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

Efficacy and Safety Study of Nitazoxanide (NTX) in the Treatment of Patients With SARS-CoC-2 Virus Infection (COVID-19). A Pilot, Randomized, Simple Blind, Placebo-controlled, Parallel-group Study

Evaluation of the efficacy and safety of NTX in adult patients (≥18 years and <60 years), with SARS-CoV-2 infection with mild symptoms of COVID-19, compared to a placebo control arm. 135 patients will be randomized to either Nitazoxanide (n=90) or placebo (n=45) (2:1). Simple blind design. Primary endpoint: eradication of virus from patients' respiratory tract secretions by the 7th day of treatment.

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.

Inclusion Criteria:

• Adult male and female patients (≥ 18 years and <60 years).
• Signature of informed consent.
• Patients with a positive test for SARS-CoV-2 and mild symptoms of COVID-19 (without severity criteria as detailed by the Ministry of Health of Argentina - MSN)

Exclusion Criteria:

• Patients under 18 years of age and over 60 years of age.
• Breastfeeding or pregnant women (with positive pregnancy blood test in women of childbearing age).
• Patients with mild pneumonia in the presence of risk factors or moderate or severe pneumonia (based on the severity criteria set by the Ministry of Health of Argentina), or patients who require mechanical ventilation at screening.
• Patients in whom NTX and/or lactose is contraindicated.
• Any other contraindication based on the judgment of the treating physician.