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

2 subjects excluded: 1 for uncontrolled diabetes mellitus and 1 for diagnosis of extrapulmonary TB. 2 additional subjects withdrew: 1 self- withdrew and the other was withdrawn for missing >14 days of study drug.

Major limitation of our study was the small sample size. Planned enrollment was 80 subjects but DSMB recommended closing the study to new enrollment after 35 subjects due to increased peripheral neuropathy in the metronidazole arm.