Linezolid to Treat Extensively-Drug Resistant Tuberculosis
Information source: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pulmonary Tuberculosis; Multidrug Resistant Tuberculosis; Extensively Drug Resistant Tuberculosis
Intervention: Immediate Start Linezolid (Drug); Delayed Start Linezolid (Drug)
Phase: Phase 2
Status: Active, not recruiting
Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID) Official(s) and/or principal investigator(s): Clifton Barry, Ph.D., Principal Investigator, Affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
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.
Clinical Details
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
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Number of Patients Converted to Sputum Culture Negative in Each Arm, With Data Censored at 4 Months.
Detailed description:
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.
Eligibility
Minimum age: 20 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
- 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.
Locations and Contacts
National Masan Tuberculosis Hospital, Changwon, Korea, Republic of
National Medical Center, Seoul, Korea, Republic of
Additional Information
Related publications: Richter E, Rüsch-Gerdes S, Hillemann D. First linezolid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2007 Apr;51(4):1534-6. Epub 2007 Jan 22. Hillemann D, Rüsch-Gerdes S, Richter E. In vitro-selected linezolid-resistant Mycobacterium tuberculosis mutants. Antimicrob Agents Chemother. 2008 Feb;52(2):800-1. Epub 2007 Dec 10. Duncan K, Barry CE 3rd. Prospects for new antitubercular drugs. Curr Opin Microbiol. 2004 Oct;7(5):460-5. Review.
Starting date: July 2008
Last updated: May 22, 2014
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