This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The primary objective of this study is to compare the safety and antimicrobial activity of a moxifloxacin-containing regimen (moxifloxacin, rifampin, pyrazinamide, ethambutol) in which moxifloxacin has been substituted for isoniazid, to the standard control regimen (isoniazid, rifampin, pyrazinamide, ethambutol) in the first two months of treatment of sputum smear-positive pulmonary tuberculosis. The assessment of antimicrobial activity will be sputum culture-conversion. Secondary objectives are: to compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimen; to determine the time to culture-conversion of the moxifloxacin regimen and the isoniazid regimen, using data from 2-, 4-, 6-, and 8-week cultures; to compare the proportion of patients with any Grade 3 or 4 adverse reactions; to compare adverse events and 2-month culture conversion rate among HIV-infected patients vs. HIV-uninfected patients; to compare the rates of treatment failure of the moxifloxacin regimen to the isoniazid regimen; and to determine whether there is delayed toxicity attributable to moxifloxacin (toxicity that becomes evident after the 2 months of moxifloxacin therapy). RESEARCH PLAN AND METHODS: This multicenter, placebo-controlled, double-blind, Phase 2 study will evaluate the effect of using moxifloxacin (M) in place of isoniazid (H), in combination with rifampin (R), pyrazinamide (Z) and ethambutol (E) on 2-month culture conversion rates among patients with sputum smear-positive pulmonary tuberculosis. The protocol will enroll HIV-infected and uninfected patients. In both study arms, treatment can be given 5-7 days per week during the first 2 weeks at the discretion of the principal investigator (only 5 doses will be counted toward completion of the four-drug phase of therapy). All doses of study medication counted toward completion of the four-drug phase of therapy will be given as directly observed therapy. The moxifloxacin dose will be the currently licensed dose of 400mg. Vitamin B6 (50 mg) will be given with each dose of therapy. Ethambutol may be discontinued if the patient's M. tuberculosis isolate is susceptible to isoniazid, rifampin, pyrazinamide, and fluoroquinolones, as demonstrated by laboratory studies. The duration of the intensive phase of therapy will be determined by the number of doses ingested, not by calendar time. Patients will complete the intensive phase when they have had 40 daily (5 days per week) directly-observed doses. This therapy must have been completed within no less than 54 days and no more than 70 days. After completion of intensive phase therapy, patients in all study arms will then be treated with an ATS/IDSA/CDC-recommended continuation phase regimen. The total duration of therapy will be 26 weeks (6 months) except for patients who have cavitation plus a positive sputum culture at the end of the intensive phase of therapy who will receive a total of 38 weeks (9 months) of therapy. Subjects who meet the inclusion criteria will be randomized in a 1:1 ration to one of two treatment arms. Because cavitation at baseline (time of diagnosis) is associated with a substantially decreased rate of 2-month culture conversion, randomization will be stratified by presence of cavitation. In addition, randomization will be stratified by geographic continent. Study Endpoints: 1. Sputum culture conversion - sputum culture obtained at the end of the intensive phase of therapy has no growth of M. tuberculosis. The end of the intensive phase of therapy will be defined by completion of the 40 required number of directly-observed doses. 2. Safety and tolerability endpoints - the primary endpoint for the analysis of safety and tolerability will be the proportion of patients who discontinue the assigned study regimen for any reason. Secondary endpoints include mortality, the occurrence of Grade 3 and 4 toxicities, and the rate and types of toxicity thought related to study drug. 3. Treatment failure - a positive sputum culture after completion of 4 months of TB treatment. All treatment failure isolates will be compared to the initial isolate using DNA fingerprinting. CLINICAL
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 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.
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