Efficacy and Safety Study of Nitazoxanide (NTX) in the Treatment of Patients With SARS-CoV-2 Virus Infection (COVID-19)

The rapid spread of COVID-19 has overwhelmed the capabilities of the Public Health System in
major nations due to the large number of critically ill patients and patients seriously
affected requiring intensive care.

Reducing the viral load, along with other epidemiological measures, including social
isolation and quarantine, may in the long run significantly reduce the R0 (Basic Reproductive
Rhythm) of infection.

To date, in our country there are no specific antiviral treatments approved by the regulatory
authorities for COVID-19, and no vaccines so far exist. Symptomatic and supportive treatment
has been the main intervention for patients with moderate to severe infection.

The lack of a drug with a demonstrated solid antiviral efficacy warrants the need to explore
new therapeutic options against SARS-CoV-2 / COVID-19.

Nitazoxanide is a widely used thiazolide, approved by the FDA and ANMAT (Argentine drug
regulatory authority) as an antiprotozoal, with a very good safety record for a variety of
indications. NTX was shown to have extensive antiviral activity against, inter alia, animal
and human coronaviruses. Indeed, it exhibits in vitro activity against MERS-CoV and other
coronaviruses, including SARS-CoV-2, where it inhibits the expression of viral protein N.
Another proposed antiviral mechanism for Nitazoxanide involves PKR and eIF2α phosphorylation
and the depletion of ATP-sensitive intracellular calcium deposits in infected cells, thereby
inducing chronic sub-lethal stress of the endoplasmic reticulum and impairing the
glycosylation of the structural protein.

Exposure in clinical trials included a specific experience on patients with uncomplicated
influenza-like illness, where the drug helped reduce the mean time for symptom relief.

The objective of this study is to evaluate the efficacy and safety of NTX (1,000mg/3 times
per day plus standard treatment for 14 days in male and female patients (≥ 18 years and <60
years) with COVID-19 infection, with mild symptoms, as compared to a control group treated
with placebo. The proposed study dose regime of Nitazoxanide 1,000 mg/3 times per day (every
8 hours) for 14 days may be modified if patients experience considerable GI adverse effects.
In these cases, the dose may be lowered to one (1) 500 mg tablet every 6 hours (2,000 mg
/day). Nitazoxanide has been also administered in other studies up to 4 g daily without
significant adverse effects or changes in ECG or other laboratory values.

The proposed treatment regimen is expected to reduce disease severity by earlier eradication
of viral load in NTX-treated patients when compared to placebo-treated patients, thus
preventing the dysregulation of the innate immune system caused by the viral infection and
modifying the high mortality in older/vulnerable populations. Early virus negativization or
viral load reduction can potentially reduce the severity of the symptoms, eventually
preventing a liable collapse of the Health Care System and ensuring a more controlled
response to the disease.

Because of its known antiviral and safety profiles, and the fact that it can be orally
administered to both adults and children, as well as its rapid availability and
affordability, Nitazoxanide appears as an interesting alternative for such a situation.

Statistical analysis: 1-tailed statistical test, with a 25% α value (or type I error) (p
value <0.025) and a power (type II error, or β value) of 0.20 (power of 80%) for superiority
of the intervention arm over the control arm. All statistical analyzes will be carried out
using STATA, version 14.0.