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
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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
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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
  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 ]

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 ]
  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 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 ]

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 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


  Other Adverse Events


  More Information
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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:

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