A Pilot Study of Methodology to Rapidly Evaluate Drugs for Bactericidal Activity, Tolerance, and Pharmacokinetics in the Treatment of Pulmonary Tuberculosis Using Isoniazid and Levofloxacin

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Tuberculosis
• Intervention / Treatment: Drug: Levofloxacin; Drug: Isoniazid; Drug: Pyridoxine hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment: 44
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• El-Sadr WM, Perlman DC, Matts JP, Nelson E, Cohn D, Telzak E, Chirgwin K, Salomon N, Olibrice M, Hafner R. Outcome of an induction regimen for the treatment of HIV-related tuberculosis (TB): evaluation of the addition of a quinolone. Int Conf AIDS. 1996 Jul 7-12;11(1):327 (abstract no TuB2358)

Study record dates

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (ESTIMATE): August 31, 2001

Study Record Updates

• Last Update Posted (ESTIMATE): August 8, 2008
• Last Update Submitted That Met QC Criteria: August 6, 2008
• Last Verified: June 1, 1995

More Information

Terms related to this study

• Keywords: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Drug Evaluation; Isoniazid; Sputum; Pyridoxine; Tuberculosis, Pulmonary; Ofloxacin; Colony Count, Microbial
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Vitamins; Vitamin B Complex; Antitubercular Agents; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Fatty Acid Synthesis Inhibitors; Levofloxacin; Ofloxacin; Vitamin B 6; Pyridoxine; Isoniazid
• Other Study ID Numbers: DATRI 008