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| Sponsor: | National Institute of Allergy and Infectious Diseases (NIAID) |
|---|---|
| Information provided by: | National Institute of Allergy and Infectious Diseases (NIAID) |
| ClinicalTrials.gov Identifier: | NCT00396084 |
Purpose
This study will evaluate the ability of 4 antibiotics to kill the bacteria that cause tuberculosis (TB). The antibiotics to be studied are linezolid, gatifloxacin, levofloxacin, and moxifloxacin. All are approved by the Brazilian health authorities to treat infections caused by germs other than TB. Seventy human immunodeficiency virus (HIV)-negative adults, aged 18-65 years, who have been newly diagnosed with pulmonary (lung) TB, will participate in this study. Study volunteers will be given one of the 4 study drugs or a comparison antibiotic, Isoniazid, which has been used around the world as a standard of care treatment for TB. Volunteers will stay in the hospital for 10 days and be given a study antibiotic 7 of those days. Blood and saliva samples will be taken. Six weeks later, volunteers will return for a final health check. All volunteers will receive 6 months of standard tuberculosis treatment.
| Condition | Intervention | Phase |
|---|---|---|
|
Tuberculosis |
Drug: Gatifloxacin Drug: Isoniazid Drug: Levofloxacin Drug: Linezolid Drug: Moxifloxacin |
Phase I Phase II |
| Study Type: | Interventional |
| Study Design: | Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study |
| Official Title: | Randomized, Open Label, Multiple Dose Phase I Study of the Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, and Moxifloxacin in HIV-non-infected Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis |
| Enrollment: | 70 |
| Study Start Date: | February 2004 |
| Study Completion Date: | December 2007 |
| Primary Completion Date: | November 2007 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Levofloxacin: Experimental
10 subjects to receive levofloxacin 1000 mg orally once daily for 7days.
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Drug: Levofloxacin
Levofloxacin 1000 mg/day x 7 days.
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Moxifloxacin: Experimental
10 subjects to receive moxifloxacin 400 mg orally once daily for 7 days.
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Drug: Moxifloxacin
Moxifloxacin 400 mg/day x 7 days.
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Linezolid once daily: Experimental
10 subjects to receive linezolid 600 mg orally once daily for 7days.
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Drug: Linezolid
Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
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Isoniazid: Active Comparator
20 subjects to receive isoniazid 300 mg orally once daily for 7days.
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Drug: Isoniazid
Isoniazid 300 mg/day x 7 days.
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Linezolid every 12 hours: Experimental
10 subjects to receive linezolid 600 mg orally every 12 hours daily for 7 days.
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Drug: Linezolid
Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
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Gatifloxacin: Experimental
10 subjects to receive gatifloxacin 400 mg orally once daily for 7 days.
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Drug: Gatifloxacin
Gatifloxacin 400 mg/day x 7 days.
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This randomized, open label, multiple dose, phase I clinical trial will evaluate and compare the early bactericidal activity (EBA) of the new fluoroquinolone antibiotics moxifloxacin, levofloxacin, and gatifloxacin, and once and twice daily 600 mg doses of linezolid, a new oxazolidinone antibiotic; compared with an isoniazid (INH) control arm in patients with newly-diagnosed sputum smear-positive pulmonary tuberculosis (TB). Secondary study objectives are to: compare results of sputum Mycobacterium tuberculosis (MTB) messenger ribonucleic acid (mRNA) clearance with results of a standard EBA study [change in sputum viable counts [colony forming units (CFU)]; compare the rate of clearance of sputum cytokine proteins with results of a standard EBA assay CFU; determine the pharmacokinetics (PK) of the study drugs (moxifloxacin, levofloxacin, gatifloxacin, linezolid, and isoniazid) in patients with smear-positive pulmonary TB; and demonstrate that lack of EBA activity is not due to low serum drug concentrations. The primary study endpoint is the projected net proportionate difference in sputum bacillary load [quantitative colony forming units (CFU) on solid media] as measured by area under the curve while receiving a single study drug. Secondary study endpoints are: rate of clearance of sputum MTB mRNA and proteins, such as 85 B alpha antigen and alpha crystallin; rate of clearance of sputum cytokine proteins; and plasma drug concentration for determination of PK profile of each study drug. Seventy human immunodeficiency virus (HIV) negative adults, aged 18-65 years, who have been newly diagnosed with pulmonary TB, will be enrolled and admitted to the Centro de Pesquisa (Clinical Research Ward) at the Hospital Universitario Cassiano Antonio de Moraes of the Universidade Federal do Espírito Santo in Vitória. The subjects will be randomized to receive gatifloxacin, levofloxacin, moxifloxacin, or INH (control), and after these arms are enrolled, they will be randomized to receive either linezolid (600 mg once daily) or linezolid (600 mg twice daily) or INH (control). During the inpatient stay, study drugs will be given for 7 days following a 2-day drug-free period when baseline sputum bacillary counts will be measured. The 7-day duration of the study drug phase will allow measurement of sputum bactericidal activity both during the first 2 days of study drug administration and between days 2 and 7 of study drug administration to gain additional information on the possible sterilizing activity of the drugs. The extended nature of these EBA studies will allow assessment of this possibility in the study drugs that would be missed if a shorter EBA study was performed. Sputum specimens will be collected for 2 days prior to initiation of study drug in order to establish a baseline quantitative culture result and then specimens will be collected daily thereafter. Sputum specimens will be processed to evaluate changes in mycobacterial mRNA/proteins and cytokine proteins. Pharmacokinetic (PK) studies will be performed after 5 days of study drug administration (Day 5). Safety evaluations including clinical examination, complete blood counts, and serum total bilirubin, aspartate aminotransferase (AST), creatinine, and urinalysis will be followed to monitor for drug toxicity. Drug susceptibility testing will be performed on an initial sputum isolate and will be repeated after completion of 7 days of study drugs, and on isolates from patients with positive sputum cultures at the day 42 study visit to assess for the development of acquired drug resistance. Isolates will be tested against INH, rifampicin, pyrazinamide, ethambutol and the subject's assigned study drug. Patients who are found to be resistant to their assigned study drug at baseline will not be analyzable. After the initial treatment, all subjects will receive 6 months of standard TB treatment outside of the hospital.
Eligibility| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contacts and Locations More Information
| Responsible Party: | HHS/NIAID/DMID ( Robert Johnson ) |
| Study ID Numbers: | 01-553, TBRU 10 |
| Study First Received: | November 3, 2006 |
| Results First Received: | November 19, 2008 |
| Last Updated: | September 16, 2009 |
| ClinicalTrials.gov Identifier: | NCT00396084 History of Changes |
| Health Authority: | United States: Institutional Review Board; Brazil: National Committee of Ethics in Research; United States: Federal Government; United States: Food and Drug Administration |
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tuberculosis, linezolid, gatifloxacin, levofloxacin, isoniazid, moxifloxacin, Brazil |
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Bacterial Infections Antimetabolites Anti-Infective Agents Molecular Mechanisms of Pharmacological Action Ofloxacin Renal Agents Anti-Bacterial Agents Gram-Positive Bacterial Infections Respiratory Tract Infections Respiratory Tract Diseases Moxifloxacin Therapeutic Uses Tuberculosis Linezolid Nucleic Acid Synthesis Inhibitors |
Isoniazid Fluoroquinolones Antilipemic Agents Anti-Infective Agents, Urinary Enzyme Inhibitors Actinomycetales Infections Pharmacologic Actions Gatifloxacin Protein Synthesis Inhibitors Lung Diseases Tuberculosis, Pulmonary Mycobacterium Infections Antitubercular Agents Fatty Acid Synthesis Inhibitors |
