Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis
Condition: Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): Gatifloxacin; Isoniazid; Levofloxacin; Linezolid; Moxifloxacin
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Gatifloxacin 400 mg/day x 7 days.; Isoniazid 300 mg/day x 7 days.; Levofloxacin 1000 mg/day x 7 days.; Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.; Moxifloxacin 400 mg/day x 7 days.
Intervention MeSH terms: Moxifloxacin; Levofloxacin; Isoniazid; Linezolid; Gatifloxacin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Brazil; gatifloxacin; isoniazid; levofloxacin; linezolid; moxifloxacin; tuberculosis