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

• Sponsor: Universidade Federal do Rio de Janeiro (Other)
• Overall Status: Completed
• CT.gov ID: NCT04552483
• Collaborator: Ministry of Science and Technology, Brazil (Other), National Research Council, Brazil (Other), ATCGen (Other), Complexo Hospitalar Municipal de São Caetano do Sul (Other), Hospital de Transplante Doutor Euryclides de Jesus Zerbini (Other), Secretaria Municipal de Saúde de Bauru (Other), Santa Casa de Misericórdia de Sorocaba (Other), Secretaria Municipal de Saúde de Guarulhos (Other), Hospital e Maternidade Therezinha de Jesus (Other), Secretaria de Estado de Saúde do Distrito Federal (Other)
• Enrollment: 392
• Location: 1
• Arms: 2
• Actual Duration (Months): 2.9
• Patients Per Site Per Month: 134.1

Study Details

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
• 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.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: Jun 8, 2020
• Actual Primary Completion Date: Aug 20, 2020
• Actual Study Completion Date: Sep 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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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;:.
• 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.

• 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; 32258920.0.1001.5257
• First Posted: Sep 17, 2020
• Last Update Posted: Nov 3, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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, Clinical Investigator, Universidade Federal do Rio de Janeiro: covid19; coronavirus; early treatment; COVID-19; new coronavirus; treatment; brazil; nitazoxanide
• Additional relevant MeSH terms: COVID-19; Coronavirus Infections; Nitazoxanide

Study Results

No Results Posted as of Nov 3, 2020