Nitazoxanide Versus Placebo for the Treatment of Hospitalized Subjects With Severe Acute Respiratory Illness

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Severe Acute Respiratory Illness

Intervention / Treatment
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* Drug: Nitazoxanide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitazoxanide (NTZ)<br>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<br>* 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.<br>* Other names: NTZ;|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>* Other names: PCB;|

What is the study measuring?
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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 |