Official Title: “TBTC Study 27/28 PK: Pharmacokinetic Issues in the Use of Moxifloxacin for Treatment of Tuberculosis”

This substudy of TBTC Studies 27 and 28 compares 1) the pharmacokinetics of moxifloxacin alone versus moxifloxacin administered with rifampin in healthy volunteers and 2) the pharmacokinetics of moxifloxacin among patients with tuberculosis being treated with multidrug therapy (isoniazid or ethambutol, rifampin, and pyrazinamide) to those of healthy volunteers receiving moxifloxacin plus rifampin. It also evaluates the association between polymorphisms of MDR1 genotype (P-glycoprotein) and rifampin pharmacokinetic parameters, the effect of polymorphisms of MDR1 genotype and/or rifampin pharmacokinetics on isoniazid pharmacokinetic parameters adjusted for N-acetyltransferase genotype (NAT2), and determines by multivariate regression analyses the associations between moxifloxacin or rifampin pharmacokinetic parameters and markers of tuberculosis disease severity including the covariates of two-month culture positivity, cavitary lung disease, Body Mass Index, weight, duration of study treatment prior to PK, co-morbidities and C-reactive protein. Healthy volunteers and TB patients receive frequent scheduled blood draws during a 24 hour period after ingesting a dose of TB drugs.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Double-Blind, Active Control, Parallel Assignment, Pharmacokinetics Study

Study Primary Completion Date: August 2007

Intervention(s) in this Clinical Trial

• Drug: moxifloxacin (with isoniazid or ethambutol, rifampin and pyrazinamide)

Primary Measures

• Compare in healthy volunteers the pharmacokinetics of moxifloxacin alone versus moxifloxacin administered with rifampin.
• Compare the pharmacokinetics of moxifloxacin among patients with tuberculosis being treated with multidrug therapy (isoniazid or ethambutol, rifampin, and pyrazinamide) to those of healthy volunteers receiving moxifloxacin plus rifampin.

Secondary Measures

• Determine variation of moxifloxacin pharmacokinetics (PK) among patients with pulmonary TB during treatment.
• Compare serum concentrations of isoniazid rifampin and pyrazinamide among patients being treated with moxifloxacin versus patients being treated with ethambutol as the fourth drug in multidrug treatment.
• Compare serum concentrations of rifampin, pyrazinamide and ethambutol among patients being treated with moxifloxacin versus patients being treated with isoniazid as the fourth drug
• Determine the association between polymorphisms of MDR1 genotype (P-glycoprotein) and rifampin PK parameters.
• Determine the effect of polymorphisms of MDR1 genotype and/or rifampin PK on isoniazid PK parameters adjusted for N-acetyltransferase genotype (NAT2).
• Determine the effects of polymorphisms of MDR1 and UGT genotypes on moxifloxacin PK parameters.
• Determine by multivariate regression analyses the associations between moxifloxacin or rifampin PK parameters and markers of disease severity.

Inclusion Criteria:

For Healthy Volunteers:

• Provision of informed consent for the study.
• Age > 18 years.
• Willingness to be available for 2 weeks of DOT.
• Willingness to be admitted to a GCRC or hospital on two occasions.
• Women of child-bearing potential must agree to practice an adequate method of birth control. Barrier methods of contraception or abstinence from sexual activity are satisfactory methods.
• Willingness to have HIV testing done if documented results are not available. (A prior negative result must be obtained within one year and consists of a negative HIV
• ELISA. A positive result must be both a positive HIV ELISA and Western Blot, or a plasma HIV PCR RNA level greater than 5000 copies/ml).
• Laboratory screening (if not already available) within 30 days of the first PK admission:
• Serum potassium within normal limits
• Hematocrit > 35%
• Absolute neutrophil count > 1000 /mm3
• AST < 3 times the upper limit of normal
• Bilirubin < 2 times the upper limit of normal
• Creatinine < 2 times the upper limit of normal
• Eligible and enrolled for medical health care sponsored by the United States federal government (such as the Veterans Administration enrollment Priority 1 through 7, VHA
• Directive 2003-003).

For Patients with Tuberculosis Enrolled in TBTC Study 27 or Study 28:

• Any patient enrolled in TBTC Study 27 or Study 28 receiving a daily (5-7 days per week) regimen.
• Provision of informed consent for the study.
• Willingness to be admitted to a GCRC or hospital on one occasion.

Exclusion Criteria:

For Healthy Volunteers:

• Karnofsky score less than 90
• Pregnancy or breast-feeding. (A negative pregnancy test is required for women of childbearing potential within 14 days before the first dose of moxifloxacin.)
• Known allergy to any fluoroquinolone or rifamycin antibiotic
• Current or planned therapy during the study with drugs having unacceptable interactions with rifampin
• History of prolonged QT syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, or ziprasidone during period of administration of moxifloxacin and for one week after treatment

For Patients with Tuberculosis Enrolled in TBTC Study 27 or Study 28:

• Severe anemia as defined by a hematocrit less than 25% (most recent value, measured within 30 days of the PK study).
• History of severe liver disease classified as Child Pugh Class C.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Centers for Disease Control and Prevention

Overall Clinical Trial Officials and Contacts

Marc Weiner, MD Study Chair VAMC and University of Texas Health Science Center San Antonio  

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00164463

Study ID Number: CDC-NCHSTP-4222

ClinicalTrials.gov Identifier: NCT00164463

Health Authority: United States: Food and Drug Administration