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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00000778

Collaborator

(none)

Enrollment

Locations

4.4

Patients Per Site

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
HIV Infections Tuberculosis	Drug: Isoniazid Drug: Pyridoxine hydrochloride Drug: Levofloxacin	Phase 1

Detailed Description

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 Design

Study Type:

Interventional

Primary Purpose:

Treatment

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

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ of Alabama at Birmingham	Birmingham	Alabama	United States	352336505
2	UCLA Med Ctr	Los Angeles	California	United States	900951793
3	Harbor - UCLA Med Ctr	Torrance	California	United States	90502
4	Broward Gen Med Ctr	Fort Lauderdale	Florida	United States	33316
5	Univ of Miami / Jackson Memorial Hosp	Miami	Florida	United States	33136
6	Univ of Illinois	Chicago	Illinois	United States	60622
7	Tulane Univ Med School	New Orleans	Louisiana	United States	701122699
8	Univ of Texas Southwestern Med Ctr of Dallas	Dallas	Texas	United States	75235
9	Univ TX Galveston	Galveston	Texas	United States	77550
10	Baylor College of Medicine / Houston Veterans Adm Med Ctr	Houston	Texas	United States	77030