Clinical trial NCT00000778: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Tuberculosis
Keywords: Isoniazid
Tuberculosis, Pulmonary
Pyridoxine
Ofloxacin
AIDS-Related Opportunistic Infections
Drug Evaluation
Acquired Immunodeficiency Syndrome
Sputum
Colony Count, Microbial
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: UCLA Med Ctr
state: California
city: Torrance
country: United States
facility: Harbor - UCLA Med Ctr
state: California
city: Fort Lauderdale
country: United States
facility: Broward Gen Med Ctr
state: Florida
city: Miami
country: United States
facility: Univ of Miami / Jackson Memorial Hosp
state: Florida
city: Chicago
country: United States
facility: Univ of Illinois
state: Illinois
city: New Orleans
country: United States
facility: Tulane Univ Med School
state: Louisiana
city: Dallas
country: United States
facility: Univ of Texas Southwestern Med Ctr of Dallas
state: Texas
city: Galveston
country: United States
facility: Univ TX Galveston
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine / Houston Veterans Adm Med Ctr
state: Texas
Study officials:
name: Hafner R
role: STUDY_CHAIR
name: Cohn J
role: STUDY_CHAIR
name: Egorin M
role: STUDY_CHAIR
References:
citation: 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)