A Phase III, Randomized, Double-Blind, Placebo Controlled Trial to Evaluate the Efficacy and Safety of Nitazoxanide in the Treatment of Uncomplicated Influenza

Trial to evaluate efficacy and safety of nitazoxanide (NTZ) in the treatment of uncomplicated influenza.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Drug: Nitazoxanide; Drug: Placebo

Detailed Description

A multicenter, randomized, double-blind, placebo controlled trial to evaluate efficacy and safety of nitazoxanide (NTZ) in the treatment of uncomplicated influenza.

• Study Type: Interventional
• Enrollment (Actual): 1030
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Morayfield, Queensland, Australia, 4506
      • Vanguard Study Site
    • Sherwood, Queensland, Australia, 4075
      • Vanguard Study Site
    • Victoria Point, Queensland, Australia, 4165
      • Vanguard Study Site
• Puerto Rico
  • Ponce, Puerto Rico, 00780
    • Vanguard Study Site
• United States
  • Alabama
    • Alabaster, Alabama, United States, 35007
      • Vanguard Study Site
    • Birmingham, Alabama, United States, 35235
      • Vanguard Study Site
    • Birmingham, Alabama, United States, 35242
      • Vanguard Study Site
    • Hoover, Alabama, United States, 35216
      • Vanguard Study Site
    • Pelham, Alabama, United States, 35124
      • Vanguard Study Site
  • Arizona
    • Goodyear, Arizona, United States, 85338
      • Vanguard Study Site
    • Tolleson, Arizona, United States, 85353
      • Vanguard Study Site
  • Arkansas
    • Hot Springs, Arkansas, United States, 71913
      • Vanguard Study Site
  • California
    • Anaheim, California, United States, 92805
      • Vanguard Study Site
    • Westminster, California, United States, 92683
      • Vanguard Study Site
  • Florida
    • Lauderdale Lakes, Florida, United States, 33319
      • Vanguard Study Site
    • Orlando, Florida, United States, 32806
      • Vanguard Study Site
  • Indiana
    • Valparaiso, Indiana, United States, 46383
      • Vanguard Study Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70124
      • Vanguard Study Site
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Vanguard Study Site
  • Montana
    • Missoula, Montana, United States, 59808
      • Vanguard Study Site
  • New York
    • Brooklyn, New York, United States, 11229
      • Vanguard Study Site
  • Ohio
    • Cincinnati, Ohio, United States, 45215
      • Vanguard Study Site
    • Columbus, Ohio, United States, 43214
      • Vanguard Study Site
    • Dayton, Ohio, United States, 45424
      • Vanguard Study Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Vanguard Study Site
  • South Dakota
    • Rapid City, South Dakota, United States, 57702
      • Vanguard Study Site
  • Tennessee
    • Jackson, Tennessee, United States, 38305
      • Vanguard Study Site
    • Smyrna, Tennessee, United States, 37167
      • Vanguard Study Site
  • Texas
    • Austin, Texas, United States, 78735
      • Vanguard Study Site
    • Carrollton, Texas, United States, 75010
      • Vanguard Study Site
    • Dallas, Texas, United States, 75204
      • Vanguard Study Site
    • Dallas, Texas, United States, 75230
      • Vanguard Study Site
    • Fort Worth, Texas, United States, 76107
      • Vanguard Study Site
    • Houston, Texas, United States, 77058
      • Vanguard Study Site
    • Pharr, Texas, United States, 78577
      • Vanguard Study Site
    • Plano, Texas, United States, 75024
      • Vanguard Study Site
    • Plano, Texas, United States, 75093
      • Vanguard Study Site
  • Utah
    • Saint George, Utah, United States, 84790
      • Vanguard Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Nitazoxanide; Two Nitazoxanide 300 mg tablets orally twice daily (b.i.d.) for 5 days	Drug: Nitazoxanide; Nitazoxanide 600 mg administered orally twice daily for five days; Other Names: NTZ; NT-300
PLACEBO_COMPARATOR: Placebo; Two Placebo tablets orally twice daily (b.i.d.) for 5 days	Drug: Placebo; Placebo administered orally twice daily for five days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 21 days
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.	Up to 21 days
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.	Up to 21 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	21 days
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.	21 days

Collaborators and Investigators

• Sponsor: Romark Laboratories L.C.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 17, 2018
• Primary Completion (ACTUAL): April 17, 2019
• Study Completion (ACTUAL): April 17, 2019

Study Registration Dates

• First Submitted: November 6, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (ACTUAL): November 8, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 28, 2022
• Last Update Submitted That Met QC Criteria: June 2, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Influenza
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Anti-Infective Agents; Antiparasitic Agents; Nitazoxanide
• Other Study ID Numbers: RM08-3004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No