TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment
TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment
This double-blind, randomized controlled trial evaluates moxifloxacin versus isoniazid in
 daily treatment during the first two months of treatment with rifampin, pyrazinamide and
 ethambutol for sputum smear-positive pulmonary tuberculosis.
The primary objective of this Phase 2 clinical trial is to compare the safety and
 antimicrobial activity of a moxifloxacin-containing regimen (moxifloxacin, rifampin,
 pyrazinamide, ethambutol [MRZE]) in which moxifloxacin has been substituted for isoniazid, to
 the standard control regimen (isoniazid, rifampin, pyrazinamide, ethambutol [HRZE]) in the
 first two months of treatment of sputum smear-positive pulmonary tuberculosis. The assessment
 of antimicrobial activity will be sputum culture-conversion. Higher rates of sputum culture
 conversion after 2 months of treatment with a moxifloxacin-containing regimen would support
 Phase 3 clinical trials of moxifloxacin in treatment regimens of less than the current 6
 month standard regimens.

 Rationale - Current treatment of smear positive pulmonary tuberculosis requires a minimum of
 6 months, a treatment duration that is challenging for patients and tuberculosis control
 programs. Therefore, a high priority in tuberculosis research is the identification of agents
 that can shorten treatment. Several fluoroquinolone antibiotics have potent activity against
 Mycobacterium tuberculosis (M. tuberculosis) in preclinical testing. Of the currently
 available fluoroquinolones, moxifloxacin has excellent activity in vitro and in animal models
 of tuberculosis, a favorable pharmacokinetic profile (serum half-life of 10-12 hours), lack
 of problematic drug-drug interactions, no need for dosage adjustment for renal and hepatic
 insufficiency, and an excellent safety profile. In addition, in the murine model of
 tuberculosis, the substitution of moxifloxacin for isoniazid resulted in significant
 reductions in the time to culture conversion and the time to sterilization when compared to
 the standard combination rifampin, isoniazid and pyrazinamide. However, moxifloxacin has not
 been fully evaluated in humans for tuberculosis treatment. There is a need to assess not only
 the anti-tuberculosis activity of moxifloxacin-containing regimens, but also the safety of
 more prolonged therapy with moxifloxacin.

 Two-month culture conversion rates are a well-accepted surrogate marker for the sterilizing
 activity of anti-tuberculosis drugs. Rifampin and pyrazinamide, the key drugs in current
 6-month regimens, markedly increase 2-month culture-conversion rates. Therefore, this study
 will use 2-month culture conversion rate as the measure of antimicrobial activity of
 moxifloxacin.
Inclusion Criteria:

 -  Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of
 expectorated or induced sputum. Patients whose sputum cultures do not grow M.
 tuberculosis and those having an M. tuberculosis isolate resistant to (one or more)
 isoniazid, rifampin, fluoroquinolones, will be discontinued from the study, but
 followed for 14 days to detect late toxicities from study therapy. Patients having
 extra-pulmonary manifestations of tuberculosis, in addition to smear-positive
 pulmonary disease, are eligible for enrollment. Sputum must be expectorated or
 induced; smear results from respiratory secretions obtained by bronchoalveolar lavage
 or bronchial wash may not be used for assessment of study eligibility.

 -  Willingness to have HIV testing performed, if HIV serostatus is not known or if the
 last documented negative HIV test was more than 6 months prior to enrollment. HIV
 testing does not need to be repeated if there is written documentation of a positive
 test (positive ELISA and Western Blot or a plasma HIV-RNA level greater than 5000
 copies/ml) at any time in the past.

 -  7 (seven) or fewer days of multidrug therapy for tuberculosis disease in the 6 months
 preceding enrollment.

 -  7 (seven) or fewer days of fluoroquinolone therapy in the 3 months preceding
 enrollment.

 -  Age > 18 years

 -  Karnofsky score of at least 60 (requires occasional assistance but is able to care for
 most of his/her needs; see Appendix B).

 -  Signed informed consent

 -  Women with child-bearing potential must agree to practice an adequate (barrier) method
 of birth control or to abstain from heterosexual intercourse during study therapy.

 -  Laboratory parameters done at, or <14 days prior to, screening:

 -  Serum amino aspartate transferase (AST) activity ≤ 3 times the upper limit of normal

 -  Serum total bilirubin level ≤ 2.5 times the upper limit of normal

 -  Serum creatinine level ≤ 2 times the upper limit of normal

 -  Complete blood count with hemoglobin level of at least 7.0 g/dL

 -  Complete blood count with platelet count of at least 50,000/mm3

 -  Serum potassium > 3.5 meq/L

 -  Negative pregnancy test (women of childbearing potential)

 Exclusion Criteria:

 -  Breast-feeding

 -  Known intolerance to any of the study drugs

 -  Known allergy to any fluoroquinolone antibiotic

 -  Concomitant disorders or conditions for which moxifloxacin (MXF), isoniazid (INH),
 rifampin (RIF), pyrazinamide (PZA), or ethambutol (EMB) are contraindicated. These
 include severe hepatic damage, acute liver disease of any cause, and acute
 uncontrolled gouty arthritis.

 -  Current or planned therapy during the intensive phase of therapy using drugs having
 unacceptable interactions with rifampin (rifabutin can be substituted for rifampin
 during the continuation phase of therapy).

 -  Current or planned antiretroviral therapy during the intensive phase of therapy.

 -  History of prolonged QT syndrome or current or planned therapy with quinidine,
 procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine during
 the intensive phase of therapy.

 -  Pulmonary silicosis

 -  Central nervous system TB