Clinical trial NCT04463264: Efficacy and Safety Study of Nitazoxanide (NTX) in the Treatment of Patients With SARS-CoV-2 Virus Infection (COVID-19)
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: COVID-19
Keywords: Nitazoxanide
Coronavirus Infections
RNA Virus Infections
Respiratory Tract Infections
Virus Diseases
Respiratory Tract Diseases
Antiparasitic Agents
Lead sponsor: Laboratorios Roemmers S.A.I.C.F.
Sponsor class: INDUSTRY
First posted: 2020-07-09
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized. Nitazoxanide : Placebo (2:1), parallel-group study
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Eradication of SARS COV-2 from patients' respiratory tract secretions by treatment day 7th.
timeFrame: 7 day
Secondary outcomes:
measure: Comparative decrease of the viral load
timeFrame: 3 - 35 days
measure: Clinical improvement
timeFrame: 1 - 35 days
measure: Pneumonia patients meeting severity criteria.
timeFrame: 1 - 35 days
measure: Number of days with fever
timeFrame: 1 - 35 days
Other outcomes:
measure: Patients requiring mechanical ventilation
timeFrame: 1 - 35 days
measure: Mortality rate.
timeFrame: 1- 35 days
measure: Lymphocyte recovery
timeFrame: 7 day
measure: ICU hospitalization.
timeFrame: 1 - 35 days
measure: Oxygen saturation
timeFrame: 1 - 35 days
measure: Days of hospitalization
timeFrame: 1 - 35 days
measure: Respiratory rate
timeFrame: 1 - 35 days
Locations:
city: Presidente Derqui
country: Argentina
facility: Hospital Universitario Austral
state: Buenos Aires, Argentina
Study officials:
affiliation: Austral University, Argentina
name: Marcelo Silva, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ashiru O, Howe JD, Butters TD. Nitazoxanide, an antiviral thiazolide, depletes ATP-sensitive intracellular Ca(2+) stores. Virology. 2014 Aug;462-463:135-48. doi: 10.1016/j.virol.2014.05.015. Epub 2014 Jun 25.
citation: Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). 2023 Aug 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554776/
citation: Chen J, Lau YF, Lamirande EW, Paddock CD, Bartlett JH, Zaki SR, Subbarao K. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol. 2010 Feb;84(3):1289-301. doi: 10.1128/JVI.01281-09. Epub 2009 Nov 11.
citation: Chang D, Mo G, Yuan X, Tao Y, Peng X, Wang FS, Xie L, Sharma L, Dela Cruz CS, Qin E. Time Kinetics of Viral Clearance and Resolution of Symptoms in Novel Coronavirus Infection. Am J Respir Crit Care Med. 2020 May 1;201(9):1150-1152. doi: 10.1164/rccm.202003-0524LE. No abstract available.
citation: Frieman M, Baric R. Mechanisms of severe acute respiratory syndrome pathogenesis and innate immunomodulation. Microbiol Mol Biol Rev. 2008 Dec;72(4):672-85, Table of Contents. doi: 10.1128/MMBR.00015-08.
citation: Haffizulla J, Hartman A, Hoppers M, Resnick H, Samudrala S, Ginocchio C, Bardin M, Rossignol JF; US Nitazoxanide Influenza Clinical Study Group. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 2014 Jul;14(7):609-18. doi: 10.1016/S1473-3099(14)70717-0. Epub 2014 May 19.
citation: Jasenosky LD, Cadena C, Mire CE, Borisevich V, Haridas V, Ranjbar S, Nambu A, Bavari S, Soloveva V, Sadukhan S, Cassell GH, Geisbert TW, Hur S, Goldfeld AE. The FDA-Approved Oral Drug Nitazoxanide Amplifies Host Antiviral Responses and Inhibits Ebola Virus. iScience. 2019 Sep 27;19:1279-1290. doi: 10.1016/j.isci.2019.07.003. Epub 2019 Aug 8.
citation: Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014 Oct;110:94-103. doi: 10.1016/j.antiviral.2014.07.014. Epub 2014 Aug 7.
citation: Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271. doi: 10.1038/s41422-020-0282-0. Epub 2020 Feb 4. No abstract available.