Pulmonary Tuberculosis Clinical Trial
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
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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