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

Primary Purpose

Tuberculosis

Status
Completed
Phase
Phase 2
Locations
Haiti
Study Type
Interventional
Intervention
Nitazoxanide
Control
Sponsored by
Weill Medical College of Cornell University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Les Centres GHESKIO

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Nitazoxanide

Control

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

time to positivity (TTP)
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
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
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
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)
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
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
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
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
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
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
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
Determine the transcriptional signature of treatment response using whole blood transcriptional profiles obtained at baseline and day 14

Full Information

First Posted
February 2, 2016
Last Updated
August 3, 2020
Sponsor
Weill Medical College of Cornell University
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1. Study Identification

Unique Protocol Identification Number
NCT02684240
Brief Title
A 14 Day Early Bactericidal Activity Study of Nitazoxanide for the Treatment of Tuberculosis
Official Title
A 14 Day Early Bactericidal Activity Study of Nitazoxanide for the Treatment of Tuberculosis
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
February 2016 (undefined)
Primary Completion Date
April 11, 2018 (Actual)
Study Completion Date
April 11, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Weill Medical College of Cornell University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nitazoxanide
Arm Type
Experimental
Arm Description
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.
Arm Title
Control
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Nitazoxanide
Other Intervention Name(s)
Nizonide, Alinia
Intervention Description
nitazoxanide 1000 mg orally twice daily with food for 14 days
Intervention Type
Other
Intervention Name(s)
Control
Intervention Description
The control arm will receive WHO standard therapy for tuberculosis with isoniazid, rifampin, pyrazinamide, and ethambutol
Primary Outcome Measure Information:
Title
time to positivity (TTP)
Description
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
Time Frame
first 14 days of anti-tuberculosis therapy
Secondary Outcome Measure Information:
Title
Number of participants with treatment-related adverse events as determined by DAIDS toxicity tables
Description
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)
Time Frame
first 14 days of anti-tuberculosis therapy
Title
Maximum plasma concentration of NTZ
Description
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
Time Frame
first 14 days of anti-tuberculosis therapy
Title
Most probable number of M tuberculosis in 1 ml of sputum
Description
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
Time Frame
first 14 days of anti-tuberculosis therapy
Title
First-line drug susceptibility (DST) of Mycobacterium tuberculosis via Mycobacterial Growth Indicator System (MGIT)
Description
To test for first-line drug susceptibility (DST) of Mycobacterium tuberculosis to isoniazid, rifampin, pyrazinamide and ethambutol via MGIT
Time Frame
first 14 days of anti-tuberculosis therapy
Title
Quantification of change in urine metabolites and correlation with change in TTP
Description
To quantify the change in urine metabolites by LC-MS technology and the correlation of this change with change in TTP.
Time Frame
first 14 days of anti-tuberculosis therapy
Title
Minimum plasma concentration of NTZ
Description
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
Time Frame
first 14 days of anti-tuberculosis therapy
Title
Area under the curve of NTZ metabolites
Description
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
Time Frame
first 14 days of anti-tuberculosis therapy
Title
Sputum concentration of NTZ
Description
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
Time Frame
first 14 days of anti-tuberculosis therapy
Title
Change in Minimum inhibitory concentration (MIC) of NTZ against Tuberculosis over 14 days
Description
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
Time Frame
first 14 days of anti-tuberculosis therapy
Title
Change in phylogeny of bacteria determined by sequencing of amplified 16S ribosomal DNA and/or metagenomic sequencing of bacterial DNA
Description
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.
Time Frame
first 14 days of anti-tuberculosis therapy
Title
Transcriptional signature of treatment response using whole blood transcriptional profiles
Description
Determine the transcriptional signature of treatment response using whole blood transcriptional profiles obtained at baseline and day 14
Time Frame
first 14 days of anti-tuberculosis therapy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel W Fitzgerald, MD
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Carl Nathan, MD
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Jean William Pape, MD
Organizational Affiliation
Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO)
Official's Role
Study Chair
Facility Information:
Facility Name
Les Centres GHESKIO
City
Port-au-Prince
Country
Haiti

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data will be shared once the trial is complete. Data is currently being analyzed.
Citations:
PubMed Identifier
19736929
Citation
de Carvalho LP, Lin G, Jiang X, Nathan C. Nitazoxanide kills replicating and nonreplicating Mycobacterium tuberculosis and evades resistance. J Med Chem. 2009 Oct 8;52(19):5789-92. doi: 10.1021/jm9010719.
Results Reference
background
PubMed Identifier
12051574
Citation
Stockis A, De Bruyn S, Gengler C, Rosillon D. Nitazoxanide pharmacokinetics and tolerability in man during 7 days dosing with 0.5 g and 1 g b.i.d. Int J Clin Pharmacol Ther. 2002 May;40(5):221-7. doi: 10.5414/cpp40221.
Results Reference
background
PubMed Identifier
23507275
Citation
Shigyo K, Ocheretina O, Merveille YM, Johnson WD, Pape JW, Nathan CF, Fitzgerald DW. Efficacy of nitazoxanide against clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013 Jun;57(6):2834-7. doi: 10.1128/AAC.02542-12. Epub 2013 Mar 18.
Results Reference
background
PubMed Identifier
32071052
Citation
Walsh KF, McAulay K, Lee MH, Vilbrun SC, Mathurin L, Jean Francois D, Zimmerman M, Kaya F, Zhang N, Saito K, Ocheretina O, Savic R, Dartois V, Johnson WD, Pape JW, Nathan C, Fitzgerald DW. Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e01956-19. doi: 10.1128/AAC.01956-19. Print 2020 Apr 21.
Results Reference
result
PubMed Identifier
33602926
Citation
Wipperman MF, Bhattarai SK, Vorkas CK, Maringati VS, Taur Y, Mathurin L, McAulay K, Vilbrun SC, Francois D, Bean J, Walsh KF, Nathan C, Fitzgerald DW, Glickman MS, Bucci V. Gastrointestinal microbiota composition predicts peripheral inflammatory state during treatment of human tuberculosis. Nat Commun. 2021 Feb 18;12(1):1141. doi: 10.1038/s41467-021-21475-y.
Results Reference
derived

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

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