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

Study Type:	Interventional
Study Design:	Randomized, Open Label, Active Control, Parallel Assignment
Condition:	Tuberculosis
Interventions:	Drug: Gatifloxacin Drug: Isoniazid Drug: Levofloxacin Drug: Linezolid Drug: Moxifloxacin

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

	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
STARTED	10	10	10	10	10	20
COMPLETED	10	10	10	9	9	18
NOT COMPLETED	0	0	0	1	1	2
Adverse Event	0	0	0	0	1	2
Withdrawal by Subject	0	0	0	1	0	0

	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
Number of Participants [units: participants]	10	10	10	10	10	20	70
Age [units: participants]
<=18 years	0	0	0	0	0	0	0
Between 18 and 65 years	10	10	10	10	10	20	70
>=65 years	0	0	0	0	0	0	0
Age [units: years] Median ( Inter-Quartile Range )	34.5 ( 27.0 to 40.0 )	43.5 ( 42.0 to 46.0 )	33.5 ( 23.0 to 42.0 )	45.0 ( 39.0 to 48.0 )	35.0 ( 25.0 to 37.0 )	33.0 ( 23.0 to 43.5 )	35.0 ( 26.0 to 44.0 )
Gender [units: participants]
Female	1	2	2	2	1	3	11
Male	9	8	8	8	9	17	59
Region of Enrollment [units: participants]
Brazil	10	10	10	10	10	20	70

Measure Type	Primary
Measure Title	Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The aAUC was calculated for 10 subjects per treatment arm (n=40).

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7days
Moxifloxacin 400 mg/Day	Moxifloxacin 400 mg/day x 7 days
Isoniazid (INH) 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days

Measured Values

	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Number of Participants Analyzed [units: participants]	10	10	10	10
Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) [units: Percentage] Mean ± Standard Deviation
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 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	ANOVA
P Value ^[3]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Mean adjusted aAUC for all 4 treatment groups over the 7 days of study drug administration
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.041

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.008

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 4 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.012

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 5 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.01

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 6 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.03

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 7 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.091

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 8 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.354

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Measure Type	Primary
Measure Title	Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Early bactericidal activity (EBA 0-2) was calculated for 10 subjects per treatment arm (n=40).

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7days
Moxifloxacin 400 mg/Day	Moxifloxacin 400 mg/day x 7 days
Isoniazid (INH) 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days

Measured Values

	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Number of Participants Analyzed [units: participants]	10	10	10	10
Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison [units: log10 cfu/ml/day] Mean ± Standard Deviation	0.35 ± 0.27	0.45 ± 0.35	0.33 ± 0.39	0.67 ± 0.17

Statistical Analysis 1 for Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison

Groups ^[1]	All groups
Method ^[2]	ANOVA
P Value ^[3]	0.05

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Mean values of EBA Days 0 to 2 for the 4 treatment groups were compared.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison

Groups ^[1]	Gatifloxacin 400 mg/Day vs. Isoniazid (INH) 300 mg/Day
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.01

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Two way comparison of INH against gatifloxacin using a simultaneous non-parametric procedure.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison

Groups ^[1]	Moxifloxacin 400 mg/Day vs. Isoniazid (INH) 300 mg/Day
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.02

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Two way comparison of INH against moxifloxacin using a simultaneous non-parametric procedure.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 4 for Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Fluoroquinolones/Isoniazid (INH) Comparison

Groups ^[1]	Levofloxacin 1000 mg/Day vs. Isoniazid (INH) 300 mg/Day
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.14

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Two way comparison of INH against levofloxacin using a simultaneous non-parametric procedure.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Measure Type	Primary
Measure Title	Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7days
Moxifloxacin 400 mg/Day	Moxifloxacin 400 mg/day x 7 days
Isoniazid (INH) 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days

Measured Values

	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Number of Participants Analyzed [units: participants]	10	10	9	9
Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison [units: log10 cfu/ml/day] Mean ± Standard Deviation	0.17 ± 0.13	0.18 ± 0.13	0.17 ± 0.09	0.08 ± 0.09

Statistical Analysis 1 for Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison

Groups ^[1]	All groups
Method ^[2]	ANOVA
P Value ^[3]	0.51

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Mean values of EBA Days 2 to 7 for the 4 treatment groups were compared.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison

Groups ^[1]	All groups
Method ^[2]	ANOVA
P Value ^[3]	0.16

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Fluoroquinolones/Isoniazid (INH) Comparison

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.036

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	EBA Days 2-7 for patients in the 3 fluoroquinolone groups were pooled and compared to bactericidal activity of patients in the INH arm.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Measure Type	Primary
Measure Title	Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	9
Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) [units: Percentage] Mean ± Standard Deviation
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 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	ANOVA
P Value ^[3]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Mean adjusted aAUC for all 3 treatment groups over the 7 days of study drug administration
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.023

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.018

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 4 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.03

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 5 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.012

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 6 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.003

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 7 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.003

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 8 for Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC)

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.004

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Measure Type	Primary
Measure Title	Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	9
Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison [units: log10 cfu/ml/day] Mean ± Standard Deviation	0.67 ± 0.35	0.18 ± 0.27	0.26 ± 0.42

Statistical Analysis 1 for Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison

Groups ^[1]	All groups
Method ^[2]	ANOVA
P Value ^[3]	<0.01

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Mean values of EBA Days 0 to 2 for the 3 treatments groups were compared.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison

Groups ^[1]	Isoniazid 300 mg/Day vs. Linezolid 600 mg/Once Daily
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	<0.01

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Two way comparison of INH against Linezolid once daily using a simultaneous non-parametric procedure.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	<0.01

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Mean EBA 0-2 of INH was compared to pooled Linezolid once daily and Linezolid twice daily results.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Measure Type	Primary
Measure Title	Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	8	10	9
Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison [units: log10 cfu/ml] Mean ± Standard Deviation	0.16 ± 0.11	0.09 ± 0.17	0.04 ± 0.11

Statistical Analysis 1 for Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison

Groups ^[1]	All groups
Method ^[2]	ANOVA
P Value ^[3]	0.25

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Mean values EBA Days 2-7 for the 3 treatment groups were compared.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison

Groups ^[1]	All groups
Method ^[2]	ANOVA
P Value ^[3]	0.42

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison

Groups ^[1]	All groups
Method ^[2]	Wilcoxon (Mann-Whitney)
P Value ^[3]	0.14

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	EBA Days 2-7 for INH was compared to that of the pooled linezolid arms.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Measure Type	Secondary
Measure Title	Maximum Plasma Drug Concentration (Cmax)
Measure Description	Maximum plasma concentration, given sampling scheme
Time Frame	Day 5 (7 time points)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7days
Moxifloxacin 400 mg/Day	Moxifloxacin 400 mg/day x 7 days
Isoniazid (INH) 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days

Measured Values

	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Number of Participants Analyzed [units: participants]	10	10	9	10
Maximum Plasma Drug Concentration (Cmax) [units: ug/ml] Median ( Full Range )	4.8 ( 3.8 to 6.4 )	15.6 ( 8.6 to 43.0 )	6.1 ( 4.5 to 9.0 )	3.6 ( 2.5 to 6.1 )

No statistical analysis provided for Maximum Plasma Drug Concentration (Cmax)

Measure Type	Secondary
Measure Title	Time to Maximum Plasma Drug Concentration (Tmax) and Half-life
Measure Description	No text entered.
Time Frame	Day 5 (7 time points)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7days
Moxifloxacin 400 mg/Day	Moxifloxacin 400 mg/day x 7 days
Isoniazid (INH) 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days

Measured Values

	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Number of Participants Analyzed [units: participants]	10	10	9	10
Time to Maximum Plasma Drug Concentration (Tmax) and Half-life [units: hours] Median ( Full Range )
Tmax	1.5 ( 1.0 to 8.0 )	1.0 ( 1.0 to 4.0 )	1.0 ( 1.0 to 2.0 )	1 ( 1.0 to 2.0 )
Half-life	6.0 ( 5.2 to 9.3 )	7.6 ( 4.4 to 19.1 )	8.1 ( 5.1 to 9.9 )	2.5 ( 1.5 to 4.9 )

No statistical analysis provided for Time to Maximum Plasma Drug Concentration (Tmax) and Half-life

Measure Type	Secondary
Measure Title	Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC)
Measure Description	No text entered.
Time Frame	Day 5 (7 time points)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7 days
Moxifloxacin 400 mg/Day	Moxifloxacin 400 mg/day x 7 days
Isoniazid (INH) 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days

Measured Values

	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Number of Participants Analyzed [units: participants]	10	10	9	10
Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) [units: ug/ml] Median ( Inter-Quartile Range )	9.5 ( 8.4 to 11.3 )	15.6 ( 12.2 to 16.6 )	12.3 ( 9.6 to 13.4 )	70.6 ( 64.0 to 76.2 )

No statistical analysis provided for Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC)

Measure Type	Secondary
Measure Title	Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours
Measure 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)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7days
Moxifloxacin 400 mg/Day	Moxifloxacin 400 mg/day x 7 days
Isoniazid (INH) 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days

Measured Values

	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Number of Participants Analyzed [units: participants]	10	10	9	10
Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours [units: ug/h/ml] Median ( Full Range )	42.8 ( 31.7 to 51.0 )	129.1 ( 103.4 to 358.3 )	55.3 ( 36.0 to 79.1 )	11.9 ( 7.1 to 37.4 )

No statistical analysis provided for Pharmacokinetic Parameters: Area Under the Curve (AUC) During First 12 and 24 Hours

Measure Type	Secondary
Measure Title	Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC)
Measure 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)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7 days
Moxifloxacin 400 mg/Day	Moxifloxacin 400 mg/day x 7 days
Isoniazid (INH) 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days

Measured Values

	Gatifloxacin 400 mg/Day	Levofloxacin 1000 mg/Day	Moxifloxacin 400 mg/Day	Isoniazid (INH) 300 mg/Day
Number of Participants Analyzed [units: participants]	10	10	9	10
Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC) [units: ug/ml] Median ( Inter-Quartile Range )	85.6 ( 70.7 to 89.7 )	129.1 ( 121.0 to 145.0 )	110.5 ( 98.9 to 121.6 )	215.2 ( 177.4 to 329.6 )

No statistical analysis provided for Area Under the Curve During First 12 or 24 Hours / Minimum Inhibitory Concentration (AUC/MIC)

Measure Type	Secondary
Measure Title	Maximum Plasma Drug Concentration (Cmax)
Measure Description	Maximum Plasma Drug Concentration (Cmax), given sampling scheme
Time Frame	Day 5 (7 time points)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	9
Maximum Plasma Drug Concentration (Cmax) [units: ug/ml] Median ( Full Range )	3.3 ( 2.5 to 5.3 )	15.0 ( 11.9 to 21.3 )	19.4 ( 11.8 to 24.9 )

No statistical analysis provided for Maximum Plasma Drug Concentration (Cmax)

Measure Type	Secondary
Measure Title	Time to Maximum Plasma Drug Concentration (Tmax) and Half-life
Measure Description	No text entered.
Time Frame	Day 5 (7 time points)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	9
Time to Maximum Plasma Drug Concentration (Tmax) and Half-life [units: hours] Median ( Full Range )
Tmax in h (apparent time of max plasma conc.)	1.0 ( 1.0 to 2.0 )	1.5 ( 1.0 to 4.0 )	1.0 ( 1.0 to 4.0 )
Half-life	3.6 ( 1.1 to 4.5 )	3.20 ( 1.5 to 5.0 )	4.56 ( 2.1 to 7.0 )

No statistical analysis provided for Time to Maximum Plasma Drug Concentration (Tmax) and Half-life

Measure Type	Secondary
Measure Title	Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours
Measure 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)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	9
Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours [units: ug/h/ml] Median ( Full Range )
AUC 0-12 (ug/h/ml)	17.0 ( 6.5 to 26.9 )	87.0 ( 47.5 to 119.3 )	116.4 ( 50.4 to 197.2 )
AUC 0-24 (ug/h/ml)	19.2 ( 6.5 to 29.0 )	96.9 ( 47.8 to 143.7 )	232.9 ( 100.8 to 394.4 )

No statistical analysis provided for Pharmacokinetic Parameters: Area Under the Curve During First 12 and 24 Hours

Measure Type	Secondary
Measure Title	Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration
Measure Description	Cmax adjusted for free drug concentrations after 5 days of monotherapy with study drugs
Time Frame	Day 5 (7 time points)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	9
Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration [units: ug/ml] Median ( Full Range )	3.1 ( 2.5 to 4.8 )	10.3 ( 8.2 to 14.7 )	13.4 ( 8.1 to 17.2 )

No statistical analysis provided for Maximum Plasma Drug Concentrations (Cmax), Adjusted for Free Drug Concentration

Measure Type	Secondary
Measure Title	Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations
Measure Description	No text entered.
Time Frame	Day 5 (7 time points)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	9
Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations [units: ug/ml] Median ( Inter-Quartile Range )	62.7 ( 51.0 to 77.3 )	20.0 ( 10.2 to 21.9 )	16.2 ( 14.3 to 23.0 )

No statistical analysis provided for Maximum Plasma Drug Concentration/Minimum Inhibitory Concentration (Cmax/MIC) Adjusted for Free Drug Concentrations

Measure Type	Secondary
Measure Title	Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations
Measure 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)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	9
Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations [units: ug/h/ml] Median ( Inter-Quartile Range )
AUC 0-12	15.3 ( 5.8 to 24.2 )	60.1 ( 32.8 to 82.3 )	80.3 ( 34.8 to 136.1 )
AUC 0-24	17.2 ( 5.8 to 26.1 )	66.8 ( 33.0 to 99.2 )	160.7 ( 134.4 to 225.8 )

No statistical analysis provided for Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations

Measure Type	Secondary
Measure Title	Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC)
Measure 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)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid, 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	9
Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC) [units: ug/h/ml] Median ( Inter-Quartile Range )
AUC 0-12/MIC	306.7 ( 229.3 to 405.2 )	107.8 ( 63.4 to 126.3 )	121.6 ( 79.8 to 141.6 )
AUC 0-24/MIC	344.6 ( 249.4 to 449.2 )	116.2 ( 71.0 to 138.4 )	243.2 ( 159.7 to 283.2 )

No statistical analysis provided for Area Under the Curve (AUC) Adjusted for Free Drug Concentrations/Minimum Inhibitory Concentration (MIC)

Measure Type	Secondary
Measure Title	Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC)
Measure Description	Determined by linear extrapolation of concentration-versus-time curve to intersection with MIC.
Time Frame	Day 5 (7 time points)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Isoniazid (INH) 300 mg/Day	Isoniazid (INH) 300 mg/day x 7 days
Linezolid 600 mg/Once Daily	Linezolid 600 mg/day x 7 days
Linezolid 600 mg/Twice Daily	Linezolid 600 mg q12h x 7 days

Measured Values

	Isoniazid (INH) 300 mg/Day	Linezolid 600 mg/Once Daily	Linezolid 600 mg/Twice Daily
Number of Participants Analyzed [units: participants]	10	10	10
Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC) [units: Percentage] Mean ( Inter-Quartile Range )	95.5 ( 76.4 to 100 )	62.8 ( 54.6 to 77.0 )	100.0 ( 100 to 100 )

No statistical analysis provided for Percent Dosing Interval Above Minimum Inhibitory Concentration (MIC)

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:	November 19, 2009
ClinicalTrials.gov Identifier:	NCT00396084 History of Changes
Health Authority:	United States: Institutional Review Board; Brazil: National Committee of Ethics in Research; United States: Food and Drug Administration; United States: Federal Government