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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Nitazoxanide
* Other: Control


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitazoxanide<br>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<br>* nitazoxanide 1000 mg orally twice daily with food for 14 days<br>* Other names: Alinia;|
| Other: Control<br>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<br>* The control arm will receive WHO standard therapy for tuberculosis with isoniazid, rifampin, pyrazinamide, and ethambutol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | first 14 days of anti-tuberculosis therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | first 14 days of anti-tuberculosis therapy | 
| 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 | first 14 days of anti-tuberculosis therapy | 
| 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 14 days of anti-tuberculosis therapy | 
| 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 | first 14 days of anti-tuberculosis therapy | 
| 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. | first 14 days of anti-tuberculosis therapy | 
| 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 | first 14 days of anti-tuberculosis therapy | 
| 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 | first 14 days of anti-tuberculosis therapy | 
| 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 | first 14 days of anti-tuberculosis therapy | 
| 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 | 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 | 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. | first 14 days of anti-tuberculosis therapy | 
| 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 | first 14 days of anti-tuberculosis therapy |