Safety and Efficacy Study of Nitazoxanide in the Treatment of Acute Uncomplicated Influenza

A Randomized, Double-Blind, Placebo Controlled Study of Nitazoxanide in Adults and Adolescents With Acute Uncomplicated Influenza

This is a randomized clinical trial designed to evaluate the safety/efficacy of two dosing regimens of oral nitazoxanide compared to placebo in the treatment of acute uncomplicated influenza in adults and adolescents. The investigators hypothesize that treatment with Nitazoxanide will reduce the duration of symptoms in patients with confirmed influenza infection. Secondarily, the investigators hypothesize that treatment with nitazoxanide will reduce the complications of influenza, severity of symptoms, time lost from work, time to return to normal daily activities.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Drug: Nitazoxanide; Drug: Nitazoxanide; Drug: Placebo

Detailed Description

A Randomized, Double-Blind, Placebo Controlled Study of Nitazoxanide in Adults and Adolescents with Acute Uncomplicated Influenza. The primary objectives of this study are to demonstrate the efficacy of nitazoxanide administered 300 mg two times per day for 5 days or 600 mg two times per day for 5 days in reducing the time to resolution of all clinical symptoms of influenza.

The study will also evaluate pharmacokinetics of nitazoxanide in a subset of 24 patients and the safety of the nitazoxanide regimen compared to a placebo via analysis of adverse events and laboratory safety tests.

Blood samples will be collected for all patients at baseline, day 7 and day 28, and for a subset of 24 patients aged 18-65 years (pharmacokinetics subset) on day 2. Urine samples will be collected at baseline and day 7. Nasal swabs will be collected at baseline and day 7 for all patients and on days 2, 3, 4 and 5 for a subset of patients (approximately 20% of patients).

• Study Type: Interventional
• Enrollment (Actual): 624
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • New York
    • Elmira, New York, United States, 14901
      • Health Sciences Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

• age 12 to 65 years

• Presence of clinical signs, respiratory symptoms and constitutional symptoms compatible with influenza infection:

  1. fever,
  2. at least one of the following respiratory symptoms: cough, sore throat, nasal discharge, nasal congestion, sneezing.
  3. At least one of the following constitutional symptoms: headache, myalgia, seats, chills, fatigue of any severity (mild, moderate, severe)
• Confirmation of Influenza A or B infection in the local community
• Onset of illness no more than 48 hours before presentation. Time of onset of illness is defined as either the earlier of (1) the time when the temperature was first measured as elevated, or (2) the time when the patient experienced the presence of at least one respiratory symptom AND the presence of at least one constitutional symptom.
• willing and able to comply with protocol requirements and provide informed consent

EXCLUSION CRITERIA:

• severity of illness requiring or anticipated to require in-hospital care

• High risk of complications from influenza as follows:

  1. persons with asthma or other chronic pulmonary diseases
  2. persons with hemodynamically significant cardiac disease
  3. persons who have immunosuppressive disorders or receiving immunosuppressive therapy
  4. persons infected with Human Immunodeficiency Virus (HIV)
  5. persons with sickle cell anemia or other hemoglobinopathies
  6. persons with diseases requiring long-term aspirin therapy
  7. persons with chronic renal dysfunction
  8. persons with liver disorders
  9. Persons with cancer
  10. Persons with chronic metabolic disease such as diabetes and inherited mitochondrial disorders
  11. Persons with neuromuscular disorders, seizure disorders, or cognitive dysfunction
  12. Residents of any age of nursing homes or long-term institutions.
• Females of child bearing age who are pregnant, breastfeeding or sexually active without birth control
• vaccination for influenza or H1N1 (Swine Flu) on or after August 1, 2010
• treatment with antiviral medication such as oseltamivir, zanamivir, amantadine, or rimantadine within 30 days of screening.
• Prior treatment with nitazoxanide within 30 days prior to screening.
• subjects with active respiratory allergies or expected to require anti-allergy medications during the study period.
• known sensitivity to nitazoxanide
• subjects unable to take oral medication
• subjects with chronic kidney or liver disease
• Presence of any other pre-existing chronic infection that is undergoing or requiring medical therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nitazoxanide, Placebo; 300 mg nitazoxanide tablet and 1 placebo tablet twice daily for 5 days	Drug: Nitazoxanide; Tablets, 300 mg (one 300 mg tablet + 1 placebo tablet) with food twice daily for 5 days; Other Names: Alinia, NTZ; Drug: Nitazoxanide; Tablets, 600 mg (two 300 mg tablets) with food twice daily for 5 days; Other Names: Alinia, NTZ
Active Comparator: Nitazoxanide, Nitazoxanide; Two 300 mg nitazoxanide tablets(600mg) twice daily for 5 days	Drug: Nitazoxanide; Tablets, 300 mg (one 300 mg tablet + 1 placebo tablet) with food twice daily for 5 days; Other Names: Alinia, NTZ; Drug: Nitazoxanide; Tablets, 600 mg (two 300 mg tablets) with food twice daily for 5 days; Other Names: Alinia, NTZ
Placebo Comparator: Placebo; 2 placebo tablets twice daily for 5 days	Drug: Placebo; Tablets, (2 tablets) twice daily with food for 5 days; Other Names: Sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Resolution of All Clinical Symptoms of Influenza as Reported by the Subjects	The primary efficacy analysis for this study was to demonstrate the efficacy of Nitazoxanide (NTZ) administered as 300 mg b.i.d. for 5 days or 600 mg b.i.d. for 5 days in reducing the time to resolution of all clinical symptoms of influenza in patients with laboratory confirmed influenza infection	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects	Time in hours (Median and Interquartile range)	at least 28 days
Mean Change (Standard Deviation)in 50% Tissue Culture Infective Dose (TCID50) Viral Titer From Baseline	Change in viral titer presented as logarithm with base 10 (log10) 50% Tissue Culture Infective Dose (TCID50)	7 days
Mean Change in RT-PCR (Reverse Transcription Polymerase Chain Reaction) Viral Titer From Baseline	Change in viral titer logarithm with base 10 (log10) Ribonucleic Acid (RNA)copies	7 days
Time to Cessation of Viral Shedding Measure by 50% Tissue Culture Infective Dose (TCID50)	Median time in hours	28 days
Time to Return to Normal Daily Activities	Time in hours as reported by patient	28 days
Symptom Severity Score Hours	Sum of the symptom severity score hours from first dose to resolution of symptoms. Patients rated each symptom's severity on a score from 0 to 3 (0=absent, 1=mild, 2=moderate, 3=severe). Total symptom severity score hours were calculated by multiplying the sum of the severity scores by duration of symptoms.	28 days
Time Loss From Work	Time loss from work	28 days
Complications of Influenza	Proportion of patients with a complication of influenza during the course of the study	28 days
Influenza Antibody Response Titer Change: Influenza A 2009 H1N1	change in influenza antibody titer for Influenza A 2009 H1N1	28 days
Influenza Antibody Response: Influenza A H3N2	Change in antibody titer for Influenza A H3N2	28 days
Influenza Antibody Response: Influenza B	Change in antibody titer for Influenza B	28 days
Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A 2009 H1N1	Proportion of patients seroprotected or seroconverted at day 28	28 days
Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A H3N2	Proportion of patients seroprotected and seroconverted at day 28	28 days
Influenza Antibody Response: Seroprotection and Seroconversion for Influenza B	Proportion of patients seroprotected and seroconverted at day 28	28 days

Collaborators and Investigators

• Sponsor: Romark Laboratories L.C.
• Investigators: Study Director: Jean-Francois Rossignol, M.D., Ph.D., Romark Laboratories L.C.

Publications and helpful links

General Publications

• Haffizulla J, Hartman A, Hoppers M, Resnick H, Samudrala S, Ginocchio C, Bardin M, Rossignol JF; US Nitazoxanide Influenza Clinical Study Group. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 2014 Jul;14(7):609-18. doi: 10.1016/S1473-3099(14)70717-0. Epub 2014 May 19.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: October 21, 2010
• First Submitted That Met QC Criteria: October 22, 2010
• First Posted (Estimated): October 25, 2010

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: September 28, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: influenza
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Anti-Infective Agents; Antiparasitic Agents; Nitazoxanide
• Other Study ID Numbers: RM08-3001