Study of Efficacy and Safety of Ivermectin for COVID-19 Prophylaxis in Post-exposure Contact or Epidemiological Link
Phase: PHASE2
Conditions: Covid19
Sponsor: Ministry of Public Health, Argentina

 
Project and Protocol 
 
Safety and Efficacy Study of oral Ivermectin in the Prophylaxis of 
COVID-19 Disease in Individuals Post-exposure to COVID- 
19 by Close Contact or Epidemiological Nexus. 
 
 
 
 
 
 
 
Chahla, Rossana Elena 
Head SI.PRO.SA (Province Health System), Ministry of Health, Tucumán, Argentina. 
 
Medina Ruiz, Luis 
President of the Medical Executive Secretary, SI.PRO.SA Tucumán, Argentina. 
 
Ortega, Eugenia Silvana 
Health Research Institute, Ministry of Health, SI.PRO.SA, Tucumán, Argentina. 
 
 
Barrenechea, Guillermo 
Health Research Institute, Ministry of Health, SI.PRO.SA, Tucumán, Argentina. 
 
Goroso, Daniel Gustavo 
Research and Technology Center, Mogi das Cruzes University, Brazil. 
Human Motor Skill Analysis Laboratory, National University of Tucumán, Tucumán, Argentina. 
 
Peral de Bruno, Maria de los Ángeles* 
Director Health Research Institute, Ministry of Health, SI.PRO.SA, Tucumán, Argentina 
Superior Institute of Biological Research (INSIBIO – CCT CONICET) Argentina. 
 
 
 
 
 
Funding: Ministry of Public Health. Tucumán, Argentina. 
 
 
Trial Registration: ClinicalTrials.gov Identifier NCT04894721 
 
 
 
 
 

INTRODUCTION 
 
1 Characteristics of SARS-CoV-2 and clinical course 
 
In December 2019, from the detection of pneumonia of unknown origin in the 
 
city of Wuhan (China), a new type of coronavirus (SARS-CoV-2) was identified 1, whose 
spread generated one of the greatest global public health crises of this generation, 
accompanied by severe socio-economic consequences worldwide 2.3. Severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus that 
causes severe acute respiratory syndrome. 
 
 
The association between SARS-CoV and SARS-CoV-2 was early supported by the 
analyzes made to the protein S (spike) that characterizes both viruses, so it was clear 
that there was an important similarity between these transmembrane structures, making 
them practically superimposable. each. The only portion that is significantly different is a 
furin-binding domain in the SARS-CoV-2 protein S, which has been speculated that it 
could expand the tropism or increase the transmissibility of the virus, compared to the 
SARS-CoV of 2003. . 4 
 
On the other hand, one of the most conserved portions of the protein is the receptor-binding 
domain (RBD), which has a similar affinity (and that according to reports may be higher) to the 
angiotesin converting enzyme type 2 (ACE2) in compared to SARS-CoV. 4 This functional 
receptor is found in tissues such as the alveolar epithelium of the lung, arterial and venous 
endothelium, smooth muscle, renal tubular epithelium, and small intestine epithelium, which 
largely explains the symptoms and clinical presentation of patients with COVID-19. 5 
 
Regarding the clinical presentation of the patients, it has been calculated that the incubation 
period of the virus is 5.1 days (95% CI 4.5 to 5.8 days), and that 97.5% of the patients will 
present symptoms at 11 days (95% CI 8.2 to 15.6 days). The average patient with COVID-
19 presents the following symptoms: fever (78%), cough (60-79%), and myalgia or fatigue 
(35.8 to 44%); 55% develop dyspnea, which appears on average 8 days after the onset of 
symptoms. Mortality has been calculated to be 5.7%, according to the study "Real 
Estimates of mortality following COVID-19" by Baud et al. 6 To the presentation of the 
symptoms, we must add the comorbidities that accompany each patient and that can 
negatively affect their diagnosis. Four. It is currently considered that, in at least one group of 
patients, severe symptoms are related to a cytokine storm produced in the context of acute 
respiratory distress syndrome that leads to impaired lung function 7. 
 
1 

The severity of COVID-19 disease is associated with a cytokine profile, which resembles 
that of secondary hemophagocytic lymphohistiocytosis (sHLH), and is characterized by 
an increase in interleukin (IL) -2, IL-7, factor granulocyte colony stimulant, interferon-γ 
inducible protein 10, monocyte chemo attractant protein 1, macrophage inflammatory 
protein 1 -α, and tumor necrosis factor-α. Mortality predictors from a recent 
retrospective, multicenter study of 150 confirmed COVID-19 cases in Wuhan, China, 
included elevated ferritin (mean 1297.6 ng / ml in non-survivors vs 614.0 ng / ml in 
survivors; p <0.001) and IL-6 (p <0.0001,) suggesting that mortality could be due to viral 
hyperinflammation. 7 However, cases have been reported where tissue and organ 
involvement was found whose concentration of ECA2 receptors is very dissimilar 
(myocardium, brain). In all of them, the common denominator was small vessel 
thrombosis, as observed in entities such as Catastrophic Antiphospholipid Syndrome 
(SAC) and Disseminated Intravascular Coagulation (DIC). 7 
 
On the other hand, a large number of patients with COVID-19 presented mild or no 
symptoms, a factor that increased, due to the high level of contagion of this virus, the 
possibility of its rapid spread in the community Four. 
 
 
2 Drug repositioning 
 
The abrupt onset and rapid dissemination of SARS-CoV-2, limited the times for the design 
and evaluation of specific drugs, therefore, together with the measures of rapid diagnosis 
and isolation, and the development of vaccines that immunize the population against to the 
virus, “pharmacological repositioning” measures have been chosen, in an effort to find 
effective therapies that counteract the most serious effects of the disease, which constitute 
approximately 15% of cases, according to the World Organization Of the health 6,8,9. 
 
The repositioning of existing drugs on the market, with established safety 
profiles, which are applied to other therapeutic indications, is a pragmatic 
strategy (which has already had good results with other drugs), cheaper and 
faster than the development of new drugs, and it can be a key tool in an 
emergency situation such as the current one. 10.11 
 
Considering that to date there are no specific therapies approved by the United 
States Food and Drug Administration (FDA) for SARS-CoV-2, different 
repositionable drugs are being investigated in clinical trials and compassionate use 
protocols based on in vitro activity (against SARS-CoV-2 and other related viruses) 
and / or in the limited clinical experience available. These studies are currently in 
different phases, and some have already shown encouraging results in terms of 
their efficacy in treating the disease. 
 
 
3 Mechanisms of action of ivermectin and background 
 
two 

In relation to ivermectin, there are several studies in progress and others completed, 
both for prophylactic use, as well as for treatment in mild and severe cases of 
COVID-19. Studies by Caly et al., Based on previous experience with ivermectin and 
its action on other viruses, suggest that ivermectin has an inhibitory effect on SARS-
CoV-2 12,13,14. 
 
Ivermectin was first introduced commercially in 1981 for use in animals, and was 
subsequently used for various diseases in humans. It has shown a wide range of 
activities, ranging from endo / ectoparasitide activity, to antiviral, antibacterial and 
anticancer activity. fifteen Since 1980 it has been included in the essential drugs list 
of the World Health Organization (WHO), with millions of doses delivered annually 
through mass drug distribution programs. 14. 
 
 
The first report on the efficacy of ivermectin in vivo, was that of its effect on parvoviruses in 
a freshwater crab (Cherax quadricarinatus) fifteen. The studies by Caly et al. Along with those 
of other groups, they have also demonstrated the efficacy of their antiviral activity against a 
wide range of viruses in vitro. It has been confirmed to inhibit IN nuclear import and 
replication of HIV-1 16. Ivermectin has also been shown to inhibit nuclear import of viral and 
host proteins, including non-structural protein 5 from simian virus SV40 (T-ag) and dengue 
virus (DENV). 13 
 
It has been shown to limit infection by RNA viruses such as DENV 1-4, West Nile 
virus, Venezuelan equine encephalitis virus (VEEV), and influenza, and this broad-
spectrum activity is believed to be due to to the action of many different RNA viruses 
on IMPα / β1 during infection 13. Ivermectin has also been shown to be effective 
against DNA pseudorabies virus (PRV), against Zika virus (ZIKV) in mice, but the 
authors acknowledged that study limitations warranted reassessment of ivermectin's 
activity against ZIKV. 12,13,17 
 
The causative agent of the current COVID-19 pandemic, SARS-CoV-2, is a 
single-stranded, positive-sense RNA virus that is closely related to the severe 
acute respiratory syndrome coronavirus (SARS-CoV). 12 
 
Studies of SARS-CoV proteins have revealed a possible role of IMPα / β1 during 
infection in the signal-dependent nucleocytoplastic closure of the SARS-CoV 
nucleocapsid protein, which may affect cell division. 12 
 
Furthermore, the SARS-CoV accessory protein, the ORF6 protein, has been shown to 
antagonize the antiviral activity of the transcription factor STAT1 by sequestering IMPα / β1 in 
the ER / Golgi rough membrane. Taken together, these reports suggest that the nuclear 
transport inhibitory activity of ivermectin may be effective against SARS-CoV- 
 
two. 12 
 
On the COVID 19 virus, ivermectin would have two types of action: extra and intracellular. 3 
 
The extracellular action is through interaction with cavities or ionophore channels present in 
the sarcolemma of the cell membrane, which electrolytically trap the corona of the virus 
capsid and prevent access to the cell. In the mechanism 
 
3 

Intracellular, it is carried out through a destabilization of the IMPORTINE heterodimer complex 
(IMPA alpha / b1), a cotransporter that would carry the virus to the nucleus. When destabilized, 
the entry of the virus to the nucleus is blocked and thus prevents viral replication. 3 
 
To this day, numerous clinical trials are being conducted around the world to evaluate 
the antiviral activity of ivermectin in the treatment (in mild and severe cases) and 
prophylaxis against COVID-19. In the database of the US National Library, you can find 
about 60 clinical studies in different phases, some of which 
 
have already yielded results. These essays can be accessed through https://www.clinicaltrials.gov/iv . 
 
In Tucumán, the IVERCAR-TUC protocol (NCT Clinical Trials NCT04701710) evaluated the 
effect of the use of ivermectin associated with iota-carrageenan in repeated doses in the oral 
cavity for prophylaxis in the group of health personnel. The use of both associated drugs 
would reduce the probability of the appearance of severe clinical manifestations of the 
disease, and reduce the viral load and the time of dissemination of the virus in the preclinical 
phase. 18 
 
On the other hand, the IDDEA protocol proposes the hypothesis of the use of 
ivermectin, dexamethasone, vitamin D3, enoxaparin and aspirin (according to the 
degree of symptoms), to reduce the risk of hospitalization in mild patients and 
mortality in severe patients. Both studies have demonstrated efficacy and safety 
based on the primary and secondary endpoints of ivermectin in relation to COVID-19. 
19.20 
 
 
 
4 Pharmacokinetics and Safety of Oral Ivermectin 
 
Ivermectin is authorized by the FDA (Food and Drug Administration), authorities of 
high sanitary surveillance and ANMAT, in the pharmaceutical forms tablets and oral 
solution for systemic absorption, and for topical administration as cream at 0.5% 
and 1%. twenty-one After its metabolization in the human body, its metabolites are 
almost exclusively eliminated in the faeces for about 12 days, while less than 1% of 
the administered dose is excreted in the urine. The plasma half-life of ivermectin is 
around 12 hours and that of the metabolites around three days. two 
 
Studies have shown the effectiveness of oral ivermectin in the treatment of endoparasites and 
ectoparasites. There are reports of its management in scabies, myiasis, onchocerciasis, migraine 
larvae of the skin and even pediculosis, to the point that today it is the drug of choice for the 
treatment and control of onchocerciasis 14. The side effects that have been reported are fever, 
headache, pruritus, edema, myalgia and arthralgia in 64% of them with the first dose, and 50% 
with the second, but of mild to moderate intensity, which subsided easily with aspirin and / or 
antihistamines. 
 
 
 
4 

Other observed effects were dizziness, drowsiness, and hypotension, which are 
mild and brief. 14.21. 
 
The drug is well tolerated in children older than 5 years, and administered orally, it does 
not cross the blood-brain barrier. It is contraindicated in pregnancy, although studies 
have been reported in which it was inadvertently administered to women in the first 
trimester of pregnancy without finding teratogenic effects. Its concomitant use with 
drugs that act on GABA receptors, barbiturates and benzodiazepines should be 
avoided. 14 
 
 
 
5 Repositioning of ivermectin for the treatment and prophylaxis of COVID-19 
 
Taking into account the above, and the imperative of reducing hospital 
admissions and the mortality rate, while optimizing health HR, our health 
system considered the study of the repositioning of the drug ivermectin for 
treatment and prophylaxis of COVID as strategic. -19. 
 
As previously evaluated in health personnel, associated with iota-carrageenan (IVERCAR-
TUC), in this case we seek to evaluate the effect of the use of oral Ivermectin on the 
appearance and eventual progression of COVID-19 disease in a population of healthy 
individuals who are exposed to contagion through close contact with a positive case of 
COVID-19 or epidemiological link. 
 
 
 
2. OBJECTIVES, HYPOTHESIS AND VARIABLES OF THE STUDY 
 
 
a 
 
The purpose of the study 
 
 
 
To evaluate the effect of the use of Ivermectin on the appearance and eventual 
progression of COVID-19 disease in a population of healthy individuals who have been 
found exposed and with a higher risk of contagion due to being close contact or 
epidemiological link 
 
 
b. Study hypothesis 
 
Treatment with ivermectin would decrease the probability of the appearance or 
progression of clinical manifestations and the appearance of severe disease, and 
decrease the viral load and the time of virus shedding. 
 
c. Study variables 
 
Comparison between both treatment groups of the following variables: 
 
Primary 
 
5 

• 
Incidence of appearance of symptoms related to infection by 
 
• 
CoVid-19 Duration of symptoms secondary to infection by Covid -19 
 
• 
Incidence of progression to severe disease 
 
• 
Incidence of clinical fall or relapse after discharge, in cases who contract 
CoVid-19 
 
• 
Incidence of reported adverse events 
• 
Incidence of CoVid-19 detection 
 
• 
Virus persistence time 
 
 
 
1. SYNOPSIS OF THE STUDY 
 
 
Code of 
Exp: 5077/410-CH-2020 
Protocol 
IP Dra. Rossana Chahla - Dr. Luis Medina Ruiz 
Medical Executive 
Secretary Monitor Center - SIPROSA Presidency 
Avellaneda Hospital 
Title of the 
Safety and Efficacy Study of oral Ivermectin in the prophylaxis of 
Study 
COVID-19 disease in individuals post-exposure by close contact or 
epidemiological link. 
Type of study 
Randomized, blinded, placebo-controlled clinical trial with Group 
Control (CG) and Treatment Group (GT). Randomization ratio: 2: 1. 
Treatment group n = 500. Placebo group n = 250 
Justification 
The emergency of COVID-19 requires the rapid development of 
strategies to avoid the impact of the disease on the population, to 
reduce the saturation of our health system and to reduce the level of 
mortality from coronavirus. 
Taking into account the characteristics of the RNA detection 
diagnostic test, which is not immediate, and that contagion control is 
essential during the first days of the development of the disease, this 
treatment with ivermectin in suspected cases of COVID-19 ( by 
epidemiological link) would contribute to the control of contagion 
during the first part of the infection, even in the absence of 
symptoms of the disease. 
Hypothesis 
Treatment with ivermectin would decrease the probability of the appearance 
or progress of clinical manifestations and the appearance of severe disease, 
and would decrease the viral load and the time of virus shedding. 
  
6 

objective 
To evaluate the effect of the use of Ivermectin on the appearance and 
principal 
eventual progression of COVID-19 disease in a population of healthy 
individuals who have been found to be exposed and at a higher risk of 
contagion due to being close contact or epidemiological link. 
 
 
 
Variables of 
Comparison between both treatment groups of the following 
study 
variables: 
Primary: 
• 
Incidence of appearance of symptoms related to CoVid-19 
• 
infection • 
Duration of symptoms secondary to Covid -19 infection • 
• 
Incidence of progression to severe disease • 
• 
Incidence of clinical fall or relapse after discharge, in cases 
• 
who contract CoVid-19 • 
Incidence of reported adverse events 
High schools: • 
• 
Incidence of CoVid-19 detection • 
• 
Virus persistence time • 
Population 
It will be made up of healthy individuals who are exposed and at a 
higher risk of contagion of COVID-19 due to being close contact or 
epidemiological link. A total of 750 individuals who meet the 
inclusion criteria will be included. 
Criteria 
from Inclusion: 
eligibility 
1. Over 18 years of either sex 
twoWomen. of childbearing age with a negative 
3. 
pregnancy test 
In a group, close contact or epidemiological link 
Four. Able to understand and give written informed consent. 
5. RT-PCR test with negative result. 
Exclusion: 
1. Known hypersensitivity or allergy to any component of the 
product under evaluation. 
twoAge. under 18 years. 
3. Use of immunosuppressants (including systemic 
corticosteroids) in the past 30 days. 
Four. Pregnant or nursing. 
5. Patients with other acute infectious diseases. 
 
 
 
7

6. Patients with autoimmune disease and / or decompensated 
chronic diseases. 
7. Who have received a vaccine for Covid 19 (1/2 dose) or who 
have taken ivermetin (prior to 30 days of the study) or who 
are participating in another study of prophylaxis for COVID. 
Discontinuation: 
1. Development of any serious or severe adverse drug reaction that, 
in the opinion of the researcher, puts the subject under study at 
risk 
2. Development of symptoms or positive test for COVID-19 
Intervention 
Randomization to Treatment Group Ivermectin 0.6mg / kg of weight in two 
doses (1st take on day 1 and 2nd take on day 7) vs. Placebo, two doses (1st take 
on day 1 and 2nd take on day 7). Control on day 7, final intervention period. 
It will be indicated for the best absorption of ivermectin that it is 
administered during lunch. The dose will be controlled per kg of 
weight, not exceeding in any case (in individuals over 70 kg) the 7 
tablets per dose. 
Design of the 
The study lasts 14 days Intervention 
study 
period: 7 days 
Post-intervention follow-up period: 14 days 
If the patient will present symptoms and positive test for COVID- 19 
the research treatment is suspended to be attended by health 
personnel with standard care for coronavirus infection and a 
post-intervention follow-up period of 21 days will be indicated. 
•   Visit 0 = Day 0: Information about the study to the patient and 
signing of the informed consent. Affiliation data, clinical control, 
comorbidities registry, and RT-PCR taking 
•   Visit 1 = Day 1: PCR results. 
Enrollment in the study. 
Randomization to treatment or 
placebo Drug dispensing or placebo 
•   Day 4: Remote monitoring. Control of 
symptoms and side effects 
•   Visit 2 = Day 7: Dispensing of the 2nd dose. Control of 
symptoms and side effects 
•   Visit 3 = Day 14: Control of symptoms and 
side effects. Completion of post-intervention 
follow-up RT-PCR test. 
 
 
8

 
Analysis 
 
statistical 
 
A descriptive statistic of all the variables analyzed will be presented. 
To compare continuous variables, a Wilcoxon test will be used, 
while for non-continuous or categorical variables, a chi-square or 
Fisher test will be used. For analysis of the interaction of variables, 
multivariate logistic regression will be used. The safety analysis will 
present the incidence rate of reported AE, describing its severity and 
its relationship with the treatment under study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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