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
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

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  
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
  Hide All Outcome Measures

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

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 method 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 method 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 method 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 method 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 method 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 method 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 method 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 method 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   [ Time Frame: Day 0 to Day 2 Monotherapy ]

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 method 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 method 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 method 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 method 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.



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

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 method 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 method 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 method 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.



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

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 method 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 method 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 method 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 method 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 method 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 method 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 method 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 method 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.



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 ]

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 method 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 method 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 method 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 ]

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 method 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 method 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 method 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.



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

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)



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

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



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

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)



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

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



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

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)



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

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)



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

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



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

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



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

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



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

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



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) ]

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



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

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)



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

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)



20.  Secondary:   Sputum mRNA Clearance Rate - Results Are Pending.   [ Time Frame: Study drug administration duration ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

21.  Secondary:   Sputum Cytokine Proteins - Results Are Pending.   [ Time Frame: Study drug administration duration ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide 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.


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