To evaluate the methodology for rapidly determining the early bactericidal activity (EBA), tolerance, and pharmacokinetics of isoniazid and levofloxacin in the treatment of pulmonary tuberculosis (TB). Traditionally, in trials for treatment of TB, a new drug is administered in combination with two or more other antituberculous agents of known effectiveness over a long period of time. In this setting, it is difficult to determine the effect of any single drug or dose level. Development of new agents for the treatment of TB may be accelerated by a methodology in which a new agent could be evaluated for activity by administering it as a single agent over a short time period. This study utilizes a method to measure the amount of bacteria present each day in the lungs.

Condition	Treatment or Intervention	Phase
HIV Infections Tuberculosis	Drug: Isoniazid  Drug: Pyridoxine hydrochloride  Drug: Levofloxacin	Phase I

Further Study Details: 

Expected Total Enrollment:  44

Traditionally, in trials for treatment of TB, a new drug is administered in combination with two or more other antituberculous agents of known effectiveness over a long period of time. In this setting, it is difficult to determine the effect of any single drug or dose level. Development of new agents for the treatment of TB may be accelerated by a methodology in which a new agent could be evaluated for activity by administering it as a single agent over a short time period. This study utilizes a method to measure the amount of bacteria present each day in the lungs.

An initial cohort of patients receive isoniazid (with pyridoxine) daily for 5 days. Sputum samples are collected daily for determination of the EBA (decline in colony-forming units/ml sputum). If the methodology is validated, additional patients are randomized to receive one of two doses of levofloxacin daily for 5 days, with determination of EBA. All patients are hospitalized for 2 days of baseline evaluation and 5 days of treatment.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria

Concurrent Medication: Allowed in all patients:

• Antacids if administered more than 2 hours before or after study drug. Allowed in isoniazid patients:
• Anticonvulsant therapy if blood levels are monitored. Allowed in levofloxacin patients:
• Acceptable medications other than antacids if administered at least 2 hours before or 1 hour after study drug.
• Anticonvulsant therapy, theophylline, or warfarin if doses are monitored.

Patients must have:

• Presumptive active pulmonary TB.
• No clinical evidence of central nervous system or miliary tuberculosis.

NOTE:

• Both HIV-positive and HIV-negative patients are eligible.

NOTE:

• Pregnant women may be enrolled in the isoniazid cohort only.

Exclusion Criteria

Co-existing Condition: Patients with the following symptoms or conditions are excluded:

• Active or suspected MAI infection.
• Active or suspected hepatitis.
• Any other serious acute infection, diabetes, chronic obstructive pulmonary disease, malignancy requiring chemotherapy, or major organ dysfunction.
• Extreme illness or toxic appearance.
• Pregnancy (if entering the levofloxacin portion of the study).

Concurrent Medication: Excluded:

• All standard TB therapies.
• Clofazimine.
• Rifabutin.
• Quinolones.
• Aminoglycosides.
• Corticosteroids.
• Pentoxifylline.
• Colony-stimulating factors.
• Interferons.
• Interleukins.
• Disulfiram (patients receiving isoniazid).

Patients with the following prior conditions are excluded:

• History of treatment-limiting intolerance or known hypersensitivity to isoniazid (in patients receiving isoniazid) or to quinolones (in patients receiving levofloxacin).
• Vomiting or diarrhea >= grade 2 at screening or within 2 days prior to screening.
• History of drug-resistant TB (in patients receiving isoniazid).

Prior Medication: Excluded:

• Any prior treatment or prophylaxis for TB if enrolling on the isoniazid cohort.
• Any anti-TB drug within the past 12 weeks, including standard drugs against TB as well as clofazimine, rifabutin, and all quinolones and aminoglycosides.
• Corticosteroids, pentoxifylline, colony-stimulating factors, interferons, or interleukins within the past 12 weeks.

Known risk factors for multi-drug resistant (MDR) TB, including:

• Domicile, shelter, or prison exposure to a known case of MDR TB within the past 6 months.
• Residence in a specific domicile, shelter, or prison cell block within 6 months of a known outbreak of MDR TB.
• Hospitalization, within the past 6 months, on a medical service or unit in which nosocomial transmission of MDR TB is known to have occurred.

Alabama
      Univ of Alabama at Birmingham, Birmingham,  Alabama,  352336505,  United States
California
      Harbor - UCLA Med Ctr, Torrance,  California,  90502,  United States
      UCLA Med Ctr, Los Angeles,  California,  900951793,  United States
Florida
      Broward Gen Med Ctr, Fort Lauderdale,  Florida,  33316,  United States
      Univ of Miami / Jackson Memorial Hosp, Miami,  Florida,  33136,  United States
Illinois
      Univ of Illinois, Chicago,  Illinois,  60622,  United States
Louisiana
      Tulane Univ Med School, New Orleans,  Louisiana,  701122699,  United States
Texas
      Univ of Texas Southwestern Med Ctr of Dallas, Dallas,  Texas,  75235,  United States
      Univ TX Galveston, Galveston,  Texas,  77550,  United States
      Baylor College of Medicine / Houston Veterans Adm Med Ctr, Houston,  Texas,  77030,  United States

Study chairs or principal investigators

Hafner R,  Study Chair
Cohn J,  Study Chair
Egorin M,  Study Chair

Study ID Numbers:  DATRI 008
Record last reviewed:  June 1995
Last Updated:  April 7, 2005
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00000778
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08