Trial Outcomes & Findings for A Phase III, Randomized, Double-Blind, Placebo Controlled Trial to Evaluate the Efficacy and Safety of Nitazoxanide in the Treatment of Uncomplicated Influenza (NCT NCT03336619)

NCT ID: NCT03336619

Last Updated: 2022-06-28

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1030 participants
• Primary outcome timeframe: Up to 21 days
• Results posted on: 2022-06-28

Participant Flow

Participant milestones

Measure	Nitazoxanide Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Overall Study STARTED	515	515
Overall Study Positive for Influenza by RT-PCR at Baseline (Intent-to-treat Infected [ITTI] Population)	314	306
Overall Study COMPLETED	301	290
Overall Study NOT COMPLETED	214	225

Reasons for withdrawal

Measure	Nitazoxanide Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Overall Study Completed Study, but not positive for influenza by RT-PCR (not included in ITTI population)	192	204
Overall Study Withdrawal by Subject	17	16
Overall Study Adverse Event	2	5
Overall Study Physician Decision	3	0

Baseline Characteristics

The Intent-to-Treat-Infected (ITTI, primary efficacy) population consisted of all subjects positive for influenza at Baseline.

Baseline characteristics by cohort

Measure	Nitazoxanide n=515 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=515 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days	Total n=1030 Participants Total of all reporting groups
Age, Continuous	35.0 years STANDARD_DEVIATION 15.11 • n=515 Participants	36.3 years STANDARD_DEVIATION 16.14 • n=515 Participants	35.6 years STANDARD_DEVIATION 15.63 • n=1030 Participants
Sex: Female, Male Female	292 Participants n=515 Participants	285 Participants n=515 Participants	577 Participants n=1030 Participants
Sex: Female, Male Male	223 Participants n=515 Participants	230 Participants n=515 Participants	453 Participants n=1030 Participants
Race/Ethnicity, Customized Black or African American	47 Participants n=515 Participants	54 Participants n=515 Participants	101 Participants n=1030 Participants
Race/Ethnicity, Customized Hispanic	194 Participants n=515 Participants	194 Participants n=515 Participants	388 Participants n=1030 Participants
Race/Ethnicity, Customized White	256 Participants n=515 Participants	260 Participants n=515 Participants	516 Participants n=1030 Participants
Race/Ethnicity, Customized Other	18 Participants n=515 Participants	7 Participants n=515 Participants	25 Participants n=1030 Participants
Weight	83.1 kg STANDARD_DEVIATION 24.28 • n=515 Participants	81.2 kg STANDARD_DEVIATION 22.58 • n=515 Participants	82.1 kg STANDARD_DEVIATION 23.45 • n=1030 Participants
BMI	29.6 kg/m^2 STANDARD_DEVIATION 7.85 • n=515 Participants	29.1 kg/m^2 STANDARD_DEVIATION 7.27 • n=515 Participants	29.3 kg/m^2 STANDARD_DEVIATION 7.57 • n=1030 Participants
Smoking Status Current Smoker	53 Participants n=515 Participants	49 Participants n=515 Participants	102 Participants n=1030 Participants
Smoking Status Past Smoker	64 Participants n=515 Participants	69 Participants n=515 Participants	133 Participants n=1030 Participants
Smoking Status Never Smoked	398 Participants n=515 Participants	397 Participants n=515 Participants	795 Participants n=1030 Participants
Time from Onset of Symptoms at First Study Drug Intake (ITTI)	26.0 hours STANDARD_DEVIATION 9.0 • n=314 Participants • The Intent-to-Treat-Infected (ITTI, primary efficacy) population consisted of all subjects positive for influenza at Baseline.	26.5 hours STANDARD_DEVIATION 8.2 • n=306 Participants • The Intent-to-Treat-Infected (ITTI, primary efficacy) population consisted of all subjects positive for influenza at Baseline.	26.2 hours STANDARD_DEVIATION 8.6 • n=620 Participants • The Intent-to-Treat-Infected (ITTI, primary efficacy) population consisted of all subjects positive for influenza at Baseline.
Presence of Anti-Influenza Antibodies at Baseline Anti-Influenza Antibodies Detected at Baseline	188 Participants n=297 Participants • Analysis population consists of subjects positive for influenza infection at Baseline who had Baseline serology samples available for detection of anti-influenza antibodies.	181 Participants n=286 Participants • Analysis population consists of subjects positive for influenza infection at Baseline who had Baseline serology samples available for detection of anti-influenza antibodies.	369 Participants n=583 Participants • Analysis population consists of subjects positive for influenza infection at Baseline who had Baseline serology samples available for detection of anti-influenza antibodies.
Presence of Anti-Influenza Antibodies at Baseline Anti-Influenza Antibodies Not Detected at Baseline	109 Participants n=297 Participants • Analysis population consists of subjects positive for influenza infection at Baseline who had Baseline serology samples available for detection of anti-influenza antibodies.	105 Participants n=286 Participants • Analysis population consists of subjects positive for influenza infection at Baseline who had Baseline serology samples available for detection of anti-influenza antibodies.	214 Participants n=583 Participants • Analysis population consists of subjects positive for influenza infection at Baseline who had Baseline serology samples available for detection of anti-influenza antibodies.

PRIMARY outcome

Timeframe: Up to 21 days

Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline.

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.

Outcome measures

Measure	Nitazoxanide n=314 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=306 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Time From First Dose to Symptom Response	155.1 hours Interval 103.7 to 266.3	153.9 hours Interval 100.2 to 270.7

SECONDARY outcome

Timeframe: Up to 21 days

Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline.

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.

Outcome measures

Measure	Nitazoxanide n=314 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=306 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Time From First Dose to Ability to Perform All Normal Activities	201.8 hours Interval 126.6 to 362.7	200.8 hours Interval 127.5 to 347.2

SECONDARY outcome

Timeframe: Up to 21 days

Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline

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.

Outcome measures

Measure	Nitazoxanide n=314 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=306 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Number of Subjects Experiencing One or More Complications of Influenza	50 Participants	45 Participants

SECONDARY outcome

Timeframe: Up to 21 days

Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline

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.

Outcome measures

Measure	Nitazoxanide n=314 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=306 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Time to Symptom Response Excluding the FLU-PRO Gastrointestinal and Eye Domains	152.2 hours Interval 100.8 to 248.9	151.7 hours Interval 97.8 to 268.7

OTHER_PRE_SPECIFIED outcome

Timeframe: 21 days

Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR at Baseline.

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.

Outcome measures

Measure	Nitazoxanide n=314 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=306 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Time to Return to Usual Health	176.6 hours Interval 120.0 to 315.0	202.1 hours Interval 126.6 to 322.1

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nitazoxanide n=396128 Diaries Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Proportion of Diaries Misclassified by Novel Response Definition	0.20131 diaries	—

POST_HOC outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nitazoxanide n=620 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Correlation Coefficient for Sustained Response and Return to Usual Health	0.51 correlation coefficient	—

POST_HOC outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nitazoxanide n=180 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=104 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Time to Return to Usual Health, Placebo-Treated Subjects by Baseline Antibody Status	224.1 hours Interval 128.0 to 359.0	261.5 hours Interval 162.0 to 504.0

POST_HOC outcome

Timeframe: 21 days

Population: The ITTI (primary efficacy) population consisted of all subjects positive for influenza by RT-PCR 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.

Outcome measures

Measure	Nitazoxanide n=314 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=306 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Time to Sustained Clinical Recovery	172.2 hours Interval 81.0 to 346.0	176.4 hours Interval 82.0 to 347.0

POST_HOC outcome

Timeframe: 21 days

Population: Placebo-treated subjects with and without anti-influenza antibodies detected at Baseline who were positive for influenza by RT-PCR.

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.

Outcome measures

Measure	Nitazoxanide n=181 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=104 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Time to Sustained Clinical Recovery by Antibody Status, Placebo-Treated Subjects	141.0 hours Interval 80.0 to 281.0	247.0 hours Interval 104.0 to 457.0

POST_HOC outcome

Timeframe: 21 days

Population: Subjects positive for influenza by RT-PCR at Baseline with anti-influenza antibodies detected in a Baseline serum sample.

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.

Outcome measures

Measure	Nitazoxanide n=109 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=104 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Time to Sustained Clinical Recovery, Subjects Without Detectable Antibodies at Baseline	175.4 hours Interval 84.0 to 321.0	247.0 hours Interval 104.0 to 457.0

POST_HOC outcome

Timeframe: 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.

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.

Outcome measures

Measure	Nitazoxanide n=94 Participants Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Placebo n=83 Participants Two Placebo tablets orally twice daily (b.i.d.) for 5 days
Time to Sustained Clinical Recovery, mITTI Population Without Detectable Antibodies at Baseline	170.3 hours Interval 80.0 to 292.0	263.8 hours Interval 121.0 to 462.0

Adverse Events

Nitazoxanide

Serious events: 2 serious events

Other events: 107 other events

Deaths: 1 deaths

Placebo

Serious events: 1 serious events

Other events: 36 other events

Deaths: 0 deaths

Serious adverse events

Measure	Nitazoxanide n=515 participants at risk Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days Nitazoxanide: Nitazoxanide 600 mg administered orally twice daily for five days	Placebo n=515 participants at risk Two Placebo tablets orally twice daily (b.i.d.) for 5 days Placebo: Placebo administered orally twice daily for five days
Injury, poisoning and procedural complications Procedural pneumothorax	0.19% 1/515 • Number of events 1 • 21 dats	0.00% 0/515 • 21 dats
Infections and infestations Typhus	0.00% 0/515 • 21 dats	0.19% 1/515 • Number of events 1 • 21 dats
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.19% 1/515 • Number of events 1 • 21 dats	0.00% 0/515 • 21 dats

Other adverse events

Measure	Nitazoxanide n=515 participants at risk Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days Nitazoxanide: Nitazoxanide 600 mg administered orally twice daily for five days	Placebo n=515 participants at risk Two Placebo tablets orally twice daily (b.i.d.) for 5 days Placebo: Placebo administered orally twice daily for five days
Gastrointestinal disorders Diarrhoea	6.6% 34/515 • Number of events 41 • 21 dats	4.9% 25/515 • Number of events 26 • 21 dats
Renal and urinary disorders Chromaturia	14.6% 75/515 • Number of events 75 • 21 dats	0.97% 5/515 • Number of events 5 • 21 dats
Gastrointestinal disorders Nausea	1.6% 8/515 • Number of events 8 • 21 dats	2.5% 13/515 • Number of events 13 • 21 dats

Additional Information

Sr. Director, Research Operations

Romark

Phone: 8132828544

Email: jessica.fulgencio@romark.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place