Metronidazole for Pulmonary Tuberculosis (South Korea)
Condition: Tuberculosis; Multi-Drug Resistant Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant
Intervention: Metronidazole; Blood Draw; CT Scan; PET Scan
Intervention MeSH terms: Metronidazole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 35.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: Mycobacterium Tuberculosis; Anaerobic; FDG-PET-HRCT; HRCT; Lesion Matrix; Tuberculosis; TB

Summary:

      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.
    

Eligibility criteria:

        -  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