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

Outcome Measures

1. Primary:

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

Hide Outcome Measure 1

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.

2. Primary:

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

Show Outcome Measure 2

3. Primary:

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

Show Outcome Measure 3

4. Primary:

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

Show Outcome Measure 4

5. Primary:

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 ]

Show Outcome Measure 5

6. Primary:

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 ]

Show Outcome Measure 6

7. Secondary:

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

Show Outcome Measure 7

8. Secondary:

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

Show Outcome Measure 8

9. Secondary:

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

Show Outcome Measure 9

10. Secondary:

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

Show Outcome Measure 10

11. Secondary:

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

Show Outcome Measure 11

12. Secondary:

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

Show Outcome Measure 12

13. Secondary:

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

Show Outcome Measure 13

14. Secondary:

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

Show Outcome Measure 14

15. Secondary:

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

Show Outcome Measure 15

16. Secondary:

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

Show Outcome Measure 16

17. Secondary:

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

Show Outcome Measure 17

18. Secondary:

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

Show Outcome Measure 18

19. Secondary:

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

Show Outcome Measure 19

More Information

Hide More Information

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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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.

Results Point of Contact:

Name/Title: John L. Johnson, M.D.
Organization: Case Western Reserve University, Tuberculosis Research Unit
phone: (216) 368-1949
e-mail: jlj@case.edu

Publications of Results:

Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, Jankus DD, Debanne SM, Charlebois ED, Maciel E, Palaci M, Dietze R. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006 Jun;10(6):605-12.

Peloquin CA, Hadad DJ, Molino LP, Palaci M, Boom WH, Dietze R, Johnson JL. Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2008 Mar;52(3):852-7. Epub 2007 Dec 10.

Dietze R, Hadad DJ, McGee B, Molino LP, Maciel EL, Peloquin CA, Johnson DF, Debanne SM, Eisenach K, Boom WH, Palaci M, Johnson JL. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med. 2008 Dec 1;178(11):1180-5. Epub 2008 Sep 11.

McGee B, Dietze R, Hadad DJ, Molino LP, Maciel EL, Boom WH, Palaci M, Johnson JL, Peloquin CA. Population pharmacokinetics of linezolid in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2009 Sep;53(9):3981-4. Epub 2009 Jun 29.

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