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

This study has been completed.

Sponsor:

Information provided by:

National Institute of Allergy and Infectious Diseases (NIAID)

ClinicalTrials.gov Identifier:

NCT00396084

First received: November 3, 2006

Last updated: June 9, 2011

Last verified: March 2010

History of Changes

Results First Received: November 19, 2008

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	TB Multi-drug Resistant
Interventions:	Drug: Gatifloxacin Drug: Levofloxacin Drug: Moxifloxacin Drug: Isoniazid Drug: Linezolid

Participant Flow

Hide Participant Flow

Recruitment Details

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.

Pre-Assignment Details

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.

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7days
Linezolid 600 mg / Once Daily	Linezolid 600 mg/once daily x 7days
Linezolid 600 mg / Twice Daily	Linezolid 600 mg twice daily 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

Participant Flow: Overall Study

	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

Baseline Characteristics

Hide Baseline Characteristics

Reporting Groups

	Description
Gatifloxacin 400 mg/Day	Gatifloxacin 400 mg/day x 7 days
Levofloxacin 1000 mg/Day	Levofloxacin 1000 mg/day x 7days
Linezolid 600 mg / Once Daily	Linezolid 600 mg/once daily x 7days
Linezolid 600 mg / Twice Daily	Linezolid 600 mg twice daily 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
Total	Total of all reporting groups

Baseline Measures

	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

Show All Outcome Measures

1. Primary:

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

Show Outcome Measure 1

2. Primary:

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

Show Outcome Measure 2

3. Primary:

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

Show Outcome Measure 3

4. Primary:

Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC) [ Time Frame: 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 [ Time Frame: Day 0 to Day 2 Monotherapy ]

Hide Outcome Measure 5

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.

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 [ Time Frame: Day 2 to Day 7 Monotherapy ]

Show Outcome Measure 6

7. Secondary:

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

Show Outcome Measure 7

8. Secondary:

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

Show Outcome Measure 8

9. Secondary:

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

Show Outcome Measure 9

10. Secondary:

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

Show Outcome Measure 11

12. Secondary:

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

Show Outcome Measure 12

13. Secondary:

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

Show Outcome Measure 13

14. Secondary:

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

Show Outcome Measure 14

15. Secondary:

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

Show Outcome Measure 18

19. Secondary:

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

Show Outcome Measure 19

20. Secondary:

Sputum mRNA Clearance Rate - Results Are Pending. [ Time Frame: Study drug administration duration ]

Results not yet posted. Anticipated Posting Date: No text entered. Safety Issue: No

21. Secondary:

Sputum Cytokine Proteins - Results Are Pending. [ Time Frame: Study drug administration duration ]

Results not yet posted. Anticipated Posting Date: No text entered. Safety Issue: No

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

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.

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.

Li L, Mahan CS, Palaci M, Horter L, Loeffelholz L, Johnson JL, Dietze R, Debanne SM, Joloba ML, Okwera A, Boom WH, Eisenach KD. Sputum Mycobacterium tuberculosis mRNA as a marker of bacteriologic clearance in response to antituberculosis therapy. J Clin Microbiol. 2010 Jan;48(1):46-51. Epub 2009 Nov 18.

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.

Responsible Party:	Director, ORA, HHS/NIAID/DMID
ClinicalTrials.gov Identifier:	NCT00396084 History of Changes
Other Study ID Numbers:	01-553, TBRU 10
Study First Received:	November 3, 2006
Results First Received:	November 19, 2008
Last Updated:	June 9, 2011
Health Authority:	Brazil: National Committee of Ethics in Research United States: Federal Government United States: Institutional Review Board United States: Food and Drug Administration

To Top