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.
