Nitazoxanide Versus Placebo for the Treatment of Hospitalized Subjects With Severe Acute Respiratory Illness (NTZ-SARI)

A Randomized Double-Blind Phase 2 Study Comparing the Efficacy, Safety, and Tolerability of Nitazoxanide Versus Placebo in Addition to Standard Care for the Treatment of Hospitalized Subjects With Severe Acute Respiratory Illness

Respiratory viruses are a significant cause of hospitalization for respiratory tract infections. This study will evaluate the safety, effectiveness, and tolerability of nitazoxanide (NTZ) in treating severe acute respiratory illness (SARI) in people who are hospitalized.

Study Overview

• Status: Completed
• Conditions: Severe Acute Respiratory Illness
• Intervention / Treatment: Drug: Nitazoxanide; Drug: Placebo

Detailed Description

Respiratory viral infections are one of the most common causes of illness in the world. These infections are major causes of SARI and can lead to severe outcomes, including hospitalization and death. NTZ is a medication that is approved in the United States and Mexico to treat gastrointestinal parasitic diseases. This study will evaluate the use of NTZ to treat SARI. The purpose of this study is to evaluate the safety, effectiveness, and tolerability of NTZ, in combination with standard care, in treating SARI in people who are hospitalized.

Participants will be hospitalized and study entry assessments will include medical assessments, blood collection, and a nasopharyngeal swab or wash. Participants will then be randomly assigned to receive NTZ or placebo for 5 days. Participants younger than 12 years will receive an oral suspension formulation of NTZ or placebo; participants 12 years and older will receive NTZ or placebo tablets. All participants will also receive standard of care treatment for acute severe viral respiratory infections, which may include antibiotics and/or treatment for influenza. They will be discharged from the hospital based on their doctors' recommendations. Participants will record their temperature and symptoms in a daily diary, which will be reviewed by study staff during study visits. Follow-up visits will occur on Days 3, 7, 14, and 28, and may occur as inpatient or outpatient visits. These visits may include the same assessments that occurred at baseline, as well as physical examinations, depending on the visit. Participants who are still hospitalized at Day 28 will be followed by study staff until they are discharged from the hospital.

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 2

Contacts and Locations

Study Locations

• Mexico
  • Coyoacan, Mexico, 04530
    • Instituto Nacional de Pediatría
  • Oaxaca, Mexico, 68050
    • Hospital General Dr. Aurelio Valdivieso
  • San Luis Potosi, Mexico, 78240
    • Hospital Central Dr. Ignacio Morones Prieto
  • Tamaulipas, Mexico, 06720
    • Hospital Infantil de Mexico Federico Gomez
  • Tlalpan, Mexico, 14000
    • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
  • Tlalpan, Mexico, 14000
    • Instituto Nacional de Enfermedades Respiratorias

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent prior to performance or initiation of any study procedures
• Age greater than or equal to 12 months of age (no upper age limit)

• Influenza-like illness (ILI), defined as (all of the following):

  • Onset of fever greater than or equal to 38°C (or hypothermia less than 36°C)
  • New or worse cough or sore throat
  • New or worse shortness of breath or difficulty breathing
• Onset of illness no more than 5 days before screening defined as when the participant experienced at least 1 respiratory symptom, constitutional symptom, or fever
• Hospitalization for ILI (decision for hospitalization will be up to the individual treating clinician), with anticipated hospitalization for more than 24 hours

• One of the following to avoid pregnancy:

  • Females who are able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use at least 1 effective form of contraception from the date of informed consent through Day 28 of study
  • Males who have not undergone surgical sterilization and are sexually active with women must agree to use condoms or have a partner use at least 1 effective form of contraception through Day 28 of study

Exclusion Criteria:

• Women who are pregnant or breastfeeding
• Clinical suspicion that etiology of illness is primarily bacterial in origin
• Prior treatment with antivirals (e.g., oseltamivir) for the current illness for more than 24 hours
• Unable to take oral medications (adults must tolerate tablets, children must tolerate suspension)
• Unable to tolerate oral food/fluids (absorption is significantly better with food)
• Prior treatment with any investigational drug therapy within 30 days prior to screening
• Known sensitivity to NTZ or any of the excipients comprising the NTZ tablets
• Prior NTZ use within 1 week
• Self-reported history of chronic kidney disease or impaired renal function (no blood or urine kidney function laboratory testing will be done prior to enrollment, but intent is to exclude disease severe enough to cause estimated creatinine clearance [CrCl] less than 30)
• Self-reported history of liver disease (no blood laboratory testing will be done prior to enrollment, but intent is to exclude disease severe enough to cause cirrhosis or total bilirubin greater than 2, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] greater than 3 times the upper limit of normal [ULN])
• Presence of any pre-existing illness that, in the opinion of the investigator, would place the participant at an unreasonably increased risk through participation in this study
• Participants who, in the judgment of the investigator, will be unlikely to comply with the requirements of this protocol
• The onset of SARI occurs after hospitalization
• Hospitalized for any reason for greater than 48 hours prior to enrollment
• Participants previously enrolled in this study
• Prior hospital discharge within 30 days
• Known chronic respiratory infection (e.g., tuberculosis, atypical mycobacterial infections)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Nitazoxanide (NTZ); Participants will receive NTZ for 5 days. Participants younger than 12 years will receive an oral suspension formulation of NTZ; participants 12 years and older will receive NTZ tablets.	Drug: Nitazoxanide; Participants 1 to 3 years old: 5 mL oral suspension (100 mg NTZ) every 12 hours for 5 days. Participants 4 to 11 years old: 10 mL oral suspension (200 mg NTZ) every 12 hours for 5 days. Participants 12 years and older: two 300-mg NTZ tablets orally twice daily for 5 days.; Other Names: NTZ
PLACEBO_COMPARATOR: Placebo; Participants will receive placebo for 5 days. Participants younger than 12 years will receive an oral suspension formulation of placebo; participants 12 years and older will receive placebo tablets.	Drug: Placebo; Participants 1 to 3 years old: 5 mL placebo oral suspension every 12 hours for 5 days. Participants 4 to 11 years old: 10 mL placebo oral suspension every 12 hours for 5 days. Participants 12 years and older: two placebo tablets orally twice daily for 5 days.; Other Names: PCB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Hospital Discharge	The time to hospital discharge measured through Day 28.	Measured through Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Hospitalized on Days 3, 7, 14, and 28	The number of study participants (e.g., adults and children) who were hospitalized on Days 3, 7, 14, and 28.	Measured at Day 3, Day 7, Day 14, and Day 28
Number of Participants Who Died Within the First 5 Days	Total Deaths of Participants, including Deaths within First 5 Days	Measured within First 5 Days
Number of Participants Who Experienced Clinical Symptoms	Measured daily through Study Day 14 and then again on Study Day 28	Measured through Day 28
Duration of Fever in Study Participants	Study participants' duration (hours) of fever measured daily through Day 14 and then again on Day 28. The total duration in hours from the visit when fever was registered for the study participant until the next visit when no fever was registered for the study participant.	Measured each day through Day 14 and on Day 28
Number of Participants Who Require Oxygen Use	Number of study participants who require use of supplemental oxygen at time points (e.g., Any time, Day 0, Day 3, Day 7, Day 14, and Day 28)	Measured through Day 28 or participants' last day of hospitalization
Number of Study Participants (e.g., Adult and Children) Admitted to the Intensive Care Unit (ICU) by Time Point (Anytime, Day 0, Day 3, Day 7, Day 14, Day 28)	Number of study participants (e.g., adult and children) admitted to the intensive care unit (ICU) by time point (Anytime, Day 0, Day 3, Day 7, Day 14, Day 28); worst case imputed.	Measured through Day 28 or participants' last day in the ICU
Study Participants (e.g., Adults, Children) Requiring Mechanical Ventilation at Study Time Points (Any Time, Day 0, Day 3, Day 7, Day 14, Day 28)	Study participants (e.g., adults, children) requiring mechanical ventilation (e.g., intubation/extubation) at study time points (Any Time, Day 0, Day 3, Day 7, Day 14, Day 28); worst case imputed.	Measured through Day 28 or participants' last day of hospitalization
Number of Study Participants With the Presence of Complications (Pneumonia, Respiratory Failure Requiring Mechanical Ventilation, Acute Respiratory Distress Syndrome [ARDS], Sepsis, or Bronchiolitis) During Study	Number of study participants (e.g., adults and children) with the presence of a complication (pneumonia, respiratory failure requiring mechanical ventilation, acute respiratory distress syndrome [ARDS], sepsis, or bronchiolitis) during the study .	Measured through Day 28 or participants' last day of hospitalization
Duration (Days) Until Affirmative Global Assessment (e.g., Answered Yes) by Study Participants (e.g., Adults, Children)	Study participant (e.g., adults and children) answers (e.g., yes) to global assessment questions measured daily through Day 14 and then again on Day 28.	Measured daily through Day 14 and on Day 28
Number of Participants Using Antibiotics/Antivirals During Hospitalization	Number of study participants taking an Antibiotic or Anti-Influenza Antiviral during first 5 days of hospitalization.	Measured through participants' first 5 days of hospitalization
Number of Participants Who Are Re-hospitalized Within 28 Days	Number of study participants (e.g., adults and children) who were re-hospitalized within 28 days (e.g., days from randomization).	Measured through Day 28
Use of Systemic Corticosteroids	Number of study participants taking Systemic Steroids during first 5 days.	Measured within First 5 Days
Presence of Virus on Nasopharyngeal (NP) Swab at Day 3 (Same Virus as Day 0)	Study participants with Detectable Virus on nasopharyngeal (NP) swab at Baseline and at Day 3.	Measured through Day 3
Number of Participants Reporting Adverse Events (AEs)	Number of study participants with at least one Adverse Event During Study Duration	Measured through Day 28 or participants' last day of hospitalization
Number of Participants Reporting Serious Adverse Events (SAEs)	Number of study participants (e.g., adults and children) reporting at least one serious adverse events (SAEs).	Measured through Day 28 or participants' last day of hospitalization
Chemistry Laboratory Assessments (Creatinine, Total Bilirubin) on Days 3, 7, and 28	Laboratory values for chemistry laboratory assessments (e.g., Creatinine and Total Bilirubin) on Days 3, 7, and 28.	Measured on Day 3, Day, 7 and Day 28
Chemistry Laboratory Assessments (ALT, AST, LDH) on Days 3, 7, and 28	Chemistry laboratory assessments (e.g., ALT, AST, and LDH) on Days 3, 7, and 28.	Measured on Day 3, Day 7, and Day 28
Chemistry Laboratory Assessment (CRP) on Days 3, 7, and 28	Lab Values for chemistry laboratory assessment (e.g., CRP) on Days 3, 7, and 28.	Measured on Day 3, Day, 7 and Day 28
Hematologic Laboratory Assessments (Neutrophils, Lymphocytes, Eosinophils, and Hematocrit) on Days 3, 7, and 28	Hematology laboratory assessments (e.g., Neutrophils, Lymphocytes, Eosinophils, and Hematocrit) on Days 3, 7, and 28.	Measured on Day 3, Day, 7 and Day 28
Hematologic Laboratory Assessment (Hemoglobin) on Days 3, 7, and 28	Hematology laboratory assessment (e.g., Hemoglobin) on Days 3, 7, and 28.	Measured on Day 3, Day, 7 and Day 28
Hematologic Laboratory Assessments (WBC, Platelets) on Days 3, 7, and 28	Lab values for hematology laboratory assessments (e.g., WBC and Platelets) on Days 3, 7, and 28.	Measured on Day 3, Day, 7 and Day 28

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Mexican Emerging Infectious Diseases Clinical Research Network
• Investigators: Study Chair: Lourdes Guerrero Almeida, M.D., Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Study Chair: Ana Gamiño, M.D., Hospital Infantil de Mexico Federico Gomez; Principal Investigator: Arturo Galindo Fraga, M.D., Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Principal Investigator: Sarbelio Moreno, M.D., Hospital Infantil de Mexico Federico Gomez; Principal Investigator: Javier Araujo Melendez, M.D., Hospital Central "Dr. Ignacio Morones Prieto"; Principal Investigator: Alejandra Ramirez Venegas, M.D., Instituto Nacional de Enfermedades Respiratorias; Principal Investigator: Beatriz Llamosas Gallardo, M.D., Instituto Nacional de Pediatría; Principal Investigator: Yuri Roldan Aragon, M.D., Hospital General Dr. Aurelio Valdivies

Publications and helpful links

General Publications

• Gamino-Arroyo AE, Guerrero ML, McCarthy S, Ramirez-Venegas A, Llamosas-Gallardo B, Galindo-Fraga A, Moreno-Espinosa S, Roldan-Aragon Y, Araujo-Melendez J, Hunsberger S, Ibarra-Gonzalez V, Martinez-Lopez J, Garcia-Andrade LA, Kapushoc H, Holley HP, Smolskis MC, Ruiz-Palacios GM, Beigel JH; Mexico Emerging Infectious Diseases Clinical Research Network (LaRed). Efficacy and Safety of Nitazoxanide in Addition to Standard of Care for the Treatment of Severe Acute Respiratory Illness. Clin Infect Dis. 2019 Nov 13;69(11):1903-1911. doi: 10.1093/cid/ciz100.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (ACTUAL): May 1, 2017
• Study Completion (ACTUAL): January 1, 2018

Study Registration Dates

• First Submitted: February 5, 2014
• First Submitted That Met QC Criteria: February 5, 2014
• First Posted (ESTIMATE): February 7, 2014

Study Record Updates

• Last Update Posted (ACTUAL): August 1, 2018
• Last Update Submitted That Met QC Criteria: July 30, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Infective Agents; Antiparasitic Agents; Nitazoxanide
• Other Study ID Numbers: NTZ-SARI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED