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

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

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.
No text entered.

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
Overall Participants Analyzed  [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

1.  Primary:

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

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 ]

3.  Primary:

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

4.  Primary:

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

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 ]

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 ]

7.  Secondary:

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

8.  Secondary:

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

9.  Secondary:

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

10.  Secondary:

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

11.  Secondary:

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

12.  Secondary:

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

13.  Secondary:

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

14.  Secondary:

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

15.  Secondary:

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

16.  Secondary:

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

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) ]

18.  Secondary:

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

19.  Secondary:

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

20.  Secondary:

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

21.  Secondary:

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

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.