- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00396084
Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis
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
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Espírito Santo
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Vitória, Espírito Santo, Brazil, 29040-091
- Universidade Federal do Espirito Santo - Duke Hubert-Yeargan Center
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California
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San Francisco, California, United States, 94110-3518
- San Francisco General Hospital - Pulmonary and Critical Care Medicine
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
-Adults, male or female, age 18 to 65 years. -Women with child-bearing potential (not surgically sterilized or postmenopausal for less than 1 year) must be using or agree to use an adequate method of birth control [condom; intravaginal spermicide (foams, jellies, sponge) and diaphragm; cervical cap or intrauterine device] during study drug treatment. -Newly diagnosed sputum smear-positive pulmonary tuberculosis as confirmed by sputum acid fast bacilli (AFB) smear and chest X-ray findings consistent with pulmonary tuberculosis. -Willing and able to provide informed consent. -Reasonably normal hemoglobin (greater than or equal to 8 gm/dL), renal function (serum creatinine less than 2 mg/dL), hepatic function [serum aspartate aminotransferase (AST) less than 1.5 times the upper limit of normal for the testing laboratory and total bilirubin less than 1.3 mg/dL], and random blood glucose less than 150 mg/dL.
Exclusion Criteria:
-Human immunodeficiency virus (HIV) infection. -Weight less than 75 percent of ideal body weight. -Presence of significant hemoptysis. Patients who cough up frank blood (more than blood streaked sputum) will not be eligible for enrollment. -Pregnant or breastfeeding women and those who are not practicing birth control. -Significant respiratory impairment (respiratory rate greater than 35/minute). -Clinical suspicion of disseminated tuberculosis or tuberculosis meningitis. -Presence of serious underlying medical illness, such as liver failure, renal failure, diabetes mellitus, chronic alcoholism, decompensated heart failure, hematologic malignancy or patients receiving myelosuppressive chemotherapy. -Patients receiving any of the following medications - monoamine oxidase inhibitors (phenelzine, tranylcypromine), adrenergic/serotonergic agonists such as pseudoephedrine and phenylpropanolamine (frequently found in cold and cough remedies), tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline, doxepin, amoxapine, etc), antipsychotics such as chlorpromazine and buspirone, serotonin re-uptake inhibitors (fluoxetine, paroxetine, sertraline, etc.), buproprion, agents known to prolong the QTc interval [erythromycin, clarithromycin, astemizole, type Ia (quinidine, procainamide, disopyramide) and III (amiodarone, sotalol) anti-arrhythmics, carbamazepine, insulin, sulfonylureas, and meperidine. -Presence of QTc prolongation (greater than 450 msec) on baseline electrocardiogram (EKG). -Allergy or contraindication to use of study drugs. -Treatment with antituberculosis medications or other antibiotics with known activity against M. tuberculosis during the preceding 6 months. -Inability to provide informed consent. -Total white blood cell count less than 3000/mm^3. -Platelet count less than 150,000/mm^3. -Patients with suspected drug resistant tuberculosis (e.g., contact to source patient with drug resistant tuberculosis, patients who have relapsed after previous treatment for tuberculosis). -Patients likely, in the opinion of the local investigator, to be unable to comply with the requirements of the study protocol.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Gatifloxacin
10 subjects to receive gatifloxacin 400 mg orally once daily for 7 days.
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Gatifloxacin 400 mg/day x 7 days.
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ACTIVE_COMPARATOR: Isoniazid
20 subjects to receive isoniazid 300 mg orally once daily for 7days.
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Isoniazid 300 mg/day x 7 days.
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EXPERIMENTAL: Levofloxacin
10 subjects to receive levofloxacin 1000 mg orally once daily for 7days.
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Levofloxacin 1000 mg/day x 7 days.
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EXPERIMENTAL: Linezolid every 12 hours
10 subjects to receive linezolid 600 mg orally every 12 hours daily for 7 days.
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Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
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EXPERIMENTAL: Linezolid once daily
10 subjects to receive linezolid 600 mg orally once daily for 7days.
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Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
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EXPERIMENTAL: Moxifloxacin
10 subjects to receive moxifloxacin 400 mg orally once daily for 7 days.
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Moxifloxacin 400 mg/day x 7 days.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)
Time Frame: Study drug administration duration - 7 days monotherapy
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The adjusted area under the curve (aAUC) for sputum colony forming units (cfu) for each day on treatment was calculated.
The aAUC represents the percentage of the expected AUC given no change in log cfu in response to study drug administration.
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Study drug administration duration - 7 days monotherapy
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Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison
Time Frame: Day 0 to Day 2 Monotherapy
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Early bactericidal activity (EBA 0-2) was calculated as the rate of fall in sputum colony forming units (cfu) (expressed in log10 units) during the first 2 days of monotherapy.
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Day 0 to Day 2 Monotherapy
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Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison
Time Frame: Day 2 to Day 7 Monotherapy
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The rate of fall in sputum cfu between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained by fitting the 6 sputum cfu values corresponding to Days 2 through 7.
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Day 2 to Day 7 Monotherapy
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Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)
Time Frame: Study drug administration duration - 7 days monotherapy
|
The adjusted area under the curve (aAUC) for sputum colony forming unit (cfu) for each day on treatment was calculated for patients in the INH arm and those in the Linezolid once daily and Linezolid twice daily arms.
The aAUC represents the percentage of the expected AUC given no change in log cfu in response to study drug administration.
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Study drug administration duration - 7 days monotherapy
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Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison
Time Frame: Day 0 to Day 2 Monotherapy
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Early bactericidal activity (EBA 0-2) was calculated as the rate of fall in sputum cfu (expressed in log10 units) during the first 2 days of monotherapy.
Mean values for the 3 treatment groups were compared.
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Day 0 to Day 2 Monotherapy
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Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison
Time Frame: Day 2 to Day 7 Monotherapy
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The rate of fall in sputum cfu between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained by fitting the 6 sputum cfu values corresponding to Days 2 through 7.
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Day 2 to Day 7 Monotherapy
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Sputum mRNA Clearance Rate - Results Are Pending.
Time Frame: Study drug administration duration
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Study drug administration duration
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Sputum Cytokine Proteins - Results Are Pending.
Time Frame: Study drug administration duration
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Study drug administration duration
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Maximum Plasma Drug Concentration (Cmax)
Time Frame: Day 5 (7 time points)
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Maximum plasma concentration, given sampling scheme
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Day 5 (7 time points)
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Time to Maximum Plasma Drug Concentration (Tmax) and Half-life
Time Frame: Day 5 (7 time points)
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Day 5 (7 time points)
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Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC)
Time Frame: Day 5 (7 time points)
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Day 5 (7 time points)
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Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours
Time Frame: Day 5 (7 time points)
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Area under the curve (AUC), from time 0-12 hours for INH or 0-24 hours for gatifloxacin, levofloxacin, and moxifloxacin.
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Day 5 (7 time points)
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Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC)
Time Frame: Day 5 (7 time points)
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Area Under the Curve (AUC) During First 12 or 24 Hours /Minimum Inhibitory Concentration.
AUC reflects total drug (bound and unbound).
MIC values were determined using protein-containing media.
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Day 5 (7 time points)
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Maximum Plasma Drug Concentration (Cmax)
Time Frame: Day 5 (7 time points)
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Maximum Plasma Drug Concentration (Cmax), given sampling scheme
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Day 5 (7 time points)
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Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours
Time Frame: Day 5 (7 time points)
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Median pharmacokinetic parameters (range).
AUC 0-12 and AUC 0-24 = area under the curve during the first 12 and 24 hours after dosing, respectively
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Day 5 (7 time points)
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Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration
Time Frame: Day 5 (7 time points)
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Cmax adjusted for free drug concentrations after 5 days of monotherapy with study drugs
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Day 5 (7 time points)
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Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations
Time Frame: Day 5 (7 time points)
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Day 5 (7 time points)
|
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Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations
Time Frame: Day 5 (7 time points)
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Median pharmacodynamic parameters (range) adjusted for free drug concentrations.
AUC 0-12 and AUC 0-24 = area under the curve during the first 12 and 24 hours after dosing, respectively
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Day 5 (7 time points)
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Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC)
Time Frame: Day 5 (7 time points)
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Area Under the Curve 0-12 (AUC 0-12) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) and AUC 0-24/MIC
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Day 5 (7 time points)
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Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC)
Time Frame: Day 5 (7 time points)
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Determined by linear extrapolation of concentration-versus-time curve to intersection with MIC.
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Day 5 (7 time points)
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Collaborators and Investigators
Publications and helpful links
General Publications
- Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, Jankus DD, Debanne SM, Charlebois ED, Maciel E, Palaci M, Dietze R. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006 Jun;10(6):605-12.
- Dietze R, Hadad DJ, McGee B, Molino LP, Maciel EL, Peloquin CA, Johnson DF, Debanne SM, Eisenach K, Boom WH, Palaci M, Johnson JL. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med. 2008 Dec 1;178(11):1180-5. doi: 10.1164/rccm.200806-892OC. Epub 2008 Sep 11.
- Millard J, Pertinez H, Bonnett L, Hodel EM, Dartois V, Johnson JL, Caws M, Tiberi S, Bolhuis M, Alffenaar JC, Davies G, Sloan DJ. Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation. J Antimicrob Chemother. 2018 Jul 1;73(7):1755-1762. doi: 10.1093/jac/dky096.
- Peloquin CA, Hadad DJ, Molino LP, Palaci M, Boom WH, Dietze R, Johnson JL. Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2008 Mar;52(3):852-7. doi: 10.1128/AAC.01036-07. Epub 2007 Dec 10.
- McGee B, Dietze R, Hadad DJ, Molino LP, Maciel EL, Boom WH, Palaci M, Johnson JL, Peloquin CA. Population pharmacokinetics of linezolid in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2009 Sep;53(9):3981-4. doi: 10.1128/AAC.01378-08. Epub 2009 Jun 29.
- Li L, Mahan CS, Palaci M, Horter L, Loeffelholz L, Johnson JL, Dietze R, Debanne SM, Joloba ML, Okwera A, Boom WH, Eisenach KD. Sputum Mycobacterium tuberculosis mRNA as a marker of bacteriologic clearance in response to antituberculosis therapy. J Clin Microbiol. 2010 Jan;48(1):46-51. doi: 10.1128/JCM.01526-09. Epub 2009 Nov 18.
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
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
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antimetabolites
- Antineoplastic Agents
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Hypolipidemic Agents
- Lipid Regulating Agents
- Anti-Bacterial Agents
- Cytochrome P-450 Enzyme Inhibitors
- Protein Synthesis Inhibitors
- Antitubercular Agents
- Pharmaceutical Solutions
- Cytochrome P-450 CYP1A2 Inhibitors
- Ophthalmic Solutions
- Anti-Infective Agents, Urinary
- Renal Agents
- Fatty Acid Synthesis Inhibitors
- Linezolid
- Moxifloxacin
- Levofloxacin
- Ofloxacin
- Gatifloxacin
- Isoniazid
Other Study ID Numbers
- 01-553
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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