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

Tuberculosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02684240
• Other study ID #: 1302013616
• Status: Completed
• Phase: Phase 2
• Start date: February 2016
• Est. completion date: April 11, 2018

Study information

• Verified date: August 2020
• Source: Weill Medical College of Cornell University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: April 11, 2018
• Est. primary completion date: April 11, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Tuberculosis

Intervention

Drug:
• Nitazoxanide
nitazoxanide 1000 mg orally twice daily with food for 14 days

Other:
• Control
The control arm will receive WHO standard therapy for tuberculosis with isoniazid, rifampin, pyrazinamide, and ethambutol

Locations

Country	Name	City	State
Haiti	Les Centres GHESKIO	Port-au-Prince

Sponsors (1)

Lead Sponsor	Collaborator
Weill Medical College of Cornell University

Country where clinical trial is conducted

Haiti, 

References & Publications (4)

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. — View 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. — View 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. — View 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 Tu — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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