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.

World-wide, there is an increasing incidence of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB). For patients diagnosed with either of these deadly diseases, effective drug treatment options are sub-optimal or non-existent. In South Korea, there are a growing number of patients not responding to any therapy who have little hope for survival without new drugs. Linezolid (LZD), an antimicrobial approved for gram positive bacterial infections, has been used off-label for drug resistant TB and is quickly becoming a sought after drug for this population, despite lack of clinical evidence of efficacy. At the present time the prohibitive cost of LZD limits widespread use; however, when patent exclusivity expires in May of 2015 it will be imperative to have examined the benefits versus risks of LZD for TB in a controlled setting. The National Masan Tuberculosis Hospital (NMTH) in Masan, South Korea and the National Medical Center in Seoul, South Korea provide us with an opportunity to systematically address questions about LZD in a highly drug-resistant population.

This is a Phase 2a, randomized, 2-arm study of LZD, which evaluated the efficacy, safety, and tolerability of LZD in subjects whose isolates have shown resistance to all known active TB drugs or who have failed to respond to any active drugs to which they are susceptible. Subjects were required to have been on a failing regimen for at least 6 months prior to study entry, with persistent sputum smear positivity, culture positivity and no significant clinical sign of response to therapy. To be considered for the study, a subject's treatment plan must have been stable without the addition of drugs to which the subjects isolate was suspected to be sensitive: however drugs may have been discontinued during this time. Subjects were stratified based upon a diagnosis of diabetes mellitus (type I and II included) using block randomization. At the primary randomization, subjects were randomly assigned either to immediately add 600 mg LZD once daily to their existing regimen or to a delay of 2 months before adding 600 mg LZD once daily to their existing regimen. A second randomization occurred after 2 consecutive negative sputum smears or at 4 months after the start of LZD therapy (whichever came first), when subjects either stayed with their current 600 mg LZD once daily or de-escalated to 300 mg LZD once daily (see Section 4.1.4 Study Schema). The second randomization was stratified on diabetes. The primary objective of this study was to evaluate the efficacy of LZD therapy, as measured by sputum culture conversion. Secondary aims of this study included: investigation of the pharmacokinetic and pharmacodynamic profiles of LZD in blood; tolerability and toxicity of prolonged LZD administration at doses of 300 mg and 600 mg daily; the rate of change of radiological findings by computed tomography (CT); the rate of relapse 12 months after discontinuation of therapy; the rate of development of drug resistance to LZD; changes in immunologic and bacterial lipid markers during LZD therapy; the correlation of whole-blood killing assays with response to LZD therapy; and effects of LZD on mitochondrial function, a potential early indicator of LZD toxicity. In a substudy, we aimed to investigate the changes in lung architecture and cellular activity during treatment using F-fluoro-2-deoxy-D-glucose - positron emission tomography-computed tomography (FDG-PET-CT) of 20 subjects on LZD therapy. Estimated total study duration for each subject was approximately 3 years.

• INCLUSION CRITERIA:

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

EXCLUSION CRITERIA:

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

Systemic lupus erythematosus, rheumatoid arthritis, or other connective tissue disease

Patients who, in the investigator's judgment, are too ill to participate in the study

History of allergy or serious adverse reaction to the LZD formulation used in this study

Patients with anticipated surgical intervention

The use of any of the following drugs within 30 days prior to study or anticipated use of these drugs within the next 60 days: (Please not, bronchodilators and cough syrup (or similar cough medicines) are allowed before and during the study if blood pressure is monitored regularly, per Contraindications, p.12, of the Zyvox Package Insert.)

Selective serotonin reuptake inhibitors (SSRIs)

Monoamine oxidase inhibitors (MAOIs)

Systemic cancer chemotherapy

Systemic corticosteroids

Systemic investigational agents

Antiretroviral medications

Growth factors

HIV vaccines

Immune globulin

Interleukins

Interferons

The need for ongoing therapy with antidepressants (SSRI, MAOI), hydroxyzine, dopaminergic agents (such as Sinemet, dopamine, and dobutamine), lithium, cyclosporine, tacrolimus, sirolimus, and levodopa (such as sinemet) while on study drug

Any other serious systemic illness requiring treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy for at least 14 days prior to study entry

Patients who the physician has reason to believe may have been non-compliant in the previous 12 months of treatment

SUBSTUDY ELIGIBILITY CRITERIA

INCLUSION CRITERIA:

Subjects who meet the inclusion criteria for main study are eligible for the substudy.

EXCLUSION CRITERIA:

Exclusion criteria for main study apply to the substudy with the exception that subjects with uncontrolled diabetes mellitus will be excluded from the substudy. The study physician may decide that a patient is healthy enough to participate in the main study but not the sub-study.

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

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.

Small sample size