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Mar. 2021〈Review Article〉

Global trends in clinical studies of ivermectin
in COVID-19
Morimasa Yagisawa, Ph.D.1,2, Patrick J. Foster, M.D.2,
Hideaki Hanaki, Ph.D.1 and Satoshi Ōmura, Ph.D.1
1

Kitasato University Ōmura Satoshi Memorial Institute2
Keio University Faculty of Pharmacy(Received for publication March 10, 2021)

Response to the initial alarm bells of the Coronavirus infection, which occurred in
Wuhan City, Hubei Province, China in November 2019, was delayed as it wasannounced to be a type of pneumonia of unknown cause. The WHO warned about
traveling to China in January 2020. After much urging, the world was ﬁnallyproperly warned, but the Chinese government did not accurately announce theoutbreak situation. Consequently, the delaying of the construction of an epidemic
prevention system worldwide has resulted in the direst infection circumstancesfacing the world today. One year has passed since the WHO named the newcoronavirus SARS-CoV-2 infection, COVID-19, and it was declared a pandemic on
the 11th of March 2020, based on the judgment that it corresponds to “aninternationally concerned public health emergency ”. Suppression of virustransmission by vaccine has ﬁnally begun. To date, the pandemic has aﬀected morethan 115 million people and killed more than 2.5 million people in 220 countries/
regions around the world. There appears to a potential for control in the near future.
However, there is a limit to the supply of vaccines and developed countries arecompeting to obtain the required amount of vaccination necessary for their own
citizens. Although the WHO is trying to secure a certain amount for developing
countries, it is predicted that a considerable period of time will be required before
COVID-19 becomes controllable.
On the other hand, with regard to therapeutic agents for COVID-19, studies beganat an early stage. The therapeutic eﬀects of hydroxychloroquine or chloroquine,
lopinavir/ritonavir combination, tocilizumab, interferon β1, as well as others, were
found to have limited eﬃcacies or no eﬀect. Remdesivir improves recovery time byas much as 30% in critically ill patients, but it is not suitable for mild to moderately
ill patients–which comprises the majority of infected individuals. Although the

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45（ 45 ）steroid drug dexamethasone is eﬀective in alleviating inﬂammatory symptoms, its
use in mild to moderately ill patients without signiﬁcant inﬂammatory symptoms is
not recommended. Currently, there are no therapeutic agents available for mildly illpatients who are being treated at home (or in self-isolating accommodations) or for
moderately ill hospitalized patients. Nothing is as helpless as a disease without a
cure.
In a situation where the number of COVID-19 patients is rapidly expanding, thenumber of deaths increasing worldwide, hydroxychloroquine, doxycycline,
azithromycin, and other drugs are ineﬀective for therapeutic purposes, an eﬀective
treatment method is being sought. An Australian research group reported that
ivermectin suppresses SARS-CoV-2 replication in an in vitro infection experiment.
Ivermectin has been widely used since 1987 for the control of river blindness andlymphatic ﬁlariasis, as well as in the treatment of scabies in humans. Because it is anextremely safe and well-known inexpensive drug, it began to be used for thetreatment and prevention of COVID-19 in Central and South American countries.
One month after the declaration of the pandemic, countries such as Iraq, Egypt, Iran,and India began to register clinical trials with the US clinical trial registration site
ClinicalTrials.gov and the WHOʼs clinical trial registration platform. The publicationof the results of the ﬁrst clinical trial of ivermectin for COVID-19 in the world wasan observational study conducted at four related hospitals in South Florida, USA.
The mortality rate of 173 patients in the ivermectin group was 15.0%, which wassigniﬁcantly (p＝0.03) superior to 25.2% of 107 patients in the control group. This
result was published as a medRxiv preprint on the 6th of June 2020, but its value was
not recognized at the time because it had not yet been peer reviewed. Following peer
review, it was published without any changes in the prestigious journal Chest on the
13th of October.
Since then, numerous clinical trials have been conducted in various countries
around the world. As of the 30th of January 2021, a total of 91 trials in 27 countries
has been recorded at these registration sites. There are 43 trials in phase 3 and 27
trials in phase 2, along with 17 observational studies. This includes 80 trials being
conducted for therapeutic purposes and 11 for the purpose of preventing the onset of
disease in close contacts and healthcare professionals.
Furthermore, by the 27th of February, the results of 42 clinical trials, including
approximately 15,000 patients (both registered and unregistered studies) have been
subjected to a meta-analysis after exclusion of biasing factors. It was found that 83%
showed improvements with early treatment, 51% improved during late-stage
treatment, and there was an 89% prevention of onset rate noted. This conﬁrms theusefulness of ivermectin. Since it is a meta-analysis based on 42 test results, it isestimated that the probability of this comprehensive judgment being a mistake is as
low as 1 in 4 trillion. In addition, two separate meta-analyses also showed the46（ 46 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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usefulness of ivermectin and their conclusions were presented to the WHO and the
US FDA with a request for an expansion of the indication of ivermectin in thetreatment of COVID-19.
In Japan, Kitasato University has been conducting a doctor-initiated phase 2
clinical trial, since September 2020. However, the progress of the study protocol
enrolling a total of 240 patients (120 in the ivermectin group and 120 in the placebogroup), has been slow. At this rate, there is concern that the clinical trial will beconcluded after a time in which the COVID-19 pandemic converges. Unlike clinical
trials conducted by pharmaceutical companies, lack of funds and human resources
are the main factors behind the delay in the progress of such clinical trials. Support
is being sought on all sides. Ivermectin has been used for more than 30 years withmore than 3.7 billion doses dispensed in Africa and Central and South America tocontrol neglected tropical diseases (NTDs). It is also widely used in elderly carefacilities to treat scabies in developed countries. Since it has been used so
extensively, pharmaceutical companies cannot expect to earn enough money torecover invested funds, even if further development is conducted to obtain an
indication for COVID-19.
In this pandemic, which qualiﬁes as an important national security issue requiring
multiple state of emergency declarations, there is no therapeutic drug available fortreatment or prevention purposes. Ivermectin, which has already been approved andwidely used, is found to be eﬀective. Although ivermectin is a potential candidate
drug, the current situation is that pharmaceutical companies are not expanding its
indications to include COVID-19. Universities and medical institutions unfamiliar
with drug development are conducting small-scale clinical trials initiated by doctors.
There seems to be a very restricted and uneager approach to the situation.
This review is written with the hope of increasing the understanding and supportof all parties, by explaining the current situation in which doctors and researchers allaround the world are actively attempting to expand the indication for ivermectin as atherapeutic/preventive drug for COVID-19. It is hoped that ivermectin will beutilized as a countermeasure for COVID-19 as soon as possible.

1. Trends in Novel Coronavirus Infections
1) Outbreak and early spread of novel coronavirus infection
The ﬁrst case of novel coronavirus infection was conﬁrmed1) in Wuhan City, Hubei Province, China on the 17th of November 2019 and a warning was issued as a pneumonia of unknown
cause. However, it was one and a half months later, on the 31st of December 2020, that Wuhan
City authorities reported2) human-to-human transmission to the World Health Organization(WHO). It was conﬁrmed3), on the 7th of January 2020, that the cause was the novel coronavirus.

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47（ 47 ）On the 11th of January, the Chinese government reported to the WHO that the outbreak was
related to the South China Seafood market in Wuhan. It was speculated that live wild animals
sold in the same market were the source of the infection. The market was closed on the 1st of January, making it impossible to pursue the source of infection. However, samples taken during theprevious month showed positive test results. The ﬁrst cases outside of China were conﬁrmed in
Thailand4) on the 13th of January, followed by Japan5) on the 15th, and South Korea6) on the 19th.
All of these cases were Chinese patients or travelers from the city of Wuhan. It was therefore
concluded that there could be no doubt that the source of this novel coronavirus infection was thearea centered on Wuhan.
The WHO published7) the Novel Coronavirus (2019-nCoV) Situation Report-1 on the 21st ofJanuary, when the number of aﬀected people in China exceeded 250, calling attention to travel toChina. The WHOʼs response at this stage was quick and appropriate. The day prior, a man in the
United States who returned from China developed the disease8), and the number of aﬀected people in the world was 282 spanning four countries. Subsequently, eight doctors in Wuhan who
warned of the outbreak of a new pneumonia at the end of the year were punished by the Chinese
authorities for spreading false information. The Chinese government did not accurately announce
the situation surrounding the outbreak. Consequently, the construction of a global epidemic prevention system was delayed, leading to the dire infection situation facing the world today.
A week later, in Japan, on the 1st of February, a Hong Kong man who disembarked from the“Diamond Princess” cruise ship on the 25th of January, turned out9) to be infected with the novel
coronavirus. Despite the ship being suddenly moved to oﬀ the coast of Daikoku Pier and placed
under quarantine for 14 days, a large infection cluster of more than 700 passengers and crew
members eventually manifested on the ship. Under such circumstances, Japan became a seriously
infected country. On the other hand, many Japanese companies have branch oﬃces in Wuhan andthe emergency evacuation of Japanese residents had become an issue. Negotiations required toevacuate Japanese citizens from Wuhan, which was under lockdown, were diﬃcult. From the ﬁrst
charter ﬂight operated on the 29th of January to the ﬁfth ﬂight on the 17th of February, a total of829 returnees arrived at Narita Airport where 9 persons (1.1%) tested positive10) for 2019-nCoV
by PCR methods.
Since unknown infectious diseases are spreading internationally and Japan is suﬀering direct
damage, it is necessary to develop domestic laws to deal with such situations. On the 1st of February, the novel coronavirus infection was classiﬁed under “designated infectious diseases” (equivalent to class 2) in the “Act on Prevention of Infectious Diseases and Medical Care for Patientswith Infectious Diseases (Infectious Diseases Act)”. This was enacted by stipulation of a government ordinance11) and as such the novel coronavirus was subject to Article 34 of the Quarantine
Law as an infectious agent. By utilization of such designations12), it became possible to deny entry
to infected individuals and begin other measures such as the hospitalization of infected persons.

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Under diﬀerent circumstances, the transmission to Europe occurred when a group of 30
sightseeing guests departed Wuhan on the 16th of January and made a 9-day tour of Italy, Switzerland, and France on their return trip. One traveler became ill in the city of Rome on the same day,with her condition gradually worsening by the 21st. On the 23rd, two additional travelling companions with this person became ill in the city of Paris and were transported to emergency carefacilities. This was the earliest case13) that was judged to be 2019-nCoV positive in Europe.
WHO Director-General Tedros visited14) China on the 27th of January to inspect the status of
the novel coronavirus infection. Despite the fact that 2,798 people in 12 countries had been infected and the spread of the infection already predicted, he refrained from declaring a global pandemic due to Chinese government authorities downplaying the situation and being wary of any
such declarations. Five days later, on the 1st of February, the infection spread to 24 countries, with
about 12,000 infected people conﬁrmed, and the situation worsened rapidly. On the other hand,the crisis management department of the WHO issued, based on past experience with the SARS
(2002), Swine Flu (2009) and MERS (2012) epidemics, a notifying document15). The document
stated the need to prepare for the event of the 2019-nCoV infection spreading worldwide.
In the United States, which would later become the worldʼs largest outbreak, the Centers for
Disease Control and Prevention (CDC) conﬁrmed16) the ﬁrst case of human-to-human transmission in the country on the 30th of January. Then, as early as the 4th of February, the Department of
Health & Human Services (HHS) made the decision, in accordance with the provisions of theFederal Food, Drugs and Cosmetics Act, that the novel coronavirus infection developed in
Wuhan, China (2019-nCoV) be regarded as an emergency related to national security. As such, anemergency response system regarding the medical system and the supply and demand management of pharmaceutical products needed to be established17).
This new type of coronavirus was named18) severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) by the International Virus Taxonomy Committee, and the WHO announced19)
on the 11th of February that the SARS-CoV-2 infection was to now be oﬃcially named Coronavirus Disease 2019 (COVID-19). At that time, the number of aﬀected people in China had alreadyexceeded 75,000, and the WHO should have declared it a pandemic. Director-General Tedros
missed this declaration opportunity and COVID-19 expanded rapidly across the entire world.
On the 20th of February, the world-renowned medical journal The New England Journal of
Medicine (NEJM) published a paper20) alerting about the threat of COVID-19 in China and announced its intended cooperation in coping with the future diﬃculties that the worldʼs medical
community would soon be facing as a result. Thereafter, all COVID-19 related papers and articles
published in the NEJM and other major medical journals the world over could be read21) freely by
non-subscribers. On the 28th of February the online edition of the NEJM, Bill Gates himself,
under the auspices of the Bill & Melinda Gates Foundation, contributed22) a perspective article
entitled “A Once-in-a-Century Pandemic?”, and proposed a list of concrete actions that leadersMar. 2021

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49（ 49 ）should immediately undertake. After enumerating important suggestions, he further stated that“there is no time to waste” as his conclusion.
According to the WHO tally23) on the 29th of February, the total number of infected people
throughout the world reached 85,403. That number included 79,394 in China, 5,304 in another 53
countries, as well as 705 international passengers and crew of the Diamond Princess cruise ship.
Further breakdown of the numbers was as follows: Korea 3,150 cases, Italy 888, Iran 388, Japan
230, Singapore 98, the United States of America 62, Germany and France at 57 each, and Spain
with 32 cases.
2) COVID-19 pandemic
The WHO, after a period of long hesitation, decided to oﬃcially declare the situation a “pandemic”. The number of worldwide countries/regions where COVID-19 infection was conﬁrmed
reached 100 on the 8th of March 2020. The cumulative number of infected people24) exceeded
100,000. On the 11th of March, the Director-General recognized that it was a global pandemic andmade a declaration25) that it corresponded to an “internationally concerned public health emergency”. When a pandemic is declared, the measures to be taken will diﬀer from country to country, but international tourist restrictions and quarantine systems will invariably be strengthened.
Under such conditions, countries much like Japan, which aim to become a tourism-oriented country, will suﬀer great economic pain as a consequence. In particular, the cumulative number of infected people in China, the country of origin of COVID-19, exceeded 80,000 on the 12th ofMarch. Thereafter, countries around the world began to refuse entry to all travelers from China. It
is estimated that the actual number of infected people in China was more than 10 times the number announced and a total of more than 2 billion people traveled during the Chinese New Year
(January 25–31), including overseas travel. As a result, the novel coronavirus infection had
spread widely both domestically and internationally.
In Japan, on the 13th of March, a “Special Measures for the Novel Coronavirus Infectious
Disease” was enacted26) as part of a Supplementary Provisions Article 1–2 of the “Act on Special
Measures for Novel Inﬂuenza and Others (Act No. 31 of 2012)”. However, by this time, the cumulative number of infected people in Japan had already reached 675. The government established the “Headquarters for Novel Coronavirus Disease Control” as part of the Cabinet Secretariat on the 26th of March and issued the “Basic coping policy for measure against new coronavirus
infection” on the 28th of March. This was carried out in order to better enhance cooperation between governmental oﬃces. However, in order to control the spread of infection in Japan and theincrease of infected people from abroad, it was necessary to implement emergency measuresfrom the 7th of April to the 6th of May. In Japan, this period also includes a timeframe that spans a
traditional long period of sequential national holidays. The state of emergency27) was issued forTokyo, Osaka, Saitama, Chiba, Kanagawa, Hyogo and Fukuoka.

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In the United States, a national state of emergency28) regarding COVID-19 was issued when
the cumulative number of infected people in the country exceeded 1,200 and it was reported that
there was a heightened sense of caution amongst the population. However, the cumulative number of the infected people, after exceeding 10,000 on the 20th of March, increased rapidly to
31,573 on the 23rd, 51,944 on the 25th, and 68,334 on the 27th. The number continued to rise andeventually exceeded China and Italy when it reached 85,228 on the 28th of March29), becoming
the highest in the world.
Thereafter, the number of infected people increased rapidly in the United States and European countries and the cumulative number of infected people worldwide exceeded 750,000 on the
31st of March: 140,640 in the United States, 101,739 in Italy, 85,195 in Spain, 61,913 in Germany, 43,977 in France, and 41,495 in Iran, etc. However, in China, the peak of the ﬁrst wave
had already passed, the number of new cases had begun to decline, and the cumulative number ofcases had now reached 82,545.
The cumulative number of infected people in the world exceeded 1 million on the 2nd of
April, 2 million on the 16th, 3 million on the 28th, 4 million on the 12th of May, and 5 million on
the 21st. After that, there were 10 million people on the 29th of June, 20 million on the 11th of August, 40 million on the 20th of October, 60 million on the 1st of December, and over 80 million on
the 31st of December 2020. When the state of increase is graphed, a downwardly convex curve iscreated, but no remarkable plateau is observed. Additionally, it is not possible to clearly distinguish between the ﬁrst, second, and third waves. Attempts to distinguish and classify the wave
pattern tend to reveal a convergence around the 20th of May 20, the second wave beginningaround the 15th of June, and the third wave starting around the 20th of October (even before convergence of the second wave). From that point on, the third wave appears to continue until thepresent day.
COVID-19 had spread to more than 220 countries/regions around the world in a short periodof time, aﬀecting 103 million people (morbidity rate of 1.31%) by the 31st of January 2021, of
which 2.22 million died (mortality rate of 2.16%), causing catastrophic damage30). Table 1 shows
the morbidity as the cumulative number of infected people and the number of deaths or mortality
in major COVID-19-infected countries. The most severe situation is in the United States, where
the infection rate is equivalent to 1 in 12.5 of the 331 million population. Speciﬁcally, 26.67 million people are aﬀected (morbidity rate of 8.1%), 450,000 people have died (mortality rate of
1.7%), and the number of new cases per day, reaching as high as 250,000 at one point in time (butit is now suppressed to 70,000 or less).
The second most impacted region in the world is India, with 10.74 million infected and morethan 150 thousand deaths. Brazil is the third most impacted with 9.17 million infected and morethan 220 thousand deaths and Russia is fourth with the number of infected people as high as 3.83
million. In Russia, however, the death toll is reported to be limited to 70 thousand. The second

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51（ 51 ）Table 1. Global COVID-19 Aﬀected and Dead Situation [As of the 31stof January 2021]

and third waves of the epidemic are also recognizable in Europe, with a cumulative total of over
3.7 million infected in the UK, 3.1 million in France, 2.8 million in Spain, 2.5 million in Italy and2.2 million in Germany. These ﬁgures have also recorded 50,000–100,000 deaths.
In Table 1 the morbidities of COVID-19 in 19 countries with more than 1 million infectedcases are shown. Compared to the global prevalence rate of 1.31%, several countries showed
more than tripled rates: the United States at 8.1%, Spain at 6.0%, the United Kingdom at 5.6%,
France at 4.9%, Argentina at 4.3%, and Italy at 4.2%. Despite preventive measures such as lockdowns and restrictions on gatherings being taken against the spread of infections in these countries, the continued spread of the infection could not be controlled.
On the other hand, the ratio of deaths among infected people is exceptionally high in Mexico
at 8.5% and serious situations exist in Iran, Peru, Italy, South Africa, Indonesia, the United Kingdom, Germany, Colombia, and Brazil where mortality rates of more than 2.5% are recognized.

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3) Recent situation in Japan
Japan was impacted by a large third wave where the number of new cases per day exceeded
3,500. Therefore, an emergency declaration was issued on the 8th of January 2021 in Tokyo andits surrounding three prefectures of Chiba, Kanagawa, and Saitama. Then, on the 14th of January,
the declaration was expanded31) to include Kyoto, Osaka, Tochigi, Gifu, Aichi, Hyogo, andFukuoka prefectures. The declaration also requested the shortening of business hours for restaurants and encouraged companies to allow their employees to work remotely from home by use of
the internet. By the 31st of January, the number of infected people in Japan was at 383,000, the37th highest in the world, and the number of deaths was kept low at 5,546 (mortality rate of
1.45%). However, it is diﬃcult to prevent the spread of infection over a short period of time, due
to the conﬁrmed invasion and existence of mutant strains from overseas. In order to prevent the
spread of COVID-19 infection, the government revised the “Act on Special Measures for New
Inﬂuenza and Others” and its enforcement order. Additionally, an amendment32) of the “Act on
the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases (theInfectious Diseases Control Law)” was carried out. This was followed by a revision33) of the“Basic Coping Policy for Measures against New Coronavirus Infection” in an attempt to enhance
eﬀective countermeasures. Despite these actions, the number of people in the downtown area andthe amount of congestion created by public commuting did not decrease as expected. Although
the number of new cases has been slowly declining the preparedness of medical facilities and attitudes towards medical care have not been improved.
It is reported that the SARS-CoV-2 mutant strain34), which became apparent in the UK fromthe beginning of December 2020, has a 1.7 times higher infectivity than the conventional strain.
It has already spread to other countries, causing a rapid increase of infected people. According to
CDC documents35), the mutant strain was also detected in the United States at the end of December, and British researchers warned that it is not only more infectious but also carries an increased
mortality risk. In addition to the mutant strain of the United Kingdom, diﬀerent types of mutants
continued to appear in mid-December in South Africa and subsequently spread to other countries.
Other mutants detected in Brazil have moved to both Japan and other European countries in January 2021. The infectivity and pathogenicity of each mutant strain is being investigated36) extensively and the susceptibility of each of the newly developed vaccines is also being examined.

2. Current Status of Therapeutic Agents and Vaccines for COVID-19
1) Search for therapeutic agents and permission for emergency use
The strong infectivity and lack of eﬀective therapeutic agents are the reasons why COVID19 has continued to spread all over the world for more than one year. However, it is not a fulminant-type of infectious disease that presents with severe symptoms and causes death in a short

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53（ 53 ）amount of time like smallpox or various hemorrhagic fevers. Nevertheless, as COVID-19 symptoms progress, it may cause death by means of serious respiratory failure and thrombosis37,38). In
addition, it is a disease that causes various ongoing prognostic symptoms called “post-acute sequelae of SARS-CoV-2 (PASC)”, or “chronic COVID syndrome (long COVID)”. Manifestations
include serious fatigue, alopecia39), cardiovascular disorders40), deterioration of memory, and olfactory/taste disorders41) that may persist for long periods of time even after recovery.
To date, anti-inﬂammatory treatment of COVID-19 with steroids such as dexamethasone42)
has been considered to be eﬀective in alleviating symptoms as symptomatic treatment. No conﬁrmed eﬀective therapeutic drug to suppress SARS-CoV-2 virus proliferation, cell binding or intracellular invasion, has yet been identiﬁed and the development of such a compound is desired.
However, in order to create a completely new therapeutic drug targeting the SARS-CoV-2 virus, itis necessary to begin with the construction of exploratory systems and make yearly research and development (R&D) plans to evaluate any such drugs. It is not possible to respond to a pandemic ofacute illness occurring in hundreds of thousands of patients in such a short period of time.
Therefore, an attempt has been made to search for a chemical entity that has a therapeutic effect or a symptom-relieving eﬀect on COVID-19 from among existing drugs43). The term “repurposing” is used to mean “use for another purpose (indication)” or “oﬀ-label use”. Repurposing
was attempted more than once in the past. This was the case with the SARS outbreak in 2002 thatbegan in Guangdong, China, and eventually spread to Vietnam and Canada with more than 8,000
infected and more than 770 dead. It was also the case in the Middle Eastern respiratory syndrome(MERS) outbreaks in Saudi Arabia, Jordan, the United Arab Emirates, Qatar and other Middle
Eastern countries (including a few cases in France, Germany, and Italy). Attempts were made totreat the outbreaks with existing anti-inﬂuenza drugs, but they were met with little success. Attempts44) are now being made to search for therapeutic drugs for COVID-19 from amongst otherapproved drugs.
ClinicalTrials.gov in the United States is a clinical trial registration site operated by the US
National Library of Medicine. It is the most trusted and used site in the world because the submitted clinical trial data is examined for its conformity with the requirements provided in the Federal
Register45) before its citation, and the registered items are updated frequently in real time.
By the 20th of April 2020, there were 605 clinical trials in 557 subjects registered on the site
for COVID-19. Among the listings were the following: 79 trials of the antimalarial drugs hydroxychloroquine and chloroquine, 9 trials of the antirheumatic drug tocilizumab, 5 trials of theanti-inﬂuenza drug favipiravir, 4 trials of the anti-AIDS combination drug lopinavir/ritonavir, 9
trials of the anti-Ebola hemorrhagic fever drug remdesivir under development by Gilead, 9 trialsof the anti-polysclerosis drug interferon β1, and others. At this time, the subject of this review, 4clinical trials of ivermectin have been registered: one from the University of Baghdad in Iraq in astudy46) to investigate the eﬀect of adding ivermectin to a combination of hydroxychloroquine54（ 54 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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and azithromycin, and three studies by Tanta University in Egypt to investigate the eﬀect of ivermectin in combination with three diﬀerent drugs. It was never imagined that more than 50 other
trials would also eventually ensue.
Apart from the progress of such clinical trials, the US Food and Drug Administration (FDA)
announced on the 28th of March 2020 that the “repurposing” of two drugs was to be carried out.
Chloroquine and hydroxychloroquine, were to be made available for use in the treatment and prevention of COVID-19. This was achieved by the granting of special permission under an Emergency Use Authorization (EUA)47) process based on the emergency response system under the authority of the U.S. Department of Health and Human Services (HHS). On the same day, thecumulative number of infected people in the United States exceeded that of China and Italy andwas the highest in the world. The use of the EUA system was praised. Following that, in the
United States, also based on the EUA, remdesivir48) on the 1st of May, convalescent patientʼs
plasma49) on the 23rd of August, bamlanivimab, a monoclonal antibody drug jointly developed by
Eli Lilly and Abcellera Biologics in Canada on the 9th of November50), and an antibody cocktail51)
developed by Regeneron on the 21st of November, all became available for possible use in thetreatment of COVID-19. However, the EUA process does not take into consideration or requirematerials to prove eﬀectiveness and safety. Due to political and economic inﬂuences, such investigations are not conducted prior to permission for use being granted. Consequently, it later became apparent that some of the medicines authorized under the EUA did not always produce theexpected clinical eﬀects. For hydroxychloroquine and chloroquine, the FDA announced the cancellation of the EUA in a News Release on the 15th of June, less than three months after the EUA
was initially issued. Hydroxychloroquine and chloroquine, the lopinavir/ritonavir combination
drug, tocilizumab, and interferon β1 were all found to have limited eﬃcacy as therapeutic agentsfor COVID-19, based on the results of a large-scale clinical trial referred to as the Solidarity
trial52) by the WHO. Although there were previous reports of negative test results regarding theeﬀects of monoclonal antibodies and convalescent patientʼs plasma, it has recently been reported
that positive results have been obtained in other large-scale trials.
Although dexamethasone is not included in the EUA, its use is recommended by the
COVID-19 Treatment Guidelines of the NIH53) and the Infectious Diseases Society of America(IDSA)54). The reason why dexamethasone was not designated as part of the EUA is that it is adrug that has already been approved by the FDA, and it is judged that the treatment of lung inﬂammation in severely ill patients with COVID-19 is already permitted as an “oﬀ-label use”. It isfurther explained that this drug has been widely used as a generic drug for a long time and it was
judged that there is no pharmaceutical company that performs the complicated application procedures required to expand the indication of the drug for COVID-19. Hydroxychloroquine has also
been used clinically for a long period of time and there are many generic formulations of it available. If it had also been managed as an “oﬀ label use” drug, in a similar approach to that used

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55（ 55 ）with dexamethasone, the situation that resulted in the revocation of the EUA designation could
have been avoided. There is criticism of hydroxychloroquine being treated diﬀerently under the
confusion of the emergency circumstances surrounding the pandemic.
A randomized, double-blind, placebo-controlled trial (NCT04280705) on remdesivir was
conducted by the Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group. It was organizedat 60 facilities in 10 countries. The ﬁnal result was published55) and stated that the average recovery period was 10 days in 541 subjects in the study group and 15 days in 521 subjects in the control group. This indicates that remdesivir was signiﬁcantly superior (p＜0.001) in its desired effects. As a consequence, the FDA changed the handling of remdesivir from EUA-designated tothat of an oﬃcially approved drug56). It should be noted here that EUA designation is valid only
under the emergency response system issued by the HHS, and EUA designated medicines cannot
be used again under normal circumstances once the designated emergency situation ceases toexist.
2) Vaccine development and clinical use
By the 30th of April 2020, there were 10 clinical trials of vaccines registered at ClinicalTrials.gov. This includes the 3 successfully developed vaccines to date: two mRNA vaccines from
Moderna and Pﬁzer/BioNTech, and one vector vaccine from Oxford University/AstraZeneca. In
addition to these three, one vaccine each by a United States and a Canadian venture company,
and ﬁve other vaccines by Chinese companies, have also been registered. In other areas, as part ofa completely new approach, 18 trials were also registered in order to study the clinical eﬀects ofconvalescent plasma obtained from patients cured of COVID-19.
Vaccine research and development, which is regarded as the most important factor in
COVID-19 countermeasures, has progressed smoothly. In the United States, the FDA issued EUA
to Pﬁzer/BioNTechʼs BNT162b2 on the 12th of December, and to Modernaʼs mRNA-1273 on the
18th of December. The vaccination process is already underway for medical workers who are athigh risk of infection and for the elderly population who are more likely to become seriously illwhen infected. In the United Kingdom, AstraZenecaʼs AZD1222 was approved on the 30th of December and vaccination has already begun. The European Union (EU) approved BNT162b2 on
the 21st of December, and mRNA-1273 on the 6th of January 2021. However, the approval of
AZD1222 was delayed secondary to problems with supply contracts and approval was notgranted until the 29th of January. It has also been reported that Russia and China have begun vaccinations utilizing their own internally developed vaccines and are in fact carrying out “vaccine
diplomacy” by supplying their vaccines to other developing countries that have not yet obtained
any vaccine supply contracts with the initial three previously mentioned companies above. In response to their own national crisis management, Israel signed a contract to obtain vaccines very
early on and publicized their own national vaccination approach; theirs was admirably the fastest

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reaction to the crisis throughout the entire world. The WHO aims to purchase a vaccine against
COVID-19 through the humanitarian “COVAX” program and supply it to developing countries
where vaccines for inoculation are not available. Already, on the 31st of December 2020, thePﬁzer/BioNTech vaccines were listed on the emergency drug list, and on the 15th of February, thevaccine manufactured by AstraZeneca/SKBio (Korea) was listed as the second vaccine57) for
COVID-19.
The FDA issued an EUA58) for the third COVID-19 vaccine in the United States on the 27thof February 2021. The EUA allows the Janssen COVID-19 Vaccine (J&J Vaccine) to be distributed in the United State for use in individuals 18 years of age and older. The J&J Vaccine is manufactured using adenovirus type 26 as a vector to deliver a piece of DNA encoding for the spike
protein of SARS-CoV-2. Humans can utilize the spike protein produced in the body to make antibodies against the virus. This particular vaccine is characterized by being able to be stored in anormal refrigerator for up to 3 months and stimulate the production of suﬃcient antibodies in the
body with a single inoculation. In terms of safety, no special adverse reactions were observed inabout 22,000 inoculations. Its eﬃcacy, in about 19,000 inoculations, suppressed the onset ofmoderate to severe/critical cases by 67%. Additionally, the vaccine was approximately 77% effective in preventing severe/critical cases 14 days after inoculation and 85% eﬀective in preventing occurrence of the disease by at least 28 days following inoculation.
Vaccine development requires several years of testing to conﬁrm eﬃcacy and safety, as well
as evaluate the adequacy and sustainability of any imparted acquired immunity. In principle, it is
not possible to develop a vaccine in a short period of time in order to respond to a rapidly out ofcontrol pandemic such as COVID-19. Vaccine use was approved as an emergency response given
the extraordinary circumstances created under the COVID-19 pandemic. As such, safety and effectiveness have not yet been suﬃciently conﬁrmed. It will require an extended amount of time
for people around the world to acquire immunity to COVID-19 once vaccination becomes commonplace, and acquired immunity does not always persist for long periods of time. Therefore, it
has also been advocated that the development of an eﬀective therapeutic drug for COVID-19 isessential.
Infection with the SARS-CoV-2 mutant, which was 1.7-fold more infectious, was conﬁrmed
in the United Kingdom, and a warning was issued59) by the European Center for Disease Prevention and Control (ECDC) on the 20th of December 2020. The mutation can be traced back to the20th of September and it has been reported that it may have contributed to the rapid expansion of
the second wave in Europe since October. The emergence and rapid increase of mutant strains
have also been observed in South Africa and it is estimated60) that the ﬁrst case can be traced backto October. In Japan, the quarantine was strengthened by designating the United Kingdom, on the
23rd of December, and South Africa, on the 25th of December, as mutant strain endemic countries.
On the 28th of December, at the Narita Airport Quarantine Station, a mutant strain was detected inMar. 2021

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57（ 57 ）a patient who had previously stayed in South Africa. In Brazil, a mutant strain was detectedaround the 20th of December and it was conﬁrmed that the infectivity was rather strong. Subsequently, just such a mutant strain was later brought into Japan61), detected by quarantine services,by a traveler from Brazil on the 10th of January 2021.
Although there are concerns that the protective eﬀects of the various vaccines against mutant
strains will be diminished, Moderna announced62) on the 25th of January that their vaccine maintains its neutralizing activity against both the British and South African mutants. Similarly, Pﬁzer,
jointly with BioNTech, announced63) on the 27th January that they proved in vitro that their vaccine demonstrates no changes in eﬀects of antibody production in the presence of key mutationsof both the UK and South African mutants. On the other hand, in South Africa, the AstraZeneca
vaccine supplied by the United Kingdom was found to have a weakened protective eﬀect against
mutant strains; as a result, vaccination with this particular vaccine was suspended64) on the 7th ofFebruary.
In Japan, the mRNA vaccine by Pﬁzer/BioNTech was approved65) as a special case consideration on the 14th of February. This vaccine also requires special handling in that it must be kept at
an ultra-low temperature of −70°C during storage/transfer. Therefore, preparations for inoculation at the municipal level of prefectures are proceeding at a very rapid pace. There is a contract
to receive a supply of the vaccine for 72 million people by the end of the year. However, the syringes for the actual vaccination process need to be procured in Japan. Since the vaccine solution
remains in the syringe barrel, it is possible to administer 6 doses from a single bottle in Europe
and the United States. The Japanese government has been negotiating with Pﬁzer, because it turns
out that each vial can be used to administer only 5 doses in Japan. There is a concern that the initial theoretical 72 million people supply number will actually turn out to be for only 60 million
people. Further behind this inconvenience is a long history of unfortunate incidences surrounding
vaccines in Japan: involving diphtheria vaccinations in 1948, the pertussis vaccine in the 1970s,
the new triple vaccine (MMR) in 1989, and on the human papillomavirus (HPV) vaccine in 2013.
In Japan, there have been many negative opinions complaining of side reactions as “vaccine-associated damage”. As a result, the R&D and clinical use of vaccines in Japan are the most delayed,secondary to administrative reasons, among developed countries due to the existence of such disputes. It is said that the inherent vulnerability of this vaccine drug collection problem needs to besigniﬁcantly announced, discussed, and addressed. It is essential to raise suﬃcient awarenessamongst the public as to the unavoidable risks/beneﬁts of vaccines in the future — especially
under such emergency circumstances as this current pandemic. In such times, it is desired to enable rapid R&D and clinical application of vaccine administration in oneʼs own home country.
The Japanese Association for Infectious Diseases has a permanent “vaccine committee” of experts that can be utilized. Such a group can explain66) in detail the developmental status, mechanisms of action, eﬃcacy, side reactions, general vaccination procedures throughout Japan, includ-58（ 58 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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ing those associated with the COVID-19 vaccine, and play a key role in the process of raisingawareness and promoting understanding of vaccines.
On the other hand, regarding the vaccine manufactured by AstraZeneca in the United Kingdom, Phase 1 and Phase 2 trials in Japan have been conducted since the end of August 2020. The
inoculation of subjects has been completed. On the 5th of February, a domestic approval application67) was submitted. There is a contract to receive a supply of 120 million doses. More than
75% of the undiluted solution will be manufactured by JCR Pharmaceuticals in Japan. Daiichi
Sankyo, Meiji Seika Pharma and KM Biologics are scheduled to carry out storage and delivery
operations for the ﬁlling of vials of undiluted solution. Takeda Pharmaceutical, which develops
vaccines manufactured by Moderna, announced68) that it started domestic phase 1 and phase 2 trials on the 21st of January. Takeda Pharmaceutical established a contract to receive a supply for 20
million people by June and an additional 5 million people by September (involving two doses). In
addition, Takeda plans to produce more than 250 million doses annually in Japan following thetechnology transfer of the recombinant protein vaccine NVX-CoV2373 being developed by Novavax in the United States. The vaccine is scheduled to begin clinical trials in Japan from aroundthe 20th of February. It is a promising prospect in that it has also shown an 89.3% eﬃcacy in aphase 3 study in the United Kingdom.
On the 9th of February, the Cabinet Secretariat and the Ministry of Health, Labor and Welfare
jointly announced69) that the government would oversee a wide variety of operations. Among
them: the securing of vaccines, the distribution systems, a summary of advance preparations, including examinations, improvement of the inoculation system, needed responses to side reactions, safety measures, and rank vaccinations for use by local governments (such as prefectures)
under a program known as “Vaccination for new coronavirus infections”. In addition, on the 12thof February, the Cabinet Secretariatʼs Countermeasures Headquarters published a revised version70) of the “Basic Coping Policy for Measures against New Coronavirus Infection”. This followed the enactment of the “Special Measures for New Coronavirus Infectious Diseases” on the
3rd of February. The established policy is clearly shown regarding the status of COVID-19 infection in Japan, the status of vaccination, the status of medical institutions, and the problem of preventing further invasion of mutant strains from abroad. In addition to all these measures, the National Institute of Infectious Diseases has also started to provide information71) entitled “About
the New Corona Vaccine”. The goal is to aim for a higher rate of vaccination among the population by widely and accurately disseminating the necessary and appropriate information requiredby medical professionals and the general public.
Vaccination is the key measure required to curb the spread of COVID-19 infection. The government will set the vaccination cost at the national uniﬁed unit price for both the ﬁrst and second
vaccinations while preparing the third supplementary budget for 2020. It was decided to pay
2,070 yen per inoculation and that the entire amount would be borne out by the national treasury.

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59（ 59 ）It has already been decided to spend 671.4 billion yen from the reserve fund for the purchase costof vaccines, and 131.4 billion yen for the purchase cost of special freezers and other incidental
costs (such as the construction of an inoculation recording system and to ensure the smooth ongoing operations of the inoculation process). In terms of the 77.6 billion yen to be used for the establishment of the system for local governments, it could be considered a part of the national budget expenditure necessary for ensuring national security. It also serves as a strong reminder as tothe huge amount of expenditures required to protect the nation with vaccines. Vaccine-based social defense requires enormous budgetary measures as part of a national strategy, but immunological defense at the individual level also requires high medical costs. For example, it is estimatedthat the amount of a single dose of a monoclonal antibody will be as much as 250,000 yen.
Plasma treatments of convalescent patients require additional screening costs to ensure seronegativity against the potential infusion of pathogens such as HIV, HBV, HCV, syphilis, and evenother possible locally transmitted infections. An inexpensive and safe anti-infective drug that can
provide therapeutic and prophylactic eﬀects by oral administration is required. Since mild or asymptomatic patients who are being followed up either at homes or in locally designated hotels
may suddenly have a change in health status and present with serious symptoms, it further increases the need for such a therapeutic agent.

3. Clinical Trial of Ivermectin for COVID-19
1) From the results of basic research to clinical trial planningIt was conﬁrmed by Caly et al. of Royal Melbourne Hospital that ivermectin (Fig. 1), which
has been approved by the FDA as an antiprotozoal drug, inhibits72) the growth of the SARSCoV-2 virus in cultured cells in vitro. In the paper published online in “Antiviral Research” on the
3rd of April 2020, they suggested possible clinical eﬃcacy in the use of ivermectin for COVID-19
in humans. One of the co-authors of the paper, Wagstaﬀ of the University of Monash, is a virologist who found73) in 2012 that ivermectin speciﬁcally inhibits the enzyme importin α/β, which is
involved in the process of translocation into the cell nucleus for HIV and dengue virus replication. It is obvious that they studied the action of ivermectin on the same RNA virus, SARSCoV-2, and accurately proved SARS-CoV-2 growth inhibition by ivermectin. In response to thisin vitro ﬁnding, clinical trials74) of ivermectin and actual clinical use have begun in various countries around the world. To date, more than 100 clinical studies have been conducted.
On the other hand, the IC50 concentration in their in vitro study to inhibit the growth of
SARS-CoV-2 was about 2 μM equivalent to 1,750 ng/mL [molecular weight of ivermectin (B1acomponent 90%, B1b component less than 10%) is calculated as 873.75]. This is 15 to 30 times
higher than the attainable serum concentration by administration of a normal dose of 200 μg/kg
body weight (about 50 ng/mL on an empty stomach, and about 130 ng/mL after meals). Much de-60（ 60 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

Fig. 1. Structure of ivermectin

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bate75~78) subsequently ensued stating that it is
impossible to use ivermectin as a therapeutic
agent for COVID-19 at its normal dose. In
those discussions, it is also argued79) that theantiviral action of ivermectin in vivo should
not only suppress viral replication, but that the
involvement of host defense functions should
also be considered.
At Kitasato University, a university-wide“COVID-19 Countermeasures Kitasato Project” was established on the 19th of March withthe aim of discovery of novel therapeutic
agents for COVID-19. In response to the paper
by Caly et al., the project has been expanded
to conduct basic studies on the action of ivermectin on the SARS-CoV-2 virus. After obtaining
several positive results, the implementation of clinical trials for ivermectin was considered. Inthat investigation, trends in global clinical trials registered at the US ClinicalTrials.gov are extremely valuable information; following the ﬁrst registration by Baghdad University in Iraq on
the 13th of April, there were three in Egypt, one in India, and two US universities. It was recognized in these doctor-initiated clinical trial protocols that objective items are set for evaluation ofoutcomes, such as reduction in mortality, shortened length of stay in the intensive care unit, shortened hospital stay, and elimination of the virus. These items are able to be expressed quantitatively. As such, bias can be avoided and real-world evidence obtained.
The cumulative number of people aﬀected by COVID-19 worldwide exceeded 1 million on
the 2nd of April 2020, a state of emergency was issued in Japan on the 7th of April, and the total
number of people aﬀected by COVID-19 worldwide was 2 million on the 16th of April. Under
these circumstances when the pandemic conditions were rapidly worsening, there was illegal use
and abuse of ivermectin in South America. It was traded on the black market and people wereeven taking ivermectin preparations marketed only for animal use. Therefore, the US FDA issued
a warning80) regarding the danger of using veterinary preparations. The pandemic continued to
expand rapidly, with the worldʼs cumulative number of aﬀected people exceeding 3 million on
the 28th of April. The situation in the United States also became much worse, leading to morethan 1 million cumulative cases and surging deaths.
Kitasato University, based on the judgment that it is necessary to examine the clinical eﬀectof ivermectin to prevent the spread of uncertain COVID-19, asked Merck & Co., Inc. to conductclinical trials of ivermectin for COVID-19 in Japan. This company has priority to submit an application for an expansion of ivermectinʼs indications, since the original approval for the manu-Mar. 2021

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61（ 61 ）facture and sale of ivermectin was conferred to it. However, the company said that it had no intention of conducting clinical trials. As a result, Kitasato University decided to conduct a doctorinitiated clinical trial, the decision of which was published81) on the 12th of May. Following thedecision to start clinical trials in Japan, the status of clinical trials overseas was extensively investigated. It was then found, somewhat surprisingly, that 14 trials were already registered on ClinicalTrials.gov by the 25th of May. Among them, except for two trials in the United States, all studies were conducted in developing countries with a large number of poor patients. It was also thenunderstood that the use of inexpensive ivermectin to treat COVID-19 could potentially yield signiﬁcantly great beneﬁts.
However, looking closely at the protocols of the trials in these developing countries, all ofthem are doctor-initiated. The scales of the trials are small due to a lack of funds. Even if the target patients could be randomized, complete blinding would not be possible due to a shortage ofmanpower. There are strong tendencies not to employ methods that involve multiple expensive
PCR tests. Judgements were made to utilize methods of low cost, such as changes in oxygen demand and the number of days required to improve symptoms. In the case of new drug development conducted by a pharmaceutical company, the cost of clinical trials can be recovered fromthe sales proﬁt of the new drug after marketing. So, even if it is a costly and labor-intensive investigation, it is actively adopted. However, in doctor-initiated trials it is not possible to hope forcost recovery and the trial is performed in the cheapest possible manner. Although these doctorinitiated trial results may appear at ﬁrst glance to be of a poor quality and biased (to eyes familiar
with the results of company-oriented clinical trials in the clinical development of traditional antiinfective agents), physicians involved in these trials are enthusiastic about avoiding bias and needto understand the attitude of seriously assessing the eﬃcacy and safety of a study drug. It must be
appreciated that they are truly striving to treat and prevent the onset of COVID-19 in patients, fornon-proﬁt motives.
As already mentioned above regarding the FDAʼs view on the clinical use of dexamethasone
for COVID-19, the use of existing drugs such as ivermectin for diseases other than its approved
indications in clinical practice is permitted as “oﬀ-label use”.
As many clinicians are well familiar with clinical responses (real-world evidence) and understand the actual possibility of oﬀ-label use, they naturally wish for approval to be granted for agiven disease. However, a particular public law requiring regulators to consider measures for oﬀlabel use was enacted in the United States in 2016. In this Act82,83) named the “21st Century CuresAct”, ”Real world evidence” is stipulated in Section 3022 of Chapter 3 (“Development”) as aquasi-Chapter C “Modern Trial Design and Evidence Development” section. A provision of Section 3021 requires that a “Novel clinical design” be devised to justify real world evidence. Thereafter, “real world evidence” obtained from such trials can be aimed at “repurposing” existing
drugs. This stipulation warns that one should not disregard evaluations or reviews that adhere to62（ 62 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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old-fashioned evidence-based medicine (EBM) that integrates clinical experience. Unfortunately,
the law was not enforced due to the change of government in the United States and it is now toolate due to the COVID-19 pandemic. This would have otherwise been the most appropriate proofof its legislative signiﬁcance.
2) Development of clinical trials worldwide
Regarding the treatment of COVID-19, many doctor-initiated clinical trials are being conducted without registering with the oﬃcial registration sites. The ﬁrst clinical trial results for ivermectin were reported on a retrospective cohort study conducted at four related hospitals by Rajter
and colleagues at the Broward Health Medical Center in South Florida, USA. It was reported in a
medRxiv preprint on the 9th of June, and following peer review, published84) (without any
changes) online on the 13th of October in the prestigious journal Chest. The subject of the study
was a comparison of mortality between a 173 study group receiving ivermectin and a 107 control
group receiving only conventional care (without receiving ivermectin). The mortality rate of theivermectin group was 15.0%, which showed improvement that was signiﬁcantly diﬀerent from
25.2% of the control group (p＝0.03). Improvements were remarkable in severe cases; the mortality rate of 38.8% in 49 patients treated with ivermectin was found to be signiﬁcantly diﬀerent(p＝0.001) from that of 80.7% in 26 patients without treatment with ivermectin.
The results of the study of Rajter et al. being conducted in Florida, where the rates of morbidity and mortality are very high in a country facing the direst pandemic situation in the world,the United States, have great implications. We decided to follow all clinical studies of ivermectin
against COVID-19 and explore its potential as a therapeutic agent. The most important source of
information was the US ClinicalTrials.gov site, and the WHO database (International Clinical
Trial Registry Platform: ICTRP) listing trials registered from around the world. Surprisingly, theICTRP had already registered 11 studies (5 in India, 2 each in Iran and Spain, and 1 case each in
Bulgaria and Nigeria), and 7 of these studies had already begun enrollment of patients. Since
then, the number of registrations for both registration sites has been 5 in May, 18 in June, 7 inJuly, 12 in August, 5 in September, 3 in October, 5 in November, 5 in December, and 8 in January
2021. According to the total up to the 30th of January, there are 57 studies from 21 countries (2studies were canceled) on the ClinicalTrials.gov site and 36 studies from 6 countries on the
ICTRP. In total, 91 studies from 27 countries have been registered. As shown in Table 2, there are
15 studies in India: 10 are in phase 2 or phase 3 clinical trials and 5 are observational studies. 12of these studies are for the purpose of treatments and the other 3 are for the purpose of preventing
the onset of disease in medical staﬀ and family members who came into contact with COVID-19
patients. The next largest number was in Egypt with 12, followed by Iran with 10, Brazil with 7,
and Argentina with 5 studies. As shown in Table 1, India has the second highest cumulative number of COVID-19 infections in the world, and Brazil has the second highest number of COVID-

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63（ 63 ）Table 2. Global clinical trials of ivermectin for COVID-19[As of the 31st of January 2021]

19 deaths in the world. Therefore, ivermectin is being intensively investigated as a repurposing
drug. On the other hand, in Egypt, the cumulative number of aﬀected people is about 40% of thatin Japan, and the problem of COVID-19 seems not to be very serious. The mortality rate there,
however, is about 5.8%, which is more than double the world average. It can be said with conﬁdence that many studies have been conducted to evaluate ivermectin as a key therapeutic agent in
the treatment of COVID-19.

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3) Search and analysis of global clinical trial results
The authors planned to summarize these clinical studies of ivermectin in COVID-19, registered worldwide, and describe the results in a review. Writing began in early October 2020 when
the second wave of COVID-19 in Japan was appearing to converge, and the cumulative numberof patients was starting to settle at about 86,000.
However, the monthly increase (about 17,000 between the end of September and the end of
October) rapidly elevated to an increase of 47,000 by the end of November. The cumulative number of patients exceeded 100,000 toward the end of October and this clearly showed the appearance of the third wave. The number of aﬀected people in the world has been steadily increasing.
That number exceeded 20 million in early August 2020, and an increase of 10 million was observed over the span of one month. From mid-October, the increasing trend85) became even stronger, and the situation began to further worsen to the extent that an increase of 20 million people
was now observed over a single monthʼs time. The cumulative number of deaths exceeded 1.25
million, and the increasing trend became stronger from around mid-November, with no sign ofconvergence.
By the end of October, when the review concept for this article was ﬁnalized, 44 studies
were registered with ClinicalTrials.gov, and 31 studies were registered with the WHOʼs ICTRP.
However, only 10 studies completed their planned number of cases, and only 7 studies actually
published their results. This was less than 10% of the total studies, making it premature to draw
conclusions from those published data. In addition, our survey of the clinical studies was limited
to those registered with registration sites. Therefore, it was necessary to devise a method for collecting the results of unregistered clinical studies such as the Rajterʼs team mentioned above.
During this period, Andy Crump, the author of a review article86) discussing the various eﬀects ofivermectin other than antiparasitic actions, forwarded a draft manuscript by Juan Chamie. The
Chamie article described the distribution of ivermectin in Peru and the number of COVID-19 patients and deaths showing the actual situation regarding the widespread use of ivermectin inSouth America. Next, David Scheim, who has proposed the hypothesis87) that ivermectin suppresses peripheral thrombus formation by suppressing the hemagglutination reaction of the
SARS-CoV-2 virus, contacted us with his proposal to collaborate with a group considering theclinical indications of ivermectin for COVID-19 in the United States.
4) FLCCC Alliance Activities
In the United States, EUA was given for chloroquine and hydroxychloroquine on the 28th ofMarch. Ten doctors in the ﬁeld of emergency care medicine, including Paul Marik of the East
Virginia Medical School (EVMS) in Virginia, established the Frontline Covid-19 Critical Care
Alliance (FLCCC)88) on the 5th of March. The purpose of this group was to treat COVID-19 patients with pulmonary inﬂammation by administering methylprednisolone intravenously, high-Mar. 2021

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65（ 65 ）dose vitamin C intravenously, vitamin B1 and low-molecular-weight heparin under a protocolcalled “MATH＋”. Focusing on the excellent results of the clinical study of ivermectin by Rajter
et al. in South Florida, the FLCCC investigated and analyzed the progress of the clinical studies
of ivermectin being conducted in various countries around the world89). It was judged that the administration of ivermectin alone was suﬃciently eﬀective for the outpatient management and theprevention of onset in close contacts. Based on that decision, the FLCCC established a new protocol90) called “I-MASK＋” on the 31st of October. It combines a single oral dose of ivermectinwith the use of a mask to prevent the spread of the infection. It was reported91) that ivermectin has
the potential to resolve the COVID-19 pandemic worldwide. FLCCC inquired with us about thestate of studies on ivermectin on COVID-19 in Japan. After being informed that Kitasato University began a doctor-initiated clinical trial on the 16th of September, the FLCCC requested to work
closely by exchanging future information.
FLCCCʼs President Pierre Kory was summoned92) as a witness by the Homeland Security andGovernmental Aﬀairs Committee of the US Senate on the 8th of December. At that time, he explained the results of the global trials of ivermectin in COVID-19 prevention and treatment, and requested an early expansion of indications for ivermectin to treat COVID-19 in the United States. In
particular, Kory complained that ivermectin was listed in the COVID-19 Treatment Guideline93) established by the NIH on the 27th of August. However, the recommendation was negative (againstuse). The inﬂuence of the NIH is so strong in the US that doctors could not even carry out “oﬀ-labeluse” of ivermectin based on an individual patientʼs clinical presentation or based on physician discretion. It was insisted that the situation be corrected by the NIH. In order to achieve this change,
FLCCCʼs Pierre Kory and Paul Marik, along with Andrew Hill, who represents the International
Ivermectin Project Team (IIPT), met with the NIH Guidelines Committee on the 6th of January 2021
to discuss the guidelines on ivermectin. They explained the results of the global clinical studies for
COVID-19 and recommended that the judgement “against” oﬀ-label use be terminated. As a resultof subsequent intensive examinations, the NIH announced its revision of the guidelines on the 14thof January. According to the revision94), the previous recommendation of “recommends against theuse of ivermectin for the treatment” of COVID-19, was revised to a neutral description of “there are
insuﬃcient data . . . . . . to recommend either for or against the use of ivermectin for the treatment”.
Following this revision, the FLCCC announced95) on the 15th of January that ivermectin was“upgraded” in the NIH guidelines under the title “Ivermectin is now one of the treatment options
for physicians and prescribers”. Furthermore, in response to the fact that the statement of revisionof the guidelines issued by the NIH on the 14th of January contained many factual misunderstandings, a public statement96) was issued on the 18th of January. The NIH published the updated
COVID-19 treatment guidelines on the 11th of February, with the section on ivermectin have beenrewritten in detail. The revision also included the clinical trial results used to review the guidelines.
The recent movement of the Infectious Diseases Society of America (IDSA) is the opposite66（ 66 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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of such a revision by the NIH. Their ﬁrst guideline97) issued on the 27th of April 2020 did not
mention ivermectin. However, a new recommendation on ivermectin use (created on the 29th ofJanuary 2021) was added to the revised edition98) published on the 5th of February (Version
3.8.0). There are 19 recommendations. Item 18 is intended for critically ill inpatients and item 19
is intended for outpatients. In their descriptions, the IDSA Committee opposes the use of ivermectin outside of clinical trials, stating that these are “Conditional recommendations,” of “verylow certainty of evidence”. This statement has not been corrected in the latest version (Version
3.10.0) issued on the 18th of February, and is inconsistent with the revision of the NIH guidelines.
Traditionally, the NIH and the IDSA have coordinated on the diagnosis and treatment of infectious diseases and clinical evaluation methods for anti-infective drugs. The two have also usually
carried out their respective activities based on a common approach. It is confusing to show diﬀering guidelines between the NIH (the Governmental research administrative organization) and the
IDSA (a specialized academic society). In fact, the recent issuance of the IDSA guidelines
following the revision of the guidelines by the NIH, could be considered a fundamental denial of
the eﬀorts of the NIH and thereby contribute to a state of increased confusion. Given the problems
that occur when clinical physicians do not administer ivermectin in accordance with the IDSA
Table 3. The excerpt of the “ Summary of the clinical trials
evidence for ivermectin in COVID-19” presented by the
FLCCC Alliance as of the 11th of January 2021

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67（ 67 ）guidelines, it is necessary to urgently revise such guidelines in accordance with the NIH guidelines.
In addition, the FLCCC Alliance summarizes and publishes the results of research andanalysis of clinical trials of ivermectin for COVID-19 conducted worldwide. The ﬁrst summary
was published on the 22nd of December 2020. Its content has been kept up to date in a timely
manner, with the addition of further information99) on the 11th of January 2021 (at the time of thewriting of this review). Since this document summarizes the world situation in a very clear andconcise manner, a portion is presented in Table 3. Based on the outcomes in a total of 6,612 patients enrolled in 27 clinical trials (8 for prophylactic and 19 for therapeutic purposes), ivermectin
was found to prevent the development of disease in COVID-19-exposed patients, accelerate patient recovery, reduce the need for hospitalization, and reduce mortality. It encourages the clinicaluse of ivermectin for COVID-19.
Based on the results of such accumulated clinical trials, the FLCCC Alliance issued a public
letter100) requesting a reconsideration of the protocol for the ivermectin clinical trials published by
the University of Oxford on the 23rd of January. The letter argues that giving placebos to a control
group of patients in trials already making use of existing oﬀ-label drugs does not ensure the lifeand health of clinical trial patients. These types of studies would be in violation of the fundamental principle of the Helsinki Convention. Ivermectin is an oﬀ-label drug and has already beenshown to be eﬀective in numerous clinical trials for COVID-19. It should be considered as a partof standard treatment. The study design is a placebo-controlled comparative study. Instead ofusing a placebo, the request was made to change the ethical setting and compare the timing, dose,or duration of treatment of ivermectin in COVID-19.
5) Meta-analysis of clinical trial results
During this COVID-19 pandemic, a major change has taken place in the ﬁelds of medical
and natural science research in terms of the usual practices of the disclosure of information. It is
now required to publish obtained test results as soon as possible. Before this, publishing in print
was done in many specialized magazines and academic journals and a form of early publication
by online services called advanced online publication, or electronic publishing, was done in acompeting fashion. Specialized journals that were only published online without publishing inprint were also extensively used and the publication of research results was becoming increasingly diverse. To date, one year has passed since the COVID-19 pandemic was declared. For example, a literature search for COVID-19 and SARS-CoV-2 on PubMed will result in more than
100,000 hits. And many of them are preliminary reports in advance of peer review — called preprints. There are ﬁrst, second, and third epidemic waves all over the world. The rapidly changing
areas of vaccine development, the emergence of mutant viruses, the appearance and exit of therapeutic drug candidates, etc., are research results that cannot wait to be published in the traditional
print format. The peer-reviewed process itself takes several months to complete. In many cases,68（ 68 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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the research results are inevitably published in the form of preprints and then peer-reviewed,
whereupon they will then remain as an oﬃcial treatise.
Most of the clinical trial results of ivermectin for COVID-19 have been published as preprints. About 20 of them have been recognized as oﬃcial treatises following peer review. Sometimes, the contents of the publication are not changed at all from their preprints, except in theform of some updates. The argument raised from regulatory authorities that preprinted publications do not always provide suﬃcient evidence is not correct. In fact, some treatises that havebeen peer-reviewed in advance and later published in print have been withdrawn at a later date.
As a ﬁnal point, it should be remembered that there is a diﬀerence in the publication method of astudy for the purpose of early publication; the certainty of evidence should be judged by comprehensively evaluating the protocol described in the study, as well as the analysis of the results.
After carefully searching for, organizing, and analyzing the clinical trial results of ivermectin
for COVID-19 announced in such preprints, a Twitter account called “@CovidAnalysis” was set
up on the web on the 26th of November 2020. In the ﬁrst edition of this site, meta-analyses of 19
clinical trials (including 8 randomized controlled trials) were displayed in bar graphs and forest
charts. These serve as very powerful visual sources of data. On this site, new study results arebeing added, one by one, from researchers around the world. In such a fashion, the meta-analysis
is being repeated and growing at the same time. For example, the second edition was updated to ameta-analysis of 22 trials on the 4th of December. By the sixth edition on the 16th of December, it
had been updated to a meta-analysis of 26 studies. The amount of information available from thissite is enormous. Medical professionals attempting to use ivermectin clinically for COVID-19 arecollaborating together to build a large real-time database. The information on the site has reachedits 37th edition101) on the 27th of February 2021. By that time, the meta-analysis has been performed on 14,906 patients in 42 clinical studies (including 21 randomized controlled trials with
2,869 patients). It reported improvements of 83% in early treatment, 51% in late treatment, and
89% in the prevention of onset of disease. Based on the results of these 42 trials, it concludes thatthe probability of this judgment on ivermectinʼs superior clinical performance being false is estimated to be 1 in 4 trillion.
Meanwhile, at IIPT, represented by a WHO consultant Andrew Hill of the Department ofPharmacology at Liverpool University, the results of 18 clinical trials conducted by 40 members
from 13 countries (in their own clinical trial organization, totaling 2,282 subjects) were metaanalysed102). A report was issued only after carrying out a repeated examination of all the items to
be analyzed, as well as the analysis methods to be used. In the meta-analysis of six of these randomized trials (of moderate to severely ill patients), the mortality rate of 14/650 (2.1%) in theivermectin group was signiﬁcantly lower (p＝0.0002) than the mortality rate of 57/597 (9.5%) in
the control group. It also conﬁrmed excellent clinical improvement with ivermectin, showing ashorter hospital stay. According to a personal letter from Hill, the IIPT holds regular meetings forMar. 2021

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69（ 69 ）the purpose of accumulating more data. Data was added for about 4,000 cases from six clinical
trials on the 5th of February, and approximately 2,200 additional cases are expected by early
March. It is predicted that additional clinical trial data for about 5,000 cases will be added by
April. Among the source countries/regions of these data, there are ten developing countries andthree developed countries (UK, France, and Spain). In the developed countries, clinical trials ofvaccines and new antiviral drugs created by advanced science and technology are being conducted and there are no companies/organizations aiming to expand the indications for the repurposing of the existing drug ivermectin. In developing countries, however, enthusiastic studies onivermectin are being conducted. If ivermectin, which is an inexpensive drug that is easily available, can cope with COVID-19, it has enormous implications for the possible treatment options
available to the poorest communities in such countries. Kitasato University, in Japan, is conducting
a doctor-initiated clinical trial, and its results, once obtained, will be added to the IIPT analysis.
When the results of such meta-analysis were obtained and collated with the clinical trial information collected so far, the meta-analysis results by more detailed experts were published103).
Teressa Lawrie of The Evidence-Based Medicine Consultancy Ltd (EBMC), a UK medical statistics consultancy and WHO data analysis consultant, provides a professional meta-analysis in support of FLCCC recommendations. Based on the detailed examination of 15 of the 27 clinical trials covered by the FLCCC (consisting of 6 with low bias and 9 with moderate bias) she reported
the meta-analysis results. The results utilize forest plots on mortality, symptom improvement,
symptom exacerbation, the required period for recovery, period until PCR becomes negative, thelength of hospital stay, the necessity of admission to the ICU or use of a ventilator, and serious
side eﬀects. It was concluded that the ivermectin group was superior in all analyzed parameters
except for side eﬀects. However, her conclusion was diﬀerent from that of the NIH committee
who performed an evaluation using the same test results.
6) Results of registered clinical trials
As of the end of January 2021, there were 55 clinical studies registered on ClinicalTrials.gov(with 2 exclusions) and 36 other clinical studies registered on the WHO site. This is a total of 91
clinical studies. Among these clinical studies registered (as seen in Table 2), 21 studies have already been completed, and the results of 18 have been published (Table 4). The order of publication in the table is the date of registration, and the study contents, judgment categories, and study
results are brieﬂy described. It is noted that most of the 18 studies104~121) have been implemented
in developing countries. These are areas where there has been much diﬃculty with COVID-19
countermeasures. Due to small sizes, some studies were completed in short periods of time. However, it can be said that the earnest desire to complete the studies as quickly as possible also conﬁrms the eﬃcacy of ivermectin in driving the progress of such studies. Of the 18 studies in thetable, 13 showed that the ivermectin test group was signiﬁcantly superior to the control group in70（ 70 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Table 4. Summary of the results of the registered clinical trials

terms of judgment categories. There are concerns that the scale of the trials, the presence or absence of masking, and the judgment categories are biased. However, in the pandemic conditionsof acute diseases such as COVID-19, where a diﬀerence between rapid deterioration and improvement of the patientʼs condition is clear, and the diﬀerences from the control group are also
clear, it is unlikely that there will be a bias as seen in clinical trials of drugs for normal chronic
diseases. As to the concern of “publication bias” (generally described as only positive results
being reported and negative results being buried), it is not a likely scenario. All of the enrolled
clinical studies shown in Table 4 are doctor-initiated clinical studies. None of these studies arecompany-oriented studies where there is a reporting obligation to the organization that bears thecost of the trial. Furthermore, some of these trials also include national security implications forthe country in question. Therefore, associated publication bias is unlikely. In particular, for clinical trials registered with ClinicalTrials.gov in the United States, it must be taken into account thata report of results122) is required.
7) Unregistered clinical studies and mass distribution of ivermectin
The ﬁrst clinical study of ivermectin in COVID-19 around the world was a retrospective
analysis by Rajter et al. in South Florida, USA. It was an observational investigation with the result that ivermectin administration correlates with a reduction of in-hospital mortality due to
COVID-19. When these ﬁndings spread on the web as a medRxiv preprint in early April of 2020,
many clinical studies were then conducted at medical institutions around the world, having diﬃculty responding to the COVID-19 pandemic, to conﬁrm the therapeutic and preventive eﬀects of

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71（ 71 ）ivermectin. Following the publication of an extensive review of ivermectinʼs antiviral activity123,124) and a commentary on its clinical application125) to COVID-19, many medical facilities
around the world began clinical studies under approvals by institutional or regional ethical review
boards. Clinical studies that are not registered with the oﬃcial clinical trial registration sites are
now being extensively conducted and the results126~132) reported.
On the other hand, in Peru, the results of in vitro studies by Caly et al. and the clinical resultsof Rajter et al. were highly evaluated. Consequently, it was decided on the 8th of May to issue
treatment guidelines for the administration of two drugs, hydroxychloroquine and ivermectin, in
mildly ill patients, and three drugs, hydroxychloroquine, azithromycin and ivermectin, in moderately and severely ill patients with COVID-19. According to a detailed study133) by ChamieQuintero et al., Peru distributes packs containing ivermectin and other medicines to the public. In
the Lima region, where distribution of the packs was delayed, it was conﬁrmed that the infection
rate of COVID-19 and mortality rate were signiﬁcantly higher compared to the other eight regions where packs had been distributed earlier. In Peru, the Ministry of Defense, the Army, theNavy, the Air Force, and the Police have mass-distributed ivermectin through an operation
against COVID-19 named “Mega-Operation Tayta (MOT)”. These eﬀorts resulted in a decreasein nationwide deaths by one fourteenth (1/14). However, that number started to increase after the
distribution was stopped due to a change of government in November. It continued to further rapidly increased by 13 times as of the 1st of December. It is expected that this trend will continue toincrease in the future (David Scheim personal communication)134). In Bolivia, a neighboring
country of Peru, ivermectin for 350,000 people was distributed free of charge from the 12th ofMay. Paraguay placed restrictions on the sale of ivermectin. In Colombia, advocates sought forpolicy decisions to prevent ivermectin abuse. It is reported that ivermectin is also distributed in
Brazil at the discretion of local governments, although not nationwide.
In the above-mentioned “@CovidAnalysis” meta-analysis site on the web, the world map
shown in Fig. 2 was displayed on the summary page (from its 26th edition) on the 5th of February
2021. It indicates countries where ivermectin is being applied as a COVID-19 countermeasure. It
illustrates the countries and provides information on each country. Figure 2 quotes the latest version on the 27th of February, notice that Japan was included in the category of “SOME REGIONS” in light green. It was included on the grounds based on an announcement by the Ministry of Health, Labor and Welfare, Japan on the 16th of June 2020. That announcement, in an
English guidance document135), stated that ivermectin, which is available as a treatment for scabies in Japan, can be used oﬀ-label for COVID-19 in the clinical management of COVID-19 patients. However, since its indication has not yet been approved for ivermectin, it has been described that it should be used only after careful consideration by clinicians and patients. In Japan,
as of June 2020, regulatory authorities have already approved the oﬀ-label use of ivermectin for
COVID-19. We will accelerate clinical trials in Japan in order to obtain expanded indications as72（ 72 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Fig. 2. Countries where ivermectin is adopted for COVID-19[quoted from Covid Analysis Version 37, Feb 27, 2021]〔https://ivmmeta.com/〕soon as possible.
The display in Fig. 2 distinguishes between cases (shades of green) where ivermectin is usedthroughout the country, where it is widely used, where it is used in a limited way, and where it isused in a mixed manner. Table 5 summarizes these distinctions and the conditions of use for eachcountry. Ivermectin is used in the treatment or prevention of COVID-19 in 24 countries aroundthe world. It has already been approved for nationwide use in 14 countries and there is an accumulation of conducted clinical study results for each of these countries. The number of countries
has also been increasing since the beginning of 2021.
Ivermectin has already been provided free of charge to endemic areas of two diseases since1987. The “Mectizan Donation Program; MDP” (in cooperation with the WHO) has distributed136) ivermectin to prevent the onset of river blindness and lymphatic ﬁlariasis. 300–400
million doses are distributed annually to approximately 70 countries/regions. A total of 3.7 billion
doses have been widely distributed over 30 years. Very few serious side eﬀects have been observed, and it is considered to be a drug whose safety has been suﬃciently conﬁrmed. Comparing
19 countries participating in the African Program for Onchocerciasis Control (APOC) with 35
countries not participating in it, has yielded interesting results. APOC participating countries
were found137) to have a COVID-19 morbidity rate 8% lower and a mortality rate 28% lower thanthose of non-AOPC participating countries. In Africa, the incidence of COVID-19 disease per

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73（ 73 ）100,000 population in countries using ivermectin for preventive chemotherapy (PCT) has beenreported138). The rate is signiﬁcantly lower (p＝0.017) than in countries that do not have PCT.
“Mectizan®” is the trade name of the dedicated ivermectin tablet used in the distribution program.
Merckʼs “Stromectol®” tablet is used for the treatment of fecal nematodes and scabies in the
United States and in Japan. For animal treatments, tablets, ointments, liquids, and injections
under the trade name “Ivomec®” are used to prevent disease damage caused by parasites and insects. More than 30 years have passed since it was placed on the market, and generic products arealso used. Under the situation where ivermectin is distributed to prevent the spread of COVID-19
infection in South America, illegal ivermectin has entered the black market. This includes iverTable 5. Global ivermectin adoption for COVID-19 (as of the 26th of February 2021)
https://ivmmeta.com

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mectin in injection form, which is used in high concentrations for cattle. It is reported that the
preparations contain 0.27% or 1.0% and that polyethylene glycol is used as a base material forsuch veterinary intended use subcutaneous injections. There was concern about the occurrence ofside eﬀects when taking such veterinary intended use injections instead of oral preparations in the
United States. The FDA issued an urgent warning letter80) stating that “Ivermectin preparations
for animals should not be taken”, but detailed background information surrounding the warning
was not given. Consequently, the FDAʼs warning falsely spread the impression that ivermectin
was prohibited for use in COVID-19, causing further confusion.
An interesting expansion of the clinical application of ivermectin can also be seen in the prevention and treatment of COVID-19 in long-term care facilities for the elderly. In such facilities,
residents and staﬀ may often be required to take ivermectin in response to outbreaks of scabies.
In France139), the prevalence of COVID-19 in facilities utilizing ivermectin for such purposes issigniﬁcantly lower when compared to that of facilities where ivermectin is not taken.

4. Is Ivermectin Not Suitable for COVID-19 Treatment?
Immediately after Calyʼs paper was published online, the Mectizan Expert Committee,
which runs the MDP, issued a statement140) that the concentration required to suppress the SARSCoV-2 virus shown in the in vitro experiments was too high when compared to that obtained by
the FDA-approved dose. When such a high dose is administered to obtain such a concentration in
the body, there are concerns that severe side eﬀects will occur. It was pointed out that since thiswas such a fundamental ﬁnding, it alone was suﬃcient to justify the ineﬀectiveness of ivermectin
use against COVID-19.
The opinion of Merck has persisted and both the NIH and the IDSA have said that it is thefundamental component comprising the dissenting opinion for the use of ivermectin against
COVID-19. The Pan American Health Organization (PAHO), which is the Americas branch of
the WHO, also cited78) the same statement and opposed the use of ivermectin for COVID-19. The
PAHO statement also emphasized that ivermectin is not included in the Solidarity Trial52), an
evaluation study of repurposing drugs for COVID-19 being conducted by the WHO. The clinicaleﬀect of ivermectin on COVID-19 is manifested, as described in a subsequent statement from the
FLCCC, by not only the suppression of SARS-CoV-2 replication, but also in the eﬀects on thebinding of the virus to the host cell, as well as eﬀects on the hostʼs own inﬂammatory responses.
This argument that it is based on such a complex mechanism is not taken into consideration at all,and the argument remains that it is only about the pharmacokinetics/pharmacodynamics (PK/PD)of ivermectin.
It has also been stated that, considering the purpose of MDP activities, if ivermectin is usedin large quantities against COVID-19 as an “oﬀ-label use”, the market would quickly run out of

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75（ 75 ）ivermectin. The WHO even issued a warning141) that current stock supplies of the drug ivermectin
might not remain adequate for patients with fecal nematodes and scabies (the original indications
for ivermectin) if the drug is used for other purposes. Furthermore, given the indication of ivermectin use for scabies, the mite that causes scabies might also become more resistant to ivermectin after prolonged exposure to low concentrations of the drug. Therefore, the use of ivermectin in
COVID-19 should be kept solely for use against the scabies mite and not be used to potentiallycontribute to a rise in resistance of the causative organism in the environment.
However, the question has been raised as to whether it is ethically correct to oppose, for suchreasons, the use of ivermectin against COVID-19. There are already dozens of clinical trial results that have been accumulated to date that demonstrate that ivermectin is eﬀective against
COVID-19. Hundreds of thousands of people worldwide are being infected and thousands continue to die every day. The debate over whether ivermectin is not suitable for COVID-19 treatment has always been taken up at the FLCCC webinar every Wednesday at 7 p.m. (US East CoastStandard Time). It was also discussed at the British Ivermectin Recommendation Development(BIRD) conference, organized by Lawrie of EBMC on the afternoon of the 20th of February(World Standard Time), with attendance of more than 70 ivermectin researchers from around theworld. The BIRD conclusions were also submitted to the WHO after a summarization of theopinions from all the participants.
1) Merck Statement and FLCCC Alliance Response
Worldwide, a total of 91 studies, 80 for treatment and 11 for prevention of onset in close
contacts, are being conducted in 27 countries. As shown in Table 2, 74 are being carried out in theform of the usual phases of clinical trials, and 17 in the form of observational studies. Looking at
the content of these trials, most of them are doctor-initiated clinical trials at the medical institution level, and only one each being conducted by a company in France and in the United States.
The ﬁrst approved company to manufacture and sale ivermectin was Merck & Co. in the UnitedStates. If this company had conducted a clinical trial to conﬁrm the eﬃcacy and safety of ivermectin for the recent COVID-19 pandemic, it could have been done in a very short period oftime. Then, a necessary and suﬃcient amount of studies could have been conducted with a large
number of cases, consultations and collaborations with regulators — the NIH, CDC and the
FDA — carried out smoothly, and an Emergency Use Authorization (EUA) could have been issued much earlier than hydroxychloroquine and remdesivir. Had this happened, it is speculated
that the widespread clinical use of ivermectin in the United States could have prevented a large
number of aﬀected and fatal cases.
Contrary to such speculation, Merck & Co. released a company statement142) dated the 4th ofFebruary 2021 stating that “Company scientists continue to carefully examine the ﬁndings of allavailable and emerging studies of ivermectin for the treatment of COVID-19 for evidence of eﬃ-

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cacy and safety. It is important to note that, to date, our analysis has identiﬁed: (1) No scientiﬁcbasis for a potential therapeutic eﬀect against COVID-19 from pre-clinical studies; (2) No meaningful evidence for clinical activity or clinical eﬃcacy in patients with COVID-19 disease; and(3) A concerning lack of safety data in the majority of studies.” This Merck statement cites the
package insert for Stromectol®, a product that the company sells, and describes details of the
productʼs indications and the known adverse events. It might be understandable that Merck has
issued this statement with the intention of exempting the company from being liable for any adverse events caused by oﬀ-label use of the product for the treatment or prevention of COVID-19.
For that purpose, Merckʼs statement (regarding the three items described above) would not havecaused any extra controversy without a description of the eﬃcacy and safety of ivermectin for
COVID-19. It has, however, created a big argument among the scientists involved in COVID-19
clinical studies, leading to controversy over the companyʼs management stance.
The FLCCC Alliance issued an oﬃcial statement143) on the 7th of February addressing thethree items presented by Merck. Such statements are signiﬁcantly diﬀerent from the results ofivermectin in terms of the eﬃcacy and safety reported by multiple expert groups around theworld, including a meta-analysis of the latest scientiﬁc literature. In this controversy, the FLCCC
Alliance side has refuted Merckʼs allegations by citing recently published papers from eightgroups around the world (ﬁve of which were published in 2021 and two in November and December 2020), oﬃcial views issued94) by the NIH on the 14th of January, and 16 other papers.
However, Merck did not provide any scientiﬁc basis to support the three items claimed in theirstatement. As a consequence, the debate has now gone silent. Regarding the eﬃcacy of COVID19, it may be argued that there is a disagreement surrounding the scale of individual trials cited as
scientiﬁc support and that the evaluations of the content of the studies are diﬀerent. However, regarding the safety of ivermectin, Merck itself has announced on its public relations page that
there were very few serious adverse events in the MDP over a period of more than 30 years. So,
contradictory points have been raised as to why there are concerns about limited safety in the useof ivermectin for COVID-19.
In addition, regarding the issue that there is no scientiﬁc basis for the potential therapeutic
eﬀect on COVID-19 from preclinical studies, much evidence is shown in the six papers144~150) offundamental research presented by the FLCCC Alliance. Furthermore, 13 papers on clinical eﬃcacy and safety also discuss the mechanism of action of ivermectin, which is the basis of clinicaleﬃcacy. Therefore, it is natural that there are criticisms that Merckʼs claim is misunderstood; it isdue to a lack of a suﬃcient search of existing documents on the topic. On the other hand, there
are many opinions surrounding the background of Merckʼs statement in that ivermectin competes
with their development of MK-4482 (EIDD-2801). This may have been the reason it was eliminated. MK-4482 is a nucleoside analog that suppresses SARS-CoV-2 virus replication like remdesivir. Whereas remdesivir is an injectable drug, MK-4482 is an orally absorbable prodrug capa-

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77（ 77 ）ble to treat mildly ill patients who are treated as outpatients or in their homes. If a therapeutic
drug with such characteristics comes to be used clinically, it will become possible to control the
COVID-19 pandemic. This would also result in even greater expectations. If both the new drug
and ivermectin are used to treat COVID-19, humans around the world will be free from the fearof COVID-19. Ivermectin should not be considered to be in competition with the new drug. In
order to respond to the counterarguments published by the FLCCC Alliance, it is necessary for
Merck to provide solid evidence and politely justify the companyʼs statements.
Decisions not to conduct clinical trials to expand the indication of ivermectin for COVID-19
are acceptable as a corporate management policy. However, it is not ethically permissible if there
is an intention to interfere with the process. In a pandemic that aﬀects more than 100 million people worldwide and kills more than 2.4 million people, many medical professionals around theworld are enthusiastically studying ivermectin as a promising therapeutic drug for COVID-19. At
the end of their oﬃcial statement, the FLCCC Alliance quoted the words of the son of the founderof Merck, George W. Merck in 1950, that “Medicine is for the people. It is not for proﬁts”.
2) Conﬂict over clinical data for ivermectin
Under ordinary circumstances, in accordance with the enactment intention82,83) of the “21stCentury Cures Act (Public Law 114-255)” promulgated in the United States in December 2016,
the expansion of indications for approved drugs such as ivermectin should be carried out in a speciﬁc manner. Speciﬁcally, under a “novel clinical trial design (Sec. 3021)” established to quickly
reﬂect the “real world evidence; RWE (Sec. 3022)” being recognized in a clinical setting. If theinnovator Merck had built a groundbreaking clinical trial design that could evaluate the drugʼs
RWE, things could have turned out diﬀerently. If a study had been built based on the evidence accumulated in the 91 registered clinical trials as discussed previously in this report, and the FDA
followed up and approved an expanded indication for treatment and prevention of COVID-19, it
could have prevented COVID-19 from spreading to 8% of the population in the United States.
This could have also avoided the tragedy of the ensuing deaths of hundreds of thousands of people. It is a very unfortunate situation that has been caused by the fact that new concepts in drug
evaluation methods suitable for the 21st century have not been realized or carried out. The oldfashioned ways of drug regulation and concepts have not yet been broken through and the consequences have been severe.
In order to ensure the safety and eﬃcacy of medicines, regulators have taken suﬃcient time
and thoroughly deliberated on a huge amount of evidence-based materials under a complete andcomprehensive examination system. It stipulates the indication targets and indication methods forthe clinical use of the drug. It also recognizes and emphasizes standard precedent. During normal
times (or peacetime), not so many people disagree with ideas and practices of such regulators in
the review of new medicines for well-known diseases for which therapeutics already exist. How-

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ever, in this current time of a raging worldwide COVID-19 pandemic, there are strong opinions
that it is impossible to promptly provide eﬀective and safe therapeutic agents with such an outdated examination approach and philosophy. The traditional regulatory concepts that many of thereviewers continue to follow are not keeping adequate pace with modern science and practices
and are not able accommodate rapidly developing RWE.
Regulators claim that “there is not enough evidence to accept it,” but the safety level of ivermectin has already been achieved by means of the MDP granting more than 3 billion doses to individuals over 30 years. They argue that there is no clear or suﬃcient evidence, and that safetyassurance when used with COVID-19 patients is inadequate. This is a situation where ethics
should be questioned as to whether it is permissible to ban patients whose lives may be able to be
saved by administering ivermectin only because absolute safety is not guaranteed. There is a needto state a legitimate reason as to why there is hesitation to use an already eﬀectively conﬁrmed
drug such as ivermectin (based on RWE) in patients with COVID-19 who could possibly even
expect to be cured with its use.
Regulators argue that existing data on the eﬃcacy of ivermectin for COVID-19 are biased inits study plans and methods, and are insuﬃcient to determine validity. A meta-analysis of 14,906
patients in the 42 clinical trials101) described above has shown suﬃcient eﬃcacy of ivermectin,with a 1 in 4 trillion chance of the conclusion being a mistake. Yet, it is still considered insuﬃcient evidence. Randomized controlled trials are regarded important by regulators. There are 21
trials employing 2,869 patients out of 42 studies. If regulators argue that studies of this magnitude
are inadequate to allow the clinical use of ivermectin in COVID-19, then legitimate and compelling explanations for such judgements should be required.
Both the meta-analysis of 15 clinical studies by Lawrie103) of the United Kingdom (who is aconsultant for WHO clinical trials) and that of 18 clinical studies102) conducted by Hill (who isalso a consultant of the WHO) in collaboration with 40 researchers from 13 countries have been
carried out. Such analyses have aﬃrmed the eﬀectiveness of ivermectin for COVID-19, after
fully analyzing for the bias of beliefs (that ivermectin was eﬀective or that the placebo was ineffective). However, the results of such a meta-analysis are rated as “insuﬃcient data” and “verylow certainty” by the panels of the NIH and the IDSA Clinical Evaluation Guidelines Committee.
It is requested that the WHO committee responds to the recommendations made by the BIRD
team151) submitted at the end of February. Furthermore, the recommendations were also sent to
the NIH and the CDC, and it will be noted whether there is a diﬀerence in the correspondence between the two. In addition, on the 19th of February, the WHO Working Group was hearing the results of a survey on the rapid decrease in excess mortality and the rapid increase after discontinuation of the mass distribution of ivermectin in Peru134). There is also a lot of interest in how theWHO handles such real-world evidence in real time.

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79（ 79 ）5. Domestic Clinical Trial of Ivermectin for COVID-19
Kitasato University has established152) the “COVID-19 Countermeasures Kitasato Project”
for the purpose of discovery of COVID-19 therapeutic agents in response to the amendment of
the “Act on Special Measures for Pandemic Inﬂuenza and New Infectious Diseases Preparedness
and Response” in Japan. Since the clinical results84) in South Florida, USA mentioned above wereexcellent, and it was thought to be necessary to obtain approval of ivermectin as an indication for
COVID-19, it was decided to conduct a doctor-initiated phase 2 clinical trial. In Japan, MSD Co.
Ltd., a subsidiary of Merck & Co., Inc. of the United States, is the sole manufacturer and distributor of ivermectin. The company has marketed 3 mg tablets, under the trade name of “Stromectol®”, since 2002 for the treatment of a rare disease, strongyloidiasis. The sale of Stromectol® wastransferred to Maruho Co., Ltd. in the April of 2006, and an additional indication for scabies wasapproved in August of that same year.
MSD Co., Ltd. might have been the best entity to conduct the phase 2 clinical trial aimed at
expanding the indication of ivermectin to COVID-19. However, it was reported that Merck &Co., Inc. of the United States had no intention of conducting clinical trials aimed at expanding
new indications for ivermectin. It should also be noted that ivermectin has also been sold formore than 30 years with multiple generic products available on the market. At that time, the company was also developing two types of vaccines (V590 and V591) and two therapeutic agents(MK-4482 and MK-7110) against COVID-19. Therefore, in the doctor-initiated phase 2 clinical
trial by Kitasato University, “Stromector®” used for the trial was purchased from Maruho Co.,
Ltd., and the cost of the clinical trial is covered by the research funding raised by donations collected by the “COVID-19 Countermeasure Kitasato Project”. A fund for “Ivermectin for COVID19 (Principal Investigator: Kunihiro Yamaoka)” by the Japan Agency for Medical Research andDevelopment (AMED) adopted an open call for participants of the “Research Program on Emerging and Re-emerging Infectious Diseases; Development of Therapeutic Drugs for Novel Coronavirus Infection (COVID-19)”. Unlike clinical trials conducted by pharmaceutical companies,
even if the clinical trial is successful and the indication expanded, there is no beneﬁt to be obtained from the results. As such, the recovery of clinical trial costs is not a consideration at all.
Therefore, this is a clinical trial with high public interest aimed at alleviating the pain and suﬀering of patients and saving human lives amidst the devastating COVID-19 pandemic.
In the domestic doctor-initiated clinical trial by Kitasato University, the draft was rewritten
several times in consultation with the regulatory authorities with the aim of making sure that the
protocol was created perfectly. After ﬁnalizing the protocol, it was registered153) in the Japan Registry of Clinical Trials (jRCT) on the 16th of September 2020. This domestic registration was automatically registered on the WHOʼs clinical trial registration site ICTRP. However, it was required to be registered separately on ClinicalTrials.gov, and the registration was accepted and80（ 80 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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listed154) on the 11th of January 2021. Initially, it was aimed to collect 240 cases by the end of December 2020, but the number of participating subjects was not able to be gathered. Even if the period had been extended by 3 months, the progress still would not have been a smooth process. In
advancing clinical trials, in accordance with the “Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals” (called “GCP Ministerial Ordinance”)155), it is necessary to explain the purpose of the clinical trial to the subjects participating and obtain their consent. However, the regulations are currently set under the assumption that the trial is a companyoriented clinical trial. Hence, the regulations are too complicated to allow for doctor-initiatedclinical trials, and it is extremely diﬃcult to obtain participants. The instructions used to obtainthe consent of the subjects have at least 18 items that should be included. Such complex explanations, as part of a company-oriented clinical trial, when given to people unfamiliar with the process do not allow for a smooth consent process. Therefore, reaching the planned number of subjects for participation is diﬃcult. In short, the progress of such clinical trials is extremely slow
due to insuﬃcient funds and a lack of human resources required to carry them out. Whether it isnecessary to conduct clinical trials based on the same concepts (of company-oriented clinical trials) being applied to doctor-initiated clinical trials should be widely discussed in the future. Regarding expanding the indications for compounds for new diseases, it seems that extensive discussion and consideration is needed.
On the other hand, clinical trials of anti-infective drugs in Japan also require strictness inorder to be conducted. Therefore, the subjects to be included in such clinical trials are limited to
inpatients at medical institutions conducting the clinical trials. However, with regard to COVID19, the number of aﬀected patients is increasing rapidly, the treatment period is long, there is ahigh possibility that the symptoms will worsen, and the number of patients accepted is limited
due to the current heavy burden on medical institutions. Only very sick and severe (including
critically ill) patients are eligible for hospitalization and treatment in Japan. It is inherently built
into the system in Japan that mildly ill patients, for whom it is important to prevent exacerbationof symptoms through appropriate management and treatment, are unable to receive inpatient
treatment. According to the administrative communication from the Ministry of Health, Laborand Welfare (MHLW), mildly ill persons are to be treated at home or at accommodation treatment
facilities without being hospitalized at medical institutions. This response system is handled by
the local governments — such as prefectures. The results of numerous clinical trials overseas have
conﬁrmed that ivermectin suppresses the worsening of symptoms in mild and moderately ill patients, shortens the recovery period, and prevents the onset of disease in those who are in close
contact with aﬀected patients. It was considered necessary to include mildly ill patients in clinical
trials in Japan as well. According to the notiﬁcation156) from the MHLWʼs Countermeasures
Headquarters, dated the 2nd of February, it has become possible to administer therapeutic agentsto mildly ill patients who are being treated at home or at accommodation facilities. It is hoped

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81（ 81 ）that this mitigation measure will further improve the ultimate progress of delayed clinical trials
and allow for the preparation of data on the eﬃcacy of ivermectin necessary for expanding its indication for COVID-19 as soon as possible.
At the House of Representatives Budget Committee on the 17th of February, a proposal regarding ivermectin, which is expected to be eﬀective as a therapeutic drug for COVID-19, wasmade. The proposal stated that ivermectin “should be maximally backed up in clinical trials sothat it can be approved as soon as possible by the government”. The Minister of Health, Laborand Welfare further replied, “It can already be used for oﬀ-label use. There is also a way to take it
at a medical institution and wait at home.” Following this, the Prime Minister of Japan mentionedthat he thinks that the drug is very important for Japan, and that he will do his best to help improve the situation. We should keep observing the types of measures that the department incharge of clinical trials of ivermectin in the MHLW will continue to take or create in the future.
The practice of “maximum eﬀort” should not be a long-term examination based on conventional
regulatory concepts. The current situation is an issue that asks for a reexamination of the standard
attitudes of administrative oﬃcers under emergency circumstances.
On the other hand, the most serious problems in COVID-19 patient survivors are sequelae157)
called post-acute sequelae of SARS-CoV-2 (PASC) or long COVID (chronic COVID syndrome).
This condition resembles one of fatigue (similar to chronic fatigue syndrome), sleep disorders,headaches, thrombosis, taste disorders, olfactory disorders, palpitations, joint pains, hair loss,
dyspnea, chest pains, loss of appetite, diarrhea, vomiting, vascular injury, myocardial infarction,
cerebral infarction, etc. A variety of sequelae are frequently observed not only in elderly patients,
but also in young patients. The nature of this process in some ways resembles chronic lead poisoning in the young that can severely negatively impact the lives of young suﬀerers well into
adulthood — even aﬀecting memory — making it diﬃcult to live normally. According to a reportfrom the US NIH, 30% of cases manifest with sequelae that last for 9 months. If the early administration of ivermectin suppresses the progression of symptoms in COVID-19 patients and allows
for early recovery, it is possible to prevent physical damage caused by such sequelae. This could
potentially contribute to an improvement in the expected prognosis in this population of patients.
Even for young people who are battling with or have survived the COVID-19 infection, reducing
the risk of such sequelae will be of great beneﬁt.

6. Conclusion
The eﬀective concentration of ivermectin against SARS-CoV-2 in an in vitro experiment72)
by Caly et al. is as high as 2 μM; in clinical practice, it is necessary to administer tens of times thenormal dose in order to obtain such a blood concentration. Therefore, there are opinions from the
IDSA98) and others that the therapeutic eﬀect of COVID-19 cannot be expected by the adminis-

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tration of the normal dose of ivermectin. However, in actual medical practice, there are many
study reports demonstrating that the administration of a normal dose does indeed show a clinicalresponse. As of the 27th of February 2021, the results of 42 clinical studies worldwide have undergone meta-analysis and concluded101) that ivermectin is eﬀective in the treatment and prevention of COVID-19. In the UK, a consensus-based recommendation by 75 healthcare professionals
from 17 countries around the world has been carried out and submitted to the WHO to further encourage the issuance of guidelines for the use of ivermectin in the treatment and prevention of
COVID-19. We must consider why such a discrepancy is occurring.
The ﬁrst consideration should be focused on the setting of the sensitivity of the SARSCoV-2 infection for experimental systems in vitro. By use of Vero/hSLAM cells, the antiviral activity of the test drug is reliably measured. The sensitivity setting is set to be as low as possible,
because it is necessary to eliminate false-positive samples. If the sensitivity is set high, the number of test drugs (noise) that give a positive reaction increases. Furthermore, if the setting is high,it becomes necessary to set secondary and tertiary tests to exclude false-positive samples. It
seems that the sensitivity of the IC50＝2 μM set by Caly et al. was appropriate because neither
false positives nor false negatives occurred. If the sensitivity of this test is set to 10 or 50 times
higher, then changes in the IC50 (IC50＝0.2 μM, IC50＝0.04 μM, respectively) might be expected.
Depending on the test cells, viral load, medium composition, and culture conditions, the experimental system in vitro can be set in diﬀerent ways. Therefore, the paper by Caly et al. merely indicated that ivermectin was found to have anti-SARS-CoV-2 activity in vitro — no more, no less.
Extrapolating the results to evaluate clinical eﬀects is too much of a leap.
There are in vivo infection experiments that can be used to connect in vitro experiments toclinical studies. In an in vivo infection experiment158) conducted at the Pasteur Institute in France,
they employed the olfactory abnormality in hamsters as an index, along with dosage, in order todetermine the equivalent dose that would be needed in humans. It was conﬁrmed that the amountof SARS-CoV-2 virus did not change between groups administered ivermectin and the control.
However, a signiﬁcant decrease in the ratio of IL-6/IL-10 in the lung was observed in the ivermectin group. It has been suggested that ivermectin might be eﬀective on COVID-19 by acting toregulate host inﬂammatory reactions. As shown in Fig. 1, ivermectin has a macrolide structure.
Like other macrolide compounds, it is known to exhibit extremely wide diverse actions159). Regulation of the hostʼs inﬂammatory response is one of those diverse eﬀects.
In Japan, in 1994, ahead of the rest of the world, a “Research Group on Novel Action ofMacrolides” was established. It was done for the purpose of clarifying actions160) other than the
antibacterial activity of macrolide compounds, such as clarithromycin. The clinical use of several
eﬀective macrolide antibiotics for the management and treatment of patients with diﬀuse lungdisease (previously designated as refractory diseases) was established. One such disease is diﬀuse
panbronchiolitis (DPB). DPB causes an obstructive respiratory dysfunction similar to cystic ﬁ-

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83（ 83 ）brosis (CF) (which occurs frequently in Westerners) and has been observed in Japan and East
Asia. Although it is a fatal and intractable disease, the long-term administration of low-dose macrolides161) has made it possible to treat and reduced the mortality rate. In elucidating the mechanism of action of macrolides on DPB, novel actions such as chlorine ion channel regulation162)
and anti-inﬂammatory actions163,164) were conﬁrmed one after another. Following the elucidationof erythromycinʼs suppressive actions on the inﬁltration of macrophages into the endothelium,
there were studies that investigated the prevention and treatment of diabetic nephropathy, as wellas the treatment of active stage Crohnʼs disease. Several studies have also been conducted investigating the inhibitory eﬀects of clarithromycin on the production of cytokines. One such study involves the suppression of excessive inﬂammatory reactions caused by inﬂuenza and other chronic
otolaryngology diseases. Prior to this, eﬀects such as these that go beyond the antibacterial activity of the macrolide antibiotics could never have been imagined. Additionally, for example, it has
been found that erythromycin exhibits prokinetic eﬀects for gastroparesis in diabetic patients.
This was discovered to be due to the motilin-like action of a metabolite. A metabolite derivative165) (which exerted no antibacterial activity) was found to enhance motilin-like activity. Bytaking advantage of such derivative165) side eﬀects, a new treatment for constipation in patientswith severe diabetes was discovered. The biological reactions of macrolide compounds have beenshown to be extremely diverse. Even though some have been elucidated, it is diﬃcult to estimate
how many other actions may have not yet been elucidated.
Although clinical trial results have been and continue to be accumulated showing that ivermectin is eﬀective in the treatment and prevention of COVID-19, basic in vitro ﬁndings that canreasonably explain its eﬀectiveness have not yet been obtained. It is considered that a wide variety of biological activities exhibited by macrolide compounds, such as the above-mentioned actions, at multiple stages could possibly serve to exert an overall and more comprehensive action/eﬀect. Although it must be further elucidated by future studies, clinical eﬃcacy can be determined by investigation of any of the following parameters: (1) antiviral activity, (2) inhibition of
the relationship between the virus and the host cell, and (3) actions related to the regulation ofhost reactions. It is necessary to prove that other eﬀects are being exerted, and it seems that suchinvestigations could be suitable research topics for basic researchers, pharmacological researchers, and clinical researchers to collaborate and elucidate on.
When the eﬀectiveness of ivermectin for the COVID-19 pandemic is conﬁrmed with the cooperation of researchers around the world and its clinical use is achieved on a global scale, it
could prove to be of great beneﬁt to humanity. It may even turn out to be comparable to the beneﬁts achieved from the discovery of penicillin — said to be one of the greatest discoveries of thetwentieth century. Here, one more use for ivermectin, which has been described as “miracle” or“wonder”166) drug, is being added. History has demonstrated that the existence of such natural
product-derived compounds with such diverse eﬀects is exceedingly rare.

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However, in order to pass on to posterity the fact that ivermectin has become widely used tocontrol the world-shattering COVID-19 pandemic, only one simple action is required: the addition of only one word, “COVID-19”, to the 9th item (of the 11 listed) under the “Antiviral” category in the “Ivermectin: The Future” section of the Nobel Lectureʼs record167) entitled “Splendid
Gift from the Earth”.
Acknowledgements and dedication
We would like to express our deep gratitude to Professor Satoshi Iwata, President of theJapan Antibiotics Research Association, and Professor Yasuo Ono, Editor-in-Chief of the journal
The Japanese Journal of Antibiotics, for allowing us to contribute this review and encouraging us
to write it. We would like to dedicate this review to Professor Arnold L. Demain, an honorary
member of the Kitasato Institute, who passed away from COVID-19 on April 3, 2020.
Conﬂict of Interest
None to declare.

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