Metronidazole for Pulmonary Tuberculosis (South Korea)
Metronidazole for Pulmonary Tuberculosis (South Korea)
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:

 -  Collection of sputum for counting of bacteria.

 -  Drawing of blood for routine blood chemistry analysis; for measuring levels of
 metronidazole; TB lipid analysis; and for testing levels of T-cells, which are part of
 an immune response.

 -  Two targeted positron emission tomography (PET) scans, each with a computed tomography
 (CT) scan, and five high-resolution CT scans.

 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.
BACKGROUND:

 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.

 AIMS:

 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.

 METHODS:

 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.
-  INCLUSION CRITERIA:

 1. Male and females age 20 and above

 2. Signs or symptoms of tuberculosis (i.e., cough that has lasted 3 weeks or longer,
 hemoptysis, chest pain, fatigue, weight loss, night sweats)

 3. Subjects with documented AFB smear-positive pulmonary tuberculosis at screening
 to NMTH

 4. Radiographic evidence of tuberculous disease of the lung(s)

 5. TB isolate resistant to at least isoniazid and rifampicin

 6. Drug Susceptibility Testing (DST) results known for ofloxacin (can be either
 sensitive or resistant)

 7. Ability and willingness to give written or oral informed consent

 8. Willingness to be an inpatient at NMTH for, at minimum, the duration of study
 drug/placebo treatment

 9. Willingness to have samples stored

 10. Available for follow-up visits

 EXCLUSION CRITERIA:

 1. People who are unwilling or unable to abstain from alcohol consumption for the study
 drug treatment duration (8 weeks)

 2. Women of childbearing potential, who are pregnant, breast feeding, or unwilling to
 avoid pregnancy by the use of appropriate contraception including oral and
 subcutaneous implantable hormonal contraceptives, condoms, diaphragm, intrauterine
 device (IUD), or abstinence from sexual intercourse at study screening and during the
 study drug/placebo treatment (two months with allowed stops) (Note: Prospective female
 participants of childbearing potential must have negative pregnancy test (urine)
 within 48 hours prior to study entry.)

 3. Subjects with pan resistant isolates

 4. Presently taking 2nd -line agents started more than 14 days prior to initial FDG-PET
 scan

 5. People with any of the following in their current medical assessment:

 1. Absolute neutrophil count less than 1000 cells/mL

 2. White Blood Cell count (WBC) less than 3.0 X 10(3)/microliter

 3. Hemoglobin less than 7.0 g/dL

 4. Platelet count less than 75,000 cells/mm(3)

 5. Serum creatinine greater than 2.0 mg/dL

 6. Aspartate aminotransferase (AST or SGOT) greater than 100 IU/L

 7. Alanine aminotransferase (ALT or SGPT) greater than 100 IU/L

 8. Total bilirubin greater than 2 mg/dL

 9. Moderate or severe peripheral neuropathy

 10. HIV-1 or HIV-2 infection

 11. History of systemic lupus erythematosus, rheumatoid arthritis, or other
 connective tissue disease

 6. Terminal illness with impending mortality

 7. History of allergy or serious adverse reaction to metronidazole or placebo formulation
 used in this study

 8. 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:

 1. Systemic cancer chemotherapy

 2. Systemic corticosteroids

 3. Systemic investigational agents

 4. Antiretroviral medications

 5. Growth factors

 6. HIV vaccines

 7. Immune globulin

 8. Interleukins

 9. Interferons

 9. The need for ongoing therapy with warfarin, phenytoin, lithium, cimetidine,
 disulfiram, ergot derivatives, cholestyramine, fosphenytoin, carbamazepine,
 cyclosporine, tacrolimus, sirolimus, amiodarone or phenobarbital while on study drug.

 10. 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

 11. Unwilling to be an inpatient at NMTH for greater than or equal to 2 months

 12. Any condition that the investigator believes would warrant exclusion