Official Title: “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 Type: Interventional

Study Design: Treatment, Pharmacokinetics Study

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.

Intervention(s) in this Clinical Trial

• Drug: Isoniazid
• Drug: Pyridoxine hydrochloride
• Drug: Levofloxacin

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

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

Overall Clinical Trial Officials and Contacts

Hafner R Study Chair   

Information obtained from ClinicalTrials.gov on March 10, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00000778

Study ID Number: DATRI 008

ClinicalTrials.gov Identifier: NCT00000778

Health Authority: United States: Federal Government

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