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

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

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: Nitazoxanide; Other: Control

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).

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Haiti
  • Port-au-Prince, Haiti
    • Les Centres GHESKIO

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: Alinia; Nizonide
Other: 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: 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)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): April 11, 2018
• Study Completion (Actual): April 11, 2018

Study Registration Dates

• First Submitted: February 2, 2016
• First Submitted That Met QC Criteria: February 11, 2016
• First Posted (Estimate): February 17, 2016

Study Record Updates

• Last Update Posted (Actual): August 5, 2020
• Last Update Submitted That Met QC Criteria: August 3, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Anti-Infective Agents; Antiparasitic Agents; Nitazoxanide
• Other Study ID Numbers: 1302013616

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared once the trial is complete. Data is currently being analyzed.