Linezolid to Treat Extensively-Drug Resistant Tuberculosis

NCT00727844 | Completed Phase 2 Results DMC

• 1 other identifier: 08-I-N167
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 2

Brief Summary

This study, conducted in Masan and Seoul, South Korea, investigated the effectiveness of linezolid (LZD) in treating patients with extensively drug resistant tuberculosis (XDR TB). Because regular medicines do not work well against XDR TB, many more people die from it than from regular TB, which can be successfully treated by taking TB medication for 6 months. Linezolid has been used to treat other kinds of infections, but has not been well studied for TB. This study examined the side effects and effectiveness of prolonged treatment with linezolid at two different doses. People 20 years of age and older who have XDR TB were eligible for this 3-year study. Participants underwent the following tests and procedures:

• LZD treatment: Patients were randomly assigned to one of two study groups. Group 1 patients were observed for 2 months before starting LZD, while group 2 patients begin taking LZD right away. Both groups began with a 600 mg daily dose of LZD. After patients stopped coughing up TB germs (or after 4 months on LZD) they were randomly assigned either to continue taking 600 mg of LZD for the rest of the study or to take a decreased dose of 300 mg. In addition to LZD, patients continued to take their currently prescribed TB medications.
• Medical history.
• Physical examinations each month during treatment.
• Sputum collections once a week or more until 3 weeks after the patient was no longer contagious.
• Blood draws every week for 16 to 24 weeks and then once a month.
• Urine collections at several time points.
• Nerve and eye examinations before starting treatment and then monthly to look for possible LZD side effects.
• CT scans of the lungs three to four times the first year and once more later in the study. For this test the patient lay on a table within the doughnut-shaped CT scanner while special X-ray pictures are taken. Patients who participated in a substudy had PET scans instead of the CT scans. For this test, the patient was given an injection into a vein of a radioactive chemical that can be detected by a special camera and viewed on a screen. The patient lay on a table within the doughnut-shaped scanner while pictures were taken.

Conditions

Pulmonary Tuberculosis; Multidrug Resistant Tuberculosis; Extensively Drug Resistant Tuberculosis

Keywords

XDR-TB; Linezolid; Drug Resistance; Computed Tomography; Pharmacokinetics; Tuberculosis; Drug Resistance Tuberculosis; MDR-TB

Outcome Measures

Primary Outcomes (1)

• Number of Patients Converted to Sputum Culture Negative in Each Arm, With Data Censored at 4 Months.

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

Study Arms (2)

Delayed Start Linezolid

EXPERIMENTAL

Subjects continued their existing regimen for 2 months after which LZD (600 mg once daily) was added. After 2 consecutive AFB negative sputum smears (not to exceed 4 months of LZD therapy), subjects were randomized to continue on 600 mg LZD once daily or to de-escalate to 300 mg once daily. Regardless of the dosage, subjects remained on LZD treatment for 18 months after sputum culture conversion or until they could no longer tolerate therapy.

Drug: Delayed Start Linezolid

Immediate Start Linezolid

EXPERIMENTAL

Upon completion of entry criteria, subjects had LZD (600 mg once daily) added to their regimen. After 2 consecutive AFB negative sputum smears (or at 4 months) subjects were randomized to continue on 600 mg LZD once daily or to de-escalate to 300 mg once daily. Regardless of the dosage, subjects remained on LZD treatment for 18 months after sputum culture conversion or until they could no longer tolerate therapy.

Drug: Immediate Start Linezolid

Interventions

Immediate Start Linezolid DRUG

Also known as: Zyvox

Immediate Start Linezolid

Delayed Start Linezolid DRUG

Also known as: Zyvox

Delayed Start Linezolid

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females age 20 and above
• Documented pulmonary tuberculosis at screening
• Radiographic evidence of tuberculous disease of the lung(s)
• History of chronic, AFB positive sputum smears and culture positive TB
• Mycobacterium species identification as Mycobacterium tuberculosis
• Confirmed resistance to INH, RIF, kanamycin, ofloxacin, and moxifloxacin by genotypic or phenotypic testing OR subjects with documented failure to respond to treatment despite DST susceptibility
• Failure to respond (after at least 6 months) to a anti-TB drug regimen including any known active agents
• Willingness to be an inpatient until 2 consecutive AFB-negative sputum smears
• When an outpatient, willing to come back for weekly tests and scheduled follow-up visits
• Willingness to have samples stored
• Ability and willingness to give written or oral informed consent

You may not qualify if:

• Subjects below 20 years of age
• Subjects who have previously been on LZD
• Women of childbearing potential, who are pregnant, breast feeding, or unwilling to avoid pregnancy (i.e., the use of appropriate contraception including oral and subcutaneous implantable hormonal contraceptives, condoms, diaphragm, intrauterine device (IUD), or abstinence from sexual intercourse). \[Note: Prospective female participants of childbearing potential must have negative pregnancy test (urine) within 48 hours prior to study entry.\]
• Men who are unwilling to use contraceptives or practice abstinence
• People with any of the following in their current medical assessments:
• Absolute neutrophil count less than 1000 cells/mL
• White blood cell count (WBC) less than 3.0 X 10(3)/microL
• Hemoglobin less than 7.0 g/dL
• Platelet count less than 75,000 cells/mm(3)
• Serum creatinine greater than 2.0 mg/dL
• Aspartate aminotransferase (AST or SGOT) greater than 100 IU/L
• Alanine aminotransferase (ALT or SGPT) greater than 100 IU/L
• Total bilirubin greater than 2.0 mg/dL
• Moderate or severe peripheral or optical neuropathy (or a history of)
• HIV-1 or HIV-2 infection

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (2)

National Masan Tuberculosis Hospital

Changwon, South Korea

Location

National Medical Center

Seoul, South Korea

Location

Related Publications (4)

• Richter E, Rusch-Gerdes S, Hillemann D. First linezolid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2007 Apr;51(4):1534-6. doi: 10.1128/AAC.01113-06. Epub 2007 Jan 22.

  PMID: 17242139 BACKGROUND

• Hillemann D, Rusch-Gerdes S, Richter E. In vitro-selected linezolid-resistant Mycobacterium tuberculosis mutants. Antimicrob Agents Chemother. 2008 Feb;52(2):800-1. doi: 10.1128/AAC.01189-07. Epub 2007 Dec 10. No abstract available.

  PMID: 18070973 BACKGROUND

• Duncan K, Barry CE 3rd. Prospects for new antitubercular drugs. Curr Opin Microbiol. 2004 Oct;7(5):460-5. doi: 10.1016/j.mib.2004.08.011.

  PMID: 15451500 BACKGROUND

• 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.

  PMID: 23075177 RESULT

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis; Tuberculosis

Interventions

Linezolid

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Small sample size

Results Point of Contact

• Title: Dr. Clifton Barry
• Organization: Tuberculosis Research Section, LCID, NIAID, NIH

cbarry@niaid.nih.gov

301-451-9554

Study Officials

• Clifton Barry, Ph.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Tuberculosis Research Section (TRS)

Study Record Dates

• First Submitted: August 1, 2008
• First Posted: August 4, 2008
• Study Start: July 1, 2008
• Primary Completion: October 1, 2012
• Study Completion: November 1, 2014
• Last Updated: March 14, 2016
• Results First Posted: February 24, 2014

Record last verified: 2014-05

Locations

KR (2)