Clinical trial NCT02684240: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
First posted: 2016-02-17
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: time to positivity (TTP)
timeFrame: first 14 days of anti-tuberculosis therapy
Secondary outcomes:
measure: Number of participants with treatment-related adverse events as determined by DAIDS toxicity tables
timeFrame: first 14 days of anti-tuberculosis therapy
measure: Maximum plasma concentration of NTZ
timeFrame: first 14 days of anti-tuberculosis therapy
measure: Most probable number of M tuberculosis in 1 ml of sputum
timeFrame: first 14 days of anti-tuberculosis therapy
measure: First-line drug susceptibility (DST) of Mycobacterium tuberculosis via Mycobacterial Growth Indicator System (MGIT)
timeFrame: first 14 days of anti-tuberculosis therapy
measure: Quantification of change in urine metabolites and correlation with change in TTP
timeFrame: first 14 days of anti-tuberculosis therapy
measure: Minimum plasma concentration of NTZ
timeFrame: first 14 days of anti-tuberculosis therapy
measure: Area under the curve of NTZ metabolites
timeFrame: first 14 days of anti-tuberculosis therapy
measure: Sputum concentration of NTZ
timeFrame: first 14 days of anti-tuberculosis therapy
measure: Change in Minimum inhibitory concentration (MIC) of NTZ against Tuberculosis over 14 days
timeFrame: first 14 days of anti-tuberculosis therapy
measure: Change in phylogeny of bacteria determined by sequencing of amplified 16S ribosomal DNA and/or metagenomic sequencing of bacterial DNA
timeFrame: first 14 days of anti-tuberculosis therapy
measure: Transcriptional signature of treatment response using whole blood transcriptional profiles
timeFrame: first 14 days of anti-tuberculosis therapy
Other outcomes:
Locations:
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO
Study officials:
affiliation: Weill Medical College of Cornell University
name: Daniel W Fitzgerald, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Medical College of Cornell University
name: Carl Nathan, MD
role: STUDY_CHAIR
affiliation: Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO)
name: Jean William Pape, MD
role: STUDY_CHAIR
References:
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.
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.
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.
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.
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.