Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00396084
• Collaborator: (none)
• Enrollment: 70
• Locations: 2
• Arms: 6
• Actual Duration (Months): 46.6
• Patients Per Site: 35
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Gatifloxacin; Drug: Isoniazid; Drug: Levofloxacin; Drug: Linezolid; Drug: Moxifloxacin	Phase 1/Phase 2

Detailed Description

Multi-drug resistant tuberculosis now affects all regions of the world and is a significant concern for national tuberculosis (TB) control programs. The development and testing of new drugs and new classes of drugs and immunotherapeutic agents are vital elements in the global response to this challenge. The fluoroquinolones and oxazolidinones represent two promising classes of drugs that show activity against Mycobacterium tuberculosis (MTB). This study is a randomized, open label, multiple dose phase I clinical trial to evaluate the early bactericidal activity (EBA) of gatifloxacin, levofloxacin, moxifloxacin, and linezolid 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 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 in patients with smear-positive pulmonary TB; and demonstrate that lack of EBA activity is not due to low serum drug concentrations. 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. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Feb 10, 2004
• Actual Primary Completion Date: Nov 23, 2007
• Actual Study Completion Date: Dec 28, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gatifloxacin 10 subjects to receive gatifloxacin 400 mg orally once daily for 7 days.	Drug: Gatifloxacin; Gatifloxacin 400 mg/day x 7 days.
Active Comparator: Isoniazid 20 subjects to receive isoniazid 300 mg orally once daily for 7days.	Drug: Isoniazid; Isoniazid 300 mg/day x 7 days.
Experimental: Levofloxacin 10 subjects to receive levofloxacin 1000 mg orally once daily for 7days.	Drug: Levofloxacin; Levofloxacin 1000 mg/day x 7 days.
Experimental: Linezolid every 12 hours 10 subjects to receive linezolid 600 mg orally every 12 hours daily for 7 days.	Drug: Linezolid; Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
Experimental: Linezolid once daily 10 subjects to receive linezolid 600 mg orally once daily for 7days.	Drug: Linezolid; Linezolid 600 mg/day x 7 days; Linezolid 600 mg every 12 hours x 7 days.
Experimental: Moxifloxacin 10 subjects to receive moxifloxacin 400 mg orally once daily for 7 days.	Drug: Moxifloxacin; Moxifloxacin 400 mg/day x 7 days.

Outcome Measures

Primary Outcome Measures

1. Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) [Study drug administration duration - 7 days monotherapy]

   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.

2. Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison [Day 0 to Day 2 Monotherapy]

   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.

3. Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison [Day 2 to Day 7 Monotherapy]

   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.

4. Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) [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.

5. Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison [Day 0 to Day 2 Monotherapy]

   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.

6. Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison [Day 2 to Day 7 Monotherapy]

   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.

Secondary Outcome Measures

1. Sputum mRNA Clearance Rate - Results Are Pending. [Study drug administration duration]

2. Sputum Cytokine Proteins - Results Are Pending. [Study drug administration duration]

3. Maximum Plasma Drug Concentration (Cmax) [Day 5 (7 time points)]

   Maximum plasma concentration, given sampling scheme

4. Time to Maximum Plasma Drug Concentration (Tmax) and Half-life [Day 5 (7 time points)]

5. Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) [Day 5 (7 time points)]

6. Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours [Day 5 (7 time points)]

   Area under the curve (AUC), from time 0-12 hours for INH or 0-24 hours for gatifloxacin, levofloxacin, and moxifloxacin.

7. Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) [Day 5 (7 time points)]

   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.

8. Maximum Plasma Drug Concentration (Cmax) [Day 5 (7 time points)]

   Maximum Plasma Drug Concentration (Cmax), given sampling scheme

9. Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours [Day 5 (7 time points)]

   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

10. Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration [Day 5 (7 time points)]

    Cmax adjusted for free drug concentrations after 5 days of monotherapy with study drugs

11. Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations [Day 5 (7 time points)]

12. Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations [Day 5 (7 time points)]

    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

13. Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) [Day 5 (7 time points)]

    Area Under the Curve 0-12 (AUC 0-12) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) and AUC 0-24/MIC

14. Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC) [Day 5 (7 time points)]

    Determined by linear extrapolation of concentration-versus-time curve to intersection with MIC.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	San Francisco General Hospital - Pulmonary and Critical Care Medicine	San Francisco	California	United States	94110-3518
2	Universidade Federal do Espirito Santo - Duke Hubert-Yeargan Center	Vitória	Espírito Santo	Brazil	29040-091

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00396084
• Other Study ID Numbers: 01-553
• First Posted: Nov 6, 2006
• Last Update Posted: Nov 8, 2018
• Last Verified: Mar 10, 2010

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by , ,: Brazil; gatifloxacin; isoniazid; levofloxacin; linezolid; moxifloxacin; tuberculosis
• Additional relevant MeSH terms: Tuberculosis; Tuberculosis, Pulmonary; Moxifloxacin; Levofloxacin; Ofloxacin; Isoniazid; Linezolid; Gatifloxacin

Study Results

Participant Flow

Recruitment Details	Screening for the trial began in February 2004 in Vitória, Brazil. Non-HIV infected adults aged 18-65 years with suspected pulmonary tuberculosis (TB) were recruited at local TB posts and the Hospital Universitario Cassiano Antonio de Moraes of the Universidade Federal do Espírito Santo (UFES) in Vitória. Enrollment was completed in October 2007.
Pre-assignment Detail	A total of 113 adults with suspected pulmonary TB were evaluated for study participation. Forty-three were excluded because they did not meet the eligibility criteria, leaving a total of 70 patients.

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Linezolid 600 mg / Once Daily	Linezolid 600 mg / Twice Daily	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7days	Linezolid 600 mg/once daily x 7days	Linezolid 600 mg twice daily x 7 days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days
Period Title: Overall Study
STARTED	10	10	10	10	10	20
COMPLETED	10	10	10	9	9	18
NOT COMPLETED	0	0	0	1	1	2

Baseline Characteristics

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Linezolid 600 mg / Once Daily	Linezolid 600 mg / Twice Daily	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day	Total
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7days	Linezolid 600 mg/once daily x 7days	Linezolid 600 mg twice daily x 7 days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days	Total of all reporting groups
Overall Participants	10	10	10	10	10	20	70
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	10 100%	10 100%	10 100%	10 100%	10 100%	20 100%	70 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	34.5 (10.1)	43.5 (6.4)	33.5 (13.4)	45.0 (12.7)	35.0 (8.4)	33.0 (11.4)	35.0 (11.2)
Sex: Female, Male (Count of Participants)
Female	1 10%	2 20%	2 20%	2 20%	1 10%	3 15%	11 15.7%
Male	9 90%	8 80%	8 80%	8 80%	9 90%	17 85%	59 84.3%
Region of Enrollment (participants) [Number]
Brazil	10 100%	10 100%	10 100%	10 100%	10 100%	20 100%	70 100%

Outcome Measures

1. Primary Outcome

Title	Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)
Description	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.
Time Frame	Study drug administration duration - 7 days monotherapy

Outcome Measure Data

Analysis Population Description

The aAUC was calculated for 10 subjects per treatment arm (n=40).

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days
Measure Participants	10	10	10	10
Day 1	0.98 (0.03)	0.98 (0.03)	0.96 (0.04)	0.95 (0.03)
Day 2	0.96 (0.03)	0.95 (0.05)	0.94 (0.06)	0.90 (0.04)
Day 3	0.92 (0.05)	0.91 (0.07)	0.91 (0.08)	0.87 (0.04)
Day 4	0.89 (0.07)	0.88 (0.08)	0.89 (0.09)	0.84 (0.04)
Day 5	0.87 (0.08)	0.85 (0.09)	0.87 (0.10)	0.81 (0.05)
Day 6	0.85 (0.08)	0.83 (0.10)	0.85 (0.10)	0.80 (0.06)
Day 7	0.82 (0.09)	0.81 (0.10)	0.83 (0.10)	0.80 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Mean adjusted aAUC for all 4 treatment groups over the 7 days of study drug administration
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Day 1. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.041
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Day 2. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Day 3. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Day 4. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Day 5. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Day 6. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.091
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Day 7. Pooled sputum bacillary load data for patients in the 3 fluoroquinolones arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.354
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Sputum mRNA Clearance Rate - Results Are Pending.
Time Frame	Study drug administration duration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Sputum Cytokine Proteins - Results Are Pending.
Time Frame	Study drug administration duration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Maximum Plasma Drug Concentration (Cmax)
Description	Maximum plasma concentration, given sampling scheme
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. Plasma samples were collected at 7 time points on the 5th day after beginning study drug monotherapy. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling.

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days
Measure Participants	10	10	9	10
Median (Full Range) [ug/ml]	4.8	15.6	6.1	3.6

5. Primary Outcome

Title	Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison
Description	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.
Time Frame	Day 0 to Day 2 Monotherapy

Outcome Measure Data

Analysis Population Description

Early bactericidal activity (EBA 0-2) was calculated for 10 subjects per treatment arm (n=40).

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days
Measure Participants	10	10	10	10
Mean (Standard Deviation) [log10 cfu/ml/day]	0.35 (0.27)	0.45 (0.35)	0.33 (0.39)	0.67 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Mean values of EBA Days 0 to 2 for the 4 treatment groups were compared.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Two way comparison of INH against gatifloxacin using a simultaneous non-parametric procedure.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Two way comparison of INH against moxifloxacin using a simultaneous non-parametric procedure.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Levofloxacin 1000 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Two way comparison of INH against levofloxacin using a simultaneous non-parametric procedure.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Primary Outcome

Title	Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison
Description	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.
Time Frame	Day 2 to Day 7 Monotherapy

Outcome Measure Data

Analysis Population Description

A total of 38 patients were analyzed for Early Bactericidal Activity (EBA) Days 2-7. One patient in the moxifloxacin arm discontinued the study drug after 4 days. One patient in the INH arm discontinued the study drug after 6 days.

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days
Measure Participants	10	10	9	9
Mean (Standard Deviation) [log10 cfu/ml/day]	0.17 (0.13)	0.18 (0.13)	0.17 (0.09)	0.08 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	Mean values of EBA Days 2 to 7 for the 4 treatment groups were compared.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	The rate of fall in sputum cfu for the 4 treatment groups between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained from fitting the 6 sputum cfu values corresponding to days 2 through 7.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day, Isoniazid (INH) 300 mg/Day
	Comments	EBA Days 2-7 for patients in the 3 fluoroquinolone groups were pooled and compared to bactericidal activity of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Primary Outcome

Title	Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)
Description	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.
Time Frame	Study drug administration duration - 7 days monotherapy

Outcome Measure Data

Analysis Population Description

The aAUC was calculated for 29 patients. One patient in the linezolid twice daily arm withdrew after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	9
Day 1	0.94 (0.06)	0.98 (0.04)	0.98 (0.04)
Day 2	0.89 (0.08)	0.97 (0.07)	0.96 (0.07)
Day 3	0.89 (0.03)	0.96 (0.07)	0.95 (0.08)
Day 4	0.85 (0.09)	0.96 (0.07)	0.94 (0.08)
Day 5	0.83 (0.10)	0.95 (0.07)	0.94 (0.08)
Day 6	0.81 (0.12)	0.95 (0.07)	0.93 (0.07)
Day 7	0.83 (0.07)	0.95 (0.07)	0.93 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Mean adjusted aAUC for all 3 treatment groups over the 7 days of study drug administration
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Day 1. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Day 2. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Day 3. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Day 4. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Day 5. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Day 6. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Day 7. Pooled sputum bacillary load data for patients in the linezolid arms were combined and compared to that of patients in the INH arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Primary Outcome

Title	Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison
Description	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.
Time Frame	Day 0 to Day 2 Monotherapy

Outcome Measure Data

Analysis Population Description

EBA 0-2 comparisons across groups were done for 29 patients. One patient in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	9
Mean (Standard Deviation) [log10 cfu/ml/day]	0.67 (0.35)	0.18 (0.27)	0.26 (0.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Mean values of EBA Days 0 to 2 for the 3 treatments groups were compared.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day
	Comments	Two way comparison of INH against Linezolid once daily using a simultaneous non-parametric procedure.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Mean EBA 0-2 of INH was compared to pooled Linezolid once daily and Linezolid twice daily results.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Time to Maximum Plasma Drug Concentration (Tmax) and Half-life
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling.

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days
Measure Participants	10	10	9	10
Tmax	1.5	1.0	1.0	1
Half-life	6.0	7.6	8.1	2.5

10. Secondary Outcome

Title	Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC)
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling.

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7 days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days
Measure Participants	10	10	9	10
Median (Inter-Quartile Range) [ug/ml]	9.5	15.6	12.3	70.6

11. Primary Outcome

Title	Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison
Description	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.
Time Frame	Day 2 to Day 7 Monotherapy

Outcome Measure Data

Analysis Population Description

One patient in the INH arm discontinued the study drug after 5 days. Days 3 and 7 cultures for another patient in the INH arm were contaminated and cfu data are not available for this patient. One patient in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	8	10	9
Mean (Standard Deviation) [log10 cfu/ml]	0.16 (0.11)	0.09 (0.17)	0.04 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	Mean values EBA Days 2-7 for the 3 treatment groups were compared.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	The rate of fall in sputum cfu for the 3 treatment groups between day 2 and day 7 of monotherapy was estimated by the slope of the linear regression obtained from fitting the 6 sputum cfu values corresponding to days 2 through 7.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Gatifloxacin 400 mg/Day, Levofloxacin 1000 mg/Day, Moxifloxacin 400 mg/Day
	Comments	EBA Days 2-7 for INH was compared to that of the pooled linezolid arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours
Description	Area under the curve (AUC), from time 0-12 hours for INH or 0-24 hours for gatifloxacin, levofloxacin, and moxifloxacin.
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. Plasma samples were collected at 7 time points on the 5th day after beginning study drug monotherapy. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling.

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days
Measure Participants	10	10	9	10
Median (Full Range) [ug/h/ml]	42.8	129.1	55.3	11.9

13. Secondary Outcome

Title	Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC)
Description	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.
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Thirty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the moxifloxacin arm was discontinued from the study before day 5 and did not undergo PK sampling

Arm/Group Title	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days	Levofloxacin 1000 mg/day x 7 days	Moxifloxacin 400 mg/day x 7 days	Isoniazid (INH) 300 mg/day x 7 days
Measure Participants	10	10	9	10
Median (Inter-Quartile Range) [ug/ml]	85.6	129.1	110.5	215.2

14. Secondary Outcome

Title	Maximum Plasma Drug Concentration (Cmax)
Description	Maximum Plasma Drug Concentration (Cmax), given sampling scheme
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Twenty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	9
Median (Full Range) [ug/ml]	3.3	15.0	19.4

15. Secondary Outcome

Title	Time to Maximum Plasma Drug Concentration (Tmax) and Half-life
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Twenty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	9
Tmax in h (apparent time of max plasma conc.)	1.0	1.5	1.0
Half-life	3.6	3.20	4.56

16. Secondary Outcome

Title	Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours
Description	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
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Twenty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	9
AUC 0-12 (ug/h/ml)	17.0	87.0	116.4
AUC 0-24 (ug/h/ml)	19.2	96.9	232.9

17. Secondary Outcome

Title	Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration
Description	Cmax adjusted for free drug concentrations after 5 days of monotherapy with study drugs
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Twenty-nine patients underwent pharmacokinetic (PK) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	9
Median (Full Range) [ug/ml]	3.1	10.3	13.4

18. Secondary Outcome

Title	Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Twenty-nine patients underwent pharmacodynamic sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	9
Median (Inter-Quartile Range) [ug/ml]	62.7	20.0	16.2

19. Secondary Outcome

Title	Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations
Description	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
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Twenty-nine patients underwent pharmacodynamic (PD) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	9
AUC 0-12	15.3	60.1	80.3
AUC 0-24	17.2	66.8	160.7

20. Secondary Outcome

Title	Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC)
Description	Area Under the Curve 0-12 (AUC 0-12) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) and AUC 0-24/MIC
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Twenty-nine patients underwent pharmacodynamic (PD) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid, 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	9
AUC 0-12/MIC	306.7	107.8	121.6
AUC 0-24/MIC	344.6	116.2	243.2

21. Secondary Outcome

Title	Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC)
Description	Determined by linear extrapolation of concentration-versus-time curve to intersection with MIC.
Time Frame	Day 5 (7 time points)

Outcome Measure Data

Analysis Population Description

Twenty-nine patients underwent pharmacodynamic (PD) sampling after receiving 5 daily doses of study drug. One subject in the linezolid twice daily arm withdrew from the study after randomization before receiving any doses of study drug.

Arm/Group Title	Isoniazid (INH) 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Arm/Group Description	Isoniazid (INH) 300 mg/day x 7 days	Linezolid 600 mg/day x 7 days	Linezolid 600 mg q12h x 7 days
Measure Participants	10	10	10
Mean (Inter-Quartile Range) [Percentage]	95.5	62.8	100.0

Adverse Events

Time Frame	Adverse event data were collected from February 2004 through October 2007.
Adverse Event Reporting Description	Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site.
Arm/Group Title	Gatifloxacin 400 mg/Day		Levofloxacin 1000 mg/Day		Linezolid 600 mg / Once Daily		Linezolid 600 mg / Twice Daily		Moxifloxacin 400 mg/Day		Isoniazid (INH) 300 mg/Day
Arm/Group Description	Gatifloxacin 400 mg/day x 7 days		Levofloxacin 1000 mg/day x 7days		Linezolid 600 mg/once daily x 7days		Linezolid 600 mg twice daily x 7 days		Moxifloxacin 400 mg/day x 7 days		Isoniazid (INH) 300 mg/day x 7 days
All Cause Mortality
	Gatifloxacin 400 mg/Day		Levofloxacin 1000 mg/Day		Linezolid 600 mg / Once Daily		Linezolid 600 mg / Twice Daily		Moxifloxacin 400 mg/Day		Isoniazid (INH) 300 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Gatifloxacin 400 mg/Day		Levofloxacin 1000 mg/Day		Linezolid 600 mg / Once Daily		Linezolid 600 mg / Twice Daily		Moxifloxacin 400 mg/Day		Isoniazid (INH) 300 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Gatifloxacin 400 mg/Day		Levofloxacin 1000 mg/Day		Linezolid 600 mg / Once Daily		Linezolid 600 mg / Twice Daily		Moxifloxacin 400 mg/Day		Isoniazid (INH) 300 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/10 (80%)		7/10 (70%)		8/10 (80%)		5/10 (50%)		7/10 (70%)		7/20 (35%)
Blood and lymphatic system disorders
Elevated Monocytes	0/10 (0%)	0	0/10 (0%)	0	2/10 (20%)	2	0/10 (0%)	0	0/10 (0%)	0	0/20 (0%)	0
Hematocrit Decreased	2/10 (20%)	2	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/20 (0%)	0
Hemoglobin Decreased	2/10 (20%)	2	0/10 (0%)	0	3/10 (30%)	3	0/10 (0%)	0	0/10 (0%)	0	0/20 (0%)	0
Gastrointestinal disorders
Diarrhea	1/10 (10%)	2	0/10 (0%)	0	2/10 (20%)	2	2/10 (20%)	2	3/10 (30%)	3	0/20 (0%)	0
Intestinal Ancyclostomiasis	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	2/20 (10%)	2
Intestinal Constipation	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	1/10 (10%)	2	0/10 (0%)	0	0/20 (0%)	0
Intestinal Strongyloidiasis	0/10 (0%)	0	0/10 (0%)	0	2/10 (20%)	2	2/10 (20%)	2	0/10 (0%)	0	2/20 (10%)	2
General disorders
Fever	0/10 (0%)	0	2/10 (20%)	2	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/20 (0%)	0
Sweating	2/10 (20%)	2	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/20 (0%)	0
Musculoskeletal and connective tissue disorders
Joint Pain	0/10 (0%)	0	2/10 (20%)	2	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	2/20 (10%)	2
Lumbar Pain	0/10 (0%)	0	1/10 (10%)	2	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/20 (0%)	0
Pain in Both Shoulders	0/10 (0%)	0	0/10 (0%)	0	1/10 (10%)	2	0/10 (0%)	0	0/10 (0%)	0	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chest Pain	2/10 (20%)	2	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	2/20 (10%)	2
Rales (or Crackles)	4/10 (40%)	5	4/10 (40%)	6	0/10 (0%)	0	0/10 (0%)	0	6/10 (60%)	13	7/20 (35%)	17
Ronchi	2/10 (20%)	3	2/10 (20%)	2	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	1/20 (5%)	2
Wheezing	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	2/20 (10%)	2
Skin and subcutaneous tissue disorders
Acne	3/10 (30%)	3	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0	0/20 (0%)	0

Limitations/Caveats

The small sample size had limited power to detect small differences in EBA between study arms even though we enrolled patients with smear-positive TB and high sputum bacillary burden to improve chances of detecting differences between treatment arms.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.