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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
History of Changes
Results First Received: November 19, 2008  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: TB Multi-drug Resistant
Interventions: Drug: Gatifloxacin
Drug: Levofloxacin
Drug: Moxifloxacin
Drug: Isoniazid
Drug: Linezolid

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

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

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

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

5.  Primary:   Difference in Sputum Bacillary Loads: Early Bactericidal Activity (EBA) Days 0 to 2; Linezolid Once Daily/Linezolid Twice Daily/Isoniazid (INH) Comparison   [ Time Frame: Day 0 to Day 2 Monotherapy ]
  Show Outcome Measure 5

6.  Primary:   Difference in Sputum Bacillary Loads: Extended Early Bactericidal Activity (EBA) From Days 2 to 7; Linezolid Once Daily/Linezolid Twice Daily/INH Comparison   [ Time Frame: Day 2 to Day 7 Monotherapy ]
  Show Outcome Measure 6

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

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

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

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

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

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

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

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

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

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

17.  Secondary:   Area Under the Curve (AUC) During First 12 and 24 Hours Adjusted for Free Drug Concentrations   [ Time Frame: Day 5 (7 time points) ]
  Show Outcome Measure 17

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

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) ]
  Show Outcome Measure 19

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

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


  Serious Adverse Events
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  Other Adverse Events
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  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