Efficacy, Safety and Tolerability of Ivermectin in Subjects Infected With SARS-CoV-2 With or Without Symptoms

Study Overview
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Brief Summary
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This study aims to evaluate the efficacy, safety and tolerability of Ivermectin in patients with mild SARS-CoV-2 infection, in the rate of progression to severe 2019 novel coronavirus disease (COVID-19). The primary efficacy endpoint is the proportion of participants with a disease control status defined as no progression of severe disease Hypothesis (H0): There is no difference between group A (ivermectin + paracetamol) and group B (ivermectin + paracetamol) in terms of the primary endpoint on day 14.

Detailed Description
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In late 2019, an unidentified viral pneumonia was detected in Wuhan, China. Later, it was declared that it was pneumonia due to a new coronavirus. The World Health Organization (WHO) officially called it COVID-19 disease (Xie and Chen 2020). Ivermectin is a broad-spectrum antiparasitic agent, developed to combat parasitic worms in veterinary use and in human medicine. This compound has been used orally in humans to treat filariasis, but is also effective against other worm-associated infections, as well as parasitic skin diseases and insect infections. It is approved for human use in several countries, to treat onchocerciasis, lymphatic filariasis, strongyloidiasis, and scabies, and recently in capillary pediculosis. When avermectins were discovered, they represented a new class of compounds that kill various ranges of disease-causing organisms, as well as pathogen vectors, inside and outside the body. Ivermectin is a semi-synthetic mixture of two chemically modified avermectins, comprising 80% 22,23-dihydroavermectin B1 and 20% 22,23-dihydroavermectin-B1b. Other diseases that have been treated with ivermectin are: trichinosis, vector insects, malaria, trypanosomiasis, allergic asthma, rosacea, bedbugs, schistosomiasis, chagas disease, epilepsy, neurological diseases. Furthermore, it has been observed to have effects as an antibiotic and anticancer (Crump 2017). In turn, Ivermectin has been described as a broad-spectrum antiviral, inhibiting nuclear import by its ability to inactivate host nuclear transport proteins, such as integrase and nonstructural protein 5 (NS5), limiting the ability to infect the western virus of the Nile in low concentrations (Yang et al. 2020), as well as inhibiting the replication of the yellow fever virus and other flaviviruses, such as dengue, and encephalitis, probably attacking the activity of nonstructural helicase 3 (Crump 2017). Ivermectin, at a dose of 150-200 mcg / kg, is the first line of treatment for river blind disease (onchocerca volvulus), lymphatic filariasis, and strongyloidiasis(Crump 2017).. French authorities approved ivermectin for humans in 1987. Shortly thereafter, Merck & Co Inc donated ivermectin for onchocerciasis control. Since then, more than two billion treatments have been distributed in Africa and Latin America for onchocerciasis and lymphatic filariasis (Chaccour et al. 2013; Smit et al. 2016). In this context, ivermectin adverse events have been mild, transient and associated with the intensity of the infection. No significant association was found between ivermectin plasma levels and adverse events(Merck & Co 2009). Wagstaff et al. published preliminary studies in in vitro cultures, where they observed that a 5000-fold reduction in the viral RNA content of cells infected with the SARS-CoV-2 virus, treated with a single dose of ivermectin (Caly et al. 2020). Ivermectin therapy has not been tested in COVID-19 subjects and is therefore intended to be used as an adjuvant treatment; therefore, all study subjects will receive ivermectin or placebo in addition to therapy that their treating physician deems appropriate. Since ivermectin is in an early phase of clinical development, the use of base therapy will ensure that all subjects, including subjects who are randomized to receive placebo, have the benefit of receiving treatment with the base therapy that is available. Research Objectives The main objective of this study is to evaluate the efficacy, safety and tolerability of ivermectin in patients with mild SARS-CoV-2 infection, in the rate of progression to severe COVID-19. Secondary objectives Quantify the replication rate of the SARS-CoV-2 virus at days 5 and 14 after diagnosis quantitatively by real-time reverse transcription polymerase chain reaction (RT-PCR). Evaluate the presence and frequency of symptoms associated with COVID-19 disease (fever, cough, myalgia, fatigue, shortness of breath, headache, diarrhea, and expectoration) daily for 14 days. Investigate the presence of adverse events associated or not with the study drug for 14 days. Search for associations between the morbidities of the evaluated subjects and the intensity of the disease. Search for a relationship between medical history of bacille Calmette Guerin (BCG) vaccines and the intensity of the disease. Evaluate the frequency of death in the subjects, associated with COVID-19.

Official Title
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Multicenter, Double-blind, Randomized, Placebo-controlled Study to Assess the Efficacy, Safety and Tolerability of Ivermectin in Mild Virus-positive Subjects (SARS-CoV)-2 With or Without Symptoms

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Ivermectin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute severe respiratory syndrome due to SARS-CoV-12 coronavirus infection defined by RT-PCR. Asymptomatic, or with mild symptoms who are taking outpatient treatment of the disease. Signed Informed Consent. Exclusion Criteria: Patients with severe disease COVID-19. Positive to proof of infection by some other virus such as influenza H1N1, SARS, etc. Recurrent urinary tract infections. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)> 5 times above its normal limits. Pregnant or lactating patients Patients receiving antihypertensive medication verapamil, the immunosuppressant cyclosporin A and / or the antipsychotic trifluoperazine. Patients with a known allergy or hypersensitivity to dewormers. Patients who are using an antioxidant supplement. Patients with a history of filariasis, strongyloidiasis, scabies, river blindness, or any parasitic disease in the last twelve months.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ivermectin<br>Ivermectin 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days | Drug: Ivermectin<br>* ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days<br>|
| Placebo Comparator: Placebo<br>Ivermectin placebo 12 mg / day for 3 days, in combination with paracetamol therapy (500 mg QID) for 14 days | Drug: Placebo<br>* Placebo of ivermectin 12 mg / day for 3 days, in combination with standard paracetamol therapy (500 mg QID) for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With a Disease Control Status Defined as no Disease Progression to Severe. | The subject is considered to have progressed to severe illness when one or more of the following criteria are present: Breathing difficulty (≥30 breaths per minute); Resting oxygen saturation ≤93%; Severe complications such as: respiratory failure, need for mechanical ventilation, septic shock, non-respiratory organic failure. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SARS-CoV-2 Viral Load, at 5 and 14 Days | To determine viral load indirectly, the Ct value of the SARS-COV-2 gene N was used on days 1, 5 and 14 of treatment, considering values greater than 37.5 as negative. | days 1, 5 and 14 | 
| Presence and Frequency of Symptoms Associated With the COVID-19 Disease | Subjects were asked to answer a symptoms dairy during 14 days, where they recorded the presence of the following symptoms; fever, cough, muscular pain, fatigue, breath difficulty, headache, diarrhea, palpitations, expectoration and Other, in the other question several subjects answer hypogeusia/ageusia, hyposmia/anosmia and backpain. The total of days anaylized were considered as 100%; 364 days for placebo patients(26 subjects x 14 days), and 420 for ivermectin subjects (30 subjects x 14 days), then the number of days reported correspond to de % of days when symptom was present. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ivermectin