International Tuberculosis Clinical Research

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(1) NIAID 15-I-N070: Radiologic and immunologic biomarkers to enhance early bactericidal activity (EBA) measurements of sterilizing drug activity in tuberculosis (NexGen EBA). This study hypothesized that drug regimens associated with higher sterilizing activity show distinct cytokine patterns and quantifiable PET/CT changes in certain lesions during the EBA period, compared to those with lesser sterilizing activity. The primary objective was to characterize, in the context of a standard EBA study, the effect of various anti-TB drugs on radiographic and immunologic markers in treatment-naive subjects with pulmonary drug sensitive TB. The study was a collaboration with the Gates Foundation (BMGF) and was conducted in South Africa from 2015-2017. The primary analyses of microbiology, PET/CT, and biomarkers data are complete and a manuscript published. Secondary analyses are ongoing. PET/CT data on new drugs and combinations is being collected through the EDCTP funded CLICK-TB consortium. (2) NIAID 16-I-N133: Using Biomarkers to Predict TB Treatment Duration. This study hypothesizes that a combination of radiographic characteristics at baseline, the rate of change of these features at one month, and markers of residual bacterial load at the end of treatment will identify TB patients who are cured with 4 months of standard treatment. The primary objective is to demonstrate that the month 18 treatment success rate of standard treatment stopped early at month 4 is not inferior to standard treatment stopped at month 6, in participants classified as lower risk for disease failure and relapse by radiographic and bacterial load markers. This is a collaboration funded by BMGF, the European and Developing Countries Clinical Trials Partnership (EDCTP), the National Natural Science Foundation of China, the China Ministry of Science and Technology, and NIH. Study enrollment began in 2017 in Western Cape, South Africa and Henan Province, China and enrolled about 310 participants into the two lower risk arms. The study is expected to conclude in FY 2023. One manuscript was published last year. Study enrollment was slowed and follow-up has been made more complicated by the COVID-19 pandemic. (3) anTBiotic consortium: This is a consortium led by GSK and includes University of Tromso, Research Center Borstel, University of Cape Town, TASK Applied Science in Cape Town to develop and advance novel anti-TB clinical drug candidates, including a novel GSK compound, meropenem, and other B-lactam antibiotics against MDR-TB. Single drugs and drug combinations are explored in 2-week NexGen EBA studies, along with biomarker-guided treatment durations that will be evaluated in future trials. The study is being conducted at TASK. The clinical phase of this study has concluded and the data are now being analyzed. This study is primarily funded by EDCTP. Data analyses have been slowed by the COVID-19 pandemic. (4) Novel Clinical Candidates to Kill TB (Click-TB) consortium: This is a consortium led by GSK and includes Research Center Borstel, University of Cape Town, TASK Applied Science in Cape Town. The aim is to identify a universal treatment regimen for TB that is ready to move into a phase 2b or 3 clinical trial. Three novel compounds and recently approved drugs will be included. Two-week NexGen EBA studies are being conducted on 2-drug combinations followed by 4-week trials of 3- or 4-drug combinations. The best 3- or 4-drug combinations will be ready for a future phase 2b or 3 clinical trial. The clinical trial is currently ongoing, conducted by TASK. This study is primarily funded by EDCTP. The conduct of the trial and data analyses have been slowed by the COVID-19 pandemic. (5) DMID Protocol Number 13-0029: Award# N01AI90500C: Feasibility and accuracy of a novel Xpert cartridge for rapid molecular detection of drug resistant Mycobacterium tuberculosis in sputum. This prospective, cross-sectional study was conducted with the Clinical Diagnostics Research Consortium (PI: Susan Dorman, Medical University of South Carolina) in China and South Korea and is now completed. The investigational Xpert XDR cartridge accurately detected Mtb mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides; primary results were published in the New England Journal of Medicine. Samples from this study will be used to develop newer Xpert cartridges.