NexGen EBA Radiologic and Immunologic Biomarkers of Sterilizing Drug Activity in Tuberculosis
Condition: Pulmonary Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      - Tuberculosis (TB) is a lung infection caused by bacteria. When people with TB cough, they
      may spread these bacteria. Researchers are looking for new TB medicines. They want to find a
      faster way to tell if a drug might combat TB.

      Objective:

      - To learn the effect of different anti-TB drugs on microbiological, radiographic and
      immunologic markers in people with TB.

      Eligibility:

      - Adults age 18-65 who weigh 30-90 kg and have common TB bacteria that can be treated with
      common TB medicines.

      Design:

        -  Participants will be admitted to the hospital for screening. They will have medical
           history, physical exam, and chest radiograph. They will give blood, urine, and sputum
           samples.

        -  Participants will be put in 1 of 8 groups.

        -  Participants will get one or a combination of TB medicines daily for about 14 days.

        -  Each day, participants:

        -  Will discuss side effects.

        -  May have a physical exam.

        -  Will spit mucus into a cup. They may breathe in saline water through a nebulizer to make
           them cough.

        -  Participants will have blood taken 3-4 times during the study

        -  Participants will have 2-3 Fluorodeoxyglucose Positron Emission Tomography/Computed
           Tomography (FDG-PET/CT) scans. FDG is a radioactive sugar molecule which helps measure
           TB disease in the lungs. It will be injected into a vein. Participants will lie in a
           scanner that takes pictures.

        -  Around study day 14, participants will leave the hospital. They will be referred to a
           local TB clinic. There they will get the standard 4 TB medicines. Those in group 8 will
           already be on these medicines and will have another FDG-PET/CT on day 28.

        -  Participants will be in the study for up to 28 days.
    

Detailed description: 
      Early bactericidal activity (EBA), which measures decline in serial sputum colony forming
      unit (CFU) counts over the first 2-14 days of treatment, has been used extensively as a means
      of initially evaluating the potency of individual or combinations of antituberculous agents.
      This approach is endorsed by the Global Alliance for TB Drug Development and the US FDA.
      However, EBA seems to correlate poorly with the relative ability of an agent to prevent
      relapse and produce a durable cure (often referred to as sterilizing activity ). The reasons
      for this discrepancy may have to do with a limitation of sputum measurements to capture
      populations that persist beyond airway surfaces in discrete lesions such as granulomas,
      nodules, or cavities. The elimination of these persistent populations depend on the
      pharmacodynamic properties of a regimen and may be better captured by biologic and functional
      markers that can reflect dynamic treatment effects within these relevant host environments.

      Recent studies of the response to TB chemotherapy have identified promising new biomarkers of
      sterilization in 2 areas. First, immunologic changes appear to have potential in small
      subject cohorts to predict sterilizing cure within 1 month after commencing treatment.
      Second, 18F-FDG PET/CT has been used in tuberculosis as a qualitative means of assessing drug
      response in small case series at multiple time points, starting as early as 1 month. PET
      activity reflects uptake and phosphorylation of FDG by neutrophils and macrophages, and CT
      provides structural information on disease pathology. Hence, PET/CT data may offer additional
      insights into lesion-specific sterilizing activity. This study will add 18F-FDG PET/CT scans
      and immunological assays at 0, 2, and (in the HRZE arm) 4 weeks to standard EBA methodology
      using regimens containing isoniazid (INH [H]), rifampin (RIF [R]), pyrazinamide (PZA [Z]),
      moxifloxacin (MXF [M]), and ethambutol (EMB [E]). We hypothesize that drug regimens
      associated with higher sterilizing activity (e.g., containing rifampin or pyrazinamide) will
      show distinctive early cytokine and chemokine patterns and discrete, quantifiable changes on
      PET/CT in certain lesion types during the 2-week period, compared to drug regimens with poor
      sterilizing activity (e.g., containing isoniazid or moxifloxacin). Demonstration of such an
      association would provide rationale for including radiologic and immunologic analysis,
      alongside conventional EBA, in early phase clinical studies of novel drugs, and would also
      provide important new insights into the biology of human and bacterial responses to TB drugs.
    

Intervention name(s): Treatment; PET/CT Scan; Sample Collection
Intervention type(s): Drug; Radiation; Procedure
Intervention description(s): Different Drug combinations; PET/CT Scans; Sample Collection
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Treatment-Response; Radiological Imaging; Biomarkers; Antitubercular Agents; Log-CFU Reduction