Linezolid to Treat Extensively-Drug Resistant Tuberculosis

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Clifton E. Barry III, Ph.D., National Institute of Allergy and Infectious Diseases (NIAID)

ClinicalTrials.gov Identifier:

NCT00727844

First received: August 1, 2008

Last updated: February 12, 2016

Last verified: May 2014

History of Changes

Results First Received: September 10, 2013

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Conditions:	Pulmonary Tuberculosis Multidrug Resistant Tuberculosis Extensively Drug Resistant Tuberculosis
Interventions:	Drug: Immediate Start Linezolid Drug: Delayed Start 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
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
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 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.
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.

Participant Flow for 2 periods

Period 1: Initial Randomization

	Initial Randomization: Immediate Start Linezolid	Initial Randomization: Delayed Start Linezolid
STARTED	21 ^[1]	20
Included in MITT Analysis	19	20
COMPLETED	19	20
NOT COMPLETED	2	0
Physician Decision	2	0

[1]	2 patients withdrawn before receiving any linezolid owing to baseline neuropathy

Period 2: Second Randomization

	2nd Randomization: Linezolid 600 mg Daily	2nd Randomization: Linezolid 300 mg Daily
STARTED	17 ^[1]	16 ^[1]
COMPLETED	17	16
NOT COMPLETED	0	0

[1]	6 patients excluded before 2nd randomization: 2 had withdrawn and 4 already dose reduced due to AE

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.
2 patients excluded in immediate start group before receiving any linezolid owing to baseline neuropathy

Reporting Groups

	Description
Immediate Start Linezolid	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	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	Total of all reporting groups

Baseline Measures

	Immediate Start Linezolid	Delayed Start Linezolid	Total
Number of Participants [units: participants]	19	20	39
Age [units: participants]
<=18 years	0	0	0
Between 18 and 65 years	19	20	39
>=65 years	0	0	0
Age [units: years] Mean (Standard Deviation)	42.1 (11.2)	40.4 (9.8)	41.2 (10.4)
Gender [units: participants]
Female	7	4	11
Male	12	16	28
Region of Enrollment [units: participants]
Korea, Republic of	19	20	39

Outcome Measures

1. Primary:

Number of Patients Converted to Sputum Culture Negative in Each Arm, With Data Censored at 4 Months. [ Time Frame: Sputum smear conversion or max 4 months after the start of Linezolid therapy. ]

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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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
Small sample size

More Information

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Certain Agreements:

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact:

Name/Title: Dr. Clifton Barry
Organization: Tuberculosis Research Section, LCID, NIAID, NIH
phone: 301-451-9554
e-mail: cbarry@niaid.nih.gov

Publications of Results:

Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, Via LE, Goldfeder LC, Kang E, Jin B, Park H, Kwak H, Kim H, Jeon HS, Jeong I, Joh JS, Chen RY, Olivier KN, Shaw PA, Follmann D, Song SD, Lee JK, Lee D, Kim CT, Dartois V, Park SK, Cho SN, Barry CE 3rd. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012 Oct 18;367(16):1508-18. doi: 10.1056/NEJMoa1201964.

Other Publications:

Richter E, Rüsch-Gerdes S, Hillemann D. First linezolid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2007 Apr;51(4):1534-6. Epub 2007 Jan 22.

Hillemann D, Rüsch-Gerdes S, Richter E. In vitro-selected linezolid-resistant Mycobacterium tuberculosis mutants. Antimicrob Agents Chemother. 2008 Feb;52(2):800-1. Epub 2007 Dec 10.

Duncan K, Barry CE 3rd. Prospects for new antitubercular drugs. Curr Opin Microbiol. 2004 Oct;7(5):460-5. Review.

Responsible Party:	Clifton E. Barry III, Ph.D., National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00727844 History of Changes
Other Study ID Numbers:	08-I-N167
Study First Received:	August 1, 2008
Results First Received:	September 10, 2013
Last Updated:	February 12, 2016
Health Authority:	United States: Food and Drug Administration

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