Trial Outcomes & Findings for Safety and Efficacy Study of Nitazoxanide in the Treatment of Acute Uncomplicated Influenza (NCT NCT01227421)

NCT ID: NCT01227421

Last Updated: 2023-10-12

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE2/PHASE3
• Target enrollment: 624 participants
• Primary outcome timeframe: Up to 28 days
• Results posted on: 2023-10-12

Participant Flow

Participant milestones

Measure	Nitazoxanide 300mg 300 mg nitazoxanide twice daily with food for 5 days	Placebo placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg 2X 300 mg controlled release tablet twice daily with food for five days
Overall Study STARTED	201	212	211
Overall Study COMPLETED	190	194	201
Overall Study NOT COMPLETED	11	18	10

Reasons for withdrawal

Measure	Nitazoxanide 300mg 300 mg nitazoxanide twice daily with food for 5 days	Placebo placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg 2X 300 mg controlled release tablet twice daily with food for five days
Overall Study Lost to Follow-up	6	7	5
Overall Study Adverse Event	2	7	2
Overall Study Withdrawal by Subject	1	2	1
Overall Study Protocol Violation	1	1	2
Overall Study Randomized in error	1	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Nitazoxanide 300mg n=201 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=212 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=211 Participants 2X 300 mg controlled release tablet twice daily with food for five days	Total n=624 Participants Total of all reporting groups
Age, Categorical <=18 years	25 Participants n=5 Participants	21 Participants n=7 Participants	20 Participants n=5 Participants	66 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	176 Participants n=5 Participants	189 Participants n=7 Participants	188 Participants n=5 Participants	553 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	5 Participants n=4 Participants
Age, Continuous	31 years STANDARD_DEVIATION 12.6 • n=5 Participants	31 years STANDARD_DEVIATION 13.3 • n=7 Participants	32 years STANDARD_DEVIATION 13.2 • n=5 Participants	31 years STANDARD_DEVIATION 13.0 • n=4 Participants
Sex: Female, Male Female	104 Participants n=5 Participants	122 Participants n=7 Participants	129 Participants n=5 Participants	355 Participants n=4 Participants
Sex: Female, Male Male	97 Participants n=5 Participants	90 Participants n=7 Participants	82 Participants n=5 Participants	269 Participants n=4 Participants
Region of Enrollment United States	201 participants n=5 Participants	212 participants n=7 Participants	211 participants n=5 Participants	624 participants n=4 Participants

PRIMARY outcome

Timeframe: Up to 28 days

Population: 624 patients were enrolled based on inclusion/exclusion criteria. The primary efficacy analysis was conducted on the 257 patients with laboratory confirmed influenza.

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

Outcome measures

Measure	Nitazoxanide 300mg n=89 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=89 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=79 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Time to Resolution of All Clinical Symptoms of Influenza as Reported by the Subjects	109.1 Hours Interval 81.5 to 151.9	116.7 Hours Interval 91.3 to 144.0	95.5 Hours Interval 71.2 to 125.8

SECONDARY outcome

Timeframe: at least 28 days

Population: 624 patients were enrolled based on inclusion/exclusion criteria. Secondary efficacy analyses were conducted on the 257 patients with laboratory confirmed influenza.

Time in hours (Median and Interquartile range)

Outcome measures

Measure	Nitazoxanide 300mg n=89 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=89 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=79 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects Sore Throat	63 Hours Interval 48.0 to 74.0	52 Hours Interval 36.0 to 72.0	50 Hours Interval 31.0 to 60.0
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects Cough	96 Hours Interval 75.0 to 117.0	104 Hours Interval 84.0 to 111.0	84 Hours Interval 60.0 to 105.0
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects Headache	42 Hours Interval 36.0 to 60.0	48 Hours Interval 39.0 to 60.0	39 Hours Interval 30.0 to 49.0
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects Myalgia	46 Hours Interval 36.0 to 52.0	46 Hours Interval 39.0 to 57.0	42 Hours Interval 30.0 to 51.0
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects Fatigue	65 Hours Interval 52.0 to 83.0	69 Hours Interval 60.0 to 72.0	60 Hours Interval 38.0 to 69.0
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects Sweats / Chills	36 Hours Interval 34.0 to 42.0	36 Hours Interval 27.0 to 42.0	36 Hours Interval 26.0 to 42.0
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects Fever	36 Hours Interval 28.0 to 41.0	31 Hours Interval 24.0 to 41.0	36 Hours Interval 24.0 to 42.0
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects Nasal Congestion	84 Hours Interval 72.0 to 92.0	81 Hours Interval 67.0 to 92.0	60 Hours Interval 48.0 to 74.0
Time to Resolution of Each Individual Symptom of Influenza as Reported by the Subjects Runny Nose	48 Hours Interval 37.0 to 82.0	42 Hours Interval 36.0 to 56.0	43 Hours Interval 36.0 to 51.0

SECONDARY outcome

Timeframe: 7 days

Population: Analysis conducted on 113 patients from intensive virologic follow up group with laboratory confirmed influenza

Change in viral titer presented as logarithm with base 10 (log10) 50% Tissue Culture Infective Dose (TCID50)

Outcome measures

Measure	Nitazoxanide 300mg n=33 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=41 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=39 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Mean Change (Standard Deviation)in 50% Tissue Culture Infective Dose (TCID50) Viral Titer From Baseline Day 2	-0.58 LOG10 Titer Standard Deviation 1.4	-0.03 LOG10 Titer Standard Deviation 1.7	-1.11 LOG10 Titer Standard Deviation 1.7
Mean Change (Standard Deviation)in 50% Tissue Culture Infective Dose (TCID50) Viral Titer From Baseline Day 3	-1.26 LOG10 Titer Standard Deviation 1.8	-1.21 LOG10 Titer Standard Deviation 2.2	-1.84 LOG10 Titer Standard Deviation 1.7
Mean Change (Standard Deviation)in 50% Tissue Culture Infective Dose (TCID50) Viral Titer From Baseline Day 4	-1.86 LOG10 Titer Standard Deviation 1.9	-1.65 LOG10 Titer Standard Deviation 1.9	-2.58 LOG10 Titer Standard Deviation 1.3
Mean Change (Standard Deviation)in 50% Tissue Culture Infective Dose (TCID50) Viral Titer From Baseline Day 5	-2.46 LOG10 Titer Standard Deviation 1.8	-2.41 LOG10 Titer Standard Deviation 1.8	-2.55 LOG10 Titer Standard Deviation 1.4
Mean Change (Standard Deviation)in 50% Tissue Culture Infective Dose (TCID50) Viral Titer From Baseline Day 7	-2.82 LOG10 Titer Standard Deviation 1.6	-2.79 LOG10 Titer Standard Deviation 1.8	-3.01 LOG10 Titer Standard Deviation 1.4

SECONDARY outcome

Timeframe: 7 days

Population: Analysis conducted on 113 patients from the intensive virologic follow up group with laboratory confirmed influenza

Change in viral titer logarithm with base 10 (log10) Ribonucleic Acid (RNA)copies

Outcome measures

Measure	Nitazoxanide 300mg n=33 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=41 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=39 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Mean Change in RT-PCR (Reverse Transcription Polymerase Chain Reaction) Viral Titer From Baseline Day 3	-1.34 LOG10 RNA copies Standard Deviation 1.4	-0.92 LOG10 RNA copies Standard Deviation 2.0	-1.64 LOG10 RNA copies Standard Deviation 1.7
Mean Change in RT-PCR (Reverse Transcription Polymerase Chain Reaction) Viral Titer From Baseline Day 2	-0.63 LOG10 RNA copies Standard Deviation 1.4	-0.22 LOG10 RNA copies Standard Deviation 1.7	-0.73 LOG10 RNA copies Standard Deviation 1.5
Mean Change in RT-PCR (Reverse Transcription Polymerase Chain Reaction) Viral Titer From Baseline Day 4	-1.75 LOG10 RNA copies Standard Deviation 1.5	-1.63 LOG10 RNA copies Standard Deviation 1.8	-2.21 LOG10 RNA copies Standard Deviation 1.4
Mean Change in RT-PCR (Reverse Transcription Polymerase Chain Reaction) Viral Titer From Baseline Day 5	-2.42 LOG10 RNA copies Standard Deviation 1.5	-2.49 LOG10 RNA copies Standard Deviation 1.7	-2.44 LOG10 RNA copies Standard Deviation 1.4
Mean Change in RT-PCR (Reverse Transcription Polymerase Chain Reaction) Viral Titer From Baseline Day 7	-2.97 LOG10 RNA copies Standard Deviation 1.3	-2.82 LOG10 RNA copies Standard Deviation 1.6	-3.08 LOG10 RNA copies Standard Deviation 1.3

SECONDARY outcome

Timeframe: 28 days

Population: Analysis performed on 107 patients from the intensive virologic follow up population with laboratory confirmed influenza

Median time in hours

Outcome measures

Measure	Nitazoxanide 300mg n=31 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=39 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=37 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Time to Cessation of Viral Shedding Measure by 50% Tissue Culture Infective Dose (TCID50)	77.0 Hours Interval 46.0 to 141.0	91.3 Hours Interval 48.0 to 143.0	71.8 Hours Interval 38.0 to 142.0

SECONDARY outcome

Timeframe: 28 days

Population: Analysis conducted on 257 patients with laboratory confirmed influenza

Time in hours as reported by patient

Outcome measures

Measure	Nitazoxanide 300mg n=89 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=89 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=79 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Time to Return to Normal Daily Activities	84.2 Hours Interval 49.0 to 117.0	82.1 Hours Interval 59.0 to 115.0	84.0 Hours Interval 60.0 to 115.0

SECONDARY outcome

Timeframe: 28 days

Population: Analysis conducted for 257 patients with laboratory confirmed influenza

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.

Outcome measures

Measure	Nitazoxanide 300mg n=89 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=89 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=79 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Symptom Severity Score Hours	1035.1 symptom score *hour Standard Deviation 765	1220.9 symptom score *hour Standard Deviation 592	1125.2 symptom score *hour Standard Deviation 681

SECONDARY outcome

Timeframe: 28 days

Population: Analysis conducted on 241 patients with laboratory confirmed influenza excluding those who are unemployed

Time loss from work

Outcome measures

Measure	Nitazoxanide 300mg n=84 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=82 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=75 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Time Loss From Work	2.6 days Interval 2.17 to 3.11	3.0 days Interval 2.43 to 3.49	3.3 days Interval 2.75 to 3.92

SECONDARY outcome

Timeframe: 28 days

Population: All patients who received at least one dose of study medication

Proportion of patients with a complication of influenza during the course of the study

Outcome measures

Measure	Nitazoxanide 300mg n=201 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=212 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=211 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Complications of Influenza Bronchitis	10 Participants	3 Participants	7 Participants
Complications of Influenza Sinusitis	6 Participants	6 Participants	2 Participants
Complications of Influenza Pneumonia	1 Participants	2 Participants	1 Participants
Complications of Influenza Pleurisy	0 Participants	1 Participants	0 Participants
Complications of Influenza Otitis	3 Participants	3 Participants	1 Participants

SECONDARY outcome

Timeframe: 28 days

Population: Member of the intensive virologic follow up group with laboratory confirmed Influenza A 2009 H1N1

change in influenza antibody titer for Influenza A 2009 H1N1

Outcome measures

Measure	Nitazoxanide 300mg n=26 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=34 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=36 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Influenza Antibody Response Titer Change: Influenza A 2009 H1N1	2 Fold change in antibody titer Interval 1.0 to 8.0	2 Fold change in antibody titer Interval 1.0 to 5.0	2 Fold change in antibody titer Interval 1.0 to 4.0

SECONDARY outcome

Timeframe: 28 days

Population: Members of the intensive virologic follow up group with laboratory confirmed influenza A H3N2

Change in antibody titer for Influenza A H3N2

Outcome measures

Measure	Nitazoxanide 300mg n=15 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=16 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=12 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Influenza Antibody Response: Influenza A H3N2	8 Fold change in antibody titer Interval 4.0 to 16.0	16 Fold change in antibody titer Interval 2.0 to 56.0	16 Fold change in antibody titer Interval 10.0 to 30.0

SECONDARY outcome

Timeframe: 28 days

Population: Members of intensive virologic follow up group with laboratory confirmed Influenza B

Change in antibody titer for Influenza B

Outcome measures

Measure	Nitazoxanide 300mg n=21 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=20 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=17 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Influenza Antibody Response: Influenza B	4 Fold change in antibody titer Interval 1.0 to 8.0	3 Fold change in antibody titer Interval 1.0 to 4.0	4 Fold change in antibody titer Interval 1.0 to 10.0

SECONDARY outcome

Timeframe: 28 days

Population: Members of intensive virologic follow up group with laboratory confirmed Influenza A 2009 H1N1

Proportion of patients seroprotected or seroconverted at day 28

Outcome measures

Measure	Nitazoxanide 300mg n=26 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=34 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=36 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A 2009 H1N1 Seroprotected at day 28	11 Participants	14 Participants	12 Participants
Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A 2009 H1N1 Seroconverted at day 28	11 Participants	12 Participants	11 Participants

SECONDARY outcome

Timeframe: 28 days

Population: Members of intensive virologic follow up group with laboratory confirmed Influenza A H3N2

Proportion of patients seroprotected and seroconverted at day 28

Outcome measures

Measure	Nitazoxanide 300mg n=15 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=16 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=12 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A H3N2 Seroprotected at day 28	14 Participants	12 Participants	12 Participants
Influenza Antibody Response: Seroprotection and Seroconversion for Patients With Influenza A H3N2 Seroconverted at day 28	13 Participants	12 Participants	12 Participants

SECONDARY outcome

Timeframe: 28 days

Population: Members of intensive virologic follow up group with laboratory confirmed Influenza B

Proportion of patients seroprotected and seroconverted at day 28

Outcome measures

Measure	Nitazoxanide 300mg n=21 Participants 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=20 Participants placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=17 Participants 2X 300 mg controlled release tablet twice daily with food for five days
Influenza Antibody Response: Seroprotection and Seroconversion for Influenza B Seroprotected at day 28	14 Participants	13 Participants	13 Participants
Influenza Antibody Response: Seroprotection and Seroconversion for Influenza B Seroconverted at day 28	12 Participants	10 Participants	13 Participants

Adverse Events

Nitazoxanide 300mg

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

Nitazoxanide 600mg

Serious events: 1 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Measure	Nitazoxanide 300mg n=201 participants at risk 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=212 participants at risk placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=211 participants at risk 2X 300 mg controlled release tablet twice daily with food for five days
Respiratory, thoracic and mediastinal disorders moderate pneumonia	0.00% 0/201	0.00% 0/212	0.47% 1/211 • Number of events 1
Respiratory, thoracic and mediastinal disorders respiratory syncytial virus type A	0.00% 0/201	0.47% 1/212 • Number of events 1	0.00% 0/211

Other adverse events

Measure	Nitazoxanide 300mg n=201 participants at risk 300 mg nitazoxanide twice daily with food for 5 days	Placebo n=212 participants at risk placebo tablet twice daily with food for 5 days	Nitazoxanide 600mg n=211 participants at risk 2X 300 mg controlled release tablet twice daily with food for five days
Renal and urinary disorders Chromaturia	3.0% 6/201 • Number of events 6	0.00% 0/212	3.8% 8/211 • Number of events 8
Gastrointestinal disorders Mild Diarrhea	2.0% 4/201 • Number of events 4	3.3% 7/212 • Number of events 7	8.1% 17/211 • Number of events 17

Additional Information

Marc Ayers

Romark Laboratories, L.C.

Phone: 813-282-8544

Email: Marc.Ayers@romark.com

Results disclosure agreements

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

Restriction type: OTHER