Influenza
Conditions
Keywords
Influenza
Brief summary
Trial to evaluate efficacy and safety of nitazoxanide (NTZ) in the treatment of uncomplicated influenza.
Detailed description
A multicenter, randomized, double-blind, placebo controlled trial to evaluate efficacy and safety of nitazoxanide (NTZ) in the treatment of uncomplicated influenza.
Interventions
DRUGNitazoxanide
Nitazoxanide 600 mg administered orally twice daily for five days
DRUGPlacebo
Placebo administered orally twice daily for five 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
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female subjects at least 12 years of age 2. Presence of clinical signs and/or symptoms consistent with an acute illness compatible with influenza infection (each of the following is required): 1. oral temperature ≥99.4°F or ≥37.4°C (obtained in office or self- measured within 12 hours prior to screening - if self-measured, subjects must also have taken an antipyretic within 4 hours prior to screening), AND 2. at least one of the following respiratory symptoms (cough, sore throat, nasal obstruction), AND 3. one of the following constitutional symptoms (fatigue, headache, myalgia, feverishness). 3. Confirmation of influenza A or B infection in the local community by one of the following means: 1. the institution's local laboratory, 2. the local public health system, 3. the national public health system, OR 4. a laboratory of a recognized national or multinational influenza surveillance scheme. 4. Onset of illness no more than 40 hours before enrollment in the trial. Note: 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 subject experienced the presence of at least one respiratory symptom AND the presence of at least one constitutional symptom. 5. Willing and able to provide written informed consent (including assent by legal guardian if under 18 years of age) and comply with the requirements of the protocol, including completion of the patient diary.
Exclusion criteria
1. Severity of illness requiring or anticipated to require in-hospital care. 2. Moderate or severe persistent asthma. 3. Cystic fibrosis in children. 4. Stage III or IV (severe or very severe) chronic obstructive pulmonary disease (COPD). 5. Class III or IV congestive heart failure (at least marked limitation of physical activity in which minimal ordinary activity results in fatigue, palpitation, dyspnea, or angina pain) 6. Arrhythmia 7. Immunosuppressive disorders or who are receiving immunosuppressive therapy (e.g., for organ or bone marrow transplants) 8. Untreated HIV infection or treated HIV infection with a CD4 count below 350 cells/mm3 in the last 6 months 9. Persons with sickle cell anemia or other hemoglobinopathies 10. Poorly controlled insulin-dependent diabetes mellitus (HBA1C \> 8%) 11. Residents of any age of nursing homes or other long-term care institutions 12. Concurrent infection at the screening examination that requires systemic antimicrobial therapy. 13. Females of childbearing potential who are either pregnant, breast-feeding or are sexually active without the use of birth control. Female subjects of child-bearing potential that are sexually active must have a negative baseline pregnancy test and must agree to continue an acceptable method of birth control for the duration of the study and for 1 month post- treatment. A double barrier method, oral birth control pills administered for at least 2 monthly cycles prior to study drug administration, an IUD, or medroxyprogesterone acetate administered intramuscularly for a minimum of one month prior to study drug administration are acceptable methods of birth control for inclusion into the study. Female subjects are considered of childbearing potential unless they are postmenopausal (absence of menstrual bleeding for 1 year - or 6 months if laboratory confirmation of hormonal status), or have had a hysterectomy, bilateral tubular ligation or bilateral oophorectomy. 14. Receipt of any dose of NTZ, oseltamivir, zanamivir, peramivir, laninamivir, baloxavir, amantadine or rimantadine within 3 days prior to screening. 15. Prior treatment with any investigational drug therapy within 30 days prior to screening. 16. Subjects with active respiratory allergies or subjects expected to require anti-allergy medications during the study period for respiratory allergies. 17. Known sensitivity to NTZ or any of the excipients comprising the NTZ tablets. 18. Subjects unable to take oral medications. 19. Presence of any pre-existing illness that, in the opinion of the Investigator, would place the subject at an unreasonably increased risk through participation in this study. 20. Subjects who, in the judgment of the Investigator, will be unlikely to comply with the requirements of this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From First Dose to Symptom Response | Up to 21 days | Subjects used the FLU-PRO questionnaire once daily in the evening to score the severity of 32 FLU-PRO symptoms. Symptom response was deemed achieved when the rating for each of the 32 FLU-PRO symptoms was ≤ its assigned threshold for 2 consecutive daily diary periods without use of symptom relief medication. The symptom response thresholds were developed by applying an algorithm to blinded symptoms data to select the set of 32 symptom thresholds most closely associated with patient-reported usual health. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From First Dose to Ability to Perform All Normal Activities | Up to 21 days | Subjects completed a diary including rating ability to perform normal activities on a scale from 0 (able to perform no normal activities) to 10 (able to perform all normal activities) daily in the evening. The time from first dose to ability to perform all normal activities is the time in hours between the first dose of study medication and that time when the subject first reported a score of 10 (able to perform all normal activities) for two consecutive daily diary periods without use of symptom relief medication. |
| Number of Subjects Experiencing One or More Complications of Influenza | Up to 21 days | Complications of influenza infection included pneumonia, otitis media, bronchitis, sinusitis, worsening of pre-existing health conditions, systemic antibiotic use for infections secondary to influenza infection, hospitalization due to influenza or complications of influenza and death. |
| Time to Symptom Response Excluding the FLU-PRO Gastrointestinal and Eye Domains | Up to 21 days | Subjects used the FLU-PRO questionnaire once daily in the evening to score the severity of 32 FLU-PRO symptoms. Symptom response was deemed achieved when the rating for each of the 25 FLU-PRO symptoms (excluding gastrointestinal and eye symptoms) was ≤ its assigned threshold for 2 consecutive daily diary periods without use of symptom relief medication. The symptom response thresholds were developed by applying an algorithm to blinded symptoms data to select the set of 25 symptom thresholds most closely associated with patient-reported usual health. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Return to Usual Health | 21 days | Subjects completed the FLU-PRO questionnaire including global assessment questions daily in the evening. The time from first dose to ability to return to usual health is the time in hours from the first dose of study medication to the first time when the subject answered Have you returned to your usual health? with yes for two consecutive daily diary periods without the use of symptom relief medication. |
| Proportion of Diaries Misclassified by Novel Response Definition | 21 days | The proportion of patient diaries misclassified by the response definition used for the primary efficacy analysis compared to patient reported usual health. A diary was considered misclassified if the response definition predicted responded and the patient reported not being at usual health or if the response definition predicted not responded and the patient reported being at usual health. |
Countries
Australia, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nitazoxanide Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days | 515 |
| Placebo Two Placebo tablets orally twice daily (b.i.d.) for 5 days | 515 |
| Total | 1,030 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 5 |
| Overall Study | Completed Study, but not positive for influenza by RT-PCR (not included in ITTI population) | 192 | 204 |
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Withdrawal by Subject | 17 | 16 |
Baseline characteristics
| Characteristic | Total | Nitazoxanide | Placebo |
|---|---|---|---|
| Age, Continuous | 35.6 years STANDARD_DEVIATION 15.63 | 35.0 years STANDARD_DEVIATION 15.11 | 36.3 years STANDARD_DEVIATION 16.14 |
| BMI | 29.3 kg/m^2 STANDARD_DEVIATION 7.57 | 29.6 kg/m^2 STANDARD_DEVIATION 7.85 | 29.1 kg/m^2 STANDARD_DEVIATION 7.27 |
| Presence of Anti-Influenza Antibodies at Baseline Anti-Influenza Antibodies Detected at Baseline | 369 Participants | 188 Participants | 181 Participants |
| Presence of Anti-Influenza Antibodies at Baseline Anti-Influenza Antibodies Not Detected at Baseline | 214 Participants | 109 Participants | 105 Participants |
| Race/Ethnicity, Customized Black or African American | 101 Participants | 47 Participants | 54 Participants |
| Race/Ethnicity, Customized Hispanic | 388 Participants | 194 Participants | 194 Participants |
| Race/Ethnicity, Customized Other | 25 Participants | 18 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 516 Participants | 256 Participants | 260 Participants |
| Sex: Female, Male Female | 577 Participants | 292 Participants | 285 Participants |
| Sex: Female, Male Male | 453 Participants | 223 Participants | 230 Participants |
| Smoking Status Current Smoker | 102 Participants | 53 Participants | 49 Participants |
| Smoking Status Never Smoked | 795 Participants | 398 Participants | 397 Participants |
| Smoking Status Past Smoker | 133 Participants | 64 Participants | 69 Participants |
| Time from Onset of Symptoms at First Study Drug Intake (ITTI) | 26.2 hours STANDARD_DEVIATION 8.6 | 26.0 hours STANDARD_DEVIATION 9 | 26.5 hours STANDARD_DEVIATION 8.2 |
| Weight | 82.1 kg STANDARD_DEVIATION 23.45 | 83.1 kg STANDARD_DEVIATION 24.28 | 81.2 kg STANDARD_DEVIATION 22.58 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 515 | 0 / 515 |
| other Total, other adverse events | 107 / 515 | 36 / 515 |
| serious Total, serious adverse events | 2 / 515 | 1 / 515 |
Outcome results
Primary
Time From First Dose to Symptom Response
Subjects used the FLU-PRO questionnaire once daily in the evening to score the severity of 32 FLU-PRO symptoms. Symptom response was deemed achieved when the rating for each of the 32 FLU-PRO symptoms was ≤ its assigned threshold for 2 consecutive daily diary periods without use of symptom relief medication. The symptom response thresholds were developed by applying an algorithm to blinded symptoms data to select the set of 32 symptom thresholds most closely associated with patient-reported usual health.
Time frame: Up to 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time From First Dose to Symptom Response | 155.1 hours |
| Placebo | Time From First Dose to Symptom Response | 153.9 hours |
p-value: 0.3765Gehan-Wilcoxon
Secondary
Number of Subjects Experiencing One or More Complications of Influenza
Complications of influenza infection included pneumonia, otitis media, bronchitis, sinusitis, worsening of pre-existing health conditions, systemic antibiotic use for infections secondary to influenza infection, hospitalization due to influenza or complications of influenza and death.
Time frame: Up to 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitazoxanide | Number of Subjects Experiencing One or More Complications of Influenza | 50 Participants |
| Placebo | Number of Subjects Experiencing One or More Complications of Influenza | 45 Participants |
p-value: 0.7382Fisher Exact
Secondary
Time From First Dose to Ability to Perform All Normal Activities
Subjects completed a diary including rating ability to perform normal activities on a scale from 0 (able to perform no normal activities) to 10 (able to perform all normal activities) daily in the evening. The time from first dose to ability to perform all normal activities is the time in hours between the first dose of study medication and that time when the subject first reported a score of 10 (able to perform all normal activities) for two consecutive daily diary periods without use of symptom relief medication.
Time frame: Up to 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time From First Dose to Ability to Perform All Normal Activities | 201.8 hours |
| Placebo | Time From First Dose to Ability to Perform All Normal Activities | 200.8 hours |
p-value: 0.6331Gehan-Wilcoxon
Secondary
Time to Symptom Response Excluding the FLU-PRO Gastrointestinal and Eye Domains
Subjects used the FLU-PRO questionnaire once daily in the evening to score the severity of 32 FLU-PRO symptoms. Symptom response was deemed achieved when the rating for each of the 25 FLU-PRO symptoms (excluding gastrointestinal and eye symptoms) was ≤ its assigned threshold for 2 consecutive daily diary periods without use of symptom relief medication. The symptom response thresholds were developed by applying an algorithm to blinded symptoms data to select the set of 25 symptom thresholds most closely associated with patient-reported usual health.
Time frame: Up to 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Symptom Response Excluding the FLU-PRO Gastrointestinal and Eye Domains | 152.2 hours |
| Placebo | Time to Symptom Response Excluding the FLU-PRO Gastrointestinal and Eye Domains | 151.7 hours |
p-value: 0.3236Gehan-Wilcoxon
Post Hoc
Correlation Coefficient for Sustained Response and Return to Usual Health
The correlation coefficient between sustained response and return to usual health was calculated for the pooled ITTI population (i.e., not by treatment group) as a measure of association between the primary endpoint response definition and its intended anchor, patient-reported return to usual health.
Time frame: 21 days
Population: The correlation coefficient between sustained response and return to usual health was to be calculated prior to unblinding including all data for subjects in the ITTI population, consistent with the misclassification rate as specified in the statistical analysis plan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitazoxanide | Correlation Coefficient for Sustained Response and Return to Usual Health | 0.51 correlation coefficient |
Other Pre-specified
Proportion of Diaries Misclassified by Novel Response Definition
The proportion of patient diaries misclassified by the response definition used for the primary efficacy analysis compared to patient reported usual health. A diary was considered misclassified if the response definition predicted responded and the patient reported not being at usual health or if the response definition predicted not responded and the patient reported being at usual health.
Time frame: 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline. Per the Statistical Analysis Plan, the response definition misclassification rate was to be calculated prior to unblinding including all data for subjects in the ITTI population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nitazoxanide | Proportion of Diaries Misclassified by Novel Response Definition | 0.20131 diaries |
Other Pre-specified
Time to Return to Usual Health
Subjects completed the FLU-PRO questionnaire including global assessment questions daily in the evening. The time from first dose to ability to return to usual health is the time in hours from the first dose of study medication to the first time when the subject answered Have you returned to your usual health? with yes for two consecutive daily diary periods without the use of symptom relief medication.
Time frame: 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Return to Usual Health | 176.6 hours |
| Placebo | Time to Return to Usual Health | 202.1 hours |
p-value: 0.0483Gehan-Wilcoxon
Post Hoc
Time to Return to Usual Health, Placebo-Treated Subjects by Baseline Antibody Status
Survival analysis of Time to Return to Usual Health was repeated for subjects with laboratory-confirmed influenza (ITTI population) who were randomized to the placebo treatment group by whether the subjects had detectable anti-influenza antibodies at Baseline.
Time frame: 21 days
Population: Subjects with laboratory-confirmed influenza (ITTI population) who were randomized to the placebo treatment group by whether the subjects had detectable anti-influenza antibodies at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Return to Usual Health, Placebo-Treated Subjects by Baseline Antibody Status | 224.1 hours |
| Placebo | Time to Return to Usual Health, Placebo-Treated Subjects by Baseline Antibody Status | 261.5 hours |
Post Hoc
Time to Sustained Clinical Recovery
Alternative means of endpoint construction were pursued to strengthen the relationship between symptoms-based endpoint measures and subject global assessments of health. Time to Sustained Clinical Recovery is an endpoint based on evidence of meaningful within-subject change sustained for the duration of the study. Time to Sustained Clinical Recovery is the time in hours from the first dose of study medication to the first time at which the subject reports a decrease in total FLU-PRO score from the previous diary with assessment that symptoms are at least somewhat better than yesterday, no oral temperature ≥100.4 F in the prior 24 hours, and no future increase in any of the FLU-PRO domains except within validated background levels.
Time frame: 21 days
Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Sustained Clinical Recovery | 172.2 hours |
| Placebo | Time to Sustained Clinical Recovery | 176.4 hours |
Post Hoc
Time to Sustained Clinical Recovery by Antibody Status, Placebo-Treated Subjects
Alternative means of endpoint construction were pursued to strengthen the relationship between symptoms-based endpoint measures and subject global assessments of health. Time to Sustained Clinical Recovery is an endpoint based on evidence of meaningful within-subject change sustained for the duration of the study. Time to Sustained Clinical Recovery is the time in hours from the first dose of study medication to the first time at which the subject reports a decrease in total FLU-PRO score from the previous diary with assessment that symptoms are at least somewhat better than yesterday, no oral temperature ≥100.4 F in the prior 24 hours, and no future increase in any of the FLU-PRO domains except within validated background levels.
Time frame: 21 days
Population: Placebo-treated subjects with and without anti-influenza antibodies detected at Baseline who were positive for influenza by RT-PCR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Sustained Clinical Recovery by Antibody Status, Placebo-Treated Subjects | 141.0 hours |
| Placebo | Time to Sustained Clinical Recovery by Antibody Status, Placebo-Treated Subjects | 247.0 hours |
Post Hoc
Time to Sustained Clinical Recovery, mITTI Population Without Detectable Antibodies at Baseline
Alternative means of endpoint construction were pursued to strengthen the relationship between symptoms-based endpoint measures and subject global assessments of health. Time to Sustained Clinical Recovery is an endpoint based on evidence of meaningful within-subject change sustained for the duration of the study. Time to Sustained Clinical Recovery is the time in hours from the first dose of study medication to the first time at which the subject reports a decrease in total FLU-PRO score from the previous diary with assessment that symptoms are at least somewhat better than yesterday, no oral temperature ≥100.4 F in the prior 24 hours, and no future increase in any of the FLU-PRO domains except within validated background levels.
Time frame: 21 days
Population: Modified ITTI population consists of subjects with laboratory-confirmed influenza infection without detectable anti-influenza antibodies at Baseline and Baseline subject-reported assessment that symptoms are present, the symptoms are not consistent with the subject's usual health, the symptoms interfere with daily activities, and the symptoms have worsened or remained the same relative to the previous day. Assessment was completed via the Baseline FLU-PRO questionnaire.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Sustained Clinical Recovery, mITTI Population Without Detectable Antibodies at Baseline | 170.3 hours |
| Placebo | Time to Sustained Clinical Recovery, mITTI Population Without Detectable Antibodies at Baseline | 263.8 hours |
Post Hoc
Time to Sustained Clinical Recovery, Subjects Without Detectable Antibodies at Baseline
Alternative means of endpoint construction were pursued to strengthen the relationship between symptoms-based endpoint measures and subject global assessments of health. Time to Sustained Clinical Recovery is an endpoint based on evidence of meaningful within-subject change sustained for the duration of the study. Time to Sustained Clinical Recovery is the time in hours from the first dose of study medication to the first time at which the subject reports a decrease in total FLU-PRO score from the previous diary with assessment that symptoms are at least somewhat better than yesterday, no oral temperature ≥100.4 F in the prior 24 hours, and no future increase in any of the FLU-PRO domains except within validated background levels.
Time frame: 21 days
Population: Subjects positive for influenza by RT-PCR at Baseline with anti-influenza antibodies detected in a Baseline serum sample.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitazoxanide | Time to Sustained Clinical Recovery, Subjects Without Detectable Antibodies at Baseline | 175.4 hours |
| Placebo | Time to Sustained Clinical Recovery, Subjects Without Detectable Antibodies at Baseline | 247.0 hours |