Linezolid to Treat Extensively-Drug Resistant Tuberculosis
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ClinicalTrials.gov Identifier: NCT00727844 |
Recruitment Status :
Completed
First Posted : August 4, 2008
Results First Posted : February 24, 2014
Last Update Posted : March 14, 2016
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Tracking Information | ||||
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First Submitted Date ICMJE | August 1, 2008 | |||
First Posted Date ICMJE | August 4, 2008 | |||
Results First Submitted Date ICMJE | September 10, 2013 | |||
Results First Posted Date ICMJE | February 24, 2014 | |||
Last Update Posted Date | March 14, 2016 | |||
Study Start Date ICMJE | July 2008 | |||
Actual Primary Completion Date | October 2012 (Final data collection date for primary outcome measure) | |||
Current Primary Outcome Measures ICMJE |
Number of Patients Converted to Sputum Culture Negative in Each Arm, With Data Censored at 4 Months. [ Time Frame: Sputum smear conversion or max 4 months after the start of Linezolid therapy. ] | |||
Original Primary Outcome Measures ICMJE | Not Provided | |||
Change History | ||||
Current Secondary Outcome Measures ICMJE | Not Provided | |||
Original Secondary Outcome Measures ICMJE | Not Provided | |||
Current Other Pre-specified Outcome Measures | Not Provided | |||
Original Other Pre-specified Outcome Measures | Not Provided | |||
Descriptive Information | ||||
Brief Title ICMJE | Linezolid to Treat Extensively-Drug Resistant Tuberculosis | |||
Official Title ICMJE | 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 | |||
Brief 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:
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. |
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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. |
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Study Type ICMJE | Interventional | |||
Study Phase ICMJE | Phase 2 | |||
Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment |
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Condition ICMJE |
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Intervention ICMJE |
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Study Arms ICMJE |
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Publications * |
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | ||||
Recruitment Status ICMJE | Completed | |||
Actual Enrollment ICMJE |
41 | |||
Original Enrollment ICMJE |
40 | |||
Actual Study Completion Date ICMJE | November 2014 | |||
Actual Primary Completion Date | October 2012 (Final data collection date for primary outcome measure) | |||
Eligibility Criteria ICMJE |
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. |
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Sex/Gender ICMJE |
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Ages ICMJE | 20 Years and older (Adult, Older Adult) | |||
Accepts Healthy Volunteers ICMJE | No | |||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | |||
Listed Location Countries ICMJE | Korea, Republic of | |||
Removed Location Countries | ||||
Administrative Information | ||||
NCT Number ICMJE | NCT00727844 | |||
Other Study ID Numbers ICMJE | 08-I-N167 | |||
Has Data Monitoring Committee | Yes | |||
U.S. FDA-regulated Product | Not Provided | |||
IPD Sharing Statement ICMJE | Not Provided | |||
Current Responsible Party | Clifton E. Barry III, Ph.D., National Institute of Allergy and Infectious Diseases (NIAID) | |||
Original Responsible Party | Not Provided | |||
Current Study Sponsor ICMJE | National Institute of Allergy and Infectious Diseases (NIAID) | |||
Original Study Sponsor ICMJE | Same as current | |||
Collaborators ICMJE | Not Provided | |||
Investigators ICMJE |
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PRS Account | National Institute of Allergy and Infectious Diseases (NIAID) | |||
Verification Date | May 2014 | |||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |