Review of the Emerging Evidence Supporting the Use of
Ivermectin in the Prophylaxis and Treatment of COVID-19
Front Line COVID-19 Critical Care Alliance
Pierre Kory, Associate Professor of Medicine, St. Luke’s Aurora Medical Center
G. Umberto Meduri, Professor of Medicine, Univ. of Tennessee Health Science Center, Memphis
Jose Iglesias, DO, Associate Professor of Medicine, Hackensack School of Medicine, Seton Hall
Joseph Varon, MD, Professor of Medicine, University of Texas Health Science Center
Keith Berkowitz, MD, Medical Director, Center for Balanced Health, New York
Howard Kornfeld, MD, Diplomate in Emergency Medicine, Director, Recovery Without Walls
Eivind Vinjevoll, MD, Critical Care and Emergency Department Chief, Volda, Norway
Scott Mitchell, MRCS, Associate Specialist, Princess Elizabeth Hospital, Guernsey
Fred Wagshul, MD, Medical Director, Lung Center of America, Dayton, Ohio
Paul E. Marik, MD, Professor of Medicine, Eastern Virginia Medical School

Corresponding Author:

Pierre Kory, MD, MPA
pierrekory@icloud.com

Dr. Meduri’s contribution is the result of work supported with the resources and use of facilities at theMemphis 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

Conflict of Interest:
The authors have no conflicts of interest to disclose with any material that is present in this manuscript.
Funding: None
Date: November 11, 2020

1 / 18

Abstract
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 todevelop a treatment protocol for, COVID-19. At the same time, many centers and groups employed amultitude 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 reducing the mortality of COVID-19. Based on a
recent series of negative published therapeutic trial results, in particular the SOLIDARITY trial,
virtually eliminates any treatment role for remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, convalescent plasma, tocilizumab, and mono-clonal antibody therapy.
Despite this growing list of failed therapeutics in COVID-19, the FLCCC recently discoveredthat ivermectin, an anti-parasitic medicine, has highly potent real-world, anti-viral, and antiinflammatory properties against SARS-CoV-2 and COVID-19. This conclusion is based on theincreasing numbers of study results reporting effectiveness, not only within in-vitro and animalmodels, but also in numerous randomized and observational controlled clinical trials. Repeated,consistent, large magnitude improvements in clinical outcomes have now been reported whenivermectin is used not only as a prophylactic agent but also in mild, moderate, and even severe diseasestates from multiple, large, randomized and observational controlled trials. However, the review that
follows of the existing evidence for ivermectin relies on “emerging” data in that, although convincing,as of November 14, 2020, 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.

Introduction
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. The group of expert critical care physicians
and thought leaders immediately began continuously reviewing the rapidly emerging basic science,translational, and clinical data in COVID-19 which then led to the early creation of a treatment
protocol for hospitalized patients called MATH+, based on the collective expertise of the group in
both the research and treatment of multiple other severe infections causing lung injury.1
Two manuscripts reviewing the scientific rationale and evolving published clinical evidencebase in support of the MATH+ protocol passed peer review and have been accepted for publication in
major medical journals at two different time points in the pandemic.2,3 The most recent paper,
currently in production, reports a 6.1% hospital mortality rate in COVID-19 patients measured in the
two U.S hospitals that systematically adopted the MATH+ protocol, a markedly decreased mortality
rate compared to the 23.9% hospital mortality rate calculated from a review of 39 studies including
2 / 18over 165,000 patients (unpublished data; available on request). For a review of the therapeutic interventions comprising the current MATH+ protocol, see Table 1 below.
Table 1. MATH+ Hospital Treatment Protocol for COVID-19
MATH+ Hospital Treatment Protocol for COVID-19 (www.flccc.net)
Medication

Indication/Initiation

Recommended dosing

Titration/Duration

Methylprednisolone

A. Mild hypoxemia:
40 mg IV bolus
requires O2 via NC tothen 20 mg IV twice daily
maintain saturation > 92%

A1. Once off O2, then taper with 20 mg dailyx 3 days then 10 mg daily x 3 days, monitor
CRP response.

B. Moderate–severe
hypoxemia (High Flow O2,NIPPV, IMV)

B1. Once off IMV, NPPV, or High flow O2, decrease
to 20 mg twice daily. Once off O2, then taperwith 20 mg/day for 3 days then 10 mg/day for
3 days.

A2. If FiO2, or CRP increase move to B.
COVID-19 Respiratory Failure protocol(see Figure 2)
Preferred: 80 mg IV bolus, followed by
80 mg / 240 ml normal saline IV infusion
at 10 ml/hr
Alternate: 40 mg IV twice daily

Ascorbic Acid

B2. If no improvement in oxygenation in 2–4 days,
double dose to 160 mg/daily.
B3. If no improvement and increase in CRP/Ferritin,move to “Pulse Dose” below.

C. Refractory Illness/
Cytokine Storm“Pulse” dose with 125 mg IV
every 6–8 hours

Continue for 3 days then decrease to 80 mg IV/daily
dose above (B). If still no response or CRP/Ferritin
high/rising, consider “Salvage Therapy” below

O2 < 4 L on hospital ward

500–1000 mg oral every 6 hours

Until discharge

O2 > 4 L or in ICU

1.5–3 g intravenously every 6 hours

Sooner of 7 days or discharge from ICU, then switch
to oral dose above

Thiamine

ICU patients

200 mg IV twice daily

Sooner of 7 days or discharge from ICU

Heparin (LMWH)

Hospital ward patientson ≤ 4 L O2

0.5 mg/kg twice daily

Until discharge then start DOAC at half dosefor 4 weeks

ICU patients or > 4 L O2

1 mg/kg twice daily

Ivermectin(should be considereda core medication)
Vitamin D

Monitor anti-Xa, target 0.2–0.5 IU/ml
Monitor anti-Xa levels, target 0.6–1.1 IU/ml

Later of: discharge from ICU or off oxygen,then decrease to hospital ward dosing above

Upon admission to hospital
and/or ICU

0.2 mg/kg – days 1 and 3

Repeat – days 6 and 8 if not recovered

Hospital ward patientson ≤ 4 L O2

Calcifediol preferred:
0.532 mg PO day 1, then 0.266 mg PO day 3
and 7 and weekly thereafter

Until discharge from ICU

Cholecalciferol:
10,000 IU/day PO or 60,000 IU day 1,
30,000 IU days 3 and 7 and then weekly
ICU patients or on > 4 L O2

Cholecalciferol 480,000 IU (30 ml) PO on
admission, then check Vitamin D level on
day 5, if < 20 ng/ml, 90,000 PO IU/day for
5 days

Until discharge from ICU

Atorvastatin

ICU Patients

80 mg PO daily

Until discharge

Melatonin

Hospitalized patients

6–12 mg PO at night

Until discharge

Zinc

Hospitalized patients

75–100 mg PO daily

Until discharge

Famotidine

Hospitalized Patients

40–80 PO mg twice daily

Until discharge

Therapeutic Plasma
Exchange

Patients refractory topulse dose steroids

5 sessions, every other day

Completion of 5 exchanges

Legend: CRP = C-Reactive Protein, DOAC = direct oral anti-coagulant, ICU = Intensive Care Unit, IMV = Invasive Mechanical Ventilation, IU = International units, IV = intravenous,
NIPPV = Non-Invasive Positive Pressure Ventilation, O2 = oxygen, PO (per os) = oral administration

3 / 18

Although the adoption of MATH+ has been considerable, it largely occurred only after the
RECOVERY and other trials were published which supported one of the main components (corticosteroids) of the combination therapy approach created at the onset of the pandemic.4-9 Despite theplethora of supportive evidence, the MATH+ protocol for hospitalized patients has not yet become
widespread. Further, the world is in a worsening crisis with the potential of again overwhelming
hospitals and ICU’s. As of November 10th, 2020, the number of deaths attributed to COVID-19 in the
United States reached 245,799 with over 3.7 million active cases, the highest number to date.10
Multiple European countries have now begun to impose new rounds of restrictions and lockdowns.11
Further compounding these alarming developments was a wave of recently published negative
results from therapeutic trials done on medicines thought effective for COVID-19, that now virtuallyeliminate any treatment role for remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, convalescent plasma, tocilizumab, and mono-clonal antibody therapy, particularly in later phases.12-17 One
year into the pandemic, the only therapy considered “proven” as an effective treatment in COVID-19
is the use of corticosteroids in patients with moderate to severe illness.18 Similarly most concerning is
the fact that little has proven effective to prevent disease progression to prevent hospitalization.
Despite this growing list of failed therapeutics in COVID-19, it now appears that ivermectin, awidely 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. Although much of the trials
data supporting this conclusion is available on medical pre-print servers or posted on clinicaltrials.gov,
most have not yet undergone peer-review. Despite this limitation, the FLCCC expert panel, in theirprolonged and continued commitment to reviewing the emerging medical evidence base, and considering the impact of the recent surge, has now reached a consensus in recommending that ivermectin
for both prophylaxis and treatment of COVID-19 should be systematically and globally adopted.
The FLCCC recommendation is based on the following set of conclusions derived from theexisting data, which will be comprehensively reviewed below:
1) Since 2012, multiple in-vitro studies have demonstrated that Ivermectin inhibits the replicationof many viruses, including influenza, Zika, Dengue and others19-27
2) Ivermectin inhibits SARS-CoV-2 replication, leading to absence of nearly all viral material by
48h in infected cell cultures28
3) Ivermectin has potent anti-inflammatory properties with in-vitro data demonstrating profoundinhibition of both cytokine production and transcription of nuclear factor-κB (NF-κB), themost potent mediator of inflammation29-31
4) Ivermectin significantly diminishes viral load and protects against organ damage whenadministered to mice upon infection with a virus similar to SARS-CoV-232
5) Ivermectin prevents transmission and development of COVID-19 disease in those exposed to
infected patients33-35,52
6) Ivermectin hastens recovery and prevents deterioration in patients with mild to moderatedisease treated early after symptoms36-41,52
4 / 18

7) Ivermectin hastens recovery and avoidance of ICU admission and death in hospitalized
patients41,42,52
8) Ivermectin reduces mortality in critically ill patients with COVID-1942,43
9) Ivermectin leads to striking reductions in case-fatality rates in regions with widespread use44-46
10) The safety, availability, and cost of ivermectin is nearly unparalleled given its near nil druginteractions along with only mild and rare side effects observed in almost 40 years of use andbillions of doses administered47
11) The World Health Organization has long included ivermectin on its “List of Essential
Medicines”48
Following is a comprehensive review of the available efficacy data as of November 8, 2020, takenfrom in-vitro, animal, clinical, and real-world studies all showing the above impacts of ivermectin in
COVID-19.

In-vitro and animal studies of ivermectin activity against SARS-CoV-2
Since 2012, a growing number of cellular studies have demonstrated that ivermectin has antiviral properties against an increasing number of RNA viruses, including influenza, Zika, HIV,
Dengue, and most importantly, SARS-CoV-2. 19-27 Caly et al first reported that ivermectin
significantly inhibits SARS-CoV-2 replication in a cell culture model, observing the near absence ofall viral material 48h after exposure to Ivermectin.28 Insights into the mechanisms of action by which
ivermectin both interferes with the entrance and replication of SARS-CoV-2 within human cells aremounting. Researchers report high binding activity to the SARS-CoV-2 spike protein thereby limiting
binding to the ACE-2 receptor and preventing cellular entry of the virus.49 Ivermectin has also beenshown to bind to or interfere with multiple essential structural and non-structural proteins required by
the virus in order to replicate.49,50 Finally, ivermectin also binds to the SARS-CoV-2 RNA-dependent
RNA polymerase (RdRp), thereby inhibiting viral replication.51
Arevalo et al investigated in a murine model infected with a type 2 family RNA coronavirus
similar to SARS-CoV-2, (mouse hepatitis virus), the response to 500 mcg/kg of ivermectin vs.
placebo.32 The study included 40 infected mice, with 20 treated with ivermectin, 20 with phosphatebuffered saline, and then 16 uninfected control mice that were also given phosphate buffered saline.
At day 5, all the mice were euthanized to obtain tissues for examination and viral load assessment.
The 20 non-ivermectin treated infected mice all showed severe hepatocellular necrosis surrounded bya severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load
(52,158 AU), while in the ivermectin treated mice a much lower viral load was measured (23,192 AU;
p<0.05), with only few livers in the ivermectin treated mice showing histopathological damage suchthat the differences between the livers from the uninfected control mice were not statisticallysignificant.
5 / 18

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 COVID-19 among human subjects based on data from three randomized controlled trials(RCT) and one retrospective observational study (OCT); however, none of the studies have been peerreviewed yet.33-35 The largest RCT was posted on the Research Square pre-print server on November
13, 2020 while the two other RCT’s have submitted data to clinicaltrials.gov, which then performed aquality control review and posted the results.33,34,52 The OCT was posted on the pre-print server
medRxiv on November 3, 2020.35
The largest RCT by Elgazzar and colleagues at Benha University in Egypt randomized 200
health care and households contacts of COVID-19 patients where 100 patients took a high dose of
0.4mg/kg on day 1 and repeated the dose on day 7 in addition to wearing personal protective
equipment (PPE), while the control group of 100 contacts wore PPE only.52 There was a large andstatistically significant reduction in contacts tesing positive by RT-PCR when treated with ivermectin
vs. controls, 2% vs 10%, p<.05.
The second largest RCT, conducted in Egypt by Shouman et al. at Zagazig University,
included 340 (228 treated, 112 control) family members of patients positive for SARS-CoV-2 via
PCR.34 Ivermectin, (approximately 0.25mg/kg) was administered twice, on the day of the positive test
and 72 hours later. After a two-week follow up, a large and statistically significant decrease in
COVID-19 symptoms among household members treated with ivermectin was found, 7.4% vs. 58.4%,
p<.001. Similarly, in another RCT conducted by Carvallo et al. in Argentina involving 229 healthy
citizens, 131 were randomized to treatment with 0.2mg of ivermectin drops taken by mouth five times
per day. After 28 days, none of those receiving ivermectin prophylaxis group had tested positive for
SARS-COV-2 versus 11.2% of patients in the control arm (p<.001).53 More recently, in a large
retrospective observational case-control study from India, Behara et al. reported that among 186 casecontrol pairs (n=372) of health care workers, they identified 169 participants that had taken some formof prophylaxis, with 115 that had taken ivermectin prophylaxis (n=38 of the COVID-19 cases and
n=77 of the controls). After matched pair analysis, they reported that in the workers who had taken
two dose ivermectin prophylaxis, the odds ratio for contracting COVID-19 was markedly decreased(0.27, 95% CI, 0.15–0.51). Notably, one dose prophylaxis was not found to be protective in this study.
Based on both their study finding and the Egyptian prophylaxis study, the All India Institute ofMedical Sciences included a consensus statement in the manuscript recommending health care
workers take two 0.3mg/kg doses of ivermectin 72 hours apart and to repeat monthly.
Further data supporting a role for ivermectin in decreasing transmission rates can be foundfrom South American countries where, in retrospect, large “natural experiments” appear to haveoccurred. For instance, beginning as early as May, various regional health ministries and governmental authorities within Peru, Brazil, and Paraguay initiated “ivermectin distribution” campaigns totheir citizen populations. In one such example from Brazil, the cities of Itajai, Macapa, and Natal
distributed massive amounts of ivermectin doses to the city’s population, where, in the case of Natal,
6 / 18

1 million doses were distributed.45 The data in Table 2 below was compiled on September 14, 2020
and was obtained from the official Brazilian government site (https://covid.saude.gov.br) and thenational press consortium by an engineer named Alan Cannel whose findings were published on thewebsite TrialSiteNews and are thus not peer-reviewed.

Table 2. Case count decreases in Brazilian cities with ivermectin distribution programs(bolded cities distributed ivermectin, neighboring city listed below did not)RegionConfirmed newcases/month

June

July

South

Itajaí
Chapecó

2123
1760

2854
1754

North

Macapá
Ananindeua

7966
1520

North East

NatalJoão Pessoa

9009
9437

AugustPopulation
2020 (1000)% August
vs. June/July

998
1405

223
224

40%
80%

2481
1521

2370
1014

503
535

45%
67%

7554
7963

1590
5384

890
817

19%
62%

Similar examples of temporally associated declines in case counts and death rates in regionsthat undertook ivermectin distribution campaigns are rapidly emerging and will be discussed in more
depth below.

Clinical studies on the efficacy of ivermectin in treating mildly ill outpatients
Currently, six studies which include a total of over 3,000 patients with mild outpatient illness havebeen completed, a set comprised of 4 RCT’s and three case series.37-40,43,54,55 Of the RCTs, thesmallest one by Podder et al. was peer-reviewed and published, two RCTs have been posted on preprint servers, and the largest RCT passed quality control review and the data is now available on
clinicaltrials.gov.
The largest RCT by Mahmud et al. was conducted in Dhaka, Bangladesh and targeted 400
patients with 363 patients completing the study.38 In this study, as in many other of the clinical studies
to be reviewed, either a tetracycline (doxycycline) or macrolide antibiotic (azithromycin) was
included as part of the treatment. The importance of including antibiotics such as doxycycline orazithromycin is unclear, however, both tetracycline and macrolide antibiotics have recognized antiinflammatory, immunomodulatory, and even antiviral effects.56-59 Although the posted data from thisstudy does not specify the amount of mildly ill outpatients vs. hospitalized patients treated, important
clinical outcomes were profoundly impacted, with increased rates of early improvement (60.7% vs.
7 / 18

44.4% p<.03) and decreased rates of clinical deterioration (8.7% vs 17.8%, p<.013). Given that mildly
ill outpatients mainly comprised the study cohort, only two deaths were observed (both in the control
group).
Another RCT by Hashim et al. in Baghdad, Iraq included 140 patients equally divided; thecontrol group received standard care, the treated group included a combination of both outpatient andhospitalized patients.43 In the 96 patients with mild-to-moderate outpatient illness, they treated 48
patients with a combination of ivermectin/doxycycline and standard of care and compared outcomesto the 48 patients treated with standard of care alone. The standard of care in this trial included many
elements of the MATH+ protocol, such as dexamethasone 6mg/day or methylprednisolone 40mg
twice per day if needed, Vitamin C 1000mg twice/day, Zinc 75–125mg/day, Vitamin D3 5000 IU/day,azithromycin 250mg/day for 5 days, and acetaminophen 500mg as needed. Although no patients ineither group progressed or died, the time to recovery was significantly shorter in the ivermectin
treated group (6.3 days vs 13.7 days, p<.0001).
Another RCT of ivermectin treatment in 116 outpatients was recently posted on the pre-print
server Research Square by Chowdhury et al. in Bangladesh.55 In this trial they compared a group of 60
patients treated with the combination of ivermectin/doxycycline to a group of 60 patients treated withhydroxychloroquine/doxycycline with a primary outcome of time to negative PCR. Although theyfound no difference in this outcome, in the treatment group, the time to symptomatic recovery
approached statistical significance (5.9 days vs. 7.0 days, p=.07). In another smaller RCT of 62
patients by Podder et al., they also found a shorter time to symptomatic recovery that approachedstatistical significance (10.1 days vs 11.5 days, p>.05, 95% CI, 0.86 – 3.67).55
Morgenstern et al. in the Dominican Republic reported a case series of 2,688 consecutive
symptomatic outpatients seeking treatment in the emergency room, the majority of whom werediagnosed using a clinical algorithm. The patients were treated with high dose ivermectin of 0.4mg/kg
for one dose along with five days of azithromycin. Only 16 of the 2,688 patients (0.59%) required
subsequent hospitalization with one death recorded.41
In another case series of 100 patients by Mushed et al. in Bangladesh, all treated with a combination of 0.2mg/kg ivermectin and doxycycline, they found that no patient required hospitalization
nor died, and all patients symptoms improved within 72 hours.36
Finally, in a case series from Argentina by Carvallo et al., they reported on a combination
protocol called IDEA which used ivermectin, aspirin, dexamethasone and enoxaparin. In the 135 mild
illness patients, all survived.37

Clinical studies of the efficacy of ivermectin in hospitalized patients
Studies of ivermectin amongst more severely ill hospitalized patients include 3 OCTs, two
RCTs, a database analysis study and one case series.39,40,42,43,60 Two of the OCTs were published in
major medical journals, with the two RCTs and one OCT and the database analysis posted on preprint servers.

8 / 18

The largest RCT in hospitalized patients, was performed concurrent with the prophylaxis study
reviewed above by Elgazzar et al. 400 patients were randomized amongst 4 treatment groups of 100
patients each.(REF) Groups 1 and 2 included mild/moderate illness patients only, with Group 1
treated with one dose 0.4mg/kg ivermectin plus standard of care (SOC) and Group 2 received
hydroxychloroquine (HCQ) 400mg twice on day 1 then 200mg twice daily for 5 days plus standard ofcare. There was a statistically significant lower rate of progresson in the ivermectin treated group (1%vs. 22%, p<.001) with no deaths and 4 deaths respectivtly. Groups 3 and 4 all included only severely
ill patients, with group 3 again treated with single dose of 0.4mg/kg plus SOC while Group 4 received
HCQ plus SOC. In this severely ill subgrop, the differences in outcomes was even larger, with again
lower rates of progression 4% vs. 30%, and 2% vs 20% mortality (p<.001).The one largely outpatient
RCT done by Hashim reviewed above also included 22 hospitalized patients in each group. In theivermectin/doxycycline treated group, there were 11 severely ill patients and 11 critically ill patients
while in the standard care group, only severely ill patients (n=22) were included due to their ethicalconcerns of including critically ill patients in the control group.43 This decision led to a marked
imbalance in the severity of illness between these hospitalized patient groups. However, despite themismatched severity of illness between groups and the small number of patients included, beneficial
differences in outcomes were seen, but not all reached statistical significance. For instance, there wasa large reduction in the rate of progression of illness (9% vs. 31.8%, p = 0.15) and, most importantly,
there was a large difference in mortality amongst the severely ill groups which reached a borderline
statistical significance, (0% vs 27.3%, p =.052). Another important finding was the surprisingly low
mortality rate of 18% found among the subset of critically ill patients, all of whom were treated with
ivermectin.
The largest OCT in hospitalized patients was done by Rajter et al. at Broward Health Hospitals
in Florida and which was recently published in the major medical journal Chest.42 They performed a
retrospective OCT on 280 consecutive treated patients and compared those treated with ivermectin to
those without. 173 patients were treated with ivermectin (almost all with a single dose) while 107 were
not. In both unmatched and propensity matched cohort comparisons, similar, large, and statisticallysignificant lower mortality was found amongst ivermectin treated patients (15.0% vs. 25.2%, p =.03).
Further, in the subgroup of patients with severe pulmonary involvement, mortality was profoundly
reduced when treated with ivermectin (38.8% vs. 80.7%, p =.001).
Another large OCT by Khan et al. in Bangladesh compared 115 pts treated with ivermectin toa standard care cohort consisting of 133 patients.39 Despite a significantly higher proportion ofpatients in the ivermectin group being male (i.e. with well-described, lower survival rates in COVID),
the groups were otherwise well matched, yet the mortality decrease was statistically significant (0.9%
vs. 6.8%, p<.05).61-63 Another OCT from Brazil was published in the form of a brief letter to the editor
by Portman-Baracco et al. Although the primary data was not provided, they reported that in 704 hospitalized patients treated with a single dose of 0.15mg/kg ivermectin compared to 704 controls, overallmortality was reduced (1.4% vs. 8.5%, HR 0.2, 95% CI 0.12-0.37, p<.0001). Similarly, in the patientson mechanical ventilation, mortality was also reduced (1.3% vs. 7.3%).64 A small study by Gorial et
al. from Baghdad, Iraq recently posted on the pre-print server medRxiv, compared 16 ivermectin
9 / 18treated patients to 71 controls. This study also reported a significant reduction in length of hospital
stay (7 days vs. 13 days, p<.001) in the ivermectin group.40 The case series by Carvallo using the
IDEA protocol, which included ivermectin, reported a 3.1% mortality rate amongst the 32 hospitalized patients treated.37
One retrospective analysis of a database of hospitalized patients compared responses inpatients receiving ivermectin, azithromycin, hydroxychloroquine or combinations of these medicines.
In this study, no benefit for ivermectin was found, however the treatment groups in this analysis all
included a number of patients who died on day 2, while in the control groups no early deaths
occurred, thus the comparison appears limited.65

Anti-inflammatory properties of ivermectin supporting efficacy in late phasediseaseThe evidence for the anti-viral activity of ivermectin from the in-vitro and animal studies is
consistent with and supportive of the efficacy demonstrated in the above prophylactic and early treatment trials; however, the large, beneficial impacts reviewed in the preceding section on hospitalized
and ICU patient populations suggest that the potent anti-inflammatory properties of ivermectin also
play a major role. This assumption is based on the fact that little viral replication is occurring in thelater phases of COVID-19, nor can virus be cultured, and only in a minority of autopsies can viralcytopathic changes be found.66,67,68 Given the general lack of viral presence or cytopathic activity latein the disease course, this supports the finding by Li et al. that it is the non-viable RNA fragments of
SARS-CoV-2 that lead to the high mortality and morbidity in COVID-19 via the provocation of an
overwhelming and injurious inflammatory response.69 Based on these insights, it appears that theincreasingly well described in-vitro properties of ivermectin as an inhibitor of inflammation are far
more clinically potent than previously recognized. The growing list of studies demonstrating the antiinflammatory properties of ivermectin include its ability to; inhibit cytokine production after
lipopolysaccharide exposure, downregulate transcription of NF-kB, and limit the production of both
nitric oxide and prostaglandin E2.29-31

Summary of the clinical evidence base for ivermectin against COVID-19
The below meta-analysis includes the mortality data from the OCTs and RCTs separately(Figure 1). The consistent and reproducible signals leading to an overall statistically significant
mortality benefit from within both study designs is remarkable, especially given that in several of thestudies treatment was initiated late in the disease course.

10 / 18

Figure 1. Meta-analysis of ivermectin clinical studies

A detailed summary of each trial which comprised the previously reviewed clinical evidence base canbe found in Table 3 below:
Table 3. Clinical studies on ivermectin efficacy in COVID-19
AUTHOR, COUNTRY, SOURCESTUDY DESIGN,
SIZE

STUDY
SUBJECTS

IVERMECTIN DOSEDOSE FREQUENCY

CLINICAL OUTCOMESREPORTED

2% vs. 10% tested
positive for COVID-19
p<.05% Ivermectin vs. % Controls

Prophylaxis Trials
Elgazzar A, Egypt
ResearchSquaredoi.org/10.21203/rs.3.rs-100956/v1

RCT
N=200

Health care andHouseholdcontacts of pts
with +COVID-19
PCR test

0.4mg/kg

Two doses, Day 1
and Day 7

Shouman W, Egypt
www.clinicaltrials.gov
NCT0442256

RCT
N=304

Householdmembers of pts
with +COVID-19
PCR test

40–60kg: 15mg
60–80kg: 18mg
> 80kg: 24mg

Two doses, 72
hours apart

7.4% vs. 58.4%
developed COVID-19
symptoms, p<.001

Carvallo H, Argentina
www.clinicaltrials.gov
NCT04425850

RCT
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

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 ofcontracting COVID-19(OR 0.27 95% CI 0.16–
0.53)

Elgazzar A, Egypt
ResearchSquaredoi.org/10.21203/rs.3.rs-100956/v1

RCT
N=400

Hospitalized
Patients

0.4 mg/kg

Once

Moderate Illness
worsened (1% vs 22%,p<.001. Severe illness
worsened 4% vs 30%,
mortality 2% vs 20%,p<.001

Rajter JC, Florida
Chest 2020
doi.org/10.1016/j.chest.2020.10.009

OCT
N=280

All hospitalized
patients

0.2 mg/kg +azithromycin

Day 1 and Day 7 if
neededOverall 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

All hospitalized
patients

12 mg

Once on admission

Mortality 0.9% vs. 6.8%,
p<.05, LOS 9 vs. 15 days,
p<.001

Clinical Trials – Hospitalized Patients

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AUTHOR, COUNTRY, SOURCESTUDY DESIGN,
SIZE

STUDY
SUBJECTS

IVERMECTIN DOSEDOSE FREQUENCY

CLINICAL OUTCOMESREPORTED

Gorial FI, Iraq
medRxiv
doi.org/10.1101/2020.07.07.20145979

OCT
N=87

All Hospitalized
patients

0.2 mg/kg +HCQ and azithromycin

Once on admission

LOS 7.6 vs. 13.2, p<.001,
0/15 vs. 2/71 died

Soto-Beccerra P, Peru
medRxiv
doi.org/10.1101/2020.10.06.20208066

OCT
N=5683,
IVM, N=563

Hospitalized
patients, database
analysisUnknown dose <48hrs
after admission

Unknown

No benefits foundHashim H, Iraq
medRxiv
doi.org/10.1101/2020.10.26.20219345

RCT
N=140

2/3 outpatients,
1/3 hospital pts

0.2 mg/kg +doxycycline

Daily for 2–3 days

Recovery time 6.3 vs 13.6
days (p<.001), 0% vs
27.3% mortality inseverely ill (p=.052)

Portman-Baracco A, Brazil
Arch Bronconeumol. 2020
Doi.org/10.1016/j.arbres.2020.06.011

OCT
N=1408All Hospitalized
patients

0.15 mg/kg

Once

Overall mortality 1.4% vs.
8.5%, HR 0.2, 95% CI
0.11-0.37, p<.0001

Carvallo H, Argentina
medRxiv
doi.org/10.1101/2020.09.10.20191619

Case Series
N= 167

Outpatients andhospitalized

24mg=mild,
36mg=moderate,
48mg=severe

Days 0 and 7

All 135 with mild illness
survived, 1/32 (3.1% of
hospitalized patients died

Mahmud R, Bangladesh
www.clinicaltrials.gov
NCT0452383

RCT
N=363

Outpatients andhospitalized

12mg +
doxycycline

Once, within 3 daysof PCR+ test

Early improvement 60.7%
vs. 44.4%, p<.03,
deterioration 8.7% vs
17.8%, p<.02

Podder CS, Bangladesh
IMC J Med Sci 2020;14(2)

RCT,
N=62

Outpatients

0.2 mg/kg

Once

Recovery time 10.1 vs11.5 days (NS), averagetime 5.3 vs 6.3 (NS)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

Chowdhury A, Bangladesh
Research Squaredoi:10.21203/rs.3.rs-38896/v1

RCT
N=116

Outpatients

0.2 mg//kg +doxycycline

Once

Recovery time 5.93 vs9.33 days (p=.071)

Morgenstern J, Dominican Republic
medRxiv
doi: https://doi.org/10.1101/2020.10.29.202
22505

Case Series
N=3,099

Outpatients andhospitalized

Outpatients:
0.4mg/kg
Hospital Patients:
0.3mg/kg

Outpatients:0.3mg/
kg x 1 dose
Inpatients:
0.3mg/kg, Days
1,2,6,7

Mortality = 0.03% in 2688
outpatients, 1% in 300
non-ICU hospitalpatients, 30.6% in 111
ICU patients

Clinical Trials – Outpatients

Epidemiological data showing impacts of widespread ivermectin use on
population mortality
Similar to the individual cities in Brazil that measured large decreases in case counts soon after
distributing ivermectin in comparison to neighboring cities without such campaigns, in Peru, thegovernment approved the use of ivermectin by decree on May 8, 2020, solely based on the in-vitro
study by Caly et al. from Australia.44,70 Soon after, multiple state health ministries initiated ivermectin
distribution campaigns in an effort to decrease what was at that time some of the highest COVID-19
morbidity and mortality rates in the world. In a recent paper posted to the preprint server Research
Square by a data analyst named Juan Chamie, two critical sets of data were compiled and compared;
first he reviewed the reports on the timing and magnitude of each regions ivermectin interventions via
a review of official communications, press releases, and the Peruvian Situation Room database inorder to confirm the dates of effective delivery, and second, data on the mortality and fatality inselected age groups over time was compiled from the registry of the National Computer System of
12 / 18

Deaths (SINADEF), and from the National Institute of Statistics and Informatics.44 With these data, he
was then able to compare the timing of major decreases in both excess deaths and case fatality rates
among 8 states in Peru with the initiation dates of their respective ivermectin distribution campaigns
as shown in Figure 2 below. Excess deaths were calculated by comparison to death rates at the sametime in the 3 years prior to the COVID-19 pandemic. The analysis was restricted solely to patientsover 60 in order to remove any confounding due to increases in infections amongst healthier younger,
adults.
Figure 2. Total Deaths/Population and Case Incidence for COVlD-19/Population in population older than 60
years old for eight Peruvian states deploying mass ivermectin treatment

Figure 3 below from the same paper presents data on the case fatality rates in patients over 60, again
among the 8 states in Peru. Note the dramatically decreased case fatality rates among older patientswith COVID-19 after ivermectin became widely distributed in those areas.

13 / 18

Figure 3. Case Fatality Rate in population older than 60 years old for eight Peruvian states deploying mass
ivermectin treatment

The reduced mortality rates achieved throughout Peru can also be seen from the analysis of the three
Brazilian cities reviewed above, shown in Table 3 below.
Table 4. 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)REGIONSTATE% CHANGE IN AVERAGE DEATHS/WEEK COMPARED TO 2 WEEKS PRIORTOTAL COVID-19
RELATED DEATHS

DEATHS/100K

South

Santa Catarina
PARANÁ
Rio Grande do Sul

–36
–3
–5

2,529
3,823
4,055

35.6
35.3
33.4

North

Amapá
AMAZONAS
Pará

–75
–42
13

678
3,892
6,344

80.2
93.9
73.7

North East

Rio Grande do NorteCEARÁ
Paraíba

–65
62
–30

2,315
8,666
2,627

66.0
95.1
65.4

Another compelling example can be seen from the data compiled from Paraguay, again by Chamie,
who noted that the government of the state of Alto Parana had launched an ivermectin distribution
campaign in early September. Although the campaign was officially described as a “de-worming”
program, this was interpreted as a guise by the regions governor to avoid reprimand or conflict with
the National Ministry of Health that recommended against use of ivermectin to treat COVID-19 in
Paraguay.71 The program began with a distribution of 30,000 boxes of ivermectin and by October 15,
14 / 18

the governor declared that there were very few cases left in the state as can be seen in Figure 4
below.46,72
Figure 4. Paraguay – COVID-19 case counts and deaths in Alto Parana (blue) after Ivermectin distribution
began (yellow highlight), compared to other departments46,73

History and safety of ivermectin
The discovery of Ivermectin in 1975 was awarded the 2015 Nobel Prize in Medicine given its global
impact in reducing onchocerciasis (river blindness), lymphatic filiariasis, and scabies in endemic areasof central Africa, Latin America, India and Southeast Asia.74 It has since been included on the
WHO’s “List of Essential Medicines.” Beyond the massive, global reductions in morbidity andmortality achieved in many low-and middle-income populations, the knowledge base establishing its
high margin of safety and low rate of adverse effects is nearly unparalleled given it is based on theexperience of billions of doses dispensed. In one example, The Meztican (ivermectin) Donation
Program established in 1987 to combat river blindness in over 33 countries provided more than 570
million treatments in its first 20 years alone.74 Numerous studies report low rates of adverse events,
with the majority mild, transient, and largely attributed to the body’s inflammatory response to thedeath of the parasites and include itching, rash, swollen lymph nodes, joint paints, fever andheadache.47 In a study which combined results from trials including over 50,000 patients, serious
events occurred in less than 1% and largely associated with administration in Loa loa.75 Further,according the pharmaceutical reference standard Lexicomp, the only medications contraindicated foruse with ivermectin are the anti-tuberculosis and cholera vaccines while the anticoagulant warfarinwould requires dose monitoring.
15 / 18

Currently, (November 8, 2020), it appears that, based on the data from the in-vitro, animal,
prophylaxis, clinical, safety, and large scale epidemiologic analyses demonstrating decreases in bothcase counts and fatality rates in regions with widespread ivermectin use, the anti-parasitic drug ivermectin should be considered a highly effective regional and global solution to the COVID-19 pandemic. A concern with this interpretation and conclusion is that, as was detailed above, many of thesetrial results have not yet passed peer review and that 5 of the 9 clinical trials were conducted using anobservational design. To address the former concern, it is hoped that the journals to which the study
manuscripts have been submitted will undertake an expedited review due to the critical importance of
those studies in providing the world the appropriate level of scientific evidence required to undertakea potentially major shift in public health policy against this pandemic.
In regards to the misplaced concerns over the soundness of observational trial findings, it must
be recognized that observational and randomized trial designs reach equivalent conclusions on
average in nearly all cases, as reported in a large Cochrane review of the topic from 2014.76 In
particular, OCTs that employ propensity-matching techniques (as in many of the above trials), findnear identical conclusions to later-conducted RCTs in many different disease states, including
coronary syndromes, critical illness, and surgery.77-79
Despite these repeated findings of equivalence between study designs, the authors recognize that,at times, there are situations where multiple OCTs may conclude a benefit of a specific intervention, while
multiple, repeated RCTs do not. In such situations where the entirety of the study design conclusions
conflict, it can be assumed that one of the sets of trial designs contain a systematic bias, un-identified
confounder, or “fatal flaw” in execution (i.e. frequent delayed therapy in RCTs, especially in critical
illness states), thus it should not be automatically assumed that such confounders or biases exist only
within OCTs. Thus, expert interpretation of trial design and data in these situations must prevail. However, as evidenced in the current review, meta-analysis, and summary table, all of the various study
design conclusions on ivermectin efficacy strongly align in the same direction and magnitude. Thus,in such a situation, it is imperative that health policy makers and academics avoid the non-evidence
based practice of repeatedly dismissing findings from OCTs while over-emphasizing the need forplacebo-controlled RCTs, given that such practices, most acutely in this pandemic, have caused harmin patient outcomes when treated with placebo. RCTs are best reserved for medicines with high risk,
high cost, and/or a truly indeterminate efficacy. To study medicines that are cheap, safe, and widely
available with a long track record of use and an existing favorable efficacy or benefit/ risk ratio, wellconducted OCTs, particularly those employing propensity matching, are not only scientifically valid
but most consistent with widely agreed-upon ethical principles, especially in a pandemic. All must
consider Declaration 37 of the World Medical Association’s “Helsinki Declaration on the EthicalPrinciples for Medical Research Involving Human Subjects,” first established in 1964, which states:
In the treatment of an individual patient, where proven interventions do not exist or otherknown interventions have been ineffective, the physician, after seeking expert advice, withinformed consent from the patient or a legally authorized representative, may use an unproven
16 / 18

intervention if in the physician’s judgement it offers hope of saving life, re-establishinghealth or alleviating suffering. This intervention should subsequently be made the object of
research, designed to evaluate its safety and efficacy. In all cases, new information must berecorded and, where appropriate, made publicly available.
In keeping with the above principle, if a physician believes, based on the current body of evidence
presented above, that it is far more likely that ivermectin will help rather than harm, it would be
unethical to either withhold treatment or to treat with a placebo. However, in such cases, especially iftreatment with ivermectin should become widespread, it is imperative that data on clinical outcomesand safety continue to be meticulously collected and expertly analyzed. In keeping with the robust andemerging evidence reviewed above, the Front Line COVID-19 Critical Care Alliance recently createda prophylaxis and early treatment approach for COVID-19 called “I-MASK+”. This protocol includes
ivermectin as a core therapy in both early treatment and prophylaxis of both high-risk patients andpost-exposure to household members with COVID-19 (Tables 5 and 6). The Front Line COVID-19
Critical Care Alliance is committed to measuring outcomes in those treated with ivermectin andreviewing all emerging results from the current and any future clinical trials of ivermectin in COVID19 (see Table 5).
In summary, based on the existing and cumulative body of evidence, we recommend the use ofivermectin in both prophylaxis and treatment for COVID-19.75 In the presence of a global COVID-19
surge, the widespread use of this safe, inexpensive, and effective intervention could lead to a drastic
reduction in transmission rates as well as the morbidity and mortality in mild, moderate, and evensevere disease phases.
Table 5. I-MASK+ Prophylaxis & Early Outpatient Treatment Protocol for COVID-19
PROPHYLAXIS PROTOCOLMEDICATIONRECOMMENDED DOSING

lvermectin

Weekly Prophylaxis for high risk individuals: 0.15–0.2 mg/kg* once weekly
Post COVID-19 exposure prophylaxis**:

0.2 mg/kg × 1 dose on day 1 and day 3

Vitamin D3

1,000–3,000 IU/day

Vitamin C

1,000 mg twice daily and Quercetin 250 mg/day

Melatonin

6 mg before bedtime (causes drowsiness)

Zinc

50 mg/day elemental zinc

Aspirin

80–100 mg/day (unless contraindicated)

Table 5. (continued)
EARLY OUTPATIENT TREATMENT PROTOCOL***

17 / 18

MEDICATIONRECOMMENDED DOSING

lvermectin

0.2 mg/kg x 1 dose on day 1 and day 3

Vitamin D3

4,000 IU/day

Vitamin C

2,000 mg 2–3 times daily and Quercetin 250 mg twice a day

Melatonin

10 mg before bedtime

Zinc

100 mg/day elemental zinc

Aspirin

325 mg/day (unless contraindicated)*

Example for a person of 50 kg (body weight): 50 kg × 0.15 mg = 7.5 mg (1 kg = 2.2 lbs)= 2.5 tablets (3mg/tablet). See table 6 forweight-based dose calculations** To use if a household member is COVID-19 positive, or if you have had prolonged exposure to a COVID-19+ patient withoutwearing a mask*** For late phase – hospitalized patients – see the FLCCC’s “MATH+” protocol on www.flccc.net

Table 6. Suggested Ivermectin Dose by Body Weight for Prophylaxis and Treatment of COVID-19
Body weight

Weekly Prophylaxis dose*

Treatment dose*(doses calculated per
upper end of weight range)(0.15 mg/kg) Weekly(0.2 mg/kg) Take two doses, day 1 and day 3(Each tablet = 3 mg; doses rounded
to nearest half tablet)(Each tablet = 3 mg; doses rounded
to nearest half tablet above )70–90 lb

32–40 kg

6 mg

(2 tablets)

8 mg(3 tablets=9 mg)

91–110 lb

41–50 kg

7.5 mg(2.5 tablets)

10 mg(3.5 tablets)

111–130 lb

51–59 kg

9 mg

(3 tablets)

12 mg(4 tablets)

131–150 lb

60–68 kg

10 mg

(3.5 tablets)

13.5 mg(4.5 tablets)

151–170 lb

69–77 kg

11.5 mg(4 tablets)

15 mg(5 tablets)

171–190 lb

78–86 kg

13 mg

(4.5 tablets)

16 mg(5.5 tablets)

191–210 lb

87–95 kg

14.3 mg(5 tablets)

18 mg(6 tablets)

211–230 lb

96–104 kg

15 mg(5 tablets)

20 mg(7 tablets=21 mg)

231–250 lb

105–113 kg

17 mg(5.5 tablets)

22 mg(7.5 tablets=22.5 mg)

251–270 lb

114–122 kg

18 mg(6 tablets)

24 mg(8 tablets)

271–290 lb

123–131 kg

19.7 mg(6.5 tablets)

26 mg(9 tablets =27 mg)

291–310 lb

132–140 kg

21.1 mg(7 tablets)

28 mg(9.5 tablets=28.5 mg)* ”Post-exposure prophylaxis” dose = 0.2mg/kg on day 1 and day 3 (i.e. for persons with a household member that tests
positive for COVID-19 or after they have had prolonged indoor exposure to a COVID-19 patient without a mask)

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