Effects of Early Use of Nitazoxanide in Patients With COVID-19

Effects of Nitazoxanide Administration to Patients in the Initial Phase of COVID-19

Multicenter, randomized, placebo-controlled, parallel, blinded, interventional, treatment clinical trial with two arms.

Population: 392 Patients with COVID-19 (Coronavirus Disease-19), confirmed by RT-PCR (Real Time polymerase chain reaction), symptomatic in the early phase of the disease.

Experimental group: 196 patients, nitazoxanide 500mg 8 / 8 hours for 5 days. Control group: 196 patients, placebo 8/8 hours for 5 days.

Study Overview

• Status: Completed
• Conditions: Covid19; Coronavirus
• Intervention / Treatment: Drug: Nitazoxanide; Drug: Placebo

Detailed Description

SARITA-2 is a multicenter, randomized, placebo-controlled, parallel, -blinded, interventional, treatment clinical trial with two arms, which aims to study the impact of nitazoxanide in the early phase of the COVID-19 (Coronavirus Disease-19).

Experimental group: 196 patients received nitazoxanide 500mg 8 / 8 hours for 5 days. Control group: 196 patients received placebo 8/8 hours for 5 days.

Population: 392 Patients with COVID-19, confirmed by RT-PCR (Real Time polymerase chain reaction), symptomatic in the early phase of the disease.

Calculation of the sample size was based on a previous study which demonstrated that 78% of Covid-19 patients in group 4 (Hospitalized without oxygen therapy), according to the WHO ordinal classification, experienced complete resolution of symptoms after receiving placebo.10 In the present trial, patients were classified as group 2 (Symptomatic and independent), and a greater degree of recovery as measured by symptom-free days (80%) was expected even after placebo. Thus, assuming an 11% increase in symptom-free days in those patients who would receive nitazoxanide compared to placebo, we would need approximately 196 patients per experimental group, admitting a beta error of 15% and alpha error of 5%, for a total n of 392 patients. Calculation of the sample size was done by G*Power 3.1.9.2 (Universität Düsseldorf, Düsseldorf, Germany).

• Study Type: Interventional
• Enrollment (Actual): 392
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Rio De Janeiro, Brazil, 21941902
    • Universidade Federal do Rio de Janeiro

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical scenario compatible with infection by the SARS-CoV-2 [Characteristic symptoms of COVID-19 (fever and / or cough and / or fatigue)
• Beginning 1 to 3 days before inclusion in the study
• Age equal or superior to 18 years
• Willingness to receive study treatment
• Providing written and informed consent or the same consent signed by a family member

Exclusion Criteria:

• Negative result of RT-PCR for SARS-COV2 collected on admission
• Impossibility to use oral medications
• History of severe liver disease (Child Pugh C class)
• Previous renal failure
• Severe heart failure (NYHA 3 or 4)
• COPD (GOLD 3 and 4)
• Neoplasia in the last 5 years
• Known autoimmune disease
• Individuals with known hypersensitivity to study drug
• Previous treatment with the study medication during the last 30 days
• Clinical suspicion of tuberculosis and bacterial pneumonia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nitazoxanide; Patients received nitazoxanide 500mg 8/8hours, for 5 days.	Drug: Nitazoxanide; Nitazoxanide 500mg 8/8 hours for 5 days in the early clinical phase of COVID-19.; Other Names: azox; annita; irose; tanisea; trinida; zoxany
Placebo Comparator: Placebo; Patients received placebo 500mg 8/8hours, for 5 days.	Drug: Placebo; Placebo 8/8 hours for 5 days in the early clinical phase of COVID-19.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days with fever	Reduction in the duration of fever of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide compared to patients treated with placebo; verified through the collection of information with the patient; quantified by the number of days that presented the symptom.	Day8
Days with cough	Reduction in the duration of cough of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide compared to patients treated with placebo; verified through the collection of information with the patient; quantified by the number of days that presented the symptom.	Day8
Days with asthenia	Reduction in the duration of asthenia of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide compared to patients treated with placebo; verified through the collection of information with the patient; quantified by the number of days that presented the symptom.	Day8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SARS-COV-2 viral load - absolute number	Compare the evolution of viral load in naso- and oropharyngeal swab in patients with COVID-19 treated with nitazoxanide or placebo on day 1; verified using the RT-PCR technique; quantified by the absolute number	Day1
SARS-COV-2 viral load - absolute number	Compare the evolution of viral load in naso- and oropharyngeal swab in patients with COVID-19 treated with nitazoxanide or placebo on day 8; verified using the RT-PCR technique; quantified by the absolute number.	Day8
SARS-COV-2 viral load - percentage	Compare the evolution of viral load in naso- and oropharyngeal swab in patients with COVID-19 treated with nitazoxanide or placebo on day 1; verified using the RT-PCR technique; quantified by the percentage change between the two groups.	Day 1
SARS-COV-2 viral load - percentage	Compare the evolution of viral load in naso- and oropharyngeal swab in patients with COVID-19 treated with nitazoxanide or placebo on day 8; verified using the RT-PCR technique; quantified by the percentage change between the two groups.	Day 8
Hospital admission rate - absolute number	Compare the hospital admission rate of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, in the period of 8 days; verified by information actively collected from patients or family members; quantified by absolute number.	Day8
Hospital admission rate - percentage	Compare the hospital admission rate of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, in the period of 8 days; verified by information actively collected from patients or family members; quantified by percentage.	Day8
Serum Interleukin-6	Compare the levels of inflammatory mediators: (interleukin [IL] -6 from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 3; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 3
Serum Interleukin-6	Compare the levels of inflammatory mediators: (interleukin [IL] -6 from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 8; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 8
Serum Interleukin-1-beta	Compare the levels of inflammatory mediators: IL-1-beta from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 3; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 3
Serum Interleukin-1-beta	Compare the levels of inflammatory mediators: IL-1-beta from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 8; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 8
Serum Interleukin-8	Compare the levels of inflammatory mediators: IL-8 from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 3; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 3
Serum Interleukin-8	Compare the levels of inflammatory mediators: IL-8 from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 8; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 8
Serum tumor necrosis factor (TNF)-alfa	Compare the levels of inflammatory mediators: tumor necrosis factor (TNF)-alfa from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 3; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 3
Serum tumor necrosis factor (TNF)-alfa	Compare the levels of inflammatory mediators: tumor necrosis factor (TNF)-alfa from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 8; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 8
Serum interferon-gamma	Compare the levels of inflammatory mediators: interferon-gamma from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 3; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 3
Serum interferon-gamma	Compare the levels of inflammatory mediators: interferon-gamma from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 8; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 8
Serum monocyte chemoattractant protein (MCP)-1	Compare the levels of inflammatory mediators: monocyte chemoattractant protein (MCP)-1 from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 3; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 3
Serum monocyte chemoattractant protein (MCP)-1	Compare the levels of inflammatory mediators: monocyte chemoattractant protein (MCP)-1 from patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 8; verified by the measurement of cytokines in patient serum by the ELISA technique; quantified by the absolute number between the two groups.	Day 8
Complete blood count	Evaluate evolution of complete blood count with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 3; verified by laboratory tests and expressed by the absolute number between the two groups.	Day 3
Complete blood count	Evaluate evolution of complete blood count with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 8; verified by laboratory tests and expressed by the absolute number between the two groups.	Day 8
C-reactive protein - absolute number	To evaluate the levels of C-reactive protein (CRP) of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 3; verified by laboratory tests and expressed by the absolute number between the two groups.	Day 3
C-reactive protein - absolute number	To evaluate the levels of C-reactive protein (CRP) of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 8; verified by laboratory tests and expressed by the absolute number between the two groups.	Day 8
C-reactive protein - percentage	To evaluate the levels of C-reactive protein (CRP) of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 3; verified by laboratory tests and expressed by the percentage between the two group.	Day 3
C-reactive protein - percentage	To evaluate the levels of C-reactive protein (CRP) of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 8; verified by laboratory tests and expressed by the percentage between the two groups.	Day 8

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events - percentage	Assess the incidence and profile of adverse events reported throughout the study, by treatment group; verified by information actively collected from patients or family members; quantified by percentage.	Day 8
Adverse events - absolute number	Assess the incidence and profile of adverse events reported throughout the study, by treatment group; verified by information actively collected from patients or family members; quantified by absolute number.	Day8
Treatment discontinuation rate - absolute number	Assess the rate of treatment discontinuation due to adverse events; verified by information actively collected from patients or family members; quantified by absolute number.	Day8
Treatment discontinuation rate - percentage	Assess the rate of treatment discontinuation due to adverse events; verified by information actively collected from patients or family members; quantified by percentage.	Day8

Collaborators and Investigators

• Sponsor: Universidade Federal do Rio de Janeiro
• Collaborators: National Research Council, Brazil; Ministry of Science and Technology, Brazil; ATCGen; Complexo Hospitalar Municipal de São Caetano do Sul; Hospital de Transplante Doutor Euryclides de Jesus Zerbini; Secretaria Municipal de Saúde de Bauru; Santa Casa de Misericórdia de Sorocaba; Secretaria Municipal de Saúde de Guarulhos; Hospital e Maternidade Therezinha de Jesus; Secretaria de Estado de Saúde do Distrito Federal
• Investigators: Principal Investigator: Patricia RM Rocco, MD, PhD, Universidade Federal do Rio de Janeiro

Publications and helpful links

General Publications

• 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.
• Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health. 2016 May-Jun;9(3):227-30. doi: 10.1016/j.jiph.2016.04.001. Epub 2016 Apr 16.
• Rajoli RK, Pertinez H, Arshad U, Box H, Tatham L, Curley P, Neary M, Sharp J, Liptrott NJ, Valentijn A, David C, Rannard SP, Aljayyoussi G, Pennington SH, Hill A, Boffito M, Ward SA, Khoo SH, Bray PG, O'Neill PM, Hong WD, Biagini G, Owen A. Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis. medRxiv. 2020 May 6:2020.05.01.20087130. doi: 10.1101/2020.05.01.20087130. Preprint.
• Pepperrell T, Pilkington V, Owen A, Wang J, Hill AM. Review of safety and minimum pricing of nitazoxanide for potential treatment of COVID-19. J Virus Erad. 2020 Apr 30;6(2):52-60. doi: 10.1016/S2055-6640(20)30017-0.

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2020
• Primary Completion (Actual): August 20, 2020
• Study Completion (Actual): September 5, 2020

Study Registration Dates

• First Submitted: September 9, 2020
• First Submitted That Met QC Criteria: September 15, 2020
• First Posted (Actual): September 17, 2020

Study Record Updates

• Last Update Posted (Actual): November 3, 2020
• Last Update Submitted That Met QC Criteria: November 1, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: treatment; COVID-19; covid19; coronavirus; nitazoxanide; early treatment; new coronavirus; brazil
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections; Anti-Infective Agents; Antiparasitic Agents; Nitazoxanide
• Other Study ID Numbers: SARITA-2; RBR-4nr86m (Other Identifier: Registro Brasileiro de Ensaios Clínicos (REBEC)); 32258920.0.1001.5257 (Other Identifier: Comitê Nacional de Ética em Pesquisa (CONEP))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The investigators plan on sharing all IPD that underlie results in a publication for editorial board, with cautious of not sharing confidential data.
• IPD Sharing Time Frame: Available as soon as the editorial board of the journal accepting the manuscript requires.
• IPD Sharing Access Criteria: Editorial board of the Journal accepting the manuscript.
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No