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A 14 Day Early Bactericidal Activity Study of Nitazoxanide for the Treatment of Tuberculosis

This study is currently recruiting participants.
Verified May 2017 by Weill Medical College of Cornell University
Sponsor:
ClinicalTrials.gov Identifier:
NCT02684240
First Posted: February 17, 2016
Last Update Posted: May 9, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Weill Medical College of Cornell University
  Purpose
This research is being done to determine if Nitazoxanide (NTZ) will cause a significant decrease in the number of M. tuberculosis bacteria in sputum after 14 days of treatment. The study is being conducted at the GHESKIO Centers in Port au Prince Haiti

Condition Intervention Phase
Tuberculosis Drug: Nitazoxanide Other: Control Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A 14 Day Early Bactericidal Activity Study of Nitazoxanide for the Treatment of Tuberculosis

Resource links provided by NLM:


Further study details as provided by Weill Medical College of Cornell University:

Primary Outcome Measures:
  • time to positivity (TTP) [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To assess the change in time in hours to positive (TTP) signal in an automated liquid media culture system (BACTEC MGIT 960, Becton Dickinson) in participants receiving NTZ over 14 days


Secondary Outcome Measures:
  • Number of participants with treatment-related adverse events as determined by DAIDS toxicity tables [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To assess the safety of 1000 mg twice daily dosing of NTZ in participants with drug-sensitive tuberculosis by grading each treatment-related adverse reaction according the DAIDS Toxicity tables (November 2014)

  • Maximum plasma concentration of NTZ [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To assess the maximum plasma concentration of NTZ via collection of whole blood samples at hours 2, 4, 6 after ingestion of 1000 mg NTZ on day 5 and day 14 of the study

  • Most probable number of M tuberculosis in 1 ml of sputum [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To quantify the number of M. tuberculosis (MTB) in sputum at baseline and at day 14 using most probable number (MPN) micro-plate assay with and without resuscitation factors added to media

  • First-line drug susceptibility (DST) of Mycobacterium tuberculosis via Mycobacterial Growth Indicator System (MGIT) [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To test for first-line drug susceptibility (DST) of Mycobacterium tuberculosis to isoniazid, rifampin, pyrazinamide and ethambutol via MGIT

  • Quantification of change in urine metabolites and correlation with change in TTP [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To quantify the change in urine metabolites by LC-MS technology and the correlation of this change with change in TTP.

  • Minimum plasma concentration of NTZ [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To assess the minimum plasma concentration of NTZ via collection of whole blood samples at 30 minutes prior to ingestion of 1000 mg of NTZ on day 5 and day 14 of the study

  • Area under the curve of NTZ metabolites [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To assess the area under the curve of NTZ metabolites (tizoxanide, tizoxanide glucuronide) via collection of whole blood samples at hour 2, 4, and 6 post-ingestion of 1000 mg of NTZ on day 5 and day 14

  • Sputum concentration of NTZ [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To assess the sputum concentration of NTZ via collection of spot sputum samples 4 hours post-ingestion of 1000 mg NTZ on day 5 and day 14 of study

  • Change in Minimum inhibitory concentration (MIC) of NTZ against Tuberculosis over 14 days [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    To assess the MIC of NTZ against tuberculosis using microplate assay at baseline and again at day 14 to determine any change in the MIC over the course of treatment

  • Change in phylogeny of bacteria determined by sequencing of amplified 16S ribosomal DNA and/or metagenomic sequencing of bacterial DNA [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    Change in phylogeny of bacteria determined by sequencing of amplified 16S ribosomal DNA and/or metagenomic sequencing of bacterial DNA over the course of 14 days and correlation of this change with change in TTP.

  • Transcriptional signature of treatment response using whole blood transcriptional profiles [ Time Frame: first 14 days of anti-tuberculosis therapy ]
    Determine the transcriptional signature of treatment response using whole blood transcriptional profiles obtained at baseline and day 14


Estimated Enrollment: 30
Study Start Date: February 2016
Estimated Study Completion Date: December 1, 2017
Estimated Primary Completion Date: November 1, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nitazoxanide
Participants with drug-sensitive tuberculous randomized to the NTZ arm will receive nitazoxanide 1000 mg po twice daily for 14 days. After this time point, participants will be switched to WHO standard tuberculosis therapy with isoniazid, rifampin, pyrazinamide and ethambutol.
Drug: Nitazoxanide
nitazoxanide 1000 mg orally twice daily with food for 14 days
Other Names:
  • Nizonide
  • Alinia
Control
Participants with drug-sensitive tuberculosis randomized to the standard therapy arm will receive WHO standard tuberculosis therapy involving isoniazid 300 mg po daily, rifampin 600 mg po daily, pyrazinamide 25 mg/kg po daily and ethambutol 15 mg/kg po daily.
Other: Control
The control arm will receive WHO standard therapy for tuberculosis with isoniazid, rifampin, pyrazinamide, and ethambutol

Detailed Description:
This is a prospective randomized two-arm 14-day, early bactericidal activity study in treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis (TB). The study will be conducted at the GHESKIO Centers in Port au Prince Haiti. Twenty patients will be randomized to receive NTZ 1 gram orally twice daily for 14 days. Ten patients will be randomized as positive controls to receive standard 4 drug tuberculosis therapy with isoniazid (H), rifampin (R), ethambutol (E), and pyrazinamide (PZA). Patients' sputum will be collected before and then every two days during 14 days of treatment, and the primary endpoint will be the change in the number of M. tuberculosis in patients' sputum. Our primary hypothesis is that NTZ will result in a significant decrease in the number of M. tuberculosis in sputum during14 days of treatment. The number of M. tuberculosis will be quantified by the time to positive (TTP) signal in hours in an automated liquid media culture system (BACTEC MGIT 960, Becton Dickinson).
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women ages 18 - 65
  • Diagnosed with pulmonary tuberculosis via: sputum-microscopy smear-positive (2+ or 3+) within 14 days plus Sputum GeneXpert positive within 14 days plus Chest radiograph consistent with M. tuberculosis within 14 days
  • TB treatment naïve at time of enrollment
  • Bodyweight > 40kg
  • Negative HIV test within 30 days
  • Able to complete activities of daily living (ADLs)
  • All participants must agree not to participate in a conception process (i.e. active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization)
  • All female participants must agree to use barrier methods such as condoms as well as hormonal contraception for dual prophylaxis.
  • Able to give informed consent and demonstrate understanding of this study and willingness to participate in this study
  • Willing to be hospitalized for 2 weeks

Exclusion Criteria:

  • Pregnancy
  • Evidence of complications of M. tuberculosis such as hemoptysis or shortness of breath
  • Extrapulmonary manifestations of M. tuberculosis
  • History of prior active tuberculosis
  • Evidence of rifampin resistance via GeneXpert
  • Previous diagnosis of diabetes or suggestion of impaired glucose metabolism via random plasma glucose
  • Previous diagnosis of HIV by any rapid HIV test or by ELISA
  • Any of the following lab abnormalities: Creatinine > 1.5 times the ULN; Random glucose > 2 times the ULN; ALT, AST, or alkaline phosphatase > 2 times the ULN; Hemoglobin < 7.5 g/dL
  • Any participant currently taking antimycobacterial therapy or within the past 30 days
  • Any concomitant illness that could compromise patient safety in this trial such as renal failure, chronic liver disease or alcoholic dependency
  • Enrolled in another clinical trial
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02684240


Contacts
Contact: Kathleen F Walsh, MD 202-256-6746 kfw2001@med.cornell.edu

Locations
Haiti
Les Centres GHESKIO Recruiting
Port-au-Prince, Haiti
Contact: Kathleen Walsh, MD    202-256-6746    kfw2001@med.cornell.edu   
Contact: Jean William Pape, MD    +509-222-0031    jwpape@gheskio.org   
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
Principal Investigator: Daniel W Fitzgerald, MD Weill Medical College of Cornell University
Study Chair: Carl Nathan, MD Weill Medical College of Cornell University
Study Chair: Jean William Pape, MD Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO)
  More Information

Publications:
Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT02684240     History of Changes
Other Study ID Numbers: NZT001
First Submitted: February 2, 2016
First Posted: February 17, 2016
Last Update Posted: May 9, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be shared once the trial is complete

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Nitazoxanide
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Antiparasitic Agents