Nitazoxanide Therapy for Patients With COVID-19 Pneumonia

• ClinicalTrials.gov Identifier: NCT04561219
• Recruitment Status: Completed
• First Posted: September 23, 2020
• Last Update Posted: October 28, 2020
• Sponsor: Universidade Federal do Rio de Janeiro
• Collaborators: Ministry of Science and Technology, Brazil; National Research Council, Brazil; Financiadora de Estudos e Projetos; ATCGen; Hospital Central da Aeronáutica, Rio de Janeiro; Hospital da Força Aérea do Galeão; Hospital Naval Marcilio Dias; Hospital Universitario Pedro Ernesto; Hospital de Força Aérea de São Paulo; Hospital das Clínicas Luzia de Pinho Melo; Complexo Hospitalar Municipal de São Caetano do Sul; Hospital Municipal de Barueri Dr Francisco Moran; Hospital Regional de Sorocaba Dr Adib Domingos Jatene; Hospital Geral de São Mateus Dr Manoel Bifulco; Santa Casa de Misericórdia de Belo Horizonte; Mater Dei Hospital, Brazil; Hospital Eduardo de Menezes; Hospital das Clínicas da Universidade Federal de Pernambuco; Hospital das Forças Armadas, Brazil; Hospital Regional da Asa Norte, Brazil; Complexo Hospitalar do Trabalhador de Curitiba; Hospital Estadual de Doenças Tropicais Dr Anuar Auad; Hospital Geral de Fortaleza
• 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: 500 Hospitalized patients with pneumonia derived from COVID-19 (Coronavirus Disease-19), either confirmed by RT-PCR (Real Time polymerase chain reaction), or suggested by typical findings on the computed tomography scan symptomatic.

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

Condition or disease	Intervention/treatment	Phase
Covid19; Corona Virus Infection; Pneumonia, Viral	Drug: Nitazoxanide; Drug: Placebo	Phase 2

Detailed Description:

SARITA-1 is a multicenter, randomized, placebo-controlled, parallel, blinded, interventional, treatment clinical trial with two arms, which aims to study the impact of nitazoxanide for hospitalized patients with pneumonia derived from COVID-19 (Coronavirus Disease-19) Experimental group: 250 patients received nitazoxanide 500mg 8 / 8 hours for 5 days. Control group: 250 patients received placebo 8/8 hours for 5 days.

Population: Patients with clinical symptoms of COVID-19: dyspnoea and/or fever and/or cough) and: either computed tomography scan suggestive of viral pneumonia or confirmatory molecular test by RT-PCR (Real Time polymerase chain reaction),

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Hospitalized patients with clinical signs of COVID-19, and either chest tomography scans suggestive of COVID-19 or confirmed by RT-PCR molecular tests, will be randomly divided into 2 groups: experimental and control groups.

Experimental group: 250 hospitalized patients diagnosed with COVID-19 derived pneumonia will receive nitazoxanide 500mg 8/8 hs for 5 days. Control group: 250 hospitalized patients diagnosed with COVID-19 derived pneumonia 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: Nitazoxanide for Moderate to Severe COVID-19 Pneumonia: a Multicenter, Randomized, Placebo-controlled, Double-Blind Clinical Trial
• Actual Study Start Date: April 19, 2020
• Actual Primary Completion Date: October 2, 2020
• Actual Study Completion Date: October 2, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Nitazoxanide; Patients received nitazoxanide 500mg 8/8hours, for 5 days.	Drug: Nitazoxanide; Nitazoxanide 500mg three times a day for 5 days; Other Names: annita; azox; irose; tanisea; trinida; zoxany
Placebo Comparator: Placebo; Patients received placebo 500mg 8/8hours, for 5 days	Drug: Placebo; Placebo three times a day for 5 days

Outcome Measures

Primary Outcome Measures :

1. Orotracheal intubation rate [ Time Frame: 14 days ]
   Compare the intubation 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 14 days; verified by clinical evolution; quantified by percentage.
2. Mechanical ventilation free days [ Time Frame: 14 days ]
   Compare the number of days patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, stayed free of mechanical ventilation, in the period of 14 days; verified by clinical evolution; quantified by absolute number.

Secondary Outcome Measures :

1. Hospitalisation days [ Time Frame: 14 days ]
   Compare the number of days patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, stayed at the hospital, in the period of 14 days; verified by clinical evolution; quantified by absolute number.
2. ICU days [ Time Frame: 14 days ]
   Compare the number of days patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, stayed at the ICU, in the period of 14 days; verified by clinical evolution; quantified by absolute number.
3. Intranasal oxygen support days [ Time Frame: 14 days ]
   Compare the number of days patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, stayed with the support of oxygen nasal cannula, in the period of 14 days; verified by clinical evolution; quantified by absolute number.
4. Mortality rate [ Time Frame: 14 days ]
   Compare the mortality 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 14 days; verified by clinical evolution; quantified by absolute number.
5. Days with fever [ Time Frame: 14 days ]
   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 clinica data; quantified by the number of days that presented the symptom.
6. Days with cough [ Time Frame: 14 days ]
   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 clinica data; quantified by the number of days that presented the symptom.
7. Days with dyspnea [ Time Frame: 14 days ]
   Reduction in the duration of dyspnea of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide compared to patients treated with placebo; verified through the collection of clinica data; quantified by the number of days that presented the symptom.
8. Radiologic findings [ Time Frame: Day1 ]
   Compare chest tomographic findings of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide compared to patients treated with placebo; verified through the collection of radiologic data; quantified by the number of patients that presented the a list of alterations.
9. Radiologic findings [ Time Frame: Day7 ]
   Compare chest tomographic findings of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide compared to patients treated with placebo; verified through the collection of radiologic data; quantified by the number of patients that presented the a list of alterations.
10. Cardiologic findings [ Time Frame: Day1 ]
    Compare echocardiographic findings of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide compared to patients treated with placebo; verified through the collection of echocardiographic data; quantified by the number of patients that presented the a list of alterations.
11. Cardiologic findings [ Time Frame: Day7 ]
    Compare echocardiographic findings of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide compared to patients treated with placebo; verified through the collection of echocardiographic data; quantified by the number of patients that presented the a list of alterations.
12. C-reactive protein - absolute number [ Time Frame: Day 1 ]
    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 1; verified by laboratory tests and expressed by the absolute number between the two groups.
13. C-reactive protein serum levels [ 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.
14. C-reactive protein serum levels [ Time Frame: Day 7 ]
    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 7; verified by laboratory tests and expressed by the absolute number between the two groups.
15. Lactate dehydrogenase (LDH) serum levels [ Time Frame: Day 1 ]
    To evaluate the levels of lactate dehydrogenase (LDH) of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
16. Lactate dehydrogenase (LDH) serum levels [ Time Frame: Day 3 ]
    To evaluate the levels of lactate dehydrogenase (LDH) 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.
17. Lactate dehydrogenase (LDH) serum levels [ Time Frame: Day 7 ]
    To evaluate the levels of lactate dehydrogenase (LDH) of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.
18. Troponin serum levels [ Time Frame: Day 1 ]
    To evaluate the levels of troponin of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
19. Troponin serum levels [ Time Frame: Day 3 ]
    To evaluate the levels of troponin 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.
20. Troponin serum levels [ Time Frame: Day 7 ]
    To evaluate the levels of troponin of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.
21. Electrolytes serum levels [ Time Frame: Day 1 ]
    To evaluate the levels of electrolytes of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
22. Electrolytes serum levels [ Time Frame: Day 3 ]
    To evaluate the levels of electrolytes 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.
23. Electrolytes serum levels [ Time Frame: Day 7 ]
    To evaluate the levels of electrolytes of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.
24. Glucose serum levels [ Time Frame: Day 1 ]
    To evaluate the levels of glucose of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
25. Glucose serum levels [ Time Frame: Day 3 ]
    To evaluate the levels of glucose 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.
26. Glucose serum levels [ Time Frame: Day 7 ]
    To evaluate the levels of glucose of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.
27. Renal function [ Time Frame: Day 1 ]
    To evaluate renal function of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
28. Renal function [ Time Frame: Day 3 ]
    To evaluate renal function 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.
29. Renal function [ Time Frame: Day 7 ]
    To evaluate renal function of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.
30. Coagulogram [ Time Frame: Day 1 ]
    To evaluate coagulogram of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
31. Coagulogram [ Time Frame: Day 3 ]
    To evaluate coagulogram 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.
32. Coagulogram [ Time Frame: Day 7 ]
    To evaluate coagulogram of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.
33. Liver function panel [ Time Frame: Day 1 ]
    To evaluate liver function panel of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
34. Liver function panel [ Time Frame: Day 3 ]
    To evaluate liver function panel 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.
35. Liver function panel [ Time Frame: Day 7 ]
    To evaluate liver function panel of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.
36. Ferritin [ Time Frame: Day 1 ]
    To evaluate ferritin of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
37. Ferritin [ Time Frame: Day 3 ]
    To evaluate ferritin 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.
38. Ferritin [ Time Frame: Day 7 ]
    To evaluate ferritin of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.
39. D-dimer [ Time Frame: Day 1 ]
    To evaluate D-dimer of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
40. D-dimer [ Time Frame: Day 3 ]
    To evaluate D-dimer 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.
41. D-dimer [ Time Frame: Day 7 ]
    To evaluate D-dimer of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.
42. Blood cell count [ Time Frame: 7 days ]
    To evaluate blood cell count of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, for 7 days; verified by laboratory tests and expressed by the absolute number between the two groups.
43. Inflammatory mediators [ Time Frame: Day 1 ]
    To evaluate D-dimer of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 1; verified by laboratory tests and expressed by the absolute number between the two groups.
44. Inflammatory mediators [ Time Frame: Day 3 ]
    To evaluate D-dimer 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.
45. Inflammatory mediators [ Time Frame: Day 7 ]
    To evaluate D-dimer of patients with COVID-19 submitted to the therapeutic protocol with nitazoxanide with patients with COVID-19 treated with placebo, on day 7; verified by laboratory tests and expressed by the absolute number between the two groups.

Other Outcome Measures:

1. Adverse events - percentage [ Time Frame: Day 14 ]
   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: Day 14 ]
   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: Day 14 ]
   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: Day 14 ]
   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) without respiratory failure (Saturation < 93% with nasal catheter of oxygen 5liters/minute) associated with chest tomographic images compatible with COVID-19.
• Clinical scenario compatible with infection by the SARS-CoV-2 [Characteristic symptoms of COVID-19 (fever and / or cough) without respiratory failure (Saturation < 93% with nasal catheter of oxygen 5liters/minute) associated with positive molecular test for COVID-19.
• Age equal or superior to 18 years
• Non-pregnant women
• Willingness to receive study treatment
• Providing written and informed consent or the same consent signed by a family member

Exclusion Criteria:

• 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

Financiadora de Estudos e Projetos

ATCGen

Hospital Central da Aeronáutica, Rio de Janeiro

Hospital da Força Aérea do Galeão

Hospital Naval Marcilio Dias

Hospital Universitario Pedro Ernesto

Hospital de Força Aérea de São Paulo

Hospital das Clínicas Luzia de Pinho Melo

Complexo Hospitalar Municipal de São Caetano do Sul

Hospital Municipal de Barueri Dr Francisco Moran

Hospital Regional de Sorocaba Dr Adib Domingos Jatene

Hospital Geral de São Mateus Dr Manoel Bifulco

Santa Casa de Misericórdia de Belo Horizonte

Mater Dei Hospital, Brazil

Hospital Eduardo de Menezes

Hospital das Clínicas da Universidade Federal de Pernambuco

Hospital das Forças Armadas, Brazil

Hospital Regional da Asa Norte, Brazil

Complexo Hospitalar do Trabalhador de Curitiba

Hospital Estadual de Doenças Tropicais Dr Anuar Auad

Hospital Geral de Fortaleza

Investigators

• Study Chair: Pedro L Silva, PhD; Universidade Federal do Rio de Janeiro
• 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: NCT04561219
• Other Study ID Numbers: SARITA-1; RBR-88bs9x ( Other Identifier: Registro Brasileiro de Ensaios Clínicos (REBEC) ); 30662420.0.1001.0008 ( Other Identifier: Comitê Nacional de Ética em Pesquisa (CONEP) )
• First Posted: September 23, 2020
• Last Update Posted: October 28, 2020
• Last Verified: October 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; Statistical Analysis Plan (SAP)
• 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

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

covid19; coronavirus; clinical trial; placebo-controlled; randomized; brazil; nitazoxanide; hospitalized patients; covid-19; sars-cov-2; new coronavirus; multicenter; double-blind

Additional relevant MeSH terms:

Coronavirus Infections; Severe Acute Respiratory Syndrome; Pneumonia, Viral; Pneumonia; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Nitazoxanide; Antiparasitic Agents; Anti-Infective Agents