Linezolid to Treat Extensively-Drug Resistant Tuberculosis
This study, conducted in Masan and Seoul, South Korea, will investigate 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 will look at 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 may be eligible for this 3-year study.
Participants undergo the following tests and procedures:
- LZD treatment: Patients are randomly assigned to one of two study groups. Group 1 patients are observed for 2 months before starting LZD, while group 2 patients begin taking LZD right away. Both groups begin with a 600 mg daily dose of LZD. After patients stop coughing up TB germs (or after 4 months on LZD) they are 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 continue 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 is 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 lies on a table within the doughnut-shaped CT scanner while special X-ray pictures are taken.
Patients who participate in a substudy will have PET scans instead of the CT scans. For this test, the patient is 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 lies on a table within the doughnut-shaped scanner while pictures are taken.
Multidrug Resistant Tuberculosis
Extensively Drug Resistant Tuberculosis
Drug: Immediate Start Linezolid
Drug: Delayed Start Linezolid
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 2a, Randomized, 2-Arm, Open-Label, Clinical Trial of the Efficacy of Linezolid Combined With Antituberculous Therapy in Subjects With Extensively Drug-Resistant (XDR) Pulmonary Tuberculosis|
- The number of days required to convert to sputum culture negative status in each treatment arm. [ Time Frame: Sputum smear conversation or max 4 months after the start of Linezolid therapy. ] [ Designated as safety issue: No ]
- The time to discontinuation of LZD due to intolerance for study drug. Number and grade of reportable adverse events (SAEs Grade 3 and above) thought to be related to LZD tx. Changes in radiographic findings by CT after 2 and 6 months of LZD trea... [ Time Frame: Up to 22 months on study. ] [ Designated as safety issue: Yes ]
|Study Start Date:||July 2008|
|Estimated Study Completion Date:||January 2015|
|Estimated Primary Completion Date:||January 2015 (Final data collection date for primary outcome measure)|
Experimental: 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.
Drug: Delayed Start Linezolid
Other Name: Zyvox
Experimental: 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.
Drug: Immediate Start Linezolid
Other Name: Zyvox
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 will evaluate 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 are 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 is suspected to be sensitive: however drugs may have been discontinued during this time. Subjects will be stratified based upon a diagnosis of diabetes mellitus (type I and II included) using block randomization. At the primary randomization, subjects will be 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 will occur after 2 consecutive negative sputum smears or at 4 months after the start of LZD therapy (whichever comes first), when subjects will either stay with their current 600 mg LZD once daily or deescalate to 300 mg LZD once daily (see Section 4.1.4 Study Schema). The second randomization will be stratified on diabetes. The primary objective of this study is to evaluate the efficacy of LZD therapy, as measured by sputum culture conversion. Secondary aims of this study include: 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 aim 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 will be approximately 3 years.
|Korea, Republic of|
|National Masan TB Hospital|
|Masan, Korea, Republic of|
|National Medical Center|
|Seoul, Korea, Republic of|
|Principal Investigator:||Clifton Barry, Ph.D.||National Institute of Allergy and Infectious Diseases (NIAID)|