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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;   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
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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 
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 


  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 ]

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 ]
  Hide Outcome Measure 3

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  

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 
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
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANOVA
P Value [4] 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] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] 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
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANOVA
P Value [4] 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] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] 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
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Wilcoxon (Mann-Whitney)
P Value [4] 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] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] 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 ]

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 ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.  

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


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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.


  More Information