HRZE Phase 2 NexGen EBA Radiologic and Immunologic Biomarkers to Enhance Early Bactericidal Activity Measurements of Sterilizing Drug Activity in Tuberculosis

Study Director
Clifton Barry
Start Date
1 / 2015
Trial Phase
Phase II
Trial Status
Current Enrollment
Target Enrollment

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, F-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), rifampin (RIF), pyrazinamide (PZA), moxifloxacin (MXF), and ethambutol (EM). 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.

Primary Outcome Measures:

  • Changes from baseline to 14 days in microbiologic, radiographic, and immunologic markers within mono- and combination-therapy arms as outlined. Additional analysis will test whether there are measureable interactions of effects of drug (on marke... [ Time Frame: 14 days ]

Secondary Outcome Measures:

  • Correlation of change in PET characteristics and change in immunological markers [ Time Frame: 14 days ]
  • Correlation of changes of PET characteristics and CFU changes [ Time Frame: 14 days ]
  • Correlation of time to Positivity (TTP) of liquid culture and CFU changes [ Time Frame: 14 days ]
Compound Associations
Regimen Associations