Evaluation of Ivermectin, Aspirin, Dexamethasone and Enoxaparin as Treatment of covid19
Conditions: Severe Acute Respiratory Syndrome, Ventilation Pneumonitis
Sponsor: Eurnekian Public Hospital

 
STUDY OFFICIAL TITLE (original title is in Spanish. This is a 
translation into English) 
Ivermectin, Corticoids, Aspirin and Enoxaparin in the 
treatment of COVID-19 
 
REGISTRY NUMBER (CLINICALTRIALS.GOV) 
NCT04425863 
 
DATE: May 29th, 2020 (last update approved by Ethics 
Committee of Eurnekian Hospital) 
 
 

IDEA 
HYPOTHESIS 
The use of Ivermectin, aspirin, enoxaparin and dexamethasone in different doses and combinations 
may reduce the effects of COVID 19, the need of ICU treatment and the mortality rate. 
 
STUDY PROTOCOL (SUMMARY) 
 
Site 
Dr. Alberto Eurnekian Hospital, Ezeiza, Province of Buenos Aires, Argentina 
Study type 
Single-centre, prospective 
Justification 
COVID-19 emergency requires the urgent development of strategies to avoid 
the impact of the disease on our population, the saturation of the health system 
and that allows us to carry out adequate treatments to reduce the mortality of 
the disease. Severe forms of the disease strongly suggest two 
pathophysiological states: Hypercoagulability and Hyperinflammation. We 
propose the use of Ivermectin associated with Aspirin, Dexamethasone and 
Enoxaparin, in patients affected by COVID-19 
Working hypothesis The early association identified between SARS-CoV with SARS-CoV-2 was 
confirmed later by tests on protein S (spike) that characterizes these two viruses, 
which prove that S proteins from both viruses are extremely similar. 
The only significantly different portion is a furin-binding domain in the SARS-
CoV-2 protein S, which has been speculated to make possible the expansion of 
tropism or the increase of virus transmission, compared to SARS-CoV from 
2003. 
On the other hand, one of the most conserved portions of the protein is the 
receptor-binding domain (RBD), which has a similar (or reportedly higher) 
affinity to angiotensin converting enzyme type 2 (ACE2) in comparison with 
SARS CoV. 
This functional receptor is found in tissues, including lung alveolar epithelium, 
arterial and venous endothelium, smooth muscle, renal tubular epithelium, and 
small intestine epithelium, largely explaining the clinical presentation of 
COVID-19 patients. 

However, the involvement of organs with a much lower concentration of these 
receptors (eg: CNS), shows that there is -at least- other form (s) of deleterious 
action. 
The incubation period for the virus has been calculated at 5.1 days (95% CI, 
4.5 to 5.8 days), and 97.5% of patients are said to have symptoms at 11 days 
(95% CI 8.2 to 15.6 days). 
A mortality of 5.7% has been calculated. 
The average COVID patient presents with fever (78%), cough (60-79%), and 
myalgia or fatigue (35.8-44%). 55% develop dyspnea, which appears on 
average 8 days after the onset of symptoms. 
To the manifestations expressed above, we must add the presence –almost 
sine qua non- of bilateral conjunctival injection, without associated secretions, 
hypogeusia, skin rash and hyposmia. 
However, in times of pandemic, any of these signs or symptoms, even in 
isolation, should put the patient under suspicion of contagion. 
Diagnostic confirmation is carried out through laboratory studies, which can be 
performed on a wide variety of biological specimens, 
Bronchoalveolar lavage samples showed the highest sensitivity (93%), 
followed by sputum (72%), nasal swabs (63%), fiberoptic bronchoscope brush 
biopsy (46%), pharyngeal swabs (32%), feces ( 29%) and, finally, blood (1%). 
A sensitivity of 91% is reported in saliva samples. 
Computed Axial Tomography (CT) is very useful as a complementary study in 
the diagnostic approach of COVID-19, since it has found a sensitivity of 97% 
(95% CI 95-98%) and a negative predictive value of 80% ( 95% CI 76 to 89%) 
when compared to RT-PCR (Reverse Transcriptase Polymerase Chain 
Reaction). Nevertheless, this does not discredit the monitoring by conventional 
radiology, if more sophisticated means are not available. 
Coronaviruses are positive single-stranded RNA viruses, members of the 
Coronaviridae family, part of the order Nidoviridae. 
There are four genera (alpha, beta, delta and gamma coronaviruses), of which 
the first two are responsible for respiratory diseases in humans and 
gastrointestinal diseases in animals. 

Species pathogenic for humans include SARS-CoV, MERS-CoV, HCoVNL63 
and HCoV-229E, HCoV-OC3 and HCoV-HKU, and the recently discovered 
SARS-CoV-2. 
En los últimos 20 años, se han registrado 3 grandes brotes de coronavirus a 
nivel mundial.                                                                                
In the last 20 years, there have been 3 major outbreaks of coronavirus 
worldwide. 
Evidence suggests that a subset of patients with severe forms of COVID 19 may 
have a syndrome known as a cytokine storm. 
The current treatment of COVID-19 is supportive (“compassionate use”), and 
respiratory failure due to acute respiratory distress syndrome (ARDS) is the 
leading cause of mortality. 
Secondary hemophagocytic lymphohistiocytosis (SHLH) is a poorly 
recognized hyperinflammatory syndrome characterized by fulminant and fatal 
hypercytokinemia with multiple organ failure. 
In adults, SHLH is most often triggered by viral infections, occurring in 3.7–
4.3% of sepsis cases. 
The cardinal features of sHLH include constant fever, cytopenias, and 
hyperferritinemia; pulmonary involvement (including ARDS) occurs in 
approximately 50% of patients. 
A cytokine profile that resembles sHLH is associated with the severity of 
COVID-19 disease, characterized by an increase in interleukin (IL) -2, IL-7, 
granulocyte colony stimulating factor, protein 10 inducible by interferon-γ, 
monocyte chemoattractant protein, 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. 
However, cases have been reported in which 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 Antiphospholidic Syndrome (SAC). 
HYPERCOAGULABILITY: More than a century ago, Virchow proposed that 
thrombus formation and spread was caused by abnormalities in three key areas: 
• 
Blood flow 
• 
The vascular wall 
• 
Blood components 
These three factors are known as Virchow's triad. 
At present the factors of the Virchow triad have been limited in greater detail: 
Circulatory stasis: abnormalities of hemorheology and turbulence in vascular 
bifurcations and stenotic regions. 

Injury to the vascular wall: abnormalities in the endothelium, such as 
atherosclerosis and associated vascular inflammation. 
Hypercoagulable state: abnormalities in the coagulation and fibrinolytic 
pathways and in platelet function associated with an increased risk of VTE and 
other cardiovascular diseases (such as coronary artery disease [CPA], heart 
failure and stroke in patients with AF). 
All lead to a state of hypercoagulability, which could explain the formation of 
microthrombosis in different locations. 
Outcomes 
1. Number of patients improving or not worsening their condition after 7 
days of treatment 
2. Number of patients needing ICU treatment after 14 days 
3. Number of deaths 30 days after enrollment 
4. Number of patients having serious adverse events after 30 days. 
Population 
Patients complying with acceptance criteria and willing to sign informed 
consent at Eurnekian Hospital in a period from May to July 
Eligibility criteria 
Inclusion criteria 
1. Adults of any sex and children with the consent of tutors or parents. 
2. Positive for COVID-19 
3. Capable of understanding and sign the informed consent in written 
form. 
 
Exclusion criteria 
4. Hypersensitivity or allergy to any of the drugs used 
5. Children under 5 years old 
6. Pregnant women 
 
Discontinuation criteria 
7. Subjects using any other compassionate medication during study 
8. Serious adverse event that may place the subject at risk according to 
the investigator’s judgement 
 
 
 

 
Treatments 
CASE 
Ivermectin Dexamethasone 
Anticoagulant 
O2/Ventilation 
Mild 
24 mg (oral 
solution 5 
mg/mL) on 
days 0 and 
7 
None 
Aspirin 1 250-
mg Tablet daily 
for 30 days 
None 
Moderate 
36 mg (oral 
solution 5 
mg/mL) on 
days 0 and 
7 
1 daily 4-mg 
injection until 
discharge 
Enoxaparina        
1 mg /Kg de 
peso (100 
UI/Kg.) dos 
veces al día 
Low – flow 
washed oxygen 
or oxygen 
concentrator 
Severe 
48 mg (oral 
solution 5 
mg/mL) on 
days 0 and 
7 
1 daily 4-mg 
injection until 
discharge 
Enoxaparin 100 
IU / kg (ca. 1 
mg/kg) daily 
until discharge 
Mechanical 
ventilation 
Study design 
All patients testing positive for COVID-19 from June 1st to July 1st who complied 
with inclusion criteria and willingly signed the informed consent were classified as 
mild, moderate, or severe cases according to the following criteria: 
Mild stage 
Moderate stage 
Severe stage 
Only 
mild 
symptoms and no 
clinical sign of 
viral pneumonia 
3 severe symptoms 
or 2 severe and 2 
mild 
symptoms. 
Clinical 
signs 
of 
viral pneumonia 
4 severe symptoms or 3 
severe symptoms and 
not less than 2 mild 
symptoms. 
Clinical 
signs of bilateral viral 
pneumonia 
 
Symptoms were classified as mild or severe according to the following table: 
MILD SYMPTOMS 
SEVERE SYMPTOMS 
Fever not above 38.5 °C 
Isolated diarrheal episodes 
Hyposmia or Hypogeusia 
Mild desaturation (93 – 96 %) 
Dyspnea without matter 
Polymyoarthralgias, Persistent headache, 
Abdominal pain 
Fever above 38.5 °C 
Diarrhea (more than 3 daily 
depositions) 
Flictenular conjunctivitis 
Strong desaturation (92% or less) 
Tachypnea (FR> 25 / minute) 
 
 
 

Statistical 
analysis 
Percentage of each of the variables measured during the study in each group will be 
presented. 
 
Overall mortality rate and mortality rate of hospitalized patients (i.e moderate and 
severe cases together) will be compared with literature values as follows: 
 
- 
Overall mortality will be compared via chi squared with the mortality rate in 
Argentina. Risk and Number Needed to Treat variables will be calculated. 
 
- 
Mortality rate of hospitalized patients will be compared with mortality rate 
of inpatients treated otherwise within the same hospital where the study was 
conducted and with literature data. Risk and Number Needed to Treat 
variables will be calculated.