regulatory authorities of the Philippines warned doctors prescribing ivermectin that
their names would be submitted to the Professional Regulation Commission and if found guilty, their
licenses could be revoked.
On March 27, an editorial in Manila Times in Philippines demanded that the regulatory authorities
“must firmly put an end to the ivermectin ‘fad’ [425].
On March 29, Kow et al. published a peer-reviewed meta-analysis of six RCTs indicating significantly
lower mortality with ivermectin (OR 0.21, 95% CI 0.11-0.42) [426];[427].
On March 30, the WHO published an updated ivermectin guideline based on a meta-analysis of five
randomized controlled trials comparing ivermectin to standard of care, ignoring other trials comparing
ivermectin to other agents, or trials using ivermectin in combination with other agents [428]. The meta-
analysis indicated 64% improvement with ivermectin (RR 0.36, 95% CI 0.17-0.75, very low certainty
evidence), with two studies (Kirti et al. [248], Niaee et al. [181]) estimated to have a high risk of bias
(due to inadequate blinding) indicating 83% improvement (RR 0.17, 95% CI 0.16-0.48) and two studies
(Beltran-Gonzalez et al. [333], López-Medina et al. [358]) estimated to have a low risk of bias indicating
a 23% improvement (RR 0.77, 95% CI 0.28-2.18). The risk ratio of one low-bias study (Mohan et al.
[302]) was deemed unestimable (due to no deaths in any of the groups), thus in effect leaving four studies
included in the result. WHO recommended not to use ivermectin in patients with COVID-19 except
in the context of a clinical trial, adding that the recommendation applied to patients with any disease
severity and any duration of symptoms.
On March 30, Politico magazine published by “a global nonpartisan politics and policy news organization”
wrote about “the rise and fall of a coronavirus ‘miracle cure’ ”, discussing recent events, interviewing
Chaccour, and ending with a mention that trials needed to draw conclusions are underway [429].
On March 30, a preprint by Chahla et al. describing an Argentinian state funded early treatment trial
suggested a significant reduction in risk of no medical release (RR 0.11, p=0.005) (NCT04784481) [430];
[431].
On March 30, Arévalo et al. published a peer-reviewed article about the effectiveness of ivermectin for
the treatment of mouse hepatitis virus (MHV), a type 2 family RNA coronavirus similar to SARS-CoV-2,
demonstrating that mice treated with ivermectin showed a better health status with a lower viral load
and less histopathological liver damage [432].
On March 30, a preprint of this article covering a period up to March 24 was posted on ResearchGate
[433].
On March 31, Reuters wrote about the WHO guideline, interviewing a co-chair of the WHO panel that
reviewed ivermectin who stated that “we certainly need more data in order to make informed decisions
. . . the data available was sparse and likely based on chance . . . we did see an increase in adverse
effects [gastrointestinal upsets and headaches] in patients that were randomised to ivermectin” [434]. A
top WHO official for clinical care response commented that “we are fighting this overuse of unproven
therapies – especially some of these repurposed drugs – in various parts of world without evidence of
efficacy . . . there can be more harm than any good”.
On March 31, the FLCCC Alliance issued a statement on the WHO guideline, criticizing it for ignoring
significant data, calling it “a hasty decision before reviewing all available data” [435]. The statement
added that “to ignore the data the way the WHO has, does a disservice to science and to public health.
It is time that as physicians we trust our own knowledge on how best to treat our patients .. . allowing
large, conflicted bureaucracies to do the thinking for us will only lead to continued and unnecessary
suffering from the pandemic”. In a video presentation, Kory commented that the WHO “made themselves
completely irrelevant today. They totally came out and showed that they are not acting in the best
interests of humanity and that their guidance should no longer be looked to or followed .. . they showed
what our system is built on. The system is just so vulnerable to influences . . . [which] leads into these
crazy actions that we can’t make sense of on the ground” [436].
On March 31, version 52 of the meta-analysis by the CovidAnalysis group indicated that 100% of the 26
included randomized controlled trials reported positive effects, with an estimated 70% overall improve-
ment (RR 0.30, 95% CI 0.20-0.46, p=0.000000000000002) [437].
34
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 CovidAnalysis 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 ineffecti-
ve 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 to-
gether, 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 CovidAnalysis 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 the
above results but instead presented a third set of mortality results, indicating a mortality of 130 per
1000 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% CI
117-78). 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 outcomes
of interest”, citing the Hill et al. meta-analysis among the trials reporting no outcomes of interest. The
new 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
35
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 treat-
ment, 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, man-
date 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 officially
available, that corticosteroids were to be avoided in prophylaxis and early treatment, and that the use
of 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 appreared to have also lead to, for example, social media and video streaming platforms
actively but inconsistently and indiscriminately censoring many subjects and groups, including ivermec-
tin 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 main-
tain 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 esta-
blishment 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
36
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 have
been 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 we-
althy 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 import-
ant issue. The US government invested USD 356 million in 60,000-100,000 doses of MK-7110, indicating a
unit 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 onchocerciasis
in Africa stated that Merck & Co/MSD had offered ivermectin at USD 1.51 per treatment, indicating a
2300 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 Emergency
Use 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 published
on 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.
37
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 Alter-
natives” 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 ap-
proved 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 pharmaceuti-
cals 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 medici-
nes.
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 para-
digm, 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 en-
tities 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 deci-
sions 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.
38
Abbreviations
SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; COVID-19: coronavirus disease 2019;
WHO: World Health Organization; PAHO: Pan American Health Organization; NIH: United States
National Institutes of Health; CDC: United States Centers for Disease Control and Prevention; FDA:
United States Food and Drug Administration Agency; EMA: European Medicine Agency; NHS: National
Health Service of the United Kingdom; MHRA: Medicines and Healthcare products Regulatory Agency
of Scotland; MALMED: Macedonian drug agency; SAHPRA: South African Health Products Regulato-
ry Authority; ICMR: Indian Council of Medical Research; CEPI: Coalition for Epidemic Preparedness
Innovations; FIND: Foundation for Innovative New Diagnostics; Gavi: Global Alliance for Vaccines and
Immunization, or Gavi, the Vaccine Alliance; BIRD: British Ivermectin Recommendation Development
Group; AAPS: Association of American Physicians and Surgeons; IDSA: Infectious Diseases Society of
America; FLCCC: Frontline COVID-19 Critical Care Alliance; I-MASK+: an ivermectin-based treat-
ment protocol by the FLCCC; MD: medical doctor; ICU: intensive care unit; RCT: randomized con-
trolled trial; MEDLINE: Medical Literature Analysis and Retrieval System Online; PubMed: a search
engine for the MEDLINE database; EMBASE: Excerpta Medica dataBASE; EudraCT: European Union
Drug Regulating Authorities Clinical Trials (clinical trials database); NCT: number of clinical trial, a
ClinicalTrials.gov identifier; HCQ: hydroxychloroquine; HIV-1: human immunodeficiency virus type 1;
MHV: mouse hepatitis virus; GABA: γ-aminobutyric acid; TMPRSS2: transmembrane protease, serine
2; D-Dimer: a fibrin degradation product; CRP: C-reactive protein; PCR: polymerase chain reaction;
HDA: host-directed agent; IC50: half maximal inhibitory concentration; EOC: Expression of Concern;
EUA: Emergency Use Authorization; CD147: Basigin (BSG), or extracellular matrix metalloproteinase
inducer (EMMPRIN), or cluster of differentiation 147; AMPK: AMP-activated protein kinase; mTOR:
mechanistic target of rapamycin; RdRp: RNA-dependent RNA polymerase; 3CLpro: 3C-like protease;
RR: relative risk, or risk ratio; CI: confidence interval; IQR: interquartile range; OR: odds ratio; r:
correlation coefficient; p: p-value.
Acknowledgements
The author wishes to thank Simon Barber for a grammar check.
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
39
References
1. CovidAnalysis. Ivermectin is effective for COVID-19: real-time meta analysis. 2021.
https://ivmmeta.com/
2. CovidAnalysis. Ivermectin for COVID-19: real-time analysis of all studies. 2021.
https://c19ivermectin.com/
3. CovidAnalysis. Global ivermectin adoption for COVID-19. 2021. https://ivmstatus.com/
4. Yagisawa M, Foster PJ, ¯
Omura HHS. Global trends in clinical studies of ivermectin in COVID-19.
Japanese Journal of Antibiotics. 2021;74(1):44–95.
http://jja-contents.wdc-jp.com/pdf/JJA74/74-1- open/74-1_44-95.pdf
5. Campbell J. Ivermectin evidence with Dr Tess Lawrie: production price. 2021.
https://youtu.be/vYF8bnmdQfY?t=2471
6. Jans DA, Wagstaff KM. Ivermectin as a broad-spectrum host-directed antiviral: the real deal? Cells.
September 2020;9(9):2100. https://doi.org/10.3390/cells9092100
7. Higazi T, Geary T, MacKenzie C. Chemotherapy in the treatment control, and elimination of
human onchocerciasis. Research and Reports in Tropical Medicine. October 2014;:77.
https://doi.org/10.2147/rrtm.s36642
8. Centers for Disease Control and Prevention. Scabies - resources for health professionals -
medications. US Department of Health & Human Services. 2021.
https://web.archive.org/web/20210319125545/https:
//www.cdc.gov/parasites/scabies/health_professionals/meds.html
9. Engelman D, Steer A. Control strategies for scabies. Tropical Medicine and Infectious Disease.
September 2018;3(3):98. https://doi.org/10.3390/tropicalmed3030098
10. A roadmap for the development of ivermectin as a complementary malaria vector control tool. The
American Journal of Tropical Medicine and Hygiene. February 2020;102(2s):3–24.
https://doi.org/10.4269/ajtmh.19-0620
11. Jans DA, Wagstaff KM. The broad spectrum host-directed agent ivermectin as an antiviral for
SARS-CoV-2? Biochemical and Biophysical Research Communications. January 2021;538:163–72.
https://doi.org/10.1016/j.bbrc.2020.10.042
12. Suputtamongkol Y, Avirutnan P, Mairiang D, Angkasekwinai N, Niwattayakul K, Yamasmith E, et
al. Ivermectin accelerates circulating nonstructural protein 1 (NS1) clearance in adult dengue patients:
a combined phase 2/3 randomized double-blinded placebo controlled trial. Clinical Infectious Diseases.
January 2021. https://doi.org/10.1093/cid/ciaa1332
13. Jiang L, Wang P, Sun Y-J, Wu Y-J. Ivermectin reverses the drug resistance in cancer cells through
EGFR/ERK/Akt/NF-kB pathway. Journal of Experimental & Clinical Cancer Research. June
2019;38(1). https://doi.org/10.1186/s13046-019-1251-7
14. Chung K, Yang C-C, Wu M-L, Deng J-F, Tsai W-J. Agricultural avermectins: an uncommon but
potentially fatal cause of pesticide poisoning. Annals of Emergency Medicine. July 1999;34(1):51–7.
https://doi.org/10.1016/s0196-0644(99)70271-4
15. Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, et al. Safety, tolerability
and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. Journal of
Clinical Pharmacology. October 2002;42(10):1122–33.
https://www.researchgate.net/publication/11094854_Safety_Tolerability_and_
Pharmacokinetics_of_Escalating_High_Doses_of_Ivermectin_in_Healthy_Adult_Subjects
16. WHO African Programme for Onchocerciasis Control. Ivermectin. 2021. https:
//web.archive.org/web/20210311193155/https://www.who.int/apoc/cdti/ivermectin/en/
17. Jittamala P, Monteiro W, Smit MR, Pedrique B, Specht S, Chaccour CJ, et al. A systematic review
and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen
40
kilograms: Is it time to reconsider the current contraindication? Downs JA, editor. PLOS Neglected
Tropical Diseases. March 2021;15(3):e0009144. https://doi.org/10.1371/journal.pntd.0009144
18. Gyapong JO, Chinbuah MA, Gyapong M. Inadvertent exposure of pregnant women to ivermectin
and albendazole during mass drug administration for lymphatic filariasis. Tropical Medicine &
International Health. November 2003;8(12):1093–101.
https://doi.org/10.1046/j.1360-2276.2003.01142.x
19. Speare R, Durrheim D. Mass treatment with ivermectin: an underutilized public health strategy.
Bulletin of the World Health Organization. 2004;82(8).
https://web.archive.org/web/20210104194334/https:
//www.who.int/bulletin/volumes/82/8/editorial30804html/en/
20. Monash University. Possible coronavirus drug identified: Ivermectin stops SARS-CoV-2 virus
growing in cell culture. 2020. https://web.archive.org/web/20200404174008/https:
//www.sciencedaily.com/releases/2020/04/200403115115.htm
21. Monash University. Lab experiments show anti-parasitic drug, Ivermectin, eliminates SARS-CoV-2
in cells in 48 hours. 2020.
https://web.archive.org/web/20200406210318/https://www.monash.edu/discovery-
institute/news-and-events/news/2020-articles/Lab- experiments-show-anti-parasitic-
drug,-Ivermectin,- eliminates-SARS-CoV-2-in- cells-in-48-hours
22. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin
inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research. June 2020;178:104787.
https://doi.org/10.1016/j.antiviral.2020.104787
23. Jans DA, Martin AJ, Wagstaff KM. Inhibitors of nuclear transport. Current Opinion in Cell
Biology. June 2019;58:50–60. https://doi.org/10.1016/j.ceb.2019.01.001
24. MedinCell. MedinCell has launched a COVID-19 research initiative based on its experience to
formulate long-acting injectable ivermectin. 2020.
https://web.archive.org/web/20210314203705/https://invest.medincell.com/wp-
content/uploads/2020/04/PR_MedinCell-Covid19-EN.pdf
25. MedinCell continues its investigational pursuit of ivermectin targeting COVID-19 patients.
TrialSite News. 2020.
https://web.archive.org/web/20200511102723/https://trialsitenews.com/medincell-
continues-its-investigational-pursuit- of-ivermectin-targeting-covid-19- patients/
26. MedinCell announces great success with capital raise of 15.6M& use of proceeds includes
ivermectin prophylactic for COVID-19. TrialSite News. 2020.
https://web.archive.org/web/20200715183357/https://www.trialsitenews.com/medincell-
announces-great-success-with- capital-raise-of-15-6me- use-of-proceeds-includes-
ivermectin-prophylactic-for-covid- 19/
27. FDA’s Center for Veterinary Medicine. Do not use ivermectin for animals as treatment for
COVID-19 in humans. 2020. https://web.archive.org/web/20200411022909/https:
//www.fda.gov/animal-veterinary/product-safety-information/fda- letter-stakeholders-
do-not-use-ivermectin- intended-animals-treatment-covid-19- humans
28. NBC Miami. Local doctor tries new coronavirus drug treatment. 2020.
https://web.archive.org/web/20200414024411/https://www.nbcmiami.com/news/local/local-
doctor-tries-new-coronavirus- drug-treatment/2219465/
29. Patel A, Desai S. Ivermectin in COVID-19 related critical illness. SSRN Electronic Journal. 2020.
https://web.archive.org/web/20210315083615/https://www.isglobal.org/documents/10179/
6022921/Patel+et+al.%20+2020+version+1.pdf/fab19388-dc3e-4593-a075- db96f4536e9d
30. Patel A, Desai S. Ivermectin in COVID-19 Related Critical Illness by Amit Patel, Sapan Desai.
SSRN Electronic Journal. 2020. https://web.archive.org/web/20200414142415/https:
//papers.ssrn.com/sol3/papers.cfm?abstract_id=3570270
41
31. “La Ivermectina fue creada para el tratamiento de humanos”. La Industria. 2020.
https://web.archive.org/web/20200608055559/http://laindustria.pe/nota/16073-la-
ivermectina-fue-creada-para- el-tratamiento-de-humanos
32. Patel AN, Desai SS, Grainger DW, Mehra MR. Usefulness of ivermectin in COVID-19 illness.
SSRN Electronic Journal. 2020. https://web.archive.org/web/20210315083837/https:
//www.isglobal.org/documents/10179/6022921/Patel+et+al.+2020+version+2.pdf/
33. Patel A. Usefulness of ivermectin in COVID-19 illness. SSRN Electronic Journal. 2020.
https://web.archive.org/web/20200602150544/https:
//papers.ssrn.com/sol3/papers.cfm?abstract_id=3580524
34. Oropeza V. La sospecha del doctor Chaccour. Pulitzer Center. 2020.
https://web.archive.org/web/20200716234039/http:
//factor.prodavinci.com/lasospechadeldoctorchaccour/
35. Bray M, Rayner C, Noël F, Jans D, Wagstaff K. Ivermectin and COVID-19: a report in Antiviral
Research widespread interest, an FDA warning, two letters to the editor and the authors'responses.
Antiviral Research. June 2020;178:104805. https://doi.org/10.1016/j.antiviral.2020.104805
36. Hoy W. Rapid response: trial of ivermectin for treatment and prophylaxis of COVID-19. BMJ.
April 2020;:m1432. https://www.bmj.com/content/369/bmj.m1432/rr-26
37. Hoy W. Re: my previous response (trial of ivermectin for treatment and prophylaxis of COVID-19)
in response to Chloroquine and hydroxychloroquine in COVID-19. BMJ. 2020;369:m1432.
https://www.bmj.com/content/369/bmj.m1432/rr-34
38. Hoy W, Diwan V. Rapid response: Re: Covid-19: a wake-up call. BMJ. 2020;369:m2021.
https://www.bmj.com/content/369/bmj.m2021/rr-2
39. Schmith VD, Zhou J(J, Lohmer LRL. The approved dose of ivermectin alone is not the ideal dose
for the treatment of COVID-19. Clinical Pharmacology & Therapeutics. June 2020;108(4):762–5.
https://doi.org/10.1002/cpt.1889
40. Aguirre-Chang G. Inclusión de la ivermectina en la primeira línea de acción terapéutica para
COVID-19. Se reporta una muy significativa disminución de la Tasa de Letalidad con su uso.
ResearchGate. 2020. https://www.researchgate.net/publication/342466502_INCLUSION_DE_LA_
IVERMECTINA_EN_LA_PRIMERA_LINEA_DE_ACCION_TERAPEUTICA_PARA_COVID-
19_Se_reporta_una_muy_significativa_disminucion_de_la_Tasa_de_Letalidad_con_su_uso
41. A randomised clinical trial of ivermectin for treatment and prophylaxis of COVID-19
(ECIT-PRO19). European Medicine Agency Clinical Trials Register. 2020.
https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001994-66/ES
42. A pilot study to evaluate the potential of ivermectin to reduce COVID-19 transmission (SAINT).
European Medicine Agency Clinical Trials Register. 2020.
https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001474-29/ES
43. Lowe D. What’s up with ivermectin? Science Translational Medicine In the Pipeline Blog. 2020.
https://web.archive.org/web/20200518021117/https:
//blogs.sciencemag.org/pipeline/archives/2020/05/11/whats-up-with-ivermectin
44. Huvepharma EOOD. Multicenter, randomized, double-blind, placebo-controlled study investigating
efficacy, safety and tolerability of ivermectin HUVE-19 in patients with proven SARS-CoV-2 infection
(COVID-19) and manifested clinical symptoms (EudraCT 2020-002091-12). European Medicine
Agency Clinical Trials Register. 2020.
https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002091-12/BG
45. Press Trust of India. Bangladesh medical team says ivermectin with antibiotic doxycycline works to
treat COVID-19 patients. Firstpost. 2020. https://web.archive.org/web/20200724160329/https:
//www.firstpost.com/health/bangladesh-medical-team-says- ivermectin-with-antibiotic-
doxycycline-works-to-treat- covid-19-patients-8381321.html
42
46. Ramos WM, Pérez MAGM, Acosta AC, Torre CEM de la, Ramos GF, Coronel AEA, et al.
Intervención de la ivermectina pre-hospitalaria para la modificación de la evolución del Covid-19.
Estudio realizado en Perú. Caretas. 2020.
https://web.archive.org/web/20200616111752/https://caretas.pe/wp-
content/uploads/2020/05/ESTUDIO-PERU-DEFINITIVO-corregido- en-Word-y-pasado-a- PDF.pdf
47. Rizzo E. Ivermectin antiviral properties and COVID-19: a possible new mechanism of action.
Naunyn-Schmiedeberg's Archives of Pharmacology. May 2020;393(7):1153–6.
https://doi.org/10.1007/s00210-020-01902-5
48. Chandna H. ICMR to review ’wonder’ drug combo used to treat Covid patients in Bangladesh. The
Print. 2020. https://web.archive.org/web/20200917183516/https://theprint.in/health/icmr-
to-review-wonder-drug- combo-used-to-treat-covid- patients-in-bangladesh/432987/
49. Peru: Minsa steps up efforts to deliver medicines home and prevent hospital congestion. Editora
Perú/Peru News Agency. 2020. https://web.archive.org/web/20210311151457/https:
//andina.pe/ingles/noticia-peru-minsa-steps- up-efforts-to-deliver-medicines- home-and-
prevent-hospital-congestion-799759.aspx
50. Ivermectin as an antiviral treatment for patients infected by SARS-COV2 (CORIVER). European
Medicine Agency Clinical Trials Register. 2020.
https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001971-33/ES
51. Servick K. A mysterious company’s coronavirus papers in top medical journals may be unraveling.
Science. June 2020. https://doi.org/10.1126/science.abd1337
52. Davey M, Kirchgaessner S, Boseley S. Surgisphere: governments and WHO changed Covid-19
policy based on suspect data from tiny US company. The Guardian. 2020.
http://www.theguardian.com/world/2020/jun/03/covid-19-surgisphere-who- world-health-
organization-hydroxychloroquine
53. Ministerio de Salud. Resolución Ministerial N°270-2020-MINSA. 2020.
https://web.archive.org/web/20210308110555/https:
//www.gob.pe/institucion/minsa/normas-legales/563764-270-2020- minsa
54. Piller C, Servick K. Two elite medical journals retract coronavirus papers over data integrity
questions. Science. June 2020. https://doi.org/10.1126/science.abd1697
55. Piller C. Who’s to blame? These three scientists are at the heart of the Surgisphere COVID-19
scandal. Science. June 2020. https://doi.org/10.1126/science.abd2252
56. Kerr L. Alguns esclarecimentos sobre a ivermectina. Portal Lucy Kerr. 2020.
https://web.archive.org/web/20200617021627/https://portallucykerr.com/alguns-
esclarecimentos-sobre-a-ivermectina/
57. An old drug tackles new tricks: ivermectin treatment in three Brazilian towns. TrialSite News.
2020. https://web.archive.org/web/20201002172248/https://trialsitenews.com/an-old-
drug-tackles-new-tricks- ivermectin-treatment-in-three-brazilian- towns/
58. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter J-J. ICON (Ivermectin in COvid
Nineteen) study: Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with
COVID19. medRxiv. June 2020. https://doi.org/10.1101/2020.06.06.20124461
59. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter J-J. Use of ivermectin is associated
with lower mortality in hospitalized patients with coronavirus disease 2019. Chest. January
2021;159(1):85–92. https://doi.org/10.1016/j.chest.2020.10.009
60. Heidary F, Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19
complementary regimen. The Journal of Antibiotics. June 2020;73(9):593–602.
https://doi.org/10.1038/s41429-020-0336-z
61. How a grass roots health movement led to acceptance of ivermectin as a COVID-19 therapy in
Peru. TrialSite News. 2020.
43
https://web.archive.org/web/20201222145639/https://trialsitenews.com/how-a-grass-
roots-health-movement-led- to-acceptance-of-ivermectin-as- a-covid-19-therapy-in- peru/
62. Alam MT, Murshed R, Bhiuyan E, Saber S, Alam RF, Robin RC. A case series of 100 COVID-19
positive patients treated with combination of ivermectin and doxycycline. Journal of Bangladesh
College of Physicians and Surgeons. June 2020;38:10–5.
https://doi.org/10.3329/jbcps.v38i0.47512
63. A randomized, double-blind, multi centre phase II, proof of concept, dose finding clinical trial on
ivermectin for the early treatment of COVID-19 (COVER). European Medicine Agency Clinical Trials
Register. 2020. https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002283-32/IT
64. Vigneri M. L’ivermectina è un farmaco straordinario ma poco noto, ha buone chance anche contro
il Coronavirus. The Post Internazionale (TPI). 2020.
https://web.archive.org/web/20210313210733/https://www.tpi.it/cronaca/coronavirus-
ivermectina-farmaco-straordinario-intervista- 20200405579792/
65. Angheben A. Covid 19: facciamo il punto sui farmaci oggi efficaci - IRCCS Ospedale Sacro Cuore
Don Calabria. IRCCS Ospedale Sacro Cuore Don Calabria. 2020.
https://web.archive.org/web/20210313211658/https://www.sacrocuore.it/covid-19-
facciamo-il-punto-sui- farmaci-oggi-efficaci/
66. El verdadero Comando COVID-19 de Iquitos: médicos independientes lograron contener el azote
del coronavirus, no el Minsa ni Essalud. Con Nuestro Perú. 2020.
https://web.archive.org/web/20200615181035/https://www.connuestroperu.com/actualidad/
entrevistas/65760-el-verdadero-comando- covid-19-de-iquitos-medicos- independientes-
lograron-contener-el-azote- del-coronavirus-no-el-minsa- ni-essalud
67. Sparavigna AC. Ivermectin for Covid-19. ResearchGate. 2020.
https://doi.org/10.5281/zenodo.3893750
68. Köppe J. Zurückgezogene Covid-19-Studien - das steckt hinter der Datenbank von Surgisphere. Der
Spiegel. 2020. https://www.spiegel.de/wissenschaft/medizin/corona-zurueckgezogene-covid-
19-studien-das-steckt- hinter-der-datenbank-von-surgisphere- a-3f5986b8-d9d6-492f-
a562-81d3bccbe4fa
69. Scheim D. Antimalarials for COVID-19 treatment: rapid reversal of oxygen status decline with the
Nobel prize-honored macrocyclic lactone ivermectin. SSRN Electronic Journal. 2020.
https://doi.org/10.2139/ssrn.3617911
70. Wang K, Chen W, Zhou Y-S, Lian J-Q, Zhang Z, Du P, et al. SARS-CoV-2 invades host cells via a
novel route: CD147-spike protein. medRxiv. March 2020.
https://doi.org/10.1101/2020.03.14.988345
71. Wang K, Chen W, Zhang Z, Deng Y, Lian J-Q, Du P, et al. CD147-spike protein is a novel route
for SARS-CoV-2 infection to host cells. Signal Transduction and Targeted Therapy. December
2020;5(1). https://doi.org/10.1038/s41392-020-00426-x
72. Clinical management of patients with COVID-19 – a guide for front-line healthcare workers.
Version 2.1, June 17, 2020. 2020.
http://web.archive.org/web/20200708033632/https://www.mhlw.go.jp/content/000646531.pdf
73. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain
attached to ACE2. In Vivo. 2020;34(5):3023–6. https://doi.org/10.21873/invivo.12134
74. Zhang P, Ni H, Zhang Y, Xu W, Gao J, Cheng J, et al. Ivermectin confers its cytotoxic effects by
inducing AMPK/mTOR-mediated autophagy and DNA damage. Chemosphere. November
2020;259:127448. https://doi.org/10.1016/j.chemosphere.2020.127448
75. Resolución Ministerial 426-2020 MINSA. Ministerio De Salud (Peru). 2020.
https://web.archive.org/web/20210315081458/https:
//cdn.www.gob.pe/uploads/document/file/874053/RM_426-2020-MINSA.pdf
44
76. Molento MB. COVID-19 and the rush for self-medication and self-dosing with ivermectin: A word
of caution. One Health. December 2020;10:100148.
https://doi.org/10.1016/j.onehlt.2020.100148
77. President of Dominican Republic’s largest private health group discusses the success of ivermectin
as a treatment for early stage COVID-19. TrialSite News. 2020.
https://web.archive.org/web/20210319114033/https://trialsitenews.com/president-of-
dominican-republics-largest-private- health-group-discusses-the-success- of-ivermectin-
as-a-treatment-for- early-stage-covid-19/
78. Scheim D. Ivermectin for COVID-19 treatment: clinical response at quasi-threshold doses via
hypothesized alleviation of CD147-mediated vascular occlusion. SSRN Electronic Journal. Elsevier BV;
2020. https://doi.org/10.2139/ssrn.3636557
79. Syed M. Ivermectin remdesivir leronlimab. Drbeen Medical Lectures.
https://youtu.be/wR6CuBu_mA8; 2020. https://youtu.be/wR6CuBu_mA8
80. Проф. Христова: Ивермектин е обещаващ препарат срещу Covid-19. Economic. 2020.
https://web.archive.org/web/20210312075642/https://www.economic.bg/bg/a/view/prof-
hristova-ivermektin-e-obeshtavasht- preparat-sreshtu-covid-19-119076
81. Gorial FI, Mashhadani S, Sayaly HM, Dakhil BD, AlMashhadani MM, Aljabory AM, et al.
Effectiveness of ivermectin as add-on therapy in COVID-19 management (pilot trial). medRxiv. July
2020. https://doi.org/10.1101/2020.07.07.20145979
82. Maurya DK. A combination of ivermectin and doxycycline possibly blocks the viral entry and
modulate the innate immune response in COVID-19 patients. chemRxiv. July 2020.
https://doi.org/10.26434/chemrxiv.12630539.v1
83. Aguirre-Chang G, Castillo-Saavedra E, Yui-Cerna M, Trujillo-Figueredo A, Córdova-Masías J.
Post-acute or prolonged COVID-19: ivermectin treatment for patients with persistent or post-acute
symptoms. ResearchGate. 2020.
https://www.researchgate.net/publication/344318845_POST-ACUTE_OR_PROLONGED_COVID-
19_IVERMECTIN_TREATMENT_FOR_PATIENTS_WITH_PERSISTENT_SYMPTOMS_OR_POST-ACUTE
84. Goodman J, Carmichael F. Coronavirus: fake cures in Latin America’s deadly outbreak. BBC.
2020. https://web.archive.org/web/20200712002646/https://www.bbc.com/news/53361876
85. Chowdhury A, Mohiuddin TM, Shahbaz M, Karim R, Islam J, Guo D, et al. A randomized trial of
ivermectin-doxycycline and hydroxychloroquine-azithromycin therapy on COVID19 patients. Research
Square. 2020. https://www.researchsquare.com/article/rs-38896/v1
86. Dr. Jean-Jacques Rajter and Dr. Juliana Cepelowicz Rajter discuss ivermectin In Broward County.
TrialSite News. 2020. https://youtu.be/nzqnAIfEbv4
87. Dr. Jean-Jacques Rajter and Dr. Juliana Cepelowicz Rajter discuss ivermectin In Broward county –
podcast S2 E 27. TrialSite News. 2020. https://trialsitenews.com/dr- jean-jacque-rajter-and-
dr-juliana-cepelowicz-rajter- discuss-ivermectin-in-broward-county- podcast-s2-e-27/
88. Peña-Silva R, Duffull SB, Steer AC, Jaramillo-Rincon SX, Gwee A, Zhu X. Pharmacokinetic
considerations on the repurposing of ivermectin for treatment of COVID-19. British Journal of Clinical
Pharmacology. July 2020;87(3):1589–90. https://doi.org/10.1111/bcp.14476
89. Arpornsuwan M, Arpornsuwan M. Early diagnosis and early management proposal in dengue
infection: new normal to applied strategy for COVID-19 infection. SSRN Electronic Journal. 2020.
https://doi.org/10.2139/ssrn.3649412
90. Vora A, Arora VK, Behera D, Tripathy SK. White paper on Ivermectin as a potential therapy for
COVID-19. Indian Journal of Tuberculosis. July 2020;67(3):448–51.
https://doi.org/10.1016/j.ijtb.2020.07.031
45
91. Aguirre- Chang G, Trujillo Figueredo A. COVID-19: post-exposure prophylaxis with ivermectin in
contacts. At homes, places of work, nursing homes, prisons, and others. ResearchGate. July 2020.
https://doi.org/10.13140/RG.2.2.34561.48483/2
92. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone. JAMA. August
2020;324(7):623. https://doi.org/10.1001/jama.2020.13170
93. Rahman A, Iqbal SA, Islam A, Niaz K, Hussain T, Siddiquee TH. Comparison of viral clearance
between ivermectin with doxycycline and hydroxychloroquine with azithromycin in COVID-19 patients.
J Bangladesh Coll Phys Surg. 2020;38:5–9. https://web.archive.org/web/20210129105721/http:
//bcpsjournal.org/mhcms-admin/media/pdf/article761.pdf
94. Empezarán a usar Ivermectina en tratamiento de pacientes covid en Cali, dice Ospina. El País.
2020.
https://web.archive.org/web/20200717042008/https://www.elpais.com.co/ultimo-minuto/
empezaran-a-usar-ivermectina- en-tratamiento-de-pacientes-covid- en-dice-ospina.html
95. Front Line COVID-19 Critical Care Alliance. FAQ on ivermectin. 2021.
https://web.archive.org/web/20210301170808/https://covid19criticalcare.com/i-mask-
prophylaxis-treatment-protocol/faq-on- ivermectin/
96. Prasad A. A meeting regarding the role of ivermectin. 2020.
https://web.archive.org/web/20201004145236/dgmhup.gov.in/DocumentsCovid19/1621.pdf
97. Pan American Health Organization. Ongoing living update of potential COVID-19 therapeutics:
summary of rapid systematic reviews - 11 August 2020. 2020.
https://web.archive.org/web/20210323105539/https:
//docs.bvsalud.org/biblioref/2020/08/1094870/pahoimseihcovid-19200016_eng.pdf
98. Davey M. What is ivermectin, and should we be using it to treat Covid-19? Guardian. 2020.
https://web.archive.org/web/20200813032207/http://www.theguardian.com/australia-
news/2020/aug/13/what-is-ivermectin-and- should-we-be-using-it- to-treat-covid-19
99. Bhattacharya R, Ray I, Mukherjee R, Chowdhury S, Kulasreshtha M, Ghosh R. Observational
study on clinical features, treatment and outcome of COVID 19 in a tertiary care centre in India – a
retrospective case series. Int J Scientific Research. October 2020;9(10):69–71.
https://doi.org/10.36106/ijsr/7232245
100. Lier AJ, Tuan JJ, Davis MW, Paulson N, McManus D, Campbell S, et al. Case report:
disseminated strongyloidiasis in a patient with COVID-19. The American Journal of Tropical Medicine
and Hygiene. October 2020;103(4):1590–2. https://doi.org/10.4269/ajtmh.20-0699
101. Espitia-Hernandez G, Munguia L, Diaz-Chiguer D, Lopez-Elizalde R, Jimenez-Ponce F. Effects of
ivermectin-azithromycin-cholecalciferol combined therapy on COVID-19 infected patients: a proof of
concept study. Biomedical Research. 2020;31(5). https://www.biomedres.info/biomedical-
research/effects-of-ivermectinazithromycincholecalciferol-combined- therapy-on-
covid19-infected-patients-a- proof-of-concept-study-14435.html
102. Weisser R. No guts, no glory. The Spectator Australia. 2020.
https://web.archive.org/web/20200817155704/https://www.spectator.com.au/2020/08/no-
guts-no-glory/
103. Well-respected Australian researcher: consider triple therapy (ivermectin, zinc, doxycycline) for
COVID-19. TrialSite News. 2020. https://web.archive.org/web/20200820141526/https:
//trialsitenews.com/well-respected-australian-researcher- consider-triple-therapy-
ivermectin-zinc-doxycycline-for- covid-19/
104. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter J-J. ICON (Ivermectin in COvid
Nineteen) study: use of ivermectin is associated with lower mortality in hospitalized patients with
COVID-19. SSRN Electronic Journal. 2020. https://doi.org/10.2139/ssrn.3631261
46
105. US National Institutes of Health. COVID-19 treatment guidelines: ivermectin (August 27, 2020).
2020. https://web.archive.org/web/20200920093445/https:
//www.covid19treatmentguidelines.nih.gov/antiviral-therapy/ivermectin/
106. Shouman W. Prophylactic ivermectin in COVID-19 contacts (NCT04422561). ClinicalTrials.gov.
2020. https://clinicaltrials.gov/ct2/show/results/NCT04422561
107. Zagazig University randomized controlled ivermectin study results confirms PI hypothesis: drug
effective against COVID-19. TrialSite News. 2020.
https://web.archive.org/web/20200830164247/https://trialsitenews.com/zagazig-
university-randomized-controlled-ivermectin- study-results-confirms-pi-hypothesis-
drug-effective-against-covid- 19/
108. Hlavinka E. Ivermectin for COVID-19: worth a shot? MedPage Today. August 27, 2020.
https://web.archive.org/web/20200828000211/https://www.medpagetoday.com/special-
reports/exclusives/88310
109. Dias I. The Brazilian city being turned into a coronavirus lab experiment. Coda. 2020.
https://web.archive.org/web/20200902222937/https:
//www.codastory.com/waronscience/brazil-covid19-ivermectin/
110. Podder CS, Chowdhury N, Sina MI, Haque WMMU. Outcome of ivermectin treated mild to
moderate COVID-19 cases: a single-centre, open-label, randomised controlled study. IMC J Med Sci.
2020;14(2):002. http://imcjms.com/registration/journal_full_text/353
111. Marchese V, Crosato V, Gulletta M, Castelnuovo F, Cristini G, Matteelli A, et al. Strongyloides
infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. Infection.
September 2020. https://doi.org/10.1007/s15010-020-01522-4
112. Elkholy KO, Hegazy O, Erdinc B, Abowali H. Ivermectin: a closer look at a potential remedy.
Cureus. September 2020;12(9):e10378. https://doi.org/10.7759/cureus.10378
113. Quadruple therapy with ivermectin is effective in treating COVID-19. The Hindu. 2020.
https://web.archive.org/web/20200917040005/https:
//www.thehindu.com/news/national/karnataka/quadruple-therapy-with-ivermectinis-
effective-in-treating-covid- 19/article32601262.ece
114. Carvallo H, Hirsch R, Farinella ME. Safety and efficacy of the combined use of ivermectin
dexamethasone, enoxaparin and aspirin against COVID 19. medRxiv. September 2020.
https://doi.org/10.1101/2020.09.10.20191619
115. CovidAnalysis. Analysis of: Safety and efficacy of the combined use of ivermectin, dexamethasone,
enoxaparin and aspirin against COVID-19. 2020.
https://web.archive.org/web/20210211203641/https://c19ivermectin.com/carvallo.html
116. Carvallo H. Ivermectin, aspirin, dexamethasone and enoxaparin as treatment of Covid 19.
ClinicalTrials.gov. 2020. https://clinicaltrials.gov/ct2/show/NCT04425863
117. Carvallo H. Dr Héctor Carvallo – présentation sur l’ivermectine en prophylaxie & traitement, +
questions – réponses (st français, english). Vimeo. 2021. https://vimeo.com/531341590
118. Carvallo H, Hirsch R, Farinella ME. Safety and efficacy of the combined use of ivermectin,
dexamethasone, enoxaparin and aspirin against COVID 19. medRxiv. September 2020.
https://doi.org/10.1101/2020.09.10.20191619
119. Coronavirus: las lecciones no aprendidas de Loreto. Caretas. 2020.
https://web.archive.org/web/20210224151105/https://caretas.pe/nacional/coronavirus-
las-lecciones-no-aprendidas- de-loreto/
120. Li N, Zhao L, Zhan X. Quantitative proteomics reveals a broad-spectrum antiviral property of
ivermectin benefiting for COVID-19 treatment. Journal of Cellular Physiology. September
2020;236(4):2959–75. https://doi.org/10.1002/jcp.30055
47
121. Khan MSI, Khan MSI, Debnath CR, Nath PN, Mahtab MA, Nabeka H, et al. Ivermectin
treatment may improve the prognosis of patients with COVID-19. Archivos de Bronconeumología.
December 2020;56(12):828–30. https://doi.org/10.1016/j.arbres.2020.08.007
122. Tilli M, Olliaro P, Gobbi F, Bisoffi Z, Bartoloni A, Zammarchi L. Neglected tropical diseases in
non-endemic countries in the era of COVID-19 pandemic: the great forgotten. Journal of Travel
Medicine. September 2020;28(1). https://doi.org/10.1093/jtm/taaa179
123. Taylor GA. Re: the BMJ interview: Anthony Fauci on COVID-19. BMJ. 2020;370:m3703.
https://www.bmj.com/content/370/bmj.m3703/rr-1
124. Godlee F, Silberner J. The BMJ interview: Anthony Fauci on COVID-19. BMJ. September
2020;370:m3703. https://doi.org/10.1136/bmj.m3703
125. Chachar AZK, Khan KA, Asif M, Tanveer K, Khaqan A, Basri R. Effectiveness of ivermectin in
SARS-CoV-2/COVID-19 patients. International Journal of Sciences. 2020;9(09):31–5.
https://doi.org/10.18483/ijsci.2378
126. Chamie J. Real-world evidence: the case of Peru. Causality between ivermectin and COVID-19
infection fatality rate. ResearchGate. 2020.
https://www.researchgate.net/publication/344469305_Real-World_Evidence_The_Case_of_
Peru_Causality_between_Ivermectin_and_COVID-19_Infection_Fatality_Rate
127. Chamie J. Real-world evidence: the case of Peru. TrialSite News. 2020.
https://web.archive.org/web/20201021075542/https://trialsitenews.com/real-world-
evidence-the-case-of- peru/
128. Francés-Monerris A, Garcia-Iriepa C, Iriepa I, Hognon C, Miclot T, Barone G, et al. Has
ivermectin virus-directed effects against SARS-CoV-2? Rationalizing the action of a potential
multitarget antiviral agent. chemRxiv. August 2020.
https://doi.org/10.26434/chemrxiv.12782258.v1
129. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, Araujo-Castillo RV. Real-world effectiveness of
hydroxychloroquine azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a
target trial emulation using observational data from a nationwide healthcare system in Peru. medRxiv.
October 2020. https://doi.org/10.1101/2020.10.06.20208066
130. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, Araujo-Castillo RV. Real-world effectiveness of
hydroxychloroquine, azithromycin and ivermectin among hospitalized COVID-19 patients: results of a
target trial emulation using observational data from a nationwide healthcare system in Peru. SSRN
Electronic Journal. 2020. https://doi.org/10.2139/ssrn.3710623
131. Yim PJ. Systemic unreported protocol violations in key ivermectin study. TrialSite News. 2021.
https://trialsitenews.com/systemic-unreported-protocol-violations- in-key-ivermectin-
study/
132. CovidAnalysis. Analysis of: Real-world effectiveness of hydroxychloroquine, azithromycin, and
ivermectin among hospitalized COVID-19 patients: results of a target trial emulation using
observational data from a nationwide healthcare system in Peru. 2020.
https://c19ivermectin.com/sotobecerrai.html
133. Mahmud R. Clinical trial of ivermectin plus doxycycline for the treatment of confirmed Covid-19
infection. ClinicalTrialsgov. 2020. https://clinicaltrials.gov/ct2/show/results/NCT04523831
134. CovidAnalysis. An analysis of: Clinical trial of ivermectin plus doxycycline for the treatment of
confirmed Covid-19 infection. 2020. https://c19ivermectin.com/mahmud.html
135. COVID-19: Goa CM Pramod Sawant launches ’home isolation kit’. 2LT News. 2020.
https://web.archive.org/web/20201013035055/https://www.2lt.com.au/covid-19-goa-cm-
pramod-sawant-launches-home- isolation-kit/
48
136. Kant S, Rastogi H, Bajpai J, Aggarwal KK. Ivermectin – a potent weapon in the anti-COVID-19
armamentarium. Indian Journal of Clinical Practice. 2020;31(5).
https://ijcp.in/Admin/CMS/PDF/6.%20ReviewArticle2_IJCP_OCT2020.pdf
137. Medtalks. Ivermectin: a potent weapon in the anti-COVID armamentarium. 2020.
https://youtu.be/HN06xiTmdZc
138. Scheim D. From cold to killer: how SARS-CoV-2 evolved without hemagglutinin esterase to
agglutinate then clot blood cells in pulmonary and systemic microvasculature. SSRN Electronic
Journal. 2020. https://doi.org/10.2139/ssrn.3706347
139. Resolución Ministerial N°839-2020-MINSA. 2020.
https://www.gob.pe/institucion/minsa/normas-legales/1264399-839-2020- minsa
140. Controversia sobre el uso de la hidroxicloroquina, azitromicina e ivermectina en tratamiento
hospitalario. Caretas. 2020. https://caretas.pe/nacional/controversia-sobre-el-uso- de-la-
hidroxicloroquina-azitromicina-e-ivermectina- en-tratamiento-hospitalario/
141. Carvallo HE. Usefulness of topic ivermectin and carrageenan to prevent contagion of Covid 19
(IVERCAR) (NCT04425850) – Study Results. ClinicalTrials.gov. 2020.
https://clinicaltrials.gov/ct2/show/results/NCT04425850
142. CovidAnalysis. Analysis of: Usefulness of topic ivermectin and carrageenan to prevent contagion
of Covid 19 (IVERCAR). 2020. https://c19ivermectin.com/carvalloprep2.html
143. Interview with Dr. Hector Carvallo: pioneer in ivermectin, iota carrageenan, bromhexine and
COVID-19. Whiteboard Doctor. 2020. https://youtu.be/CB6Bvi_g-w8
144. Guerrero R, Bravo LE, Muñoz E, Ardila EKG, Guerrero E. COVID-19: The ivermectin African
enigma. Colombia Médica. November 2020;51(4):e-2014613.
https://doi.org/10.25100/cm.v51i4.4613
145. CovidAnalysis. Analysis of: COVID-19: the ivermectin African enigma. 2020.
https://c19ivermectin.com/guerrero.html
146. Hashim HA, Maulood MF, Rasheed AM, Fatak DF, Kabah KK, Abdulamir AS. Controlled
randomized clinical trial on using Ivermectin with Doxycycline for treating COVID-19 patients in
Baghdad Iraq. medRxiv. October 2020. https://doi.org/10.1101/2020.10.26.20219345
147. CovidAnalysis. Analysis of: Controlled randomized clinical trial on using ivermectin with
doxycycline for treating COVID-19 patients in Baghdad, Iraq. 2020.
https://c19ivermectin.com/hashim.html
148. Gupta PSS, Biswal S, Panda SK, Ray AK, Rana MK. Binding mechanism and structural insights
into the identified protein target of COVID-19 and importin-αwith in-vitro effective drug ivermectin.
Journal of Biomolecular Structure and Dynamics. October 2020;:1–10.
https://doi.org/10.1080/07391102.2020.1839564
149. Turkia M. The History of Methylprednisolone, Ascorbic Acid, Thiamine, and Heparin Protocol
and I-MASK+ Ivermectin Protocol for COVID-19. Cureus. December 2020.
https://doi.org/10.7759/cureus.12403
150. FLCCC Alliance. I-MASK+ Protocol. 2020.
https://covid19criticalcare.com/covid-19-protocols/i-mask- plus-protocol/
151. Aguirre-Chang G, Trujillo Figueredo A. COVID-19: efficacy of pre-exposure prophylaxis with
ivermectin in exposed persons. ResearchGate. October 2020.
https://www.researchgate.net/publication/347890660_COVID-19_EFFICACY_OF_PRE-
EXPOSURE_PROPHYLAXIS_WITH_IVERMECTIN_IN_EXPOSED_PERSONS
152. r/covidlonghaulinfo. Reddit. 2020. https://www.reddit.com/r/covidlonghaulinfo/
49
153. Behera P, Patro BK, Singh AK, Chandanshive PD, S.R. RK, Pradhan SK, et al. Role of
ivermectin in the prevention of COVID-19 infection among healthcare workers in India: a matched
case-control study. medRxiv. November 2020. https://doi.org/10.1101/2020.10.29.20222661
154. Behera P, Patro BK, Singh AK, Chandanshive PD, R. RS, Pradhan SK, et al. Role of ivermectin
in the prevention of SARS-CoV-2 infection among healthcare workers in India: a matched case-control
study. Adrish M, editor. PLOS ONE. February 2021;16(2):e0247163.
https://doi.org/10.1371/journal.pone.0247163
155. Morgenstern J, Redondo JN, León AD, Canela JM, Castro NT, Tavares J, et al. The use of
compassionate ivermectin in the management of symptomatic outpatients and hospitalized patients
with clinical diagnosis of Covid-19 at the Centro Medico Bournigal and at the Centro Medico Punta
Cana, Grupo Rescue, Dominican Republic, from May 1 to August 10, 2020. J Clin Trials. 2020;11(59).
https://www.longdom.org/open-access/the-use-of- compassionate-ivermectin-in-the-
management-of-symptomatic-outpatients- and-hospitalized-patients-with-clinical.pdf
156. Cadegiani FA, Goren A, Wambier CG, McCoy J. Early COVID-19 therapy with azithromycin plus
nitazoxanide ivermectin or hydroxychloroquine in outpatient settings significantly reduced symptoms
compared to known outcomes in untreated patients. medRxiv. November 2020.
https://doi.org/10.1101/2020.10.31.20223883
157. Cadegiani FA, Goren A, McCoy J, Wambier CG. Hydroxychloroquine nitazoxanide and
ivermectin have similar effects in early COVID-19: a head-to-head comparison of the Pre-AndroCoV
trial. Research Square. October 2020. https://doi.org/10.21203/rs.3.rs-98106/v1
158. CovidAnalysis. Analysis of: Early COVID-19 therapy with azithromycin plus nitazoxanide,
ivermectin or hydroxychloroquine in outpatient settings significantly reduced symptoms compared to
known outcomes in untreated patients. 2020. https://c19ivermectin.com/cadegianii.html
159. France: the ivermectin dossier before the council of state. Covexit. 2021.
https://web.archive.org/web/20210120110202/https://covexit.com/france-the-ivermectin-
dossier-before-the-council- of-state/
160. Turkia M. FLCCC Alliance MATH+ ascorbic acid and I-MASK+ ivermectin protocols for
COVID-19 – a brief review. SSRN Electronic Journal. 2020.
https://doi.org/10.2139/ssrn.3723854
161. CovidAnalysis. Analysis of: FLCCC Alliance MATH+ ascorbic acid and I-MASK+ ivermectin
protocols for COVID-19 — a brief review. 2020. https://c19ivermectin.com/turkia.html
162. Krolewiecki A, Lifschitz A, Moragas M, Travacio M, Valentini R, Alonso DF, et al. Antiviral
effect of high-dose ivermectin in adults with COVID-19: a pilot randomised controlled, open label,
multicentre trial. SSRN Electronic Journal. 2020. https://doi.org/10.2139/ssrn.3714649
163. Camprubí D, Almuedo-Riera A, Martí-Soler H, Soriano A, Hurtado JC, Subirà C, et al. Lack of
efficacy of standard doses of ivermectin in severe COVID-19 patients. Dorlo TPC, editor. PLOS ONE.
November 2020;15(11):e0242184. https://doi.org/10.1371/journal.pone.0242184
164. CovidAnalysis. Analysis of: Lack of efficacy of standard doses of ivermectin in severe COVID-19
patients. 2020. https://c19ivermectin.com/camprubi.html
165. Alan Cannell talks COVID-19: nobody likes cheap solutions – podcast S2 E41. TrialSite News.
2020. https://trialsitenews.com/alan-cannell-talks-covid- 19-nobody-likes-cheap-
solutions-podcast-s2-e41/
166. Elgazzar A, Hany B, Youssef SA, Hany B, Hafez M, Moussa H. Efficacy and safety of ivermectin
for treatment and prophylaxis of COVID-19 pandemic. Research Square. November 2020.
https://doi.org/10.21203/rs.3.rs-100956/v1
167. CovidAnalysis. Analysis of: Efficacy and safety of ivermectin for treatment and prophylaxis of
COVID-19 pandemic. 2020. https://c19ivermectin.com/elgazzarpep.html
50
168. Kory P, Meduri GU, Iglesias J, Varon J, Berkowitz K, Kornfeld H, et al. Review of the emerging
evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19. OSF
Preprints. November 2020. https://doi.org/10.31219/osf.io/wx3zn
169. CovidAnalysis. Analysis of: Utility of ivermectin and doxycycline combination for the treatment
of SARS-CoV-2. 2020. https://c19ivermectin.com/spoorthi.html
170. Spoorthi V, Sasank S. Utility of ivermectin and doxycycline combination for the treatment of
SARS-CoV-2. IAIM. 2020;7(10):177–82.
http://iaimjournal.com/wp-content/uploads/2020/10/iaim_2020_0710_23.pdf
171. Carvallo H, Hirsch R, Alkis P, Contreras V. Study of the efficacy and safety of topical ivermectin
+ iota-carrageenan in the prophylaxis against COVID-19 in health personnel. Journal of Biomedical
Research and Clinical Investigation. November 2020;2(1).
https://doi.org/10.31546/2633-8653.1007
172. CovidAnalysis. Analysis of: Study of the efficacy and safety of topical ivermectin +
iota-carrageenan in the prophylaxis against COVID-19 in health personnel. 2020.
https://c19ivermectin.com/carvalloprep.html
173. Hirsch RR, Carvallo HE. Covid 19 and ivermectin prevention and treatment update. Journal of
Infectious Diseases & Travel Medicine. 2020;4(S1). https://doi.org/10.23880/jidtm-16000s1-007
174. Kamen J. Facebook censored our posts. And that just might cost many people their lives.
Medium. 2020.
https://web.archive.org/web/20210305164645/https://joyce-kamen.medium.com/facebook-
censored-our-posts-and- that-just-might-cause-many- people-their-lives-be3c9e09acbd
175. Budhiraja S, Soni A, Jha V, Indrayan A, Dewan A, Singh O, et al. Clinical profile of first 1000
COVID-19 cases admitted at tertiary care hospitals and the correlates of their mortality: an Indian
experience. medRxiv. November 2020. https://doi.org/10.1101/2020.11.16.20232223
176. CovidAnalysis. Analysis of: Clinical profile of first 1000 COVID-19 cases admitted at tertiary care
hospitals and the correlates of their mortality: an Indian experience. 2020.
https://c19ivermectin.com/budhirajai.html
177. Early outpatient treatment: an essential part of a COVID-19 solution. Full committee hearing.
U.S. Senate Committee on Homeland Security & Governmental Affairs. 2020.
https://www.hsgac.senate.gov/hearings/early-outpatient-treatment-an- essential-part-
of-a-covid-19- solution
178. Fareed G. My reflections on the suppression of early C19 treatment. Twitter. 2021.
https://web.archive.org/web/20210323122411/https:
//twitter.com/GeorgeFareed2/status/1360717827359997952?s=20
179. CovidAnalysis. HCQ is effective for COVID-19 when used early: analysis of 143 studies. 2020.
https://web.archive.org/web/20201119043548/https://hcqmeta.com/
180. Jha A. Opinion: the snake-oil salesmen of the Senate. New York Times. 2020.
https://web.archive.org/web/20201204013806/https:
//www.nytimes.com/2020/11/24/opinion/hydroxychloroquine-covid.html
181. Niaee MS, Gheibi N, Namdar P, Allami A, Zolghadr L, Javadi A, et al. Ivermectin as an adjunct
treatment for hospitalized adult COVID-19 patients: a randomized multi-center clinical trial. Research
Square. November 2020. https://doi.org/10.21203/rs.3.rs-109670/v1
182. CovidAnalysis. Analysis of: Ivermectin as an adjunct treatment for hospitalized adult COVID-19
patients: a randomized multi-center clinical trial. 2020. https://c19ivermectin.com/niaee.html
183. Ladapo JA. Opinion: too much caution is killing Covid patients. Wall Street Journal. 2020.
https://web.archive.org/web/20210310063317/https://www.wsj.com/articles/too-much-
caution-is-killing-covid- patients-11606238928
51
184. CovidAnalysis. Ivermectin is effective for COVID-19: analysis of 20 studies. 2020.
https://web.archive.org/web/20201126092305/https://ivmmeta.com/
185. Syed M. How ivermectin helps against SARS-COV-2? Drbeen Medical Lectures; 2020.
https://youtu.be/JEO7Adv3tVI
186. Zhang X, Song Y, Ci X, An N, Ju Y, Li H, et al. Ivermectin inhibits LPS-induced production of
inflammatory cytokines and improves LPS-induced survival in mice. Inflammation Research. November
2008;57(11):524–9. https://doi.org/10.1007/s00011-008-8007-8
187. Ci X, Li H, Yu Q, Zhang X, Yu L, Chen N, et al. Avermectin exerts anti-inflammatory effect by
downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase
activation pathway. Fundamental & Clinical Pharmacology. August 2009;23(4):449–55.
https://doi.org/10.1111/j.1472-8206.2009.00684.x
188. Zhang X, Song Y, Xiong H, Ci X, Li H, Yu L, et al. Inhibitory effects of ivermectin on nitric oxide
and prostaglandin E2 production in LPS-stimulated RAW 264.7 macrophages. International
Immunopharmacology. March 2009;9(3):354–9. https://doi.org/10.1016/j.intimp.2008.12.016
189. Mittal N, Mittal R. Inhaled route and anti-inflammatory action of ivermectin: Do they hold
promise in fighting against COVID-19? Medical Hypotheses. January 2021;146:110364.
https://doi.org/10.1016/j.mehy.2020.110364
190. Andersson U, Ottestad W, Tracey KJ. Extracellular HMGB1: a therapeutic target in severe
pulmonary inflammation including COVID-19? Molecular Medicine. May 2020;26(1).
https://doi.org/10.1186/s10020-020-00172-4
191. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic
administration of ivermectin. International Journal of Antimicrobial Agents. January
2021;57(1):106248. https://doi.org/10.1016/j.ijantimicag.2020.106248
192. Bernigaud C, Guillemot D, Ahmed-Belkacem A, Grimaldi-Bensouda L, Lespine A, Berry F, et al.
Bénéfice de l’ivermectine : de la gale à la COVID-19 un exemple de sérendipité. Annales de
Dermatologie et de Vénéréologie. December 2020;147(12):A194.
https://doi.org/10.1016/j.annder.2020.09.231
193. CovidAnalysis. Analysis of: Ivermectin benefit: from scabies to COVID-19, an example of
serendipity. 2020. https://c19ivermectin.com/bernigaud.html
194. CovidAnalysis. Analysis of: COVID-19: uso de ivermectina. 2020.
https://c19ivermectin.com/alonso.html
195. Ahmed S, Karim MM, Ross AG, Hossain MS, Clemens JD, Sumiya MK, et al. A five-day course
of ivermectin for the treatment of COVID-19 may reduce the duration of illness. International Journal
of Infectious Diseases. February 2021;103:214–6. https://doi.org/10.1016/j.ijid.2020.11.191
196. CovidAnalysis. Analysis of: A five day course of ivermectin for the treatment of COVID-19 may
reduce the duration of illness. 2020. https://c19ivermectin.com/ahmed.html
197. CovidAnalysis. Analysis of: The effect of using ivermectin to control COVID-19 in Chiapas. 2020.
https://c19ivermectin.com/chamie.html
198. Luna C. Repartirán 10 mil kits con Ivermectina para combatir Covid-19 en Tuxtla. El Sie7e.
2020. https://web.archive.org/web/20200905213121/https://www.sie7edechiapas.com/post/
repartir%C3%A1n-10-mil-kits- con-ivermectina-para-combatir-covid- 19-en-tuxtla
199. Chamie J. Covid19Crusher: Ignoring the national guidelines, the Mexican State of Chiapas has
decided to treat early with teams going door to door and giving a cocktail of drugs with ivermectin
since July. Twitter. 2020. https://web.archive.org/web/20201203104414/https:
//twitter.com/Covid19Crusher/status/1334448128922165248
200. FLCCC Alliance. FLCCC Alliance calls on national health authorities to immediately review
medical evidence showing the efficacy of ivermectin for the prevention of COVID-19 and as an early
outpatient treatment. 2020.
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