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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nitazoxanide, Placebo | Active Comparator | 300 mg nitazoxanide tablet and 1 placebo tablet twice daily for 5 days |
|
| Nitazoxanide, Nitazoxanide | Active Comparator | Two 300 mg nitazoxanide tablets(600mg) twice daily for 5 days |
|
| Placebo | Placebo Comparator | 2 placebo tablets twice daily for 5 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nitazoxanide | Drug | Tablets, 300 mg (one 300 mg tablet + 1 placebo tablet) with food twice daily for 5 days |
|
| 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 |
| 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 |
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INCLUSION CRITERIA
age 12 to 65 years
Presence of clinical signs, respiratory symptoms and constitutional symptoms compatible with influenza infection:
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:
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
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| Name | Affiliation | Role |
|---|---|---|
| Jean-Francois Rossignol, M.D., Ph.D. | Romark Laboratories L.C. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Health Sciences Research Center | Elmira | New York | 14901 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24852376 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Nitazoxanide 300mg | 300 mg nitazoxanide twice daily with food for 5 days |
| FG001 | Placebo | placebo tablet twice daily with food for 5 days |
| FG002 | Nitazoxanide 600mg | 2X 300 mg controlled release tablet twice daily with food for five days |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Nitazoxanide 300mg | 300 mg nitazoxanide twice daily with food for 5 days |
| BG001 | Placebo | placebo tablet twice daily with food for 5 days |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | 624 patients were enrolled based on inclusion/exclusion criteria. The primary efficacy analysis was conducted on the 257 patients with laboratory confirmed influenza. | Posted | Median | Inter-Quartile Range | Hours | Up to 28 days |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Nitazoxanide 300mg | 300 mg nitazoxanide twice daily with food for 5 days |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| moderate pneumonia | Respiratory, thoracic and mediastinal disorders | Patient experienced influenza symptoms 18 hours prior to 600mg NTZ enrollment. Patient had Body Mass Index (BMI) 48.5, history of osteoarthritis & hypertension. Tests reveal 2009 H1N1. Investigator noted adverse event was not related to study drug. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Chromaturia | Renal and urinary disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Marc Ayers | Romark Laboratories, L.C. | 813-282-8544 | Marc.Ayers@romark.com |
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| ID | Term |
|---|---|
| D007251 | Influenza, Human |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D009976 | Orthomyxoviridae Infections |
| D012327 | RNA Virus Infections |
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| ID | Term |
|---|---|
| C041747 | nitazoxanide |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D002241 | Carbohydrates |
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| Nitazoxanide | Drug | Tablets, 600 mg (two 300 mg tablets) with food twice daily for 5 days |
|
|
| Placebo | Drug | Tablets, (2 tablets) twice daily with food for 5 days |
|
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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 |
| Withdrawal by Subject |
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| Protocol Violation |
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| Randomized in error |
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| BG002 | Nitazoxanide 600mg | 2X 300 mg controlled release tablet twice daily with food for five days |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
placebo tablet twice daily with food for 5 days |
| OG002 | Nitazoxanide 600mg | 2X 300 mg controlled release tablet twice daily with food for five days |
|
|
| Secondary | Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects | Time in hours (Median and Interquartile range) | 624 patients were enrolled based on inclusion/exclusion criteria. Secondary efficacy analyses were conducted on the 257 patients with laboratory confirmed influenza. | Posted | Median | Inter-Quartile Range | Hours | at least 28 days |
|
|
|
| Secondary | 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) | Analysis conducted on 113 patients from intensive virologic follow up group with laboratory confirmed influenza | Posted | Mean | Standard Deviation | LOG10 Titer | 7 days |
|
|
|
| Secondary | 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 | Analysis conducted on 113 patients from the intensive virologic follow up group with laboratory confirmed influenza | Posted | Mean | Standard Deviation | LOG10 RNA copies | 7 days |
|
|
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| Secondary | Time to Cessation of Viral Shedding Measure by 50% Tissue Culture Infective Dose (TCID50) | Median time in hours | Analysis performed on 107 patients from the intensive virologic follow up population with laboratory confirmed influenza | Posted | Median | Inter-Quartile Range | Hours | 28 days |
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| Secondary | Time to Return to Normal Daily Activities | Time in hours as reported by patient | Analysis conducted on 257 patients with laboratory confirmed influenza | Posted | Median | Inter-Quartile Range | Hours | 28 days |
|
|
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| Secondary | 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. | Analysis conducted for 257 patients with laboratory confirmed influenza | Posted | Mean | Standard Deviation | symptom score *hour | 28 days |
|
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| Secondary | Time Loss From Work | Time loss from work | Analysis conducted on 241 patients with laboratory confirmed influenza excluding those who are unemployed | Posted | Mean | 95% Confidence Interval | days | 28 days |
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| Secondary | Complications of Influenza | Proportion of patients with a complication of influenza during the course of the study | All patients who received at least one dose of study medication | Posted | Number | Participants | 28 days |
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| Secondary | Influenza Antibody Response Titer Change: Influenza A 2009 H1N1 | change in influenza antibody titer for Influenza A 2009 H1N1 | Member of the intensive virologic follow up group with laboratory confirmed Influenza A 2009 H1N1 | Posted | Median | Inter-Quartile Range | Fold change in antibody titer | 28 days |
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| Secondary | Influenza Antibody Response: Influenza A H3N2 | Change in antibody titer for Influenza A H3N2 | Members of the intensive virologic follow up group with laboratory confirmed influenza A H3N2 | Posted | Median | Inter-Quartile Range | Fold change in antibody titer | 28 days |
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| Secondary | Influenza Antibody Response: Influenza B | Change in antibody titer for Influenza B | Members of intensive virologic follow up group with laboratory confirmed Influenza B | Posted | Median | Inter-Quartile Range | Fold change in antibody titer | 28 days |
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| Secondary | Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A 2009 H1N1 | Proportion of patients seroprotected or seroconverted at day 28 | Members of intensive virologic follow up group with laboratory confirmed Influenza A 2009 H1N1 | Posted | Number | Participants | 28 days |
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| Secondary | Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A H3N2 | Proportion of patients seroprotected and seroconverted at day 28 | Members of intensive virologic follow up group with laboratory confirmed Influenza A H3N2 | Posted | Number | Participants | 28 days |
|
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| Secondary | Influenza Antibody Response: Seroprotection and Seroconversion for Influenza B | Proportion of patients seroprotected and seroconverted at day 28 | Members of intensive virologic follow up group with laboratory confirmed Influenza B | Posted | Number | Participants | 28 days |
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|
| 0 |
| 201 |
| 10 |
| 201 |
| EG001 | Placebo | placebo tablet twice daily with food for 5 days | 1 | 212 | 7 | 212 |
| EG002 | Nitazoxanide 600mg | 2X 300 mg controlled release tablet twice daily with food for five days | 1 | 211 | 25 | 211 |
|
| respiratory syncytial virus type A | Respiratory, thoracic and mediastinal disorders | Patient presented influenza type symptoms 44 hours prior to enrollment to placebo group. Completed medication & symptoms resolved. Day 17, admitted to hospital with hypertensive emergency. Investigator noted adverse event not related to study drug. |
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| Mild Diarrhea | Gastrointestinal disorders |
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Presentation and/or publication is encouraged provided the Sponsor is notified in advance and given the opportunity to review the manuscript or abstract 30 days prior to its submission for presentation at a scientific meeting or for publication in a scientific journal. The investigators will have complete autonomy regarding the content and wording including the decision of whether or not to publish.
| D014777 | Virus Diseases |
| D012140 | Respiratory Tract Diseases |
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| Sore Throat |
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| Cough |
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| Headache |
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| Myalgia |
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| Fatigue |
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| Fever |
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| Day 5 |
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| Day 7 |
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| Day 4 |
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| Day 5 |
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| Day 7 |
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| Title | Measurements |
|---|---|
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| Pneumonia |
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| Pleurisy |
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| Otitis |
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