Influenza
Conditions
Keywords
influenza, influenza like illness
Brief summary
This is a randomized clinical trial designed to evaluate oral nitazoxanide compared to a placebo in the treatment of acute uncomplicated influenza in adults. We hypothesize that treatment with nitazoxanide will reduce the duration of symptoms in patients with confirmed influenza infection. Secondarily, we 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, and viral shedding.
Detailed description
The study is conducted at approximately 25 sites in the United States. Subjects selected based on symptoms will be randomized to receive oral nitazoxanide or placebo twice daily for 5 days. Subjects will be monitored by daily by telephone or home visit to monitor symptoms and complications of influenza for safety and will be referred for medical care as required. Subjects will complete a diary twice daily to record the presence and severity of symptoms, ability to perform normal daily activities and time lost from work. Complications of influenza (including sinusitis, otitis, bronchitis, pneumonia, central nervous system disease) and other adverse events will be reported. Nasopharyngeal swabs will be collected at Baseline (Day 0) and Day 7 for all patients and on Days 1 through 4 for a subset of patients to test for influenza A (including novel H1N1), influenza B and 17 other respiratory viruses by RT-PCR and culture and to evaluate quantitative viral shedding. The primary analysis will be for patients with confirmed influenza, and secondary analyses will be conducted for subjects with any respiratory virus and for all treated subjects.
Interventions
DRUGNitazoxanide
Tablet, 500 mg with food twice daily for 5 days
DRUGPlacebo
Tablet, twice daily with food for 5 days
Sponsors
Romark Laboratories L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 65 years * Fever, respiratory symptoms and constitutional symptoms compatible with influenza infection * Influenza A or B infection in the local community * Onset of illness no more than 48 hours before presentation * Willing and able to provide comply with protocol requirements
Exclusion criteria
* Severity of illness requiring or anticipated to require in-hospital care * High risk of complications from influenza per IDSA (Infectious Diseases Society of America) guidelines or current CDC (Centers for Disease Control) criteria * Females pregnant, breast-feeding or sexually active without birth control * Vaccination for seasonal influenza or H1N1 on or after August 1, 2009 * Treatment with antiviral medication for influenza within 1 month prior to screening * Treatment with nitazoxanide or any investigational drug within 1 month prior to screening * Known sensitivity to nitazoxanide or any excipients * Unable to take oral medications * Chronic kidney or liver disease or known impaired hepatic and/or renal function * Other pre-existing chronic infection undergoing or requiring medical therapy * Pre-existing illness placing subject at unreasonably increased risk by participation in study * Unlikely to comply with the requirements of this protocol
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time to Resolution of All Clinical Symptoms of Influenza (Subjects With Confirmed Influenza Infection) | Up to 28 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Resolution of All Clinical Symptoms of Influenza (All Treated Subjects) | Up to 28 days | — |
| Time to Return to Normal Daily Activity (Subjects With Confirmed Influenza) | Up to 28 days | — |
| Overall Severity of Disease Score | Up to 14 days | Subjects recorded a severity score for 10 flu symptoms on a 0-3 scale BID for 7-14 days.The severity score for each symptom was multiplied by the number of hours scored at that severity for the entire time the subject maintained a diary (a sneezing score of 1 for 12 hours and 0 for 10 hours =1\*12 + 0\*10=12). This is symptom severity score\*hours.Symptom severity score\*hours for each of the symptoms were added for an overall symptom severity score\*hours (if symptom severity score\*hours for 10 symptoms were 12, 10, 9, 8, 7, 10, 10, 10, 5, 5, overall symptom severity score\*hours=86).Overall symptom severity score\*hours were divided by the number of hours that the subject kept a diary for a standardized continuous measure of severity of the course of illness (if overall symptom severity score\*hours=86 and the subject maintained a diary for 100 hours Overall Severity of Disease Score=0.86). Overall Severity of Disease Score can range 0-30 with higher scores indicating more severe symptoms. |
| Time to Resolution of All Clinical Symptoms of Influenza (Subjects Infected With Any Respiratory Virus) | Up to 28 days | — |
| Complications of Influenza Including Secondary Illnesses, Antibiotic Use and Hospitalizations (Subjects With Confirmed Influenza) | Up to 28 days | — |
| Time to Cessation of Viral Shedding (Subjects With Confirmed Influenza) | 28 days | — |
| Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza) | 4 days | — |
| Time Lost From Work (Subjects With Confirmed Influenza) | Up to 28 days | — |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled at 11 primary care health centers throughout the United States in the last months of the 2009/2010 flu season
Participants by arm
| Arm | Count |
|---|---|
| Nitazoxanide Nitazoxanide : Tablet, 500 mg with food twice daily for 5 days | 37 |
| Placebo Placebo : Tablet, twice daily with food for 5 days | 42 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 |
Baseline characteristics
| Characteristic | Placebo | Nitazoxanide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 37 Participants | 79 Participants |
| Age, Continuous | 37.9 years STANDARD_DEVIATION 13.3 | 38.6 years STANDARD_DEVIATION 14.4 | 38.2 years STANDARD_DEVIATION 13.8 |
| Region of Enrollment United States | 42 participants | 37 participants | 79 participants |
| Sex: Female, Male Female | 26 Participants | 21 Participants | 47 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 37 | 6 / 42 |
| serious Total, serious adverse events | 0 / 37 | 0 / 42 |
Outcome results
Primary
Time to Resolution of All Clinical Symptoms of Influenza (Subjects With Confirmed Influenza Infection)
Time frame: Up to 28 days
Population: All subjects with laboratory confirmed influenza who took at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Resolution of All Clinical Symptoms of Influenza (Subjects With Confirmed Influenza Infection) | 55.0 hours |
| Placebo | Time to Resolution of All Clinical Symptoms of Influenza (Subjects With Confirmed Influenza Infection) | 91.5 hours |
Secondary
Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza)
Time frame: 4 days
Population: All subjects with laboratory confirmed influenza enrolled in the intensive virologic follow up substudy who received at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nitazoxanide | Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza) | Baseline | 0 Quantitative PCR RNA Copies | Standard Deviation 0 |
| Nitazoxanide | Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza) | Day 2 | 0 Quantitative PCR RNA Copies | Standard Deviation 0 |
| Nitazoxanide | Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza) | Day 3 | 0 Quantitative PCR RNA Copies | Standard Deviation 0 |
| Nitazoxanide | Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza) | Day 4 | 0 Quantitative PCR RNA Copies | Standard Deviation 0 |
| Placebo | Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza) | Day 4 | -176946354 Quantitative PCR RNA Copies | Standard Deviation 375523235 |
| Placebo | Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza) | Baseline | 0 Quantitative PCR RNA Copies | Standard Deviation 0 |
| Placebo | Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza) | Day 3 | -176973304 Quantitative PCR RNA Copies | Standard Deviation 374681622 |
| Placebo | Change in Influenza Virus Titer Assessed by Quantitative RT-PCR (Subjects With Confirmed Influenza) | Day 2 | -175183057 Quantitative PCR RNA Copies | Standard Deviation 373069697 |
Secondary
Complications of Influenza Including Secondary Illnesses, Antibiotic Use and Hospitalizations (Subjects With Confirmed Influenza)
Time frame: Up to 28 days
Population: All subjects with laboratory confirmed influenza who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitazoxanide | Complications of Influenza Including Secondary Illnesses, Antibiotic Use and Hospitalizations (Subjects With Confirmed Influenza) | 1 Participants |
| Placebo | Complications of Influenza Including Secondary Illnesses, Antibiotic Use and Hospitalizations (Subjects With Confirmed Influenza) | 1 Participants |
Secondary
Overall Severity of Disease Score
Subjects recorded a severity score for 10 flu symptoms on a 0-3 scale BID for 7-14 days.The severity score for each symptom was multiplied by the number of hours scored at that severity for the entire time the subject maintained a diary (a sneezing score of 1 for 12 hours and 0 for 10 hours =1\*12 + 0\*10=12). This is symptom severity score\*hours.Symptom severity score\*hours for each of the symptoms were added for an overall symptom severity score\*hours (if symptom severity score\*hours for 10 symptoms were 12, 10, 9, 8, 7, 10, 10, 10, 5, 5, overall symptom severity score\*hours=86).Overall symptom severity score\*hours were divided by the number of hours that the subject kept a diary for a standardized continuous measure of severity of the course of illness (if overall symptom severity score\*hours=86 and the subject maintained a diary for 100 hours Overall Severity of Disease Score=0.86). Overall Severity of Disease Score can range 0-30 with higher scores indicating more severe symptoms.
Time frame: Up to 14 days
Population: All subjects with laboratory confirmed influenza who received at least one dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nitazoxanide | Overall Severity of Disease Score | 5.4 overall severity score | Standard Deviation 3.3 |
| Placebo | Overall Severity of Disease Score | 6.2 overall severity score | Standard Deviation 3.6 |
Secondary
Time Lost From Work (Subjects With Confirmed Influenza)
Time frame: Up to 28 days
Population: All subjects with laboratory confirmed influenza who received at least one dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Nitazoxanide | Time Lost From Work (Subjects With Confirmed Influenza) | 3.64 hours |
| Placebo | Time Lost From Work (Subjects With Confirmed Influenza) | 4.36 hours |
Secondary
Time to Cessation of Viral Shedding (Subjects With Confirmed Influenza)
Time frame: 28 days
Population: All subjects with laboratory confirmed influenza enrolled in the intensive virologic follow up substudy who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Cessation of Viral Shedding (Subjects With Confirmed Influenza) | 95.5 hours |
| Placebo | Time to Cessation of Viral Shedding (Subjects With Confirmed Influenza) | 83.3 hours |
Secondary
Time to Resolution of All Clinical Symptoms of Influenza (All Treated Subjects)
Time frame: Up to 28 days
Population: All subjects who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Resolution of All Clinical Symptoms of Influenza (All Treated Subjects) | 119.8 hours |
| Placebo | Time to Resolution of All Clinical Symptoms of Influenza (All Treated Subjects) | 102.6 hours |
Secondary
Time to Resolution of All Clinical Symptoms of Influenza (Subjects Infected With Any Respiratory Virus)
Time frame: Up to 28 days
Population: All subjects with any laboratory confirmed viral infection who took at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Resolution of All Clinical Symptoms of Influenza (Subjects Infected With Any Respiratory Virus) | 118.0 hours |
| Placebo | Time to Resolution of All Clinical Symptoms of Influenza (Subjects Infected With Any Respiratory Virus) | 88.8 hours |
Secondary
Time to Return to Normal Daily Activity (Subjects With Confirmed Influenza)
Time frame: Up to 28 days
Population: All subjects with laboratory confirmed influenza who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Return to Normal Daily Activity (Subjects With Confirmed Influenza) | 48.5 hours |
| Placebo | Time to Return to Normal Daily Activity (Subjects With Confirmed Influenza) | 57.5 hours |