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Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

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In March 2020, an expert panel called the Front Line COVID-19 Critical Care Alliance (FLCCC) was created and led by Professor Paul E. Marik, with the goal of continuously reviewing the rapidly emerging basic science, translational, and clinical data in order to gain insight into and to develop a treatment protocol for COVID-19. At the same time, many centers and groups employed a multitude of novel therapeutic agents empirically, and within clinical trials, often during inappropriate time points during this now well-described multi-phase disease. Either as a result of these frequent trial design failures, or due to the lack of their insufficient anti-viral or anti-inflammatory properties, nearly all trialed agents have proven ineffective in treating COVID-19 as of November 11, 2020. Based on a recent series of negative published therapeutic study results, in particular the SOLIDARITY trial, they now virtually eliminate any treatment role for remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, convalescent plasma, tocilizumab, and monoclonal antibody therapy. Despite this growing list of failed therapeutics in COVID-19, the FLCCC recently discovered that ivermectin, an anti-parasitic medicine, has highly potent real-world, anti-viral, and anti-inflammatory properties against SARS-CoV-2 and COVID-19. This conclusion is based on the increasing numbers of study results reporting effectiveness, not only within vitro and animal models, but also in numerous randomized and observational controlled clinical trials. Repeated, large magnitude improvements in clinical outcomes have now been recorded when ivermectin is used not only as a prophylactic agent but also in mild, moderate, and even severe disease states. The review that follows of the existing evidence for ivermectin relies on “emerging” data in that, although compelling, only a minority of studies have been published in peer-reviewed publications with the majority of results compiled from manuscripts uploaded to medicine pre-print servers or posted on clinicaltrials.gov.
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Review of the Emerging Evidence Demonstrating the Efficacy
of Ivermectin in the Prophylaxis and Treatment of COVID-19
Pierre Kory, MD1*, G. Umberto Meduri, MD2†, Jose Iglesias, DO3, Joseph Varon, MD4 , Keith
Berkowitz, MD5 , Howard Kornfeld, MD6 , Eivind Vinjevoll, MD7 , Scott Mitchell, MBChB8 , Fred
Wagshul, MD9, Paul E. Marik, MD10
1 Front-Line Covid-19 Critical Care Alliance.
2 Memphis VA Medical Center - Univ. of Tennessee Health Science Center, Memphis, TN.
3 Hackensack School of Medicine, Seton Hall, NJ.
4 University of Texas Health Science Center, Houston, TX.
5 Center for Balanced Health, New York
6 Recovery Without Walls
7 Volda Hospital, Volda, Norway
8 Princess Elizabeth Hospital, Guernsey, UK
9 Lung Center of America, Dayton, Ohio
10 Eastern Virginia Medical School
* Correspondence:
Corresponding Author: Pierre Kory, MD, MPA
pkory@flccc.net
1 These authors have contributed equally to this work
Dr. Meduri’s contribution is the result of work supported with the resources and use of facilities at
the Memphis VA Medical Center. The contents of this commentary do not represent the views of
the U.S. Department of Veterans Affairs or the United States Government
Keywords
Ivermectin, COVID-19, infectious disease, pulmonary infection, respiratory failure
Manuscript Length
Number of words: 8185; lines: 790; tables: 4; figures: 7.
Abstract
In March 2020, the Front Line COVID-19 Critical Care Alliance (FLCCC) was created and led by
Professor Paul E. Marik to continuously review the rapidly emerging basic science, translational, and
clinical data to develop a treatment protocol for COVID-19. The FLCCC then recently discovered
that ivermectin, an anti-parasitic medicine, has highly potent anti-viral and anti-inflammatory
properties against COVID-19. They then identified repeated, consistent, large magnitude
improvements in clinical outcomes in multiple, large, randomized and observational controlled trials
in both prophylaxis and treatment of COVID-19. Further, data showing impacts on population wide
health outcomes have resulted from multiple, large “natural experiments” that occurred when various
Efficacy of Ivermectin in COVID-19
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2
city mayors and regional health ministries within South American countries initiated “ivermectin
distribution” campaigns to their citizen populations in the hopes the drug would prove effective. The
tight, reproducible, temporally associated decreases in case counts and case fatality rates in each of
those regions compared to nearby regions without such campaigns, suggest that ivermectin may
prove to be a global solution to the pandemic. This was further evidenced by the recent incorporation
of ivermectin as a prophylaxis and treatment agent for COVID-19 in the national treatment
guidelines of Belize, Macedonia, and the state of Uttar Pradesh in Northern India, populated by 210
million people. To our knowledge, the current review is the earliest to compile sufficient clinical data
to demonstrate the strong signal of therapeutic efficacy as it is based on numerous clinical trials in
multiple disease phases. One limitation is that half the controlled trials have been published in peer-
reviewed publications, with the remainder taken from manuscripts uploaded to medicine pre-print
servers. Although it is now standard practice for trials data from pre-print servers to immediately
influence therapeutic practices during the pandemic, given the controversial therapeutics adopted as a
result of this practice, the FLCCC argues that it is imperative that our major national and
international health care agencies devote the necessary resources to more quickly validate these
studies and confirm the major, positive epidemiological impacts that have been recorded when
ivermectin is widely distributed among populations with a high incidence of COVID-19 infections.
Introduction
In March 2020, an expert panel called the Front Line COVID-19 Critical Care Alliance (FLCCC)
1
was created and led by Professor Paul E. Marik.
1
The group of expert critical care physicians and
2
thought leaders immediately began continuously reviewing the rapidly emerging basic science,
3
translational, and clinical data in COVID-19 which then led to the early creation of a treatment
4
protocol for hospitalized patients based on the core therapeutic interventions of methylprednisolone,
5
ascorbic acid, thiamine and heparin (MATH+), with the “+” referring to multiple, optional adjunctive
6
treatments. The MATH+ protocol was based on the collective expertise of the group in both the
7
research and treatment of multiple other severe infections causing lung injury.
8
Two manuscripts reviewing different aspects of both the scientific rationale and evolving
9
published clinical evidence in support of the MATH+ protocol were published in major medical
10
journals at two different time points in the pandemic (Kory et al., 2020;Marik et al., 2020). The most
11
recent paper reported a 6.1% hospital mortality rate in COVID-19 patients measured in the two U.S
12
hospitals that systematically adopted the MATH+ protocol (Kory et al., 2020). This was a markedly
13
decreased mortality rate compared to the 23.0% hospital mortality rate calculated from a review of 45
14
studies including over 230,000 patients (unpublished data; available on request).
15
Although the adoption of MATH+ has been considerable, it largely occurred only after the
16
treatment efficacy of the majority of the protocol components (corticosteroids, ascorbic acid, heparin,
17
statins, Vitamin D, melatonin) were either validated in subsequent randomized controlled trials or
18
more strongly supported with large observational data sets in COVID-19 (Entrenas Castillo et al.,
19
2020;Horby et al., 2020;Jehi et al., 2020;Nadkarni et al., 2020;Rodriguez-Nava et al., 2020;Zhang et
20
al., 2020a;Zhang et al., 2020b). Despite the plethora of supportive evidence, the MATH+ protocol for
21
hospitalized patients has not yet become widespread. Further, the world is in a worsening crisis with
22
the potential of again overwhelming hospitals and ICU’s. As of December 31st, 2020, the number of
23
deaths attributed to COVID-19 in the United States reached 351,695 with over 7.9 million active
24
1
https://www.flccc.net
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3
cases, the highest number to date.
2
Multiple European countries have now begun to impose new
25
rounds of restrictions and lockdowns.
3
26
Further compounding these alarming developments was a wave of recently published results
27
from therapeutic trials done on medicines thought effective for COVID-19 which found a lack of
28
impact on mortality with use of remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, con-
29
valescent plasma, tocilizumab, and mono-clonal antibody therapy (Agarwal et al., 2020;Consortium,
30
2020;Hermine et al., 2020;Salvarani et al., 2020).
4
One year into the pandemic, the only therapy
31
considered “proven” as a life-saving treatment in COVID-19 is the use of corticosteroids in patients
32
with moderate to severe illness (Horby et al., 2020). Similarly, most concerning is the fact that little
33
has proven effective to prevent disease progression to prevent hospitalization.
34
Fortunately, it now appears that ivermectin, a widely used anti-parasitic medicine with known
35
anti-viral and anti-inflammatory properties is proving a highly potent and multi-phase effective
36
treatment against COVID-19. Although growing numbers of the studies supporting this conclusion
37
have passed through peer review, approximately half of the remaining trials data are from manuscripts
38
uploaded to medical pre-print servers, a now standard practice for both rapid dissemination and
39
adoption of new therapeutics throughout the pandemic. The FLCCC expert panel, in their prolonged
40
and continued commitment to reviewing the emerging medical evidence base, and considering the
41
impact of the recent surge, has now reached a consensus in recommending that ivermectin for both
42
prophylaxis and treatment of COVID-19 should be systematically and globally adopted.
43
The FLCCC recommendation is based on the following set of conclusions derived from the existing
44
data, which will be comprehensively reviewed below:
45
1) Since 2012, multiple in vitro studies have demonstrated that Ivermectin inhibits the
46
replication of many viruses, including influenza, Zika, Dengue and others (Mastrangelo et al.,
47
2012;Wagstaff et al., 2012;Tay et al., 2013;Götz et al., 2016;Varghese et al., 2016;Atkinson et
48
al., 2018;Lv et al., 2018;King et al., 2020;Yang et al., 2020).
49
2) Ivermectin inhibits SARS-CoV-2 replication and binding to host tissue via several observed
50
and proposed mechanisms (Caly et al., 2020a).
51
3) Ivermectin has potent anti-inflammatory properties with in vitro data demonstrating profound
52
inhibition of both cytokine production and transcription of nuclear factor-κB (NF-κB), the
53
most potent mediator of inflammation (Zhang et al., 2008;Ci et al., 2009;Zhang et al., 2009).
54
4) Ivermectin significantly diminishes viral load and protects against organ damage in multiple
55
animal models when infected with SARS-CoV-2 or similar coronaviruses (Arevalo et al.,
56
2020;de Melo et al., 2020).
57
5) Ivermectin prevents transmission and development of COVID-19 disease in those exposed to
58
infected patients (Behera et al., 2020;Bernigaud et al., 2020;Carvallo et al., 2020b;Elgazzar et
59
al., 2020;Hellwig and Maia, 2020;Shouman, 2020).
60
6) Ivermectin hastens recovery and prevents deterioration in patients with mild to moderate
61
disease treated early after symptoms (Carvallo et al., 2020a;Elgazzar et al., 2020;Gorial et al.,
62
2020;Khan et al., 2020;Mahmud, 2020;Morgenstern et al., 2020;Robin et al., 2020).
63
7) Ivermectin hastens recovery and avoidance of ICU admission and death in hospitalized
64
patients (Elgazzar et al., 2020;Hashim et al., 2020;Khan et al., 2020;Niaee et al.,
65
2020;Portmann-Baracco et al., 2020;Rajter et al., 2020;Spoorthi V, 2020).
66
2
https://www.worldometers.info/coronavirus/country/us/
3
https://www.npr.org/sections/coronavirus-live-updates/2020/12/15/946644132/some-european-countries-batten-
down-for-the-holidays-with-new-coronavirus-lockdo
4
https://www.lilly.com/news/stories/statement-activ3-clinical-trial-nih-covid19
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8) Ivermectin reduces mortality in critically ill patients with COVID-19 (Elgazzar et al.,
67
2020;Hashim et al., 2020;Rajter et al., 2020).
68
9) Ivermectin leads to striking reductions in case-fatality rates in regions with widespread use
69
(Chamie, 2020).
5
70
10) The safety, availability, and cost of ivermectin is nearly unparalleled given its near nil drug
71
interactions along with only mild and rare side effects observed in almost 40 years of use and
72
billions of doses administered (Kircik et al., 2016).
73
11) The World Health Organization has long included ivermectin on its “List of Essential
74
Medicines”.
6
75
Following is a comprehensive review of the available efficacy data as of December 12, 2020, taken
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from in vitro, animal, clinical, and real-world studies all showing the above impacts of ivermectin in
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COVID-19.
78
History of ivermectin
In 1975, Professor Satoshi Omura at the Kitsato institute in Japan isolated an
79
unusual Streptomyces bacteria from the soil near a golf course along the south east coast of Honshu,
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Japan. Omura, along with William Campbell, found that the bacterial culture could cure mice
81
infected with the roundworm Heligmosomoides polygyrus. Campbell isolated the active compounds
82
from the bacterial culture, naming them "avermectins" and the bacterium Streptomyces avermitilis for
83
the compounds' ability to clear mice of worms (Crump and Omura, 2011). Despite decades of
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searching around the world, the Japanese microorganism remains the only source of avermectin ever
85
found. Ivermectin, a derivative of avermectin, then proved revolutionary. Originally introduced as a
86
veterinary drug, it soon after made historic impacts in human health, improving the nutrition, general
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health and well-being of billions of people worldwide ever since it was first used to treat
88
Onchocerciasis (river blindness) in humans in 1988. It proved ideal in many ways, given that it was
89
highly effective, broad-spectrum, safe, well tolerated and could be easily administered (Crump and
90
Omura, 2011). Although it was used to treat a variety of internal nematode infections, it was most
91
known as the essential mainstay of two global disease elimination campaigns that has nearly
92
eliminated the world of two of its most disfiguring and devastating diseases. The unprecedented
93
partnership between Merck & Co. Inc., and the Kitasato Institute combined with the aid of
94
international health care organizations has been recognized by many experts as one of the greatest
95
medical accomplishments of the 20th century. One example was the decision by Merck & Co to
96
donate ivermectin doses to support the Meztican Donation Program which then provided over 570
97
million treatments in its first 20 years alone (Tambo et al.). Ivermectins’ impacts in controlling
98
Onchocerciasis and Lymphatic filariasis, diseases which blighted the lives of billions of the poor and
99
disadvantaged throughout the tropics, is why its discoverers were awarded the Nobel Prize in
100
Medicine in 2015 and the reason for its inclusion on the WHO’s “List of Essential Medicines.”
101
Further, it has also been used to successfully overcome several other human diseases and new uses
102
for it are continually being found (Crump and Omura, 2011).
103
104
Pre-Clinical Studies of Ivermectin’s activity against SARS-CoV-2
5
https://trialsitenews.com/an-old-drug-tackles-new-tricks-ivermectin-treatment-in-three-brazilian-towns/
6
https://www.who.int/publications/i/item/WHOMVPEMPIAU201907
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Since 2012, a growing number of cellular studies have demonstrated that ivermectin has anti-viral
105
properties against an increasing number of RNA viruses, including influenza, Zika, HIV, Dengue,
106
and most importantly, SARS-CoV-2 (Mastrangelo et al., 2012;Wagstaff et al., 2012;Tay et al.,
107
2013;Götz et al., 2016;Varghese et al., 2016;Atkinson et al., 2018;Lv et al., 2018;King et al.,
108
2020;Yang et al., 2020). Insights into the mechanisms of action by which ivermectin both interferes
109
with the entrance and replication of SARS-CoV-2 within human cells are mounting. Caly et al first
110
reported that ivermectin significantly inhibits SARS-CoV-2 replication in a cell culture model,
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observing the near absence of all viral material 48h after exposure to ivermectin (Caly et al., 2020b).
112
However, some questioned whether this observation is generalizable clinically given the inability to
113
achieve similar tissue concentrations employed in their experimental model using standard or even
114
massive doses of ivermectin (Bray et al., 2020;Schmith et al., 2020). It should be noted that the
115
concentrations required for effect in cell culture models bear little resemblance to human physiology
116
given the absence of an active immune system working synergistically with a therapeutic agent such
117
as ivermectin. Further, prolonged durations of exposure to a drug likely would require a fraction of
118
the dosing in short term cell model exposure. Further, multiple co-existing or alternate mechanisms
119
of action likely explain the clinical effects observed, such as the competitive binding of ivermectin
120
with the host receptor-binding region of SARS-CoV-2 spike protein, as proposed in six molecular
121
modeling studies (Dayer, 2020;Hussien and Abdelaziz, 2020;Lehrer and Rheinstein, 2020;Maurya,
122
2020;Nallusamy et al., 2020;Suravajhala et al., 2020). In four of the studies, ivermectin was
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identified as having the highest or among the highest of binding affinities to spike protein S1 binding
124
domains of SARS-CoV-2 among hundreds of molecules collectively examined, with ivermectin not
125
being the particular focus of study in four of these studies (Scheim, 2020). This is the same
126
mechanism by which viral antibodies, in particular, those generated by the Pfizer and Moderna
127
vaccines, contain the SARS-CoV-2 virus. The high binding activity of ivermectin to the SARS-CoV-
128
2 spike protein could limit binding to either the ACE-2 receptor or sialic acid receptors, respectively
129
either preventing cellular entry of the virus or preventing hemagglutination, a recently proposed
130
pathologic mechanism in COVID-19 (Dasgupta J, 2020;Dayer, 2020;Lehrer and Rheinstein,
131
2020;Maurya, 2020;Scheim, 2020). Ivermectin has also been shown to bind to or interfere with
132
multiple essential structural and non-structural proteins required by the virus in order to replicate
133
(Lehrer and Rheinstein, 2020;Sen Gupta et al., 2020). Finally, ivermectin also binds to the SARS-
134
CoV-2 RNA-dependent RNA polymerase (RdRp), thereby inhibiting viral replication (Swargiary,
135
2020).
136
Arevalo et al investigated in a murine model infected with a type 2 family RNA coronavirus
137
similar to SARS-CoV-2, (mouse hepatitis virus), the response to 500 mcg/kg of ivermectin vs.
138
placebo (Arevalo et al., 2020). The study included 40 infected mice, with 20 treated with ivermectin,
139
20 with phosphate buffered saline, and then 16 uninfected control mice that were also given
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phosphate buffered saline. At day 5, all the mice were euthanized to obtain tissues for examination
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and viral load assessment. The 20 non-ivermectin treated infected mice all showed severe
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hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration
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associated with a high hepatic viral load (52,158 AU), while in the ivermectin treated mice a much
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lower viral load was measured (23,192 AU; p<0.05), with only few livers in the ivermectin treated
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mice showing histopathological damage such that the differences between the livers from the
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uninfected control mice were not statistically significant.
147
Dias De Melo and colleagues recently posted the results of a study they did with golden
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hamsters that were intranasally inoculated with SARS-CoV-2 virus, and at the time of the infection,
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the animals also received a single subcutaneous injection of ivermectin at a dose of 0.4mg/kg on day
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1 (de Melo et al., 2020). Control animals received only the physiologic solution. They found the
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following among the ivermectin treated hamsters; a dramatic reduction in anosmia (33.3% vs 83.3%,
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p=.03) which was also sex-dependent in that the male hamsters exhibited a reduction in clinical score
153
Efficacy of Ivermectin in COVID-19
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6
while the treated female hamsters failed to show any sign of anosmia. They also found significant
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reductions in cytokine concentrations in the nasal turbinate’s and lungs of the treated animals despite
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the lack of apparent differences in viral titers.
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Despite these mounting insights into the existing and potential mechanisms of action of
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ivermectin both as a prophylactic and treatment agent, it must be emphasized that significant research
158
gaps remain and that many further in vitro and animal studies should be undertaken to better define
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not only these mechanisms but also to further support ivermectin’s role as a prophylactic agent,
160
especially in terms of the optimal dose and frequency required.
161
Pre-Clinical studies of ivermectin’s anti-inflammatory properties
Given that little viral replication occurs in the later phases of COVID-19, nor can virus be cultured,
162
and only in a minority of autopsies can viral cytopathic changes be found (Perera et al., 2020;Polak et
163
al., 2020;Young et al., 2020), the most likely pathophysiologic mechanism is that identified by Li et
164
al. where they showed that the non-viable RNA fragments of SARS-CoV-2 leads to a high mortality
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and morbidity in COVID-19 via the provocation of an overwhelming and injurious inflammatory
166
response (Li et al., 2013). Based on these insights and the clinical benefits of ivermectin in late phase
167
disease to be reviewed below, it appears that the increasingly well described in vitro properties of
168
ivermectin as an inhibitor of inflammation are far more clinically potent than previously recognized.
169
The growing list of studies demonstrating the anti-inflammatory properties of ivermectin include its
170
ability to; inhibit cytokine production after lipopolysaccharide exposure, downregulate transcription
171
of NF-kB, and limit the production of both nitric oxide and prostaglandin E2 (Zhang et al., 2008;Ci et
172
al., 2009;Zhang et al., 2009).
173
Exposure prophylaxis studies of ivermectin’s ability to prevent transmission
of COVID-19
Data is also now available showing large and statistically significant decreases in the transmission of
174
COVID-19 among human subjects based on data from three randomized controlled trials (RCT) and
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five observational controlled trials (OCT) with four of the eight (two of them RCT’s) published in
176
peer-reviewed journals (Behera et al., 2020;Bernigaud et al., 2020;Carvallo et al., 2020b;Chala,
177
2020;Elgazzar et al., 2020;Hellwig and Maia, 2020;Shouman, 2020).
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Elgazzar and colleagues at Benha University in Egypt randomized 200 health care and
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households contacts of COVID-19 patients where the intervention group consisted of 100 patients
180
given a high dose of 0.4mg/kg on day 1 and a second dose on day 7 in addition to wearing personal
181
protective equipment (PPE), while the control group of 100 contacts wore PPE only (Elgazzar et al.,
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2020). They reported a large and statistically significant reduction in contacts testing positive by RT-
183
PCR when treated with ivermectin vs. controls, 2% vs 10%, p<.05.
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Shouman conducted an RCT at Zagazig University in Egypt, including 340 (228 treated, 112
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control) family members of patients positive for SARS-CoV-2 via PCR (Shouman, 2020).
186
Ivermectin, (approximately 0.25mg/kg) was administered twice, on the day of the positive test and 72
187
hours later. After a two-week follow up, a large and statistically significant decrease in COVID-19
188
symptoms among household members treated with ivermectin was found, 7.4% vs. 58.4%, p<.001.
189
Recently Alam et al from Bangladesh performed a prospective observational study of 118
190
patients that were evenly split into those that volunteered for either the treatment or control arms,
191
described as a persuasive approach. Although this method, along with the study being unblinded
192
likely led to confounders, the differences between the two groups were so large (6.7% vs. 73.3%, p
193
<.001) and similar to the other prophylaxis trial results that confounders alone are unlikely to explain
194
Efficacy of Ivermectin in COVID-19
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7
such a result (Alam et al., 2020). Carvallo et al also performed a prospective observational trial where
195
they gave healthy volunteers ivermectin and carrageenan daily for 28 days and matched them to
196
similarly healthy controls who did not take the medicines (Carvallo et al., 2020b). Of the 229 study
197
subjects, 131 were treated with 0.2mg of ivermectin drops taken by mouth five times per day. After
198
28 days, none of those receiving ivermectin prophylaxis group had tested positive for SARS-COV-2
199
versus 11.2% of patients in the control arm (p<.001). In a much larger follow-up observational
200
controlled trial by the same group that included 1,195 health care workers, they found that over a 3-
201
month period, there were no infections recorded among the 788 workers that took weekly ivermectin
202
prophylaxis while 58% of the 407 controls had become ill with COVID-19. This study demonstrates
203
that protection against transmission can be achieved among high-risk health care workers by taking
204
12mg once weekly (Carvallo et al., 2020b). The Carvallo IVERCAR protocol was also separately
205
tested in a prospective RCT by the Health Ministry of Tucuman, Argentina where they found that
206
among 234 health care workers, the intervention group that took 12 mg once weekly, only 3.4%
207
contracted COVID-19 vs. 21.4% of controls, p<.0001(Chala, 2020).
208
The need for weekly dosing in the Carvallo study over a 4 month period may not have been
209
necessary given that, in a recent RCT from Dhaka, Bangladesh, the intervention group (n=58) took
210
12mg only once monthly for a similar 4 month period and also reported a large and statistically
211
significant decrease in infections compared to controls, 6.9% vs. 73.3%, p<.05 (Alam et al., 2020).
212
Then, in a large retrospective observational case-control study from India, Behera et al. reported that
213
among 186 case-control pairs (n=372) of health care workers, they identified 169 participants that
214
had taken some form of prophylaxis, with 115 that had taken ivermectin prophylaxis (Behera et al.,
215
2020). After matched pair analysis, they reported that in the workers who had taken two dose
216
ivermectin prophylaxis, the odds ratio for contracting COVID-19 was markedly decreased (0.27,
217
95% CI, 0.15–0.51). Notably, one dose prophylaxis was not found to be protective in this study.
218
Based on both their study finding and the Egyptian prophylaxis study, the All-India Institute of
219
Medical Sciences instituted a prophylaxis protocol for their health care workers where they now take
220
two 0.3mg/kg doses of ivermectin 72 hours apart and repeat the dose monthly.
221
Data which further illuminates the protective role of ivermectin against COVID-19 comes
222
from a study of nursing home residents in France which reported that in a facility that suffered a
223
scabies outbreak where all 69 residents and 52 staff were treated with ivermectin (Behera et al.,
224
2020), they found that during the time period surrounding this event, 7/69 residents fell ill with
225
COVID-19 (10.1%). In this group with an average age of 90 years, only one resident required oxygen
226
support and no resident died. In a matched control group of residents from surrounding facilities,
227
they found 22.6% of residents fell ill and 4.9% died.
228
Likely the most definitive evidence supporting the efficacy of ivermectin as a prophylaxis
229
agent was published recently in the International Journal of Anti-Microbial agents where a group of
230
researchers analyzed data using the prophylactic chemotherapy databank administered by the WHO
231
along with case counts obtained by Worldometers, a public data aggregation site used by among
232
others, the Johns Hopkins University (Hellwig and Maia, 2020). When they compared the data from
233
countries with active ivermectin mass drug administration programs for the prevention of parasite
234
infections, they discovered that the COVID-19 case counts were significantly lower in the countries
235
with recently active programs, to a high degree of statistical significance, p<.001.
236
Figure 1 below presents a meta-analysis performed by the study authors of the controlled
237
ivermectin prophylaxis trials in COVID-19.
238
239
240
241
242
Efficacy of Ivermectin in COVID-19
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8
Figure 1. Meta-analysis of ivermectin prophylaxis trials in COVID-19
243
Figure 1 legend: OBS: Observational study, RCT: Randomized Controlled Trial Symbols: Squares: indicate treatment
effect of an individual study. Large diamond: reflect summary of study design immediately above. Small diamond: sum
effect of all trial designs. Size of each symbol correlates with the size of the confidence interval around the point estimate
of treatment effect with larger sizes indicating a more precise confidence interval.
Further data supporting a role for ivermectin in decreasing transmission rates can be found
244
from South American countries where, in retrospect, large “natural experiments” appear to have
245
occurred. For instance, beginning as early as May, various regional health ministries and govern-
246
mental authorities within Peru, Brazil, and Paraguay initiated “ivermectin distribution” campaigns to
247
their citizen populations (Chamie, 2020). In one such example from Brazil, the cities of Itajai,
248
Macapa, and Natal distributed massive amounts of ivermectin doses to their city’s population, where,
249
in the case of Natal, 1 million doses were distributed.
7
The distribution campaign of Itajai began in
250
mid-July, and in Natal they began on June 30th , and in Macapa, the capital city of Amapa and others
251
nearby incorporated ivermectin into their treatment protocols in late May after they were particularly
252
hard hit in April. The data in Table 1 below was obtained from the official Brazilian government site
253
and the national press consortium and show large decreases in case counts in the three cities soon
254
after distribution began compared to their neighboring cities without such campaigns.
255
The decreases in case counts among the three Brazilian cities shown in Table 1 was also
256
associated with reduced mortality rates as seen in Table 2 below.
257
7
https://trialsitenews.com/an-old-drug-tackles-new-tricks-ivermectin-treatment-in-three-brazilian-towns/
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
9
Table 1. Comparison of case count decreases among Brazilian cities with and without ivermectin
distribution campaigns (bolded cities distributed ivermectin, neighboring regional city below did
not)
REGION
NEW CASES
JULY
POPULATION
2020 (1000)
% DECLINE IN NEW
CASES BETWEEN JUNE
AND AUGUST 2020
South
Itajaí
2854
223
53%
Chapecó
1754
224
 20 %
North
Macapá
2481
503
70%
Ananindeua
1521
535
 30 %
North East
Natal
7554
890
82%
João Pessoa
7963
817
 43 %
Table 2. Change in death rates among neighboring regions in Brazil (bolded regions contained a
major city that distributed Ivermectin to its citizens, the other regions did not)
REGION
STATE
% CHANGE IN AVERAGE DEATHS/
WEEK COMPARED TO 2 WEEKS PRIOR
South
Santa Catarina
36 %
PARANÁ
– 3%
Rio Grande do Sul
– 5%
North
Amapá
75 %
AMAZONAS
42%
Pará
+ 13%
North East
Rio Grande do Norte
65 %
CEARÁ
+ 62%
Paraíba
30%
Clinical studies on the efficacy of ivermectin in treating mildly ill
outpatients
Currently, seven trials which include a total of over 3,000 patients with mild outpatient illness have
258
been completed, a set comprised of 7 RCT’s and four case series (Babalola et al.;Cadegiani et al.,
259
2020;Carvallo et al., 2020a;Chaccour et al., 2020;Chowdhury et al., 2020;Espitia-Hernandez et al.,
260
2020;Gorial et al., 2020;Hashim et al., 2020;Khan et al., 2020;Mahmud, 2020;Podder et al.,
261
2020;Ravikirti et al., 2021).
262
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
10
The largest, a double blinded RCT by Mahmud et al. was conducted in Dhaka, Bangladesh
263
and targeted 400 patients with 363 patients completing the study (Mahmud, 2020). In this study, as in
264
many other of the clinical studies to be reviewed, either a tetracycline (doxycycline) or macrolide
265
antibiotic (azithromycin) was included as part of the treatment. The importance of including
266
antibiotics such as doxycycline or azithromycin is unclear, however, both tetracycline and macrolide
267
antibiotics have recognized anti-inflammatory, immunomodulatory, and even antiviral effects (58-
268
61). Although the posted data from this study does not specify the amount of mildly ill outpatients vs.
269
hospitalized patients treated, important clinical outcomes were profoundly impacted, with increased
270
rates of early improvement (60.7% vs. 44.4% p<.03) and decreased rates of clinical deterioration
271
(8.7% vs 17.8%, p<.02). Given that mildly ill outpatients mainly comprised the study cohort, only
272
two deaths were observed (both in the control group).
273
Ravikirti performed a double-blind RCT of 115 patients, ang although the primary outcome
274
of PCR positivity on Day 6 was no different, the secondary outcome of mortality was 0%vs. 6.9%,
275
p=.019 (Ravikirti et al., 2021). Babalola in Nigeria also performed a double blind-RCT of 62
276
patients, and, in contrast to Ravikirti, they found a significant difference in viral clearance between
277
both the low and high dose treatment groups and controls in a dose dependent fashion, p=.006
278
(Babalola et al.).
279
Another RCT by Hashim et al. in Baghdad, Iraq included 140 patients equally divided; the
280
control group received standard care, the treated group included a combination of both outpatient and
281
hospitalized patients (Hashim et al., 2020). In the 96 patients with mild-to-moderate outpatient
282
illness, they treated 48 patients with a combination of ivermectin/doxycycline and standard of care
283
and compared outcomes to the 48 patients treated with standard of care alone. The standard of care in
284
this trial included many elements of the MATH+ protocol, such as dexamethasone 6mg/day or
285
methylprednisolone 40mg twice per day if needed, Vitamin C 1000mg twice/day, Zinc 75–
286
125mg/day, Vitamin D3 5000 IU/day, azithromycin 250mg/day for 5 days, and acetaminophen
287
500mg as needed. Although no patients in either group progressed or died, the time to recovery was
288
significantly shorter in the ivermectin treated group (6.3 days vs 13.7 days, p<.0001).
289
Chaccour et al conducted a small, double-blinded RCT in Spain where they randomized 24
290
patients to ivermectin vs placebo and although they found no difference in PCR positivity at day 7,
291
they did find statistically significant decreases in viral loads, patient days of anosmia (76 vs 158,
292
p<.05), and patient days with cough (68 vs 98, p<.05) (Chaccour et al., 2020).
293
Another RCT of ivermectin treatment in 116 outpatients was performed by Chowdhury et al.
294
in Bangladesh where they compared a group of 60 patients treated with the combination of
295
ivermectin/doxycycline to a group of 60 patients treated with hydroxychloroquine/doxycycline with a
296
primary outcome of time to negative PCR (Chowdhury et al., 2020). Although they found no
297
difference in this outcome, in the treatment group, the time to symptomatic recovery approached
298
statistical significance (5.9 days vs. 7.0 days, p=.07). In another smaller RCT of 62 patients by
299
Podder et al., they also found a shorter time to symptomatic recovery that approached statistical
300
significance (10.1 days vs 11.5 days, p>.05, 95% CI, 0.86 3.67) (Podder et al., 2020).
301
A medical group in the Dominican Republic reported a case series of 2,688 consecutive
302
symptomatic outpatients seeking treatment in the emergency room, the majority of whom were
303
diagnosed using a clinical algorithm. The patients were treated with high dose ivermectin of
304
0.4mg/kg for one dose along with five days of azithromycin. Only 16 of the 2,688 patients (0.59%)
305
required subsequent hospitalization with one death recorded (Morgenstern et al., 2020).
306
In another case series of 100 patients in Bangladesh, all treated with a combination of
307
0.2mg/kg ivermectin and doxycycline, they found that no patient required hospitalization nor died,
308
and all patients’ symptoms improved within 72 hours (Robin et al., 2020).
309
A case series from Argentina reported on a combination protocol which used ivermectin,
310
aspirin, dexamethasone and enoxaparin. In the 135 mild illness patients, all survived (Carvallo et al.,
311
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
11
2020a). Similarly, a case series from Mexico of 28 consecutively treated patients with ivermectin, all
312
were reported to have recovered with an average time to full recovery of only 3.6 days (Espitia-
313
Hernandez et al., 2020).
314
315
Clinical studies of the efficacy of ivermectin in hospitalized patients
Studies of ivermectin amongst more severely ill hospitalized patients include 6 RCT’s, 5 OCTs, and a
316
database analysis study (Ahmed et al., 2020;Budhiraja et al., 2020;Chachar et al., 2020;Elgazzar et
317
al., 2020;Gorial et al., 2020;Hashim et al., 2020;Khan et al., 2020;Niaee et al., 2020;Portmann-
318
Baracco et al., 2020;Rajter et al., 2020;Soto-Becerra et al., 2020;Spoorthi V, 2020).
319
The largest RCT in hospitalized patients was performed concurrent with the prophylaxis
320
study reviewed above by Elgazzar et al (Elgazzar et al., 2020). 400 patients were randomized
321
amongst 4 treatment groups of 100 patients each. Groups 1 and 2 included mild/moderate illness
322
patients only, with Group 1 treated with one dose 0.4mg/kg ivermectin plus standard of care (SOC)
323
and Group 2 received hydroxychloroquine (HCQ) 400mg twice on day 1 then 200mg twice daily for
324
5 days plus standard of care. There was a statistically significant lower rate of progression in the
325
ivermectin treated group (1% vs. 22%, p<.001) with no deaths and 4 deaths respectively. Groups 3
326
and 4 all included only severely ill patients, with group 3 again treated with single dose of 0.4mg/kg
327
plus SOC while Group 4 received HCQ plus SOC. In this severely ill subgroup, the differences in
328
outcomes were even larger, with lower rates of progression 4% vs. 30%, and mortality 2% vs 20%
329
(p<.001).
330
The one largely outpatient RCT done by Hashim reviewed above also included 22
331
hospitalized patients in each group. In the ivermectin/doxycycline treated group, there were 11
332
severely ill patients and 11 critically ill patients while in the standard care group, only severely ill
333
patients (n=22) were included due to their ethical concerns of including critically ill patients in the
334
control group (45). This decision led to a marked imbalance in the severity of illness between these
335
hospitalized patient groups. However, despite the mismatched severity of illness between groups and
336
the small number of patients included, beneficial differences in outcomes were seen, but not all
337
reached statistical significance. For instance, there was a large reduction in the rate of progression of
338
illness (9% vs. 31.8%, p = 0.15) and, most importantly, there was a large difference in mortality
339
amongst the severely ill groups which reached a borderline statistical significance, (0% vs 27.3%, p
340
=.052). Another important finding was the surprisingly low mortality rate of 18% found among the
341
subset of critically ill patients, all of whom were treated with ivermectin.
342
A recent RCT from Iran found a dramatic reduction in mortality with ivermectin use (Niaee et
343
al., 2020). Among multiple ivermectin treatment arms (different ivermectin dosing strategies were
344
used in the intervention arms), the average mortality was reported as 3.3% while the average
345
mortality within the standard care and placebo arms was 18.8%, with an OR of 0.18 (95% CI 0.06-
346
0.55, p<.05).
347
Spoorthi and Sasanak performed a prospective RCT of 100 hospitalized patients whereby
348
they treated 50 with ivermectin and doxycycline while the 50 controls were given a placebo
349
consisting of Vitamin B6 (Spoorthi V, 2020). Although no deaths were reported in either group, the
350
ivermectin treatment group had a shorter hospital LOS 3.7 days vs 4.7 days, p=.03, and a shorter time
351
to complete resolution of symptoms, 6.7 days vs 7.9 days, p=.01.
352
The largest OCT (n=280) in hospitalized patients was done by Rajter et al. at Broward Health
353
Hospitals in Florida and was recently published in the major medical journal Chest (43). They
354
performed a retrospective OCT with a propensity matched design on 280 consecutive treated patients
355
and compared those treated with ivermectin to those without. 173 patients were treated with
356
ivermectin (160 received a single dose, 13 received a 2nd dose at day 7) while 107 were not (Rajter et
357
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
12
al., 2020). In both unmatched and propensity matched cohort comparisons, similar, large, and statisti-
358
cally significant lower mortality was found amongst ivermectin treated patients (15.0% vs. 25.2%, p
359
=.03). Further, in the subgroup of patients with severe pulmonary involvement, mortality was
360
profoundly reduced when treated with ivermectin (38.8% vs. 80.7%, p =.001).
361
Another large OCT in Bangladesh compared 115 pts treated with ivermectin to a standard
362
care cohort consisting of 133 patients (Khan et al., 2020). Despite a significantly higher proportion of
363
patients in the ivermectin group being male (i.e., with well-described, lower survival rates in
364
COVID), the groups were otherwise well matched, yet the mortality decrease was statistically
365
significant (0.9% vs. 6.8%, p<.05). The largest OCT is a study from Brazil which included almost
366
1,500 patients (Portmann-Baracco et al., 2020). Although the primary data was not provided, they
367
reported that in 704 hospitalized patients treated with a single dose of 0.15mg/kg ivermectin
368
compared to 704 controls, overall mortality was reduced (1.4% vs. 8.5%, HR 0.2, 95% CI 0.12-0.37,
369
p<.0001). Similarly, in the patients on mechanical ventilation, mortality was also reduced (1.3% vs.
370
7.3%). A small study from Baghdad, Iraq compared 16 ivermectin treated patients to 71 controls
371
(Gorial et al., 2020). This study also reported a significant reduction in length of hospital stay (7.6
372
days vs. 13.2 days, p<.001) in the ivermectin group. In a study reporting on the first 1000 patients
373
treated in a hospital in India, they found that in the 34 patients treated with ivermectin alone, all
374
recovered and were discharged, while in the over 900 patients treated with other agents, there was an
375
overall mortality of 11.1% (Budhiraja et al., 2020).
376
One retrospective analysis of a database of hospitalized patients compared responses in
377
patients receiving ivermectin, azithromycin, hydroxychloroquine or combinations of these medicines.
378
In this study, no benefit for ivermectin was found, however the treatment groups in this analysis all
379
included a number of patients who died on day 2, while in the control groups no early deaths
380
occurred, thus the comparison appears limited (Soto-Becerra et al., 2020).
381
Meta-analyses of the above controlled treatment trials were performed by the study authors
382
focused on the two important clinical outcomes: time to clinical recovery and mortality (Figures 2
383
and 3). The consistent and reproducible signals leading to large overall statistically significant
384
benefits from within both study designs is remarkable, especially given that in several of the studies
385
treatment was initiated late in the disease course.
386
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
13
Figure 2. Meta-analysis of the outcome of time to clinical recovery from randomized
controlled trials of ivermectin treatment in COVID-19
Figure 2 legend: Multi: multiple day dosing regimen. Single: single dose regimen Symbols: Squares: indicate treatment
387
effect of an individual study. Large diamond: reflect summary of study design immediately above. Small diamond: sum
388
effect of all trial designs. Size of each symbol correlates with the size of the confidence interval around the point estimate
389
of treatment effect with larger sizes indicating a more precise confidence interval.
390
Figure 3. Meta-analysis of the outcome of mortality from controlled trials of ivermectin
treatment in COVID-19
391
392
Figure 3 legend: OBS: Observational study, RCT: Randomized Controlled Trial. Symbols: Squares: indicate treatment
393
effect of an individual study. Large diamond: reflect summary of study design immediately above. Small diamond: sum
394
effect of all trial designs. Size of each symbol correlates with the size of the confidence interval around the point estimate
395
of treatment effect with larger sizes indicating a more precise confidence interval.
396
397
Details of the prophylaxis, early, and late treatment trials of ivermectin in COVID-19 can be found in
398
Table 3 below.
399
400
401
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
14
Table 3. Clinical studies assessing the efficacy of ivermectin in the prophylaxis and treatment
of COVID-19
Prophylaxis Trials
AUTHOR, COUNTRY, SOURCE
STUDY DESIGN,
SIZE
STUDY
SUBJECTS
IVERMECTIN
DOSE
DOSE
FREQUENCY
CLINICAL
OUTCOMES
REPORTED
Shouman W, Egypt
www.clinicaltrials.gov
NCT04422561
RCT
N=340
Household
members of pts
with +COVID-
19 PCR test
4060kg: 15mg
6080kg: 18mg
> 80kg: 24mg
Two doses, 72
hours apart
7.4% vs. 58.4%
developed COVID-19
symptoms, p<.001
Elgazzar A, Egypt
ResearchSquare
doi.org/10.21203/rs.3.rs-100956/v1
RCT
N=200
Health care and
Household
contacts of pts
with +COVID-
19 PCR test
0.4mg/kg
Two doses, Day
1 and Day 7
2% vs. 10% tested
positive for COVID-
19 p<.05
Chala R. Argentina
NCT04701710
Clinicaltrials.gov
RCT
N=234
Health Care
Workers
12mg
Every 7 days
3.4% vs. 21.4%,
p=.0001.
Carvallo H, Argentina
Journal of Biochemical Research and
Investigation
doi.org/10.31546/2633-8653.1007
OCT
N=229
Healthy patients
negative for
COVID-19 PCR
0.2mg drops
1 drop five times
a day x 28 days
0.0% vs. 11.2%
contracted COVID-19
p<.001
Alam MT. Bangladesh
European J Med Hlth Sciences
10.24018/ejmed.2020.2.6.599
OCT
N=118
Health Care
Workers
12mg
Monthly
6.9% vs. 73.3%, p<.05
Carvallo H. Argentina
Journal of Biochemical Research and
Investigation
doi.org/10.31546/2633-8653.1007
OCT
N=1,195
Health Care
Workers
12 mg
Once weekly for
up to ten weeks
0.0% of the 788
workers taking
ivermectin vs. 58% of
the 407 controls
contracted COVID-19.
Behera P, India
medRxiv
doi.org/10.1101/2020.10.29.20222661
OCT
N=186 case
control pairs
Health Care
Workers
0.3 mg/kg
Day 1 and Day 4
2 doses reduced odds
of contracting
COVID-19 (OR 0.27
95% CI 0.160.53)
Bernigaud C. France
Annales de Dermatologie et de
Venereologie
doi.org/10.1016/j.annder.2020.09.231
OCT
N=69 case control
pairs
Nursing Home
Residents
0.2 mg/kg
Once
10.1% vs. 22.6%
residents contracted
COVID-19
0.0% vs 4.9%
mortality
Hellwig M. USA
J Antimicrobial Agents
doi.org/10.1016/j.ijantimicag.2020.106
248
OCT
N=52 countries
Countries with
and without
IVM
prophylaxis
programs
Unknown
Variable
Significantly lower-
case incidence of
COVID-19 in African
countries with IVM
prophylaxis programs
p<.001
Clinical Trials Outpatients
% Ivermectin vs.
% Controls
AUTHOR, COUNTRY, SOURCE
STUDY DESIGN,
SIZE
STUDY
SUBJECTS
IVERMECTIN
DOSE
DOSE
FREQUENCY
CLINICAL
OUTCOMES
REPORTED
Mahmud R, Bangladesh
www.clinicaltrials.gov
NCT0452383
DB-RCT
N=363
Outpatients and
hospitalized
12mg +
doxycycline
Once, within 3
days of PCR+
test
Early improvement
60.7% vs. 44.4%,
p<.03, deterioration
8.7% vs 17.8%, p<.02
Chowdhury A, Bangladesh
Research Square
DB-RCT
N=116
Outpatients
0.2 mg//kg +
doxycycline
Once
Recovery time 5.9 vs
9.3 days (p=.07)
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
15
doi.org/10.21203/rs.3.rs-38896/v1
Ravikirti, India
medRxiv
doi.org/10.1101/2021.01.05.21249310
DB-RCT
N=115
Mild-moderate
illness
12mg
Daily for 2 days
No diff in day 6 PCR+
0% vs 6.9% mortality,
p=.019
Babalola OE, Nigeria
medRxiv
doi.org/10.1101/2021.01.05.21249131
DB-RCT
N=62
Mild-moderate
illness
6mg and 12 mg
Every 48h x 2
weeks
Time to viral
clearance: 4.6 days
high dose vs 6.0 days
low dose vs 9.1 days
control (p=.006)
Podder CS, Bangladesh
IMC J Med Sci 2020;14(2)
RCT
N=62
Outpatients
0.2 mg/kg
Once
Recovery time 10.1 vs
11.5 days (NS),
average time 5.3 vs
6.3 (NS)
Chaccour C. Spain
Research Square
doi.org/10.21203/rs.3.rs-116547/v1
RCT
N=24
Outpatients
0.4mg/kg
Once
No diff in PCR+ Day
7, lower viral load
days 4 and 7, (p<.05),
76 vs 158 pt. days of
anosmia (p<.05), 68
vs 98 pt. days of
cough (p<.05)
Morgenstern J, Dominican Republic
medRxiv
doi.org/10.1101/2020.10.29.20222505
Case Series
N=3,099
Outpatients and
hospitalized
Outpatients:
0.4mg/kg
Hospital Patients:
0.3mg/kg
Outpatients:0.3m
g/kg x 1 dose
Inpatients:
0.3mg/kg, Days
1,2,6,7
Mortality = 0.03% in
2688 outpatients, 1%
in 300 non-ICU
hospital patients,
30.6% in 111 ICU
patients
Carvallo H, Argentina
medRxiv
doi.org/10.1101/2020.09.10.20191619
Case Series
N=167
Outpatients and
hospitalized
24mg=mild,
36mg=moderate,
48mg=severe
Days 0 and 7
All 135 with mild
illness survived, 1/32
(3.1% of hospitalized
patients died
Alam A, Bangladesh, J of Bangladesh
College Phys and Surg, 2020;38:10-15
doi.org/10.3329/jbcps.v38i0.47512
Case series
N=100
Outpatients
0.2 mg/kg/kg +
doxycycline
Once
All improved within
72 hours
Espatia-Hernandez G, Mexico
Biomedical Research
www.biomedres.info/biomedi..-proof-
of-concept-study-14435.html
Case Series
N=28
Outpatients
6mg
Days 1,2, 7, 8
All pts recovered
Average recovery time
3.6 days
Clinical Trials Hospitalized Patients
% Ivermectin vs.
% Controls
AUTHOR, COUNTRY, SOURCE
STUDY DESIGN,
SIZE
STUDY
SUBJECTS
IVERMECTIN
DOSE
DOSE
FREQUENCY
CLINICAL
OUTCOMES
REPORTED
Elgazzar A, Egypt
ResearchSquare
doi.org/10.21203/rs.3.rs-100956/v1
OL-RCT
N=400
Hospitalized
Patients
0.4 mg/kg
Once
Moderately Ill:
worsened 1% vs 22%,
p<.001. Severely ill:
worsened 4% vs 30%
mortality 2% vs 20%
both with p<.001
Niaee S. M.
Research Square
doi.org/10.21203/rs.3.rs-109670/v1
DB-RCT
N=180
Hospitalized
Patients
0.2, 0.3, 0.4 mg/kg
(3 dosing strategies)
Once vs. Days
1,3,5
Mortality 3.3% vs.
18.3%. OR 0.18, (.06-
0.55, p<.05)
Hashim H, Iraq
medRxiv
doi.org/10.1101/2020.10.26.20219345
SB-RCT
N=140
2/3 outpatients,
1/3 hospital pts
0.2 mg/kg +
doxycycline
Daily for 23
days
Recovery time 6.3 vs
13.6 days (p<.001),
0% vs 27.3%
mortality in severely
ill (p=.052)
Spoorthi S, India
AIAM, 2020; 7(10):177-182
RCT
N=100
Hospitalized
Patients
0.2mg/kg+
Doxycycline
Once
Shorter Hospital LOS,
3.7 vs. 4.7 days,
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
16
p=.03, faster
resolution of
symptoms, 6.7 vs 7.9
days, p=.01
Ahmed S. Dhaka, Bangladesh
International Journal of Infectious
Disease
doi.org/10.1016/j.ijid.2020.11.191
DB-RCT
N=72
Hospitalized
Patients
12mg
Daily for 5 days
Faster viral clearance
9.7 vs 12.7 days,
p=.02
Chachar AZK, Pakistan
Int J Sciences
doi.org/10.18483/ijSci.2378
DB-RCT
N=50
Hospitalized
Patients-Mild
12mg
Two doses Day
1, one dose Day
2
64% vs 60%
asymptomatic by Day
7
Portman-Baracco A, Brazil
Arch Bronconeumol. 2020
doi.org/10.1016/j.arbres.2020.06.011
OCT
N=1408
Hospitalized
patients
0.15 mg/kg
Once
Overall mortality
1.4% vs. 8.5%, HR
0.2, 95% CI 0.12-0.37,
p<.0001
Soto-Beccerra P, Peru
medRxiv
doi.org/10.1101/2020.10.06.20208066
OCT
N=5683,
IVM, N=563
Hospitalized
patients,
database
analysis
Unknown dose
<48hrs after
admission
Unknown
No benefits found
Rajter JC, Florida
Chest 2020
doi.org/10.1016/j.chest.2020.10.009
OCT
N=280
Hospitalized
patients
0.2 mg/kg +
azithromycin
Day 1 and Day 7
if needed
Overall mortality
15.0% vs. 25.2%,
p=.03, Severe illness
mortality 38.8% vs.
80.7%, p=.001
Khan X, Bangladesh
Arch Bronconeumol. 2020
doi.org/10.1016/j.arbres.2020.08.007
OCT
N=248
Hospitalized
patients
12 mg
Once on
admission
Mortality 0.9% vs.
6.8%, p<.05, LOS 9
vs. 15 days, p<.001
Gorial FI, Iraq
medRxiv
doi.org/10.1101/2020.07.07.20145979
OCT
N=87
Hospitalized
patients
0.2 mg/kg +
HCQ and
azithromycin
Once on
admission
LOS 7.6 vs. 13.2 days,
p<.001, 0/15 vs. 2/71
died
Budiraja S. India
medRxiv
doi.org/10.1101/2020.11.16.20232223
OCT
N=1000
IVM=34
Hospitalized
Patients
n/a
n/a
100% IVM pts
recovered
11.1% mortality in
non-IVM treated pts
Legend: DB-RCT = double-blind randomized controlled trial, HCQ = hydroxychloroquine, IVM = ivermectin, LOS = Length of stay, NS = non-
statistically significant, p>.05, OCT = observational controlled trial, OL = open label, PCR polymerase chain reaction, RCT = randomized controlled
trial, SB-RCT =single blind, randomized controlled trial
402
Ivermectin in post-COVID-19 syndrome
Increasing reports of persistent, vexing, and even disabling symptoms after recovery from acute
403
COVID-19 have been reported and which many have termed the condition as “long Covid” and
404
patients as “long haulers”, estimated to occur in approximately 10% of cases (Callard and Perego,
405
2020;Rubin, 2020;Siegelman, 2020). Generally considered as a post-viral syndrome consisting of a
406
chronic and sometimes disabling constellation of symptoms which include, in order, fatigue,
407
shortness of breath, joint pains and chest pain. Many patients describe their most disabling symptom
408
as impaired memory and concentration, often with extreme fatigue, described as “brain fog”, and are
409
highly suggestive of the condition myalgic encephalomyelitis/chronic fatigue syndrome, a condition
410
well-reported to begin after viral infections, in particular with Epstein-Barr virus. Although no
411
specific treatments have been identified for long COVID, a recent manuscript by Aguirre-Chang et al
412
from the National University of San Marcos in Peru reported on the experience with ivermectin in
413
such patients (Aguirre-Chang, 2020). They treated 33 patients who were between 4 and 12 weeks
414
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
17
from the onset of symptoms with escalating doses of ivermectin; 0.2mg/kg for 2 days if mild,
415
0.4mg/kg for 2 days if moderate, with doses extended if symptoms persisted. They found that in
416
87.9% of the patients, resolution of all symptoms was observed after two doses with an additional 7%
417
reporting complete resolution after additional doses. Their experience suggests the need for
418
controlled studies to better test efficacy in this vexing syndrome.
419
Epidemiological data showing impacts of widespread ivermectin use on
population case counts and case fatality rates
Similar to the individual cities in Brazil that measured large decreases in case counts soon after
420
distributing ivermectin in comparison to neighboring cities without such campaigns, in Peru, the
421
government approved the use of ivermectin by decree on May 8, 2020, solely based on the in vitro
422
study by Caly et al. from Australia (Chamie, 2020).
8
Soon after, multiple state health ministries
423
initiated ivermectin distribution campaigns in an effort to decrease what was at that time some of the
424
highest COVID-19 morbidity and mortality rates in the world. Juan Chamie, a data analyst and
425
member of the FLCCC Alliance recently posted a paper based on two critical sets of data that he
426
compiled and compared; first he identified the timing and magnitude of each region’s ivermectin
427
interventions via a review of official communications, press releases, and the Peruvian Situation
428
Room database in order to confirm the dates of effective delivery, and second, he extracted data on
429
the total all-cause deaths from the region along with COVID-19 case counts in selected age groups
430
over time from the registry of the National Computer System of Deaths (SINADEF), and from the
431
National Institute of Statistics and Informatics (Chamie, 2020). It should be noted that he restricted
432
his analyses to only those citizens over 60 years old in order to avoid the confounding of rises in the
433
numbers of infected younger patients. With these data, he was then able to compare the timing of
434
major decreases in this age group of both total COVID-19 cases and total deaths per 1000,000 people
435
among 8 states in Peru with the initiation dates of their respective ivermectin distribution campaigns
436
as shown in Figure 4 below.
437
8
https://trialsitenews.com/trialsite-news-original-documentary-in-peru-about-ivermectin-and-covid-19/
Efficacy of Ivermectin in COVID-19
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18
Figure 4. Decrease in total case incidences and total deaths/population of COVID-19 in the over
60 population among 8 Peruvian states after deploying mass ivermectin distribution campaigns
Figure 5 below from the same study presents data on the case fatality rates in patients over 60,
438
again among the 8 states in Peru. Note the dramatically decreased case fatality rates among older
439
patients with COVID-19 after ivermectin became widely distributed in those areas.
440
Figure 5. Monthly reported case fatality rates among patients over 60 in eight Peruvian states
after deploying mass ivermectin treatment.
In an even more telling example, Chamie compared the case counts and fatality rates of the 8
441
states above with the city of Lima, where ivermectin was not distributed nor widely used in treatment
442
during the same time period. Figure 6 below compares the lack of significant or sustained reductions
443
in case counts or fatalities in Lima with the dramatic reductions in both outcomes among the 8 states
444
with widespread ivermectin distribution.
445
Efficacy of Ivermectin in COVID-19
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19
Figure 6. Covid-19 case fatalities and total deaths with and without mass ivermectin in
different states of Peru
Legend: Daily total deaths, case fatalities and case incidence for COVID-19 in populations of patients age 60 and above
for eight states in Peru deploying early mass ivermectin treatments vs. the state of Lima, including the capital city, where
ivermectin treatment was applied months later.
446
Another compelling example can be seen from the data compiled from Paraguay, again by
447
Chamie, who noted that the government of the state of Alto Parana had launched an ivermectin
448
distribution campaign in early September. Although the campaign was officially described as a “de-
449
worming” program, this was interpreted as a guise by the regions’ governor to avoid reprimand or
450
conflict with the National Ministry of Health that recommended against use of ivermectin to treat
451
COVID-19 in Paraguay.
9
The program began with a distribution of 30,000 boxes of ivermectin and
452
by October 15, the governor declared that there were very few cases left in the state as can be seen in
453
Figure 7 below.
10
454
9
https://public.tableau.com/profile/jchamie#!/vizhome/COVID-19PARAGUAY/Paraguay
10
https://public.tableau.com/profile/jchamie#!/vizhome/COVID-19PARAGUAY/Paraguay
Efficacy of Ivermectin in COVID-19
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20
Figure 7. Paraguay – COVID-19 case counts and deaths in Alto Parana (bolded blue line)
after ivermectin distribution began compared to other regions.
455
The clinical evidence base for ivermectin against COVID-19
A summary of the statistically significant results from the above controlled trials are as follows:
456
Controlled trials in the prophylaxis of COVID-19 (8 studies)
457
All 8 available controlled trial results show statistically significant reductions in transmission
458
3 RCT’s with large statistically significant reductions in transmission rates, N=774 patients
459
(Chala, 2020;Elgazzar et al., 2020;Shouman, 2020)
460
5 OCT’s with large statistically significant reductions in transmission rates, N=2052 patients
461
(Alam et al., 2020;Behera et al., 2020;Bernigaud et al., 2020;Carvallo et al., 2020b;Hellwig
462
and Maia, 2020)
463
Controlled trials in the treatment of COVID-19 (19 studies)
464
5 RCT’s with statistically significant impacts in time to recovery or hospital length of stay
465
(Elgazzar et al., 2020;Hashim et al., 2020;Mahmud, 2020;Niaee et al., 2020;Spoorthi V,
466
2020)
467
1 RCT with a near statistically significant decrease in time to recovery, p=.07, N=130
468
(Chowdhury et al., 2020)
469
1 RCT with a large, statistically significant reduction in the rate of deterioration or
470
hospitalization, N=363 (Mahmud, 2020)
471
2 RCT’s with a statistically significant decrease in viral load, days of anosmia and cough,
472
N=85 (Chaccour et al., 2020;Ravikirti et al., 2021)
473
Efficacy of Ivermectin in COVID-19
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21
3 RCT’s with large, statistically significant reductions in mortality (N=695) (Elgazzar et al.,
474
2020;Niaee et al., 2020;Ravikirti et al., 2021)
475
1 RCT with a near statistically significant reduction in mortality, p=0.052 (N=140) (Hashim
476
et al., 2020)
477
3 OCT’s with large, statistically significant reductions in mortality (N=1,688) (Khan et al.,
478
2020;Portmann-Baracco et al., 2020;Rajter et al., 2020)
479
480
Safety of Ivermectin
481
482
Numerous studies report low rates of adverse events, with the majority mild, transient, and largely
483
attributed to the body’s inflammatory response to the death of the parasites and include itching, rash,
484
swollen lymph nodes, joint paints, fever and headache (Kircik et al., 2016). In a study which
485
combined results from trials including over 50,000 patients, serious events occurred in less than 1%
486
and largely associated with administration in Loa loa (Gardon et al., 1997). Further, according to the
487
pharmaceutical reference standard Lexicomp, the only medications contraindicated for use with
488
ivermectin are the concurrent administration of anti-tuberculosis and cholera vaccines while the
489
anticoagulant warfarin would require dose monitoring. Another special caution is that
490
immunosuppressed or organ transplant patients who are on calcineurin inhibitors such as tacrolimus
491
or cyclosporine or the immunosuppressant sirolimus should have close monitoring of drug levels
492
when on ivermectin given that interactions exist which can affect these levels. A longer list of drug
493
interactions can be found on the drugs.com database, with nearly all interactions leading to a
494
possibility of either increased or decreased blood levels of ivermectin. Given studies showing
495
tolerance and lack of adverse effects in human subjects given escalating high doses of ivermectin,
496
toxicity is unlikely although a reduced efficacy due to decreased levels may be a concern (Guzzo et
497
al., 2002)..
498
Concerns of safety in the setting of liver disease are unfounded given that, to our knowledge,
499
only two cases of liver injury have ever been reported in association with ivermectin, with both cases
500
rapidly resolved without need for treatment. (Sparsa et al., 2006;Veit et al., 2006). Further, no dose
501
adjustments are required in patients with liver disease. Some have described ivermectin as potentially
502
neurotoxic, yet one study performed a search of a global pharmaceutical database and found only 28
503
cases of serious neurological adverse events such as ataxia, altered consciousness, seizure, or tremor
504
(Chandler, 2018). Potential explanations included the effects of concomitantly administered drugs
505
which increase absorption past the blood brain barrier or polymorphisms in the mdr-1 gene.
506
However, the total number of reported cases suggests that such events are rare. Finally, ivermectin
507
has been used safely in pregnant women, children, and infants.
508
Discussion
Currently, as of December 14, 2020, the accumulating evidence demonstrating the safety and
509
efficacy of ivermectin in COVID-19 strongly supports its immediate use on a risk/benefit calculation
510
in the context of a pandemic. Large-scale epidemiologic analyses validate the findings of in vitro,
511
animal, prophylaxis, and clinical studies. Regions of the world with widespread ivermectin use have
512
demonstrated a sizable reduction in case counts, hospitalizations, and fatality rates. This approach
513
should be urgently considered in the presence of an escalating COVID-19 pandemic and as a bridge
514
to vaccination. A recent systematic review of eight RCTs by Australian researchers, published as a
515
pre-print, similarly concluded that ivermectin treatment led to a reduction in mortality, time to
516
clinical recovery, the incidence of disease progression, and duration of hospital admission in patients
517
across all stages of clinical severity (Kalfas et al., 2020). Our current review includes a total of 6,612
518
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
22
patients from 27 controlled studies [16 of them were RCTs, 5 double blinded, one single blinded, (n=
519
2,503)]; 11 published in peer-reviewed journals including 3,900 patients.
520
Pre-print publications have exploded during the COVID-19 pandemic. Except for
521
hydroxychloroquine and convalescent plasma that were widely adopted before availability of any
522
clinical data to support, almost all subsequent therapeutics were adopted after pre-print publication
523
and prior to peer review. Examples include remdesivir, corticosteroids, and monoclonal antibodies.
524
An even more aggressive example of rapid adoption was the initiation of inoculation programs using
525
novel mRNA vaccines prior to review of either pre-print or peer-reviewed trials data by physicians
526
ordering the inoculations for patients.
11
In all such situations, both academia and governmental
527
health care agencies relaxed their standard to rise to the needs dictated by the pandemic.
528
In the context of ivermectin’s long standing safety record, low cost, and wide availability
529
along with the consistent, reproducible, large magnitude findings on transmission rates, need for
530
hospitalization, mortality, and population-wide control of COVID-19 case and fatality rates in areas
531
with widespread ivermectin distribution, insisting on the remaining studies to pass peer review prior
532
to widespread adoption appears to be imprudent and to deviate from the now established standard
533
approach towards adoption of new therapeutics during the pandemic. In fact, insisting on such a
534
barrier to adoption would actually violate this new standard given that 12 of the 24 controlled trials
535
have already been published in peer reviewed journals.
536
In regard to concerns over the validity of observational trial findings, it must be recognized
537
that in the case of ivermectin; 1) half of the trials employed a randomized, controlled trial design (12
538
of the 24 reviewed above), and 2) that observational and randomized trial designs reach equivalent
539
conclusions on average in nearly all diseases studied, as reported in a large Cochrane review of the
540
topic from 2014 (Anglemyer et al., 2014). In particular, OCTs that employ propensity-matching
541
techniques (as in the Rijter study from Florida), find near identical conclusions to later-conducted
542
RCTs in many different disease states, including coronary syndromes, critical illness, and surgery
543
(Dahabreh et al., 2012;Lonjon et al., 2014;Kitsios et al., 2015). Similarly, as evidenced in the
544
prophylaxis (Figure 1) and treatment trial (Figures 2 and 3) meta-analyses as well as the summary
545
trials table (Table 3), the entirety of the benefits found in both OCT and RCT trial designs align in
546
both direction and magnitude of benefit. Such a consistency of benefit amongst numerous trials of
547
varying designs from multiple different countries and centers around the world is both unique in the
548
history of evidence-based medicine and provides strong, additional support to the conclusions
549
reached in this review. All must consider Declaration 37 of the World Medical Association’s
550
“Helsinki Declaration on the Ethical Principles for Medical Research Involving Human Subjects,”
551
first established in 1964, which states:
552
In the treatment of an individual patient, where proven interventions do not exist or other
553
known interventions have been ineffective, the physician, after seeking expert advice, with
554
informed consent from the patient or a legally authorized representative, may use an
555
unproven intervention if in the physician’s judgement it offers hope of saving life, re-
556
establishing health or alleviating suffering. This intervention should subsequently be made
557
the object of research, designed to evaluate its safety and efficacy. In all cases, new
558
information must be recorded and, where appropriate, made publicly available.
559
The continued challenges faced by health care providers in deciding on appropriate
560
therapeutic interventions in patients with COVID-19 would be greatly eased if more updated and
561
definitive evidence-based guidance came from the leading governmental health care agencies.
562
Currently, in the United States, the treatment guidelines for COVID-19 are issued by the National
563
11
https://www.wsj.com/articles/u-k-begins-rollout-of-pfizers-covid-19-vaccine-in-a-first-for-the-west-11607419672
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
23
Institutes of Health (NIH). Unfortunately, the NIH’s recommendation on the use of ivermectin in
564
COVID-19 patients was last updated on August 27, 2020. At that time, ivermectin received a
565
recommendation of A-III against use outside of a clinical trial. An A-III recommendation, per the
566
NIH recommendation scheme, means that it was a strong opinion (A), and based on expert opinion
567
only (III) given that presumably little clinical evidence existed at the time to otherwise inform that
568
recommendation.
569
Based on the totality of the clinical and epidemiologic evidence presented in this review, and
570
in the context of a worsening pandemic in parts of the globe where ivermectin is not widely used, the
571
authors believe the recommendation must be immediately updated to support and guide the nation’s
572
health care providers. One aspect that the NIH expert panel may debate is on the grade of
573
recommendation that should be assigned to ivermectin. Based on the NIH rating scheme, the
574
strongest recommendation possible would be an A-I in support of ivermectin which requires “one or
575
more randomized trials with clinical outcomes and/or laboratory endpoints.” Given that data from
576
16 randomized controlled trials (RCT’s) demonstrate consistent and large improvements in “clinical
577
outcomes” such as transmission rates, hospitalization rates, and death rates, it appears that the criteria
578
for an A-I level recommendation has been exceeded. However, although troubling to consider, if
579
experts somehow conclude that the entirety of the available RCT data should be invalidated and
580
dismissed given that either; they were conducted outside of US shores and not by US pharmaceutical
581
companies or academic research centers, that some studies were small or of “low quality”, or that
582
such data from foreign countries are not generalizable to American patients, an A-II level
583
recommendation would then have to be considered. In the context of worsening pandemic conditions,
584
when considering a safe, low-cost, widely available early treatment option, even an A-II would result
585
in immediate, widespread adoption by providers in the treatment of COVID-19. The criteria for an
586
A-II requires supportive findings from “one of more well-designed non-randomized, or observational
587
cohort studies”. Fortunately, there are many such studies on ivermectin in COVID-19, with one of
588
the largest and best designed being Dr. Rijter’s study from Florida, published in the major peer-
589
reviewed medical journal Chest, where they used propensity matching, a technique accorded by
590
many to be as valid a design as RCT’s. Thus, at a minimum, an A-II recommendation is met, which
591
again would and should lead to immediate and widespread adoption in early outpatient treatment, an
592
area that has been little investigated and is devoid of any highly effective therapies at the time of this
593
writing. Further, it is clear that these data presented far exceed any other NIH strength or quality level
594
such as moderate strength (B), weak strength (C) or grade III quality. To merit the issuance of these
595
lower grades of recommendation would require both a dismissal of the near entirety of the evidence
596
presented in this review in addition to a risk benefit calculation resulting in the belief that the risks of
597
widespread ivermectin use would far exceed any possible benefits in the context of rising case
598
counts, deaths, lockdowns, unemployment, evictions, and bankruptcies.
599
It is the authors opinion, that based on the totality of these data, the use of ivermectin as a
600
prophylactic and early treatment option should receive an A-I level recommendation by the NIH in
601
support of use by the nation’s health care providers. When, or if, such a recommendation is issued,
602
the Front Line COVID-19 Critical Care Alliance has developed a prophylaxis and early treatment
603
protocol for COVID-19 (I-MASK+), centered around ivermectin combined with masking, social
604
distancing, hand hygiene, Vitamin D, Vitamin C, quercetin, melatonin, and zinc, with all components
605
known for either their anti-viral, anti-inflammatory, or preventive actions (Table 4). The I-MASK+
606
protocol suggests treatment approaches for prophylaxis of high-risk patients, post-exposure
607
prophylaxis of household members with COVID-19, and an early treatment approach for patients ill
608
with COVID-19.
609
610
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
24
Table 4. I-MASK+ Prophylaxis & Early Outpatient Treatment Protocol for COVID-19
Prophylaxis Protocol
MEDICATION
RECOMMENDED DOSING
lvermectin
Prophylaxis for high-risk individuals:
0.2 mg/kg per dose* one dose today, 2nd dose in 48 hours, then one dose every 2 weeks
Post COVID-19 exposure prophylaxis***: 0.2 mg/kg per dose, one dose today, 2nd dose in 48 hours
Vitamin D3
1,0003,000 IU/day
Vitamin C
1,000 mg twice daily
Quercetin
250 mg/day
Melatonin
6 mg before bedtime (causes drowsiness)
Zinc
50 mg/day of elemental zinc
Early Outpatient Treatment Protocol****
MEDICATION
RECOMMENDED DOSING
lvermectin
0.2 mg/kg per dose one dose daily for minimum of 2 days, continue daily until recovered (max 5 days)
Vitamin D3
4,000 IU/day
Vitamin C
2,000 mg 23 times daily and Quercetin 250 mg twice a day
Melatonin
10 mg before bedtime (causes drowsiness)
Zinc
100 mg/day elemental zinc
Aspirin
325 mg/day (unless contraindicated)
* Example for a person of 60 kg body weight: 60 kg × 0.2 mg = 12 mg (1 kg = 2.2 lbs) = 4 tablets (3mg/tablet). To convert pounds, divide weight in
pounds by 11: example for a person of 165 pounds: 165 ÷ 11 = 15 mg
** The dosing may be updated as further scientific studies emerge.
*** To use if a household member is COVID-19 positive, or if you have had prolonged exposure to a COVID-19+ patient without wearing a mask
**** For late phase hospitalized patients see the FLCCC’s “MATH+” protocol on www.flccc.net
611
In summary, based on the existing and cumulative body of evidence, we recommend the use
612
of ivermectin in both prophylaxis and treatment for COVID-19. In the presence of a global COVID-
613
19 surge, the widespread use of this safe, inexpensive, and effective intervention would lead to a
614
drastic reduction in transmission rates and the morbidity and mortality in mild, moderate, and even
615
severe disease phases. The authors are encouraged and hopeful at the prospect of the many favorable
616
public health and societal impacts that would result once adopted for use.
617
Acknowledgements
None
Contribution to the field statement
Efficacy of Ivermectin in COVID-19
This is a provisional file, not the final typeset article
25
COVID-19 has caused a worldwide pandemic that has caused over 1.5 million global deaths along
with continued rising case counts, lockdowns, unemployment and recessions in multiple countries. In
response, the Front Line COVID-19 Critical Care Alliance (FLCCC), formed early in the pandemic,
began to review the rapidly emerging basic science, translational, and clinical data to develop
effective treatment protocols. The supportive evidence and rationale for their highly effective hospital
treatment protocol called “MATH+” was recently published in a major medical journal. More
recently, during their ongoing review of the studies on a wide range of both novel and repurposed
drugs, they identified that ivermectin, a widely used anti-parasitic medicine with known anti-viral
and anti-inflammatory properties is proving a highly potent and multi-phase effective treatment
against COVID-19. This manuscript comprehensively reviews the diverse and increasing amount of
available evidence from studies on ivermectin which then concludes with the FLCCC consensus
recommendation that ivermectin for both the prophylaxis and treatment of COVID-19 should be
systematically and globally adopted with the achievable goal of saving countless lives and reversing
the rising and persistent transmission rates in many areas of the world.
Figures
618
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict of interest.
Author Contributions
Study conception and design: Pierre Kory, G. Umberto Meduri, Howard Kornfeld, Keith Berkowitz.
Acquisition of data: Scott Mitchell, Eivind Norjevoll, Paul Marik, Fred Wagshul Analysis and
interpretation of data: Paul Marik, Pierre Kory Drafting of manuscript: Pierre Kory Critical revision:
Umberto Meduri, Joseph Varon.
Funding
There was no funding involved for this project.
Acknowledgments
None.
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... Despite the exact mechanism of action being unknown, trials continue to indicate an effect. In the end of October, Front Line COVID-19 Critical Care (FLCCC) alliance provided a review of ivermectin trials [19]. In one trial, ivermectin prevented appearance of symptoms in the outpatients' family members by a factor of seven (7% vs 58%) (NCT04422561). ...
... In a health personnel trial with ivermectin and iota carrageenan, infections were reduced from 11% to zero (NCT04425850). In another health personnel ivermectin prophylaxis trial, infections were reduced from 10% to 2% [19]. ...
... The idea seems to have emerged from successful grassroots experimentation in Iquitos. Epidemiological statistics indicate a declining trend in excess mortality [19]. Ivermectin has subsequently been distributed in many areas of Brazil, Bolivia, and Argentina. ...
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An alliance of established experts on critical care, Front Line COVID-19 Critical Care Alliance (FLCCC), has published two protocols for treatment of COVID-19. The first one, methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+), is intended for hospital and intensive care unit treatment of pulmonary phases of the disease. It is based on affordable, commonly available components: anti-inflammatory corticosteroids (methylprednisolone, "M"), high-dose vitamin C infusion (ascorbic acid, "A"), vitamin B1 (thiamine, "T"), anticoagulant heparin ("H"), antiparasitic agent ivermectin, and supplemental components ("+") including melatonin, vitamin D, elemental zinc, and magnesium. The MATH+ protocol has received scarce attention due to the World Health Organization (WHO) advising against the use of corticosteroids in the beginning of the pandemic. In addition, randomized controlled clinical trials were required as a condition for adoption of the protocol. As the hospital mortality rate of MATH+ treated patients was approximately a quarter of the rate of patients receiving a standard of care, the authors of the protocol considered performing such trials unethical. Other parties have later performed clinical trials with corticosteroids and anticoagulants, which has led to a more widespread adoption of these components. In October 2020, ivermectin was upgraded from an optional component to an essential component of the protocol. According to the authors, ivermectin is considered the first agent effective for both prophylaxis (prevention) of COVID-19 and for treatment of all phases of COVID-19 including outpatient treatment of the early symptomatic phase. Therefore, at the end of October 2020, a separate ivermectin-based I-MASK+ protocol for prophylaxis and early outpatient treatment of COVID-19 was published.
... There have been a number of favorable reports on agents not ordinarily considered as antivirals. These include famotidine, nitazoxanide, fluvoxamine, and ivermectin [68][69][70][71][72][73][74][75]. A small randomized control study of fluvoxamine in outpatients showed no clinical deterioration versus 8.7% placebo [70]. ...
... There have now been a number of trials including several randomized controlled studies suggesting benefit with ivermectin both in prevention and in treatment of COVID-19 [75]. In a matched case control study in India ivermectin prophylaxis yielded a 73% reduction in infection of health-care workers [71]. ...
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Introduction: COVID-19 has several overlapping phases. Treatment has focused on the late stage of the disease in hospital. Yet, the continuation of the pandemic is by propagation of the disease in outpatients. The current public health strategy relies solely on vaccines to prevent disease. Areas Covered: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results with subject numbers of 100 or more on, and used a targeted search to find announcements of unpublished trial results. As of 2/15/2021, we found 111 publications reporting findings in human studies on 14 classes of agents, and on 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care, the rest all in hospitalized patients. Remdesivir and convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but the supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries. Expert Opinion: Worldwide vaccination is now underway. Vaccines and antibodies are highly antigen specific and new variants are appearing. There is a need for treatment of outpatients who contract the disease, in addition to mass immunization. We call on public health authorities to authorize treatments with known low risk and potential benefit for use in parallel with mass immunization.
... The MOA of ivermectin for prevention of Covid-19, reportedly seen in small studies (161), is also not clear to the authors. Why would the anti-viral MOA of ivermectin have a preventable effect if the patient has not been infected yet? ...
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Frontiers requested research on how a systems approach can explore the mechanisms of cardiovascular complications in Covid-19. The focus of this paper will thus be on these detailed mechanisms. It will elucidate the integrated pathogenic pathways based on an extensive review of literature. Many severe Covid-19 cases and deaths occur in patients with chronic cardiovascular comorbidities. To help understand all the mechanisms of this interaction, Covid-19 complications were integrated into a pre-existing systems-based coronary heart disease (CHD) model. Such a complete model could not be found in literature. A fully integrative view could be valuable in identifying new pharmaceutical interventions, help understand how health factors influence Covid-19 severity and give a fully integrated explanation for the Covid-19 death spiral phenomenon seen in some patients. Covid-19 data showed that CHD hallmarks namely, Hypercoagulability, Hypercholesterolemia, Hyperglycemia/Hyperinsulinemia, Inflammation and Hypertension have an important effect on disease severity. The pathogenic pathways that Covid-19 activate in CHD were integrated into the CHD model. This fully integrated model presents a visual explanation of the mechanism of interaction between CHD and Covid-19 complications. This includes a detailed integrated explanation of the death spiral as a result of interactions between Inflammation, endothelial cell injury, Hypercoagulability and hypoxia. Additionally, the model presents the aggravation of this death spiral through the other CHD hallmarks namely, Hyperglycemia/Hyperinsulinemia, Hypercholesterolemia, and/or Hypertension. The resulting model further suggests systematically how the pathogenesis of nine health factors (stress, exercise, smoking, etc.) and seven pharmaceutical interventions (statins, salicylates, thrombin inhibitors, etc.) may either aggravate or suppress Covid-19 severity. A strong association between CHD and Covid-19 for all the investigated health factors and pharmaceutical interventions, except for β-blockers, was found. It is further discussed how the proposed model can be extended in future to do computational analysis to help assess the risk of Covid-19 in cardiovascular disease. With insight gained from this study, recommendations are made for future research in potential new pharmacotherapeutics. These recommendations could also be beneficial for cardiovascular disease, which killed five times more people in the past year than Covid-19.
... On April 22, FLCCC's article published as a preprint in 2020 [236], provisionally accepted to Frontiers of Pharmacology, peer-reviewed but subsequently retracted post-peer-review [237]; [238]; [239], was published in American Journal of Therapeutics [240]. ...
Preprint
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Second part of the timeline covering a period from April 2021 to June 2021 *** Topics: WHO's role and its funding, Gavi, COVAX, Trusted News Initiative, International Fact-Checking Network, the role of private philantrophy, Frontiers issue, comparison to the H1N1 pandemic, new treatment protocols, causal modeling. *** Other parts: *** Part 0: https://www.researchgate.net/publication/348077948 *** Part 1: https://doi.org/10.13140/RG.2.2.13705.36966 *** Part 3: https://doi.org/10.13140/RG.2.2.23081.72805 *** Part 4: https://doi.org/10.13140/RG.2.2.26000.53767 *** Part 5: https://doi.org/10.13140/RG.2.2.35015.16807 *** Additional notes (Feb-Apr 2022): https://doi.org/10.13140/RG.2.2.24356.55682 ***
... On March 1, the abstract of the already peer-reviewed and provisionally accepted ivermectin review by Kory et al. with over 86,000 views was removed from Frontiers of Pharmacology [261]. A media statement published the next day by the chief executive editor stated that the article made "a series of strong, unsupported claims based on studies with insufficient statistical significance, and at times, without the use of control groups. ...
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First part part of the timeline covering a period from April 2020 to March 2021 (this is an extended version of an earlier preprint written on March 24, 2021. Changes: Abstract, Introduction, April 26, September 25, December 7, February 9, March 15, from March 22 to March 31, Discussion) *** Other parts: Part 0: https://www.researchgate.net/publication/348077948 *** *** Part 2: https://doi.org/10.13140/RG.2.2.16973.36326 *** Part 3: https://doi.org/10.13140/RG.2.2.23081.72805 *** Part 4: https://doi.org/10.13140/RG.2.2.26000.53767 *** Part 5: https://doi.org/10.13140/RG.2.2.35015.16807 *** Additional notes (Feb-Apr 2022): https://doi.org/10.13140/RG.2.2.24356.55682 ***
... On March 1, the abstract of the already peer-reviewed and provisionally accepted ivermectin review by Kory et al. with over 86,000 views was removed from Frontiers of Pharmacology. 248 A media statement published the next day by the chief executive editor stated that the article made "a series of strong, unsupported claims based on studies with insufficient statistical significance, and at times, without the use of control groups. Further, the authors promoted their own specific ivermectin-based treatment which is inappropriate for a review article and against our editorial policies . . . ...
Preprint
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This is an outdated version of the first part of the timeline. Please see current versions *** Part 0: https://www.researchgate.net/publication/348077948 *** Part 1: https://doi.org/10.13140/RG.2.2.13705.36966 *** Part 2: https://doi.org/10.13140/RG.2.2.16973.36326 *** Part 3: https://doi.org/10.13140/RG.2.2.23081.72805 *** Part 4: https://doi.org/10.13140/RG.2.2.26000.53767 *** Part 5: https://doi.org/10.13140/RG.2.2.35015.16807 *** Additional notes (Feb-Apr 2022): https://doi.org/10.13140/RG.2.2.24356.55682 ***
Article
The global number of deaths due to COVID-19 is almost at the two million mark, with over 35 000 deaths in South Africa. Although there are hopes of a safe and effective vaccination programme, the increasing number of COVID-19 cases in the country is putting a significant strain on the healthcare system. Ivermectin, an antiparasitic drug, has been widely published on social media platforms and news outlets as a so-called miracle drug for the treatment of COVID-19. Ivermectin is not registered in SA as a drug for human use, but rather as a veterinary and agricultural product. Currently, from a small number of randomised controlled trials (RCTs), there does seem to be a signal of evidence for the use of ivermectin in the management of COVID-19. Pharmacists must, however, remain cognisant of their ethical responsibilities as well as the applicable regulations that prohibit the procurement and dispensing of any unregistered medicine.
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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organspecific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology, but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19 and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines.
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OBJECTIVE To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India. DESIGN Open label, parallel arm, phase II, multicentre, randomised controlled trial. SETTING 39 public and private hospitals across India. PARTICIPANTS 464 adults (≥18 years) admitted to hospital (screened 22 April to 14 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/ fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm). INTERVENTIONS Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study. MAIN OUTCOME MEASURE Composite of progression to severe disease (PaO2/ FiO2 <100 mm Hg) or all cause mortality at 28 days post-enrolment. RESULTS Progression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval −0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54). CONCLUSION Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralising antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of covid-19. TRIAL REGISTRATION Clinical Trial Registry of India CTRI/2020/04/024775.
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The severe acute respiratory syndrome-coronavirus-2 pandemic has had devastating health and socio-economic implications worldwide. Epidemiologic data indicate that SARS-CoV2 is spread by respiratory droplets and contact. The lack of acquired human immunity to the virus and the absence of a vaccine, has meant that current management strategies aimed at virus containment through mask wearing, social distancing and enforced lockdowns. Although the World Health Organization recommends 1,5 meters distancing to minimize transmission, recent studies have demonstrated high stability in aerosols and transmission distances up to 10 meters from emission sources . Health care workers are at particular risk from SARS-CoV-2. At present, no reliable prophylactic therapy exists to minimize their risk of acquiring SARS-CoV-2, and so they rely solely upon hand hygiene and the wearing of appropriate personal protective equipment (PPE), which is often in limited supply. Several studies have shown that the salivary gland and tongue express the ACE2 receptor, suggesting that the oral cavity is a perfect host for the invasion of COVID. Theoretically, agents that can inhibit viral adhesion and replication within the primary sites of viral entry (the nasal and oral cavity), may have a role in preventing SARS-CoV-2 transmission. Use of these agents prophylactically, would be especially beneficial in health care workers, particularly given the delay in results from viral RNA detection diagnostic test and the fact that many infected patients may have mild or no symptoms of the virus in the early stages. Two possible substances have been identified as candidate prophylactic agents in the fight against SARS-CoV-2. Carrageenans are naturally occurring extracts from the Rhodophyceas seaweed. Recently, the viricidal capacity of carrageenan has been reported, through inhibition of viral- host cell adhesion and early replication. Iota-carrageenan demonstrates potent antiviral activity in vitro, reducing rhinovirus, herpes simplex virus and the Japanese encephalitis virus reproduction and their cytopathic effects. Similarly, ivermectin has also been shown to posess antiviral activity against a whole host of RNA viruses (Zika, dengue, yellow fever, human immunodeficiency virus type 1). Thus, the combination of both products can provide an extra protection for those at risk of contagion.
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Background and objectives: Various existing non-antiviral drugs are being used to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based mostly on existing data from previous coronavirus outbreaks. Ivermectin is one of such agents being widely used to treat early-stage of COVID-19. This study evaluated the outcome of ivermectin treated mild to moderate COVID-19 cases compared to usual care. Methods: This open-label randomised controlled study was conducted at a sub-district (Upazila) health complex from 1st May 2020 to the end of July 2020. Consecutive RT-PCR positive eligible COVID-19 patients were randomised into control and intervention arms. In the intervention arm, ivermectin 200 micrograms/kg single dose was administered orally in addition to usual care and was followed up till recovery. Repeat RT-PCR was done on day ten since the first positive result. The end point with regard to treatment outcome was time required for the resolution of symptoms from the onset of the symptoms and following enrollement in the study. Results: A total of 62 mild to moderate COVID-19 patients were enrolled in the study. There were 30 patients in the control arm and 32 patients in the intervention arm. Total recovery time from the onset of symptoms to complete resolution of symptoms of the patients in the intervention arm was 10.09 ± 3.236 days, compared to 11.50 ± 5.32 days in the control arm (95% CI -0.860,3.627, p>. 05) and was not significantly different. The mean recovery time after enrolment in the intervention arm was 5.31 ± 2.48 days, which also did not differ significantly from the control arm of 6.33 ± 4.23 days (95% CI – 0.766, 2.808, p> 0.05). Results of negative repeat RT- PCR were not significantly different between control and intervention arms (control 90% vs intervention 95%, p>.05). Conclusion: Ivermectin had no beneficial effect on the disease course over usual care in mild to moderate COVID-19 cases.
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Highlights • COVID-19 patients receiving ivermectin became SARS-CoV-2 negative more quickly • Fewer ivermectin-treated patients developed respiratory distress • Ivermectin-treated COVID-19 patients had shorter hospital stays • Ivermectin is associated with a lower mortality rate in COVID-19 patients
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Objective The vitamin D endocrine system may have a variety of actions on cells and tissues involved in COVID-19 progression especially by decreasing the Acute Respiratory Distress Syndrome. Calcifediol can rapidly increase serum 25OHD concentration. We therefore evaluated the effect of calcifediol treatment, on Intensive Care Unit Admission and Mortality rate among Spanish patients hospitalized for COVID-19. Design parallel pilot randomized open label, double-masked clinical trial. Setting university hospital setting (Reina Sofia University Hospital, Córdoba Spain.) Participants 76 consecutive patients hospitalized with COVID-19 infection, clinical picture of acute respiratory infection, confirmed by a radiographic pattern of viral pneumonia and by a positive SARS-CoV-2 PCR with CURB65 severity scale (recommending hospital admission in case of total score > 1). Procedures All hospitalized patients received as best available therapy the same standard care, (per hospital protocol), of a combination of hydroxychloroquine (400 mg every 12 hours on the first day, and 200 mg every 12 hours for the following 5 days), azithromycin (500 mg orally for 5 days. Eligible patients were allocated at a 2 calcifediol:1 no calcifediol ratio through electronic randomization on the day of admission to take oral calcifediol (0.532 mg), or not. Patients in the calcifediol treatment group continued with oral calcifediol (0.266 mg) on day 3 and 7, and then weekly until discharge or ICU admission. Outcomes of effectiveness included rate of ICU admission and deaths. Results Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50%) p value X² Fischer test p < 0.001. Univariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment versus without Calcifediol treatment: 0.02 (95%CI 0.002-0.17). Multivariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment vs Without Calcifediol treatment ICU (adjusting by Hypertension and T2DM): 0.03 (95%CI: 0.003-0.25). Of the patients treated with calcifediol, none died, and all were discharged, without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged. Conclusion Our pilot study demonstrated that administration of a high dose of Calcifediol or 25-hydroxyvitamin D, a main metabolite of vitamin D endocrine system, significantly reduced the need for ICU treatment of patients requiring hospitalization due to proven COVID-19. Calcifediol seems to be able to reduce severity of the disease, but larger trials with groups properly matched will be required to show a definitive answer.
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Background Thromboembolic disease is common in coronavirus disease-19 (COVID-19). There is limited evidence on association of in-hospital anticoagulation (AC) with outcomes and postmortem findings. Objective To examine association of AC with in-hospital outcomes and describe thromboembolic findings on autopsies. Methods A retrospective analysis examining association of AC with mortality, intubation and major bleeding. We also conducted sub-analyses on association of therapeutic vs prophylactic AC initiated ≤48 hours from admission. We describe thromboembolic disease contextualized by pre-mortem AC among consecutive autopsies. Results Among 4,389 patients, median age was 65 years with 44% female. Compared to no AC (n=1530, 34.9%), therapeutic (n=900, 20.5%) and prophylactic AC (n=1959, 44.6%) were associated with lower in-hospital mortality (adjusted hazard ratio [aHR]=0.53; 95%CI: 0.45-0.62, and aHR=0.50; 95%CI: 0.45-0.57, respectively), and intubation (aHR 0.69; 95%CI: 0.51-0.94, and aHR 0.72; 95% CI: 0.58-0.89, respectively). When initiated ≤48 hours from admission, there was no statistically significant difference between therapeutic (n=766) vs. prophylactic AC (n=1860) (aHR 0.86, 95%CI: 0.73-1.02; p=0.08). Overall, 89 patients (2%) had major bleeding adjudicated by clinician review, with 27/900 (3.0%) on therapeutic, 33/1959 (1.7%) on prophylactic, and 29/1,530 (1.9%) on no AC. Of 26 autopsies, 11 (42%) had thromboembolic disease not clinically suspected and 3/11 (27%) were on therapeutic AC. Conclusions AC was associated with lower mortality and intubation among hospitalized COVID-19 patients. Compared to prophylactic AC, therapeutic AC was associated with lower mortality, though not statistically significant. Autopsies revealed frequent thromboembolic disease. These data may inform trials to determine optimal AC regimens.
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Introduction COVID-19 disease progresses through a number of distinct phases. The management of each phase is unique and specific. The pulmonary phase of COVID-19 is characterized by an organizing pneumonia with profound immune dysregulation, activation of clotting, and a severe microvascular injury culminating in severe hypoxemia. The core treatment strategy to manage the pulmonary phase includes the combination of methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+ protocol). The rationale for the MATH+ protocol is reviewed in this paper. Areas covered We provide an overview on the pathophysiological changes occurring in patients with COVID-19 respiratory failure and a treatment strategy to reverse these changes thereby preventing progressive lung injury and death. Expert opinion While there is no single ‘Silver Bullet’ to cure COVID-19, we believe that the severely disturbed pathological processes leading to respiratory failure in patients with COVID-19 organizing pneumonia will respond to the combination of Methylprednisone, Ascorbic acid, Thiamine, and full anticoagulation with Heparin (MATH+ protocol).We believe that it is no longer ethically acceptable to limit management to ‘supportive care’ alone, in the face of effective, safe, and inexpensive medications that can effectively treat this disease and thereby reduce the risk of complications and death.
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As COVID-19 (coronavirus disease 2019) continues to rapidly spread throughout the world, the incidence varies greatly among different countries. These differences raise the question whether nations with a lower incidence share any medical commonalities that could be used not only to explain that lower incidence but also to provide guidance for potential treatments elsewhere. Such a treatment would be particularly valuable if it could be used as a prophylactic against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) transmission, thereby effectively slowing the spread of the disease while we await the wide availability of safe and effective vaccines. Here, we show that countries with routine mass drug administration of prophylactic chemotherapy including ivermectin have a significantly lower incidence of COVID-19. Prophylactic use of ivermectin against parasitic infections is most common in Africa and we hence show that the reported correlation is highly significant both when compared among African nations as well as in a worldwide context. We surmise that this may be connected to ivermectin's ability to inhibit SARS-CoV-2 replication, which likely leads to lower infection rates. However, other pathways must exist to explain the persistence of such an inhibitory effect after serum levels of ivermectin have declined. It is suggested that ivermectin be evaluated for potential off-label prophylactic use in certain cases to help bridge the time until a safe and effective vaccine becomes available.
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https://www.researchgate.net/publication/344318845_POST-ACUTE_OR_PROLONGED_COVID-19_IVERMECTIN_TREATMENT_FOR_PATIENTS_WITH_PERSISTENT_SYMPTOMS_OR_POST-ACUTE