Trial Outcomes & Findings for Linezolid to Treat Extensively-Drug Resistant Tuberculosis (NCT NCT00727844)

NCT ID: NCT00727844

Last Updated: 2016-03-14

Results Overview

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 41 participants
• Primary outcome timeframe: Sputum smear conversion or max 4 months after the start of Linezolid therapy.
• Results posted on: 2016-03-14

Participant Flow

Study patients recruited from 12/2008 to 5/2011 at the National Masan Hospital, Changwon, Korea and the National Medical Center, Seoul, Korea.

Participant milestones

Measure	2nd Randomization: Linezolid 600 mg Daily 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.	Initial Randomization: Immediate Start Linezolid Upon completion of entry criteria, subjects immediately added linezolid 600 mg once daily to their ongoing TB treatment regimen.	Initial Randomization: Delayed Start Linezolid Subjects continued their existing treatment regimen for 2 additional months after which linezolid 600 mg once daily was added.	2nd Randomization: Linezolid 300 mg Daily 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.
Initial Randomization STARTED	0	21	20	0
Initial Randomization Included in MITT Analysis	0	19	20	0
Initial Randomization COMPLETED	0	19	20	0
Initial Randomization NOT COMPLETED	0	2	0	0
Second Randomization STARTED	17	0	0	16
Second Randomization COMPLETED	17	0	0	16
Second Randomization NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Measure	2nd Randomization: Linezolid 600 mg Daily 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.	Initial Randomization: Immediate Start Linezolid Upon completion of entry criteria, subjects immediately added linezolid 600 mg once daily to their ongoing TB treatment regimen.	Initial Randomization: Delayed Start Linezolid Subjects continued their existing treatment regimen for 2 additional months after which linezolid 600 mg once daily was added.	2nd Randomization: Linezolid 300 mg Daily 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.
Initial Randomization Physician Decision	0	2	0	0

Baseline Characteristics

Linezolid to Treat Extensively-Drug Resistant Tuberculosis

Baseline characteristics by cohort

Measure	Immediate Start Linezolid n=19 Participants 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.	Delayed Start Linezolid n=20 Participants 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 n=39 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	19 Participants n=5 Participants	20 Participants n=7 Participants	39 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	42.1 years STANDARD_DEVIATION 11.2 • n=5 Participants	40.4 years STANDARD_DEVIATION 9.8 • n=7 Participants	41.2 years STANDARD_DEVIATION 10.4 • n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	4 Participants n=7 Participants	11 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	16 Participants n=7 Participants	28 Participants n=5 Participants
Region of Enrollment Korea, Republic of	19 participants n=5 Participants	20 participants n=7 Participants	39 participants n=5 Participants

PRIMARY outcome

Timeframe: Sputum smear conversion or max 4 months after the start of Linezolid therapy.

Outcome measures

Measure	Immediate Start Linezolid n=19 Participants 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.	Delayed Start Linezolid n=20 Participants 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.
Number of Patients Converted to Sputum Culture Negative in Each Arm, With Data Censored at 4 Months.	15 participants	7 participants

Adverse Events

Clinically Significant AEs

Serious events: 25 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Measure	Clinically Significant AEs n=38 participants at risk 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.
Blood and lymphatic system disorders anemia	15.8% 6/38 • Number of events 7 • 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. 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.
Infections and infestations fever	2.6% 1/38 • Number of events 1 • 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. 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.
Gastrointestinal disorders esophageal hemorrhage	2.6% 1/38 • Number of events 1 • 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. 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) colon cancer	2.6% 1/38 • Number of events 1 • 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. 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.
Respiratory, thoracic and mediastinal disorders hemoptysis	2.6% 1/38 • Number of events 1 • 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. 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.
Hepatobiliary disorders hepatitis	7.9% 3/38 • Number of events 3 • 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. 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.
Hepatobiliary disorders hyperbilirubinemia	2.6% 1/38 • Number of events 1 • 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. 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.
Respiratory, thoracic and mediastinal disorders pneumonia	7.9% 3/38 • Number of events 4 • 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. 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.
Nervous system disorders neurologic reaction to psychotic drug	2.6% 1/38 • Number of events 1 • 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. 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.
Blood and lymphatic system disorders neutropenia	2.6% 1/38 • Number of events 1 • 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. 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.
Eye disorders optic neuropathy	18.4% 7/38 • Number of events 9 • 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. 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.
Nervous system disorders peripheral neuropathy	15.8% 6/38 • Number of events 6 • 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. 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.
Musculoskeletal and connective tissue disorders rhabdomyolysis	5.3% 2/38 • Number of events 2 • 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. 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.
Respiratory, thoracic and mediastinal disorders shortness of breath	2.6% 1/38 • Number of events 1 • 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. 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.
Ear and labyrinth disorders vertigo	2.6% 1/38 • Number of events 1 • 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. 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.

Other adverse events

Measure	Clinically Significant AEs n=38 participants at risk 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.
Eye disorders cataract	2.6% 1/38 • Number of events 1 • 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. 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.
Gastrointestinal disorders diarrhea	5.3% 2/38 • Number of events 2 • 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. 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.
Hepatobiliary disorders hepatitis	2.6% 1/38 • Number of events 1 • 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. 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.
Endocrine disorders hyperglycemia	7.9% 3/38 • Number of events 3 • 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. 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.
Musculoskeletal and connective tissue disorders hyperuricemia	5.3% 2/38 • Number of events 2 • 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. 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.
Nervous system disorders peripheral neuropathy	39.5% 15/38 • Number of events 15 • 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. 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.

Additional Information

Dr. Clifton Barry

Tuberculosis Research Section, LCID, NIAID, NIH

Phone: 301-451-9554

Email: cbarry@niaid.nih.gov

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place