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

• ClinicalTrials.gov Identifier: NCT04552483
• Recruitment Status: Completed
• First Posted: September 17, 2020
• Last Update Posted: November 3, 2020
• Sponsor: Universidade Federal do Rio de Janeiro
• Collaborators: Ministry of Science and Technology, Brazil; National Research Council, 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
• Information provided by (Responsible Party): Jose Roberto Lapa e Silva, Universidade Federal do Rio de Janeiro

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Covid19; Coronavirus	Drug: Nitazoxanide; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 392 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Patients diagnosed with COVID-19 will be randomly divided into 2 groups: experimental and control groups.

Experimental group: 196 patients diagnosed with COVID-19 confirmed by RT-PCR will receive nitazoxanide 500mg 8/8 hs for 5 days. Control group: 196 patients diagnosed with COVID-19 confirmed by RT-PCR will receive placebo 8/8 hs for 5 days.

• Masking: Double (Participant, Care Provider)
• Masking Description: Patients were randomly allocated into one of the two groups: A or B. Patients received labelled medication: A or B, by the pharmacist. Patients received an identification number, so care providers, outcomes assessors and investigators did not know anything regarding the patients' groups.
• Primary Purpose: Treatment
• Official Title: Effects of Nitazoxanide Administration to Patients in the Initial Phase of COVID-19
• Actual Study Start Date: June 8, 2020
• Actual Primary Completion Date: August 20, 2020
• Actual Study Completion Date: September 5, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Days with fever [ Time Frame: Day8 ]
   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.
2. Days with cough [ Time Frame: Day8 ]
   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.
3. Days with asthenia [ Time Frame: Day8 ]
   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.

Secondary Outcome Measures :

1. SARS-COV-2 viral load - absolute number [ Time Frame: Day1 ]
   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
2. SARS-COV-2 viral load - absolute number [ Time Frame: Day8 ]
   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.
3. SARS-COV-2 viral load - percentage [ Time Frame: Day 1 ]
   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.
4. SARS-COV-2 viral load - percentage [ Time Frame: Day 8 ]
   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.
5. Hospital admission rate - absolute number [ Time Frame: Day8 ]
   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.
6. Hospital admission rate - percentage [ Time Frame: Day8 ]
   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.
7. Serum Interleukin-6 [ Time Frame: Day 3 ]
   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.
8. Serum Interleukin-6 [ Time Frame: Day 8 ]
   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.
9. Serum Interleukin-1-beta [ Time Frame: Day 3 ]
   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.
10. Serum Interleukin-1-beta [ Time Frame: Day 8 ]
    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.
11. Serum Interleukin-8 [ Time Frame: Day 3 ]
    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.
12. Serum Interleukin-8 [ Time Frame: Day 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.
13. Serum tumor necrosis factor (TNF)-alfa [ Time Frame: Day 3 ]
    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.
14. Serum tumor necrosis factor (TNF)-alfa [ Time Frame: Day 8 ]
    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.
15. Serum interferon-gamma [ Time Frame: Day 3 ]
    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.
16. Serum interferon-gamma [ Time Frame: Day 8 ]
    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.
17. Serum monocyte chemoattractant protein (MCP)-1 [ Time Frame: Day 3 ]
    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.
18. Serum monocyte chemoattractant protein (MCP)-1 [ Time Frame: Day 8 ]
    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.
19. Complete blood count [ Time Frame: Day 3 ]
    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.
20. Complete blood count [ Time Frame: Day 8 ]
    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.
21. C-reactive protein - absolute number [ Time Frame: Day 3 ]
    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.
22. C-reactive protein - absolute number [ Time Frame: Day 8 ]
    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.
23. C-reactive protein - percentage [ Time Frame: Day 3 ]
    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.
24. C-reactive protein - percentage [ Time Frame: Day 8 ]
    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.

Other Outcome Measures:

1. Adverse events - percentage [ Time Frame: Day 8 ]
   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.
2. Adverse events - absolute number [ Time Frame: Day8 ]
   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.
3. Treatment discontinuation rate - absolute number [ Time Frame: Day8 ]
   Assess the rate of treatment discontinuation due to adverse events; verified by information actively collected from patients or family members; quantified by absolute number.
4. Treatment discontinuation rate - percentage [ Time Frame: Day8 ]
   Assess the rate of treatment discontinuation due to adverse events; verified by information actively collected from patients or family members; quantified by percentage.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Brazil

Universidade Federal do Rio de Janeiro

Rio De Janeiro, Brazil, 21941902

Sponsors and Collaborators

Universidade Federal do Rio de Janeiro

Ministry of Science and Technology, Brazil

National Research Council, 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

More Information

Publications:

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. Review.

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. Review.

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. pii: 2020.05.01.20087130. doi: 10.1101/2020.05.01.20087130. Update in: Br J Clin Pharmacol. 2020 Oct 21;:.

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.

• Responsible Party: Jose Roberto Lapa e Silva, Clinical Investigator, Universidade Federal do Rio de Janeiro
• ClinicalTrials.gov Identifier: NCT04552483
• 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) )
• First Posted: September 17, 2020
• Last Update Posted: November 3, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Time Frame: Available as soon as the editorial board of the journal accepting the manuscript requires.
• Access Criteria: Editorial board of the Journal accepting the manuscript.

• 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

Keywords provided by Jose Roberto Lapa e Silva, Universidade Federal do Rio de Janeiro:

covid19; coronavirus; early treatment; COVID-19; new coronavirus; treatment; brazil; nitazoxanide

Additional relevant MeSH terms:

Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Nitazoxanide; Antiparasitic Agents; Anti-Infective Agents