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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

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ClinicalTrials.gov Identifier: NCT00396084
Recruitment Status : Completed
First Posted : November 6, 2006
Results First Posted : June 25, 2009
Last Update Posted : June 13, 2011
Sponsor:
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition: TB Multi-drug Resistant
Interventions: Drug: Gatifloxacin
Drug: Levofloxacin
Drug: Moxifloxacin
Drug: Isoniazid
Drug: Linezolid

  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

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

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) ]
  Show Outcome Measure 18

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 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

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

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.


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
First Submitted: November 3, 2006
First Posted: November 6, 2006
Results First Submitted: November 19, 2008
Results First Posted: June 25, 2009
Last Update Posted: June 13, 2011