Clinical trial NCT00396084
Conditions: Tuberculosis
Keywords: Brazil gatifloxacin isoniazid levofloxacin linezolid moxifloxacin tuberculosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2004-02-10; Completion date: 2007-12-28
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the ability of 4 antibiotics to kill the bacteria that cause tuberculosis (TB). The antibiotics to be studied are linezolid, gatifloxacin, levofloxacin, and moxifloxacin. All are approved by the Brazilian health authorities to treat infections caused by germs other than TB. Seventy human immunodeficiency virus (HIV)-negative adults, aged 18-65 years, who have been newly diagnosed with pulmonary (lung) TB, will participate in this study. Study volunteers will be given one of the 4 study drugs or a comparison antibiotic, Isoniazid, which has been used around the world as a standard of care treatment for TB. Volunteers will stay in the hospital for 10 days and be given a study antibiotic 7 of those days. Blood and saliva samples will be taken. Six weeks later, volunteers will return for a final health check. All volunteers will receive 6 months of standard tuberculosis treatment.

Detailed description:
Multi-drug resistant tuberculosis now affects all regions of the world and is a significant concern for national tuberculosis (TB) control programs. The development and testing of new drugs and new classes of drugs and immunotherapeutic agents are vital elements in the global response to this challenge. The fluoroquinolones and oxazolidinones represent two promising classes of drugs that show activity against Mycobacterium tuberculosis (MTB). This study is a randomized, open label, multiple dose phase I clinical trial to evaluate the early bactericidal activity (EBA) of gatifloxacin, levofloxacin, moxifloxacin, and linezolid compared with an isoniazid (INH) control arm in patients with newly-diagnosed sputum smear-positive pulmonary tuberculosis (TB). Secondary study objectives are to: compare results of sputum MTB messenger ribonucleic acid (mRNA) clearance with results of a standard EBA study \[change in sputum viable counts \[colony forming units (CFU)\]; compare the rate of clearance of sputum cytokine proteins with results of a standard EBA assay CFU; determine the pharmacokinetics (PK) of the study drugs in patients with smear-positive pulmonary TB; and demonstrate that lack of EBA activity is not due to low serum drug concentrations. Seventy human immunodeficiency virus (HIV) negative adults, aged 18-65 years, who have been newly diagnosed with pulmonary TB, will be enrolled and admitted to the Centro de Pesquisa (Clinical Research Ward) at the Hospital Universitario Cassiano Antonio de Moraes of the Universidade Federal do Espírito Santo in Vitória. The subjects will be randomized to receive gatifloxacin, levofloxacin, moxifloxacin, or INH (control), and after these arms are enrolled, they will be randomized to receive either linezolid (600 mg once daily) or linezolid (600 mg twice daily) or INH (control). During the inpatient stay, study drugs will be given for 7 days following a 2-day drug-free period when baseline sputum bacillary counts will be measured. The 7-day duration of the study drug phase will allow measurement of sputum bactericidal activity both during the first 2 days of study drug administration and between days 2 and 7 of study drug administration to gain additional information on the possible sterilizing activity of the drugs. The extended nature of these EBA studies will allow assessment of this possibility in the study drugs that would be missed if a shorter EBA study was performed. Sputum specimens will be collected for 2 days prior to initiation of study drug in order to establish a baseline quantitative culture result and then specimens will be collected daily thereafter. Sputum specimens will be processed to evaluate changes in mycobacterial mRNA/proteins and cytokine proteins. PK studies will be performed after 5 days of study drug administration (Day 5). Safety evaluations including clinical examination, complete blood counts, and serum total bilirubin, aspartate aminotransferase (AST), creatinine, and urinalysis will be followed to monitor for drug toxicity. Drug susceptibility testing will be performed on an initial sputum isolate and will be repeated after completion of 7 days of study drugs, and on isolates from patients with positive sputum cultures at the day 42 study visit to assess for the development of acquired drug resistance. Isolates will be tested against INH, rifampicin, pyrazinamide, ethambutol and the subject's assigned study drug. Patients who are found to be resistant to their assigned study drug at baseline will not be analyzable. After the initial treatment, all subjects will receive 6 months of standard TB treatment outside of the hospital.

Arms: arm 1: 10 subjects to receive gatifloxacin 400 mg orally once daily for 7 days. arm 2: 20 subjects to receive isoniazid 300 mg orally once daily for 7days. arm 3: 10 subjects to receive levofloxacin 1000 mg orally once daily for 7days. arm 4: 10 subjects to receive linezolid 600 mg orally every 12 hours daily for 7 days. arm 5: 10 subjects to receive linezolid 600 mg orally once daily for 7days. arm 6: 10 subjects to receive moxifloxacin 400 mg orally once daily for 7 days.
Interventions: intervention 1: Gatifloxacin intervention 2: Isoniazid intervention 3: Levofloxacin intervention 4: Linezolid intervention 5: Moxifloxacin
Intervention descriptions: intervention 1: Gatifloxacin 400 mg/day x 7 days. intervention 2: Isoniazid 300 mg/day x 7 days. intervention 3: Levofloxacin 1000 mg/day x 7 days. intervention 4: Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days. intervention 5: Moxifloxacin 400 mg/day x 7 days.

Protocol documents: