Clinical trial NCT04407507: Efficacy, Safety and Tolerability of Ivermectin in Subjects Infected With SARS-CoV-2 With or Without Symptoms
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Keywords: Ivermectin
Lead sponsor: Investigacion Biomedica para el Desarrollo de Farmacos S.A. de C.V.
Sponsor class: OTHER
First posted: 2020-05-29
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

1. Patients with severe disease COVID-19.
2. Positive to proof of infection by some other virus such as influenza H1N1, SARS, etc.
3. Recurrent urinary tract infections.
4. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)\> 5 times above its normal limits.
5. Pregnant or lactating patients
6. Patients receiving antihypertensive medication verapamil, the immunosuppressant cyclosporin A and / or the antipsychotic trifluoperazine.
7. Patients with a known allergy or hypersensitivity to dewormers.
8. Patients who are using an antioxidant supplement.
9. Patients with a history of filariasis, strongyloidiasis, scabies, river blindness, or any parasitic disease in the last twelve months.

Primary outcomes:
measure: Participants With a Disease Control Status Defined as no Disease Progression to Severe.
timeFrame: 14 days
Secondary outcomes:
measure: SARS-CoV-2 Viral Load, at 5 and 14 Days
timeFrame: days 1, 5 and 14
measure: Presence and Frequency of Symptoms Associated With the COVID-19 Disease
timeFrame: 14 days
Other outcomes:
Locations:
city: Zapopan
country: Mexico
facility: Investigacion Biomédica para el Desarrollo de Fármacos S.A. de C.V.
state: Jalisco
Study officials:
affiliation: Centro de Investigación Farmacéutica Especializada de Occidente S.C.
name: Alma M Perez, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3.
citation: Chaccour CJ, Kobylinski KC, Bassat Q, Bousema T, Drakeley C, Alonso P, Foy BD. Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination. Malar J. 2013 May 7;12:153. doi: 10.1186/1475-2875-12-153.
citation: Smit MR, Ochomo E, Aljayyoussi G, Kwambai T, Abong'o B, Bayoh N, Gimnig J, Samuels A, Desai M, Phillips-Howard PA, Kariuki S, Wang D, Ward S, Ter Kuile FO. Efficacy and Safety of High-Dose Ivermectin for Reducing Malaria Transmission (IVERMAL): Protocol for a Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Trial in Western Kenya. JMIR Res Protoc. 2016 Nov 17;5(4):e213. doi: 10.2196/resprot.6617.
citation: Xie M, Chen Q. Insight into 2019 novel coronavirus - An updated interim review and lessons from SARS-CoV and MERS-CoV. Int J Infect Dis. 2020 May;94:119-124. doi: 10.1016/j.ijid.2020.03.071. Epub 2020 Apr 1.
citation: Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, Jans DA. The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antiviral Res. 2020 May;177:104760. doi: 10.1016/j.antiviral.2020.104760. Epub 2020 Mar 3.