Metronidazole for Pulmonary Tuberculosis (South Korea)
|ClinicalTrials.gov Identifier: NCT00425113|
Recruitment Status : Completed
First Posted : January 22, 2007
Results First Posted : July 10, 2013
Last Update Posted : July 10, 2013
|First Submitted Date ICMJE||January 19, 2007|
|First Posted Date ICMJE||January 22, 2007|
|Results First Submitted Date||February 7, 2013|
|Results First Posted Date||July 10, 2013|
|Last Update Posted Date||July 10, 2013|
|Start Date ICMJE||December 2006|
|Primary Completion Date||October 2012 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Changes in TB Lesion Sizes Using High Resolution Computed Tomography (HRCT). [ Time Frame: 6 months. ]
Lesions were defined as nodules (<2 mm, 2-<4 mm, and 4-10 mm), consolidations, collapse, cavities, fibrosis, bronchial thickening, tree-in-bud opacities, and ground glass opacities. Each CT was divided into six zones (upper, middle, and lower zones of the right and left lungs) and independently scored for the above lesions by three separate radiologists blinded to treatment arm. A fourth radiologist adjudicated any scores that were widely discrepant among the initial three radiologists. The HRCT score was determined by visually estimating the extent of the above lesions in each lung zone as follows: 0=0% involvement; 1= 1-25% involvement; 2=26-50% involvement; 3=51-75% involvement; and 4=76-100% involvement. A composite score for each lesion was calculated by adding the score for each specific abnormality in the 6 lung zones and dividing by 6, with the change in composite score measured at 2 and 6 months compared to baseline. Composite sums of all 10 composite scores are reported.
|Original Primary Outcome Measures ICMJE
||Changes in TB lesion sizes.|
|Change History||Complete list of historical versions of study NCT00425113 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Time to Sputum Culture Conversion to Negative on Solid Medium [ Time Frame: 2 months ]|
|Original Secondary Outcome Measures ICMJE
||Change in time to sputum conversion.|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Metronidazole for Pulmonary Tuberculosis (South Korea)|
|Official Title ICMJE||A Randomized, Double-Blind, Placebo-Controlled Phase II Study of Metronidazole Combined With Antituberculous Chemotherapy vs. Antituberculous Chemotherapy With Placebo in Subjects With Multi-Drug Resistant Pulmonary Tuberculosis|
This study will evaluate the effect of adding metronidazole to standard second-line therapy for tuberculosis in patients who have multi-drug resistant tuberculosis (MDR-TB) of the lungs. It will evaluate the safety and tolerability of metronidazole in combination with antituberculosis agents. Metronidazole is a drug widely used to treat bacterial and parasitic infections occurring in environments with very little oxygen such as the human colon. Nine million new cases of sputum-positive tuberculosis are diagnosed worldwide each year.
Patients ages 20 and older who have symptoms of TB, who have been treated for tuberculosis but whose disease is multi-drug resistant, and who are not pregnant or breast feeding may be eligible for this study. They will be recruited in the National Masan Tuberculosis Hospital (NMTH), Masan, Republic of Korea. Patients will undergo the following tests and procedures:
Patients will receive either an 8-week course of standard second-line agents plus placebo (sugar pill) or an 8-week course of standard agents plus metronidazole. The subjects, doctors and researchers will not know which patients are taking the metronidazole until after the first 2 years of the trial. A total of 60 patients will be assigned to two cohorts of 30 patients each. After 8 weeks, all patients will return to the standard of care chemotherapy, according to normal procedures at NMTH.
Side effects of metronidazole commonly reported are vaginal discharge, symptoms of Candida cervicitis and vaginitis, headache, nausea and vomiting, and dizziness. Peripheral neuropathy, an abnormal condition of the nerves, may also be a side effect. The precise incidence of neuropathy is unknown but is usually related to the duration of metronidazole use. It can almost always be reversed when the drug is discontinued. Serious side effects, though rare, may include leukopenia and thrombocytopenia (disorders in the blood), seizures and other central nervous system problems, and hepatitis.
This study may or may not have a direct benefit for participants. However, it is possible that patients' drug-resistant disease may be more effectively treated as a result of metronidazole. The study may help identify new methods for measuring drug effectiveness during TB studies.
Despite significant in vitro data that metronidazole is active against Mycobacterium tuberculosis (MTB) maintained under anaerobic conditions, the utility of this agent has not been evaluated carefully in human disease due to lack of efficacy in murine models of tuberculosis (TB). Unlike disease in rodents, however, human disease is characterized by discrete types of lesions including both aerobic (cavities) and anaerobic (caseous necrotic nodules) areas. Recent experiments in non-human primates have demonstrated that closed caseous necrotic lesions are highly anoxic and are, therefore, likely to contain anaerobic bacilli highly susceptible to metronidazole. Recent studies in TB-infected rabbits have shown that metronidazole therapy is highly effective in an animal model that recapitulates this feature of human disease. Both of these studies support the possibility that metronidazole may have unique activity against an anaerobic sub-population of bacilli in human disease. Such sub-populations may be responsible for the extended duration of chemotherapy typically employed in tuberculosis chemotherapy, as anoxic bacteria are highly resistant to the sterilizing effects of front-line tuberculosis agents. One small clinical trial of metronidazole in an Indian population also suggests that this agent may have a significant unappreciated role in the control of human tuberculosis.
The major aim of this study is to evaluate the ability of metronidazole to kill an anaerobic sub-population of Mycobacterium tuberculosis within multi-drug resistant tuberculosis (MDR-TB) patients. In order to address this sub-population in the context of disease, this study combines traditional measurements of drug efficacy, including the rate of sputum clearance of organisms, with a functional imaging technique, [(18) F]-fluoro-2-deoxy-D-glucose -positron emission tomography - high-resolution computed tomography (FDG-PET-HRCT) that has not previously been applied to monitoring tuberculosis chemotherapy. In addition, this clinical trial will evaluate the tolerability and preliminary efficacy of metronidazole (500 mg three times a day (t.i.d.) when given in combination with standard second-line antituberculous treatment.
Type of study to be conducted:
Randomized, double-blinded, placebo controlled phase II study.
Population to be Studied:
The study population will be drawn from subjects at the National Masan Tuberculosis Hospital (NMTH), Changwon, Republic of Korea. Subjects presenting at NMTH who have been previously treated with first-line agents and who are multi-drug resistant (MDR), defined as having TB isolates that are resistant to at least isoniazid and rifampicin, and are therefore eligible for second-line antituberculous drug therapy will be included.
Treatment Regimen and Treatment Period(s):
All patients will receive either: (1) an 8-week course of standard second-line agents plus placebo t.i.d., or (2) an 8-week course of standard second-line agents plus 500 mg t.i.d. metronidazole. In total, sixty subjects will be accrued into two cohorts of 30 patients each. After 8 weeks, all subjects will revert to standard of care (SOC) chemotherapy according to normal procedures at NMTH. According to hospital standard of care, patients are continued on second-line medications for 18-24 months following sputum culture conversion.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||February 2013|
|Primary Completion Date||October 2012 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||20 Years and older (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Korea, Republic of|
|Removed Location Countries|
|NCT Number ICMJE||NCT00425113|
|Other Study ID Numbers ICMJE||999907041
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )|
|Study Sponsor ICMJE||National Institute of Allergy and Infectious Diseases (NIAID)|
|Collaborators ICMJE||Not Provided|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||May 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP