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Linezolid to Treat Extensively-Drug Resistant Tuberculosis

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ClinicalTrials.gov Identifier: NCT00727844
Recruitment Status : Completed
First Posted : August 4, 2008
Results First Posted : February 24, 2014
Last Update Posted : March 14, 2016
Sponsor:
Information provided by (Responsible Party):
Clifton E. Barry III, Ph.D., 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
Conditions Pulmonary Tuberculosis
Multidrug Resistant Tuberculosis
Extensively Drug Resistant Tuberculosis
Interventions Drug: Immediate Start Linezolid
Drug: Delayed Start Linezolid
Enrollment 41
Recruitment Details Study patients recruited from 12/2008 to 5/2011 at the National Masan Hospital, Changwon, Korea and the National Medical Center, Seoul, Korea.
Pre-assignment Details  
Arm/Group Title Initial Randomization: Immediate Start Linezolid Initial Randomization: Delayed Start Linezolid 2nd Randomization: Linezolid 600 mg Daily 2nd Randomization: Linezolid 300 mg Daily
Hide Arm/Group Description Upon completion of entry criteria, subjects immediately added linezolid 600 mg once daily to their ongoing TB treatment regimen. Subjects continued their existing treatment regimen for 2 additional months after which linezolid 600 mg once daily was added. After conversion to negative sputum smears (or receipt of 4 months of therapy), patients underwent a second randomization, stratified according to diabetes mellitus status, either to continue receiving linezolid at a dose of 600 mg per day or to receive a lower dose, 300 mg per day, for an additional 18 months or until therapy was stopped owing to side effects or laboratory abnormalities. After conversion to negative sputum smears (or receipt of 4 months of therapy), patients underwent a second randomization, stratified according to diabetes mellitus status, either to continue receiving linezolid at a dose of 600 mg per day or to receive a lower dose, 300 mg per day, for an additional 18 months or until therapy was stopped owing to side effects or laboratory abnormalities.
Period Title: Initial Randomization
Started 21 [1] 20 0 0
Included in MITT Analysis 19 20 0 0
Completed 19 20 0 0
Not Completed 2 0 0 0
Reason Not Completed
Physician Decision             2             0             0             0
[1]
2 patients withdrawn before receiving any linezolid owing to baseline neuropathy
Period Title: Second Randomization
Started 0 0 17 [1] 16 [1]
Completed 0 0 17 16
Not Completed 0 0 0 0
[1]
6 patients excluded before 2nd randomization: 2 had withdrawn and 4 already dose reduced due to AE
Arm/Group Title Immediate Start Linezolid Delayed Start Linezolid Total
Hide Arm/Group Description Upon completion of entry criteria, subjects will have LZD (600 mg once daily) added to their regimen. After 2 consecutive AFB negative sputum smears (or at 4 months) subjects will be randomized to continue on 600 mg LZD once daily or to de-escalate to 300 mg once daily. Regardless of the dosage, subjects will remain on LZD treatment for 18 months after sputum culture conversion or until they can no longer tolerate therapy. Subjects will continue their existing regimen for 2 months after which LZD (600 mg once daily) will be added. After 2 consecutive AFB negative sputum smears (not to exceed 4 months of LZD therapy), subjects will be randomized to continue on 600 mg LZD once daily or to de-escalate to 300 mg once daily. Regardless of the dosage, subjects will remain on LZD treatment for 18 months after sputum culture conversion or until they can no longer tolerate therapy. Total of all reporting groups
Overall Number of Baseline Participants 19 20 39
Hide Baseline Analysis Population Description
2 patients excluded in immediate start group before receiving any linezolid owing to baseline neuropathy
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 20 participants 39 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
19
 100.0%
20
 100.0%
39
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 19 participants 20 participants 39 participants
42.1  (11.2) 40.4  (9.8) 41.2  (10.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 20 participants 39 participants
Female
7
  36.8%
4
  20.0%
11
  28.2%
Male
12
  63.2%
16
  80.0%
28
  71.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Korea, Republic of Number Analyzed 19 participants 20 participants 39 participants
19 20 39
1.Primary Outcome
Title Number of Patients Converted to Sputum Culture Negative in Each Arm, With Data Censored at 4 Months.
Hide Description [Not Specified]
Time Frame Sputum smear conversion or max 4 months after the start of Linezolid therapy.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Immediate Start Linezolid Delayed Start Linezolid
Hide Arm/Group Description:
Upon completion of entry criteria, subjects will have LZD (600 mg once daily) added to their regimen. After 2 consecutive AFB negative sputum smears (or at 4 months) subjects will be randomized to continue on 600 mg LZD once daily or to de-escalate to 300 mg once daily. Regardless of the dosage, subjects will remain on LZD treatment for 18 months after sputum culture conversion or until they can no longer tolerate therapy.
Subjects will continue their existing regimen for 2 months after which LZD (600 mg once daily) will be added. After 2 consecutive AFB negative sputum smears (not to exceed 4 months of LZD therapy), subjects will be randomized to continue on 600 mg LZD once daily or to de-escalate to 300 mg once daily. Regardless of the dosage, subjects will remain on LZD treatment for 18 months after sputum culture conversion or until they can no longer tolerate therapy.
Overall Number of Participants Analyzed 19 20
Measure Type: Number
Unit of Measure: participants
15 7
Time Frame Data were collected for the duration of the study subject's participation in the trial, up to 3 years. 39 subjects were included in the overall analysis but only 38 were at risk for AE because 1 subject did not receive LZD.
Adverse Event Reporting Description AEs were collected on beginning treatment with LZD. AEs are not stratified by LZD dosage because all patients initiated LZD at 600 mg daily but then were subsequently randomized to either continue 600 mg or 300 mg daily. Thus a subject with AE on 300 mg likely reflects prior 600 mg dosing in addition to the current 300 mg dosing.
 
Arm/Group Title Clinically Significant AEs
Hide Arm/Group Description All clinically significant adverse events, regardless of relationship to linezolid. This includes all SAEs, all AEs grade 3 and above, and all neuropathies grade 2 and above.
All-Cause Mortality
Clinically Significant AEs
Affected / at Risk (%)
Total   --/--    
Hide Serious Adverse Events
Clinically Significant AEs
Affected / at Risk (%) # Events
Total   25/38 (65.79%)    
Blood and lymphatic system disorders   
anemia  6/38 (15.79%)  7
neutropenia  1/38 (2.63%)  1
Ear and labyrinth disorders   
vertigo  1/38 (2.63%)  1
Eye disorders   
optic neuropathy  7/38 (18.42%)  9
Gastrointestinal disorders   
esophageal hemorrhage  1/38 (2.63%)  1
Hepatobiliary disorders   
hepatitis  3/38 (7.89%)  3
hyperbilirubinemia  1/38 (2.63%)  1
Infections and infestations   
fever  1/38 (2.63%)  1
Musculoskeletal and connective tissue disorders   
rhabdomyolysis  2/38 (5.26%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
colon cancer  1/38 (2.63%)  1
Nervous system disorders   
neurologic reaction to psychotic drug  1/38 (2.63%)  1
peripheral neuropathy  6/38 (15.79%)  6
Respiratory, thoracic and mediastinal disorders   
hemoptysis  1/38 (2.63%)  1
pneumonia  3/38 (7.89%)  4
shortness of breath  1/38 (2.63%)  1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Clinically Significant AEs
Affected / at Risk (%) # Events
Total   24/38 (63.16%)    
Endocrine disorders   
hyperglycemia  3/38 (7.89%)  3
Eye disorders   
cataract  1/38 (2.63%)  1
Gastrointestinal disorders   
diarrhea  2/38 (5.26%)  2
Hepatobiliary disorders   
hepatitis  1/38 (2.63%)  1
Musculoskeletal and connective tissue disorders   
hyperuricemia  2/38 (5.26%)  2
Nervous system disorders   
peripheral neuropathy  15/38 (39.47%)  15
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Clifton Barry
Organization: Tuberculosis Research Section, LCID, NIAID, NIH
Phone: 301-451-9554
EMail: cbarry@niaid.nih.gov
Layout table for additonal information
Responsible Party: Clifton E. Barry III, Ph.D., National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00727844    
Other Study ID Numbers: 08-I-N167
First Submitted: August 1, 2008
First Posted: August 4, 2008
Results First Submitted: September 10, 2013
Results First Posted: February 24, 2014
Last Update Posted: March 14, 2016