(1) NIAID 15-I-N070: Radiologic and immunologic biomarkers to enhance early bactericidal activity (EBA) measurements of sterilizing drug activity in tuberculosis (TB). The study hypothesizes 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. If true, this would provide a rationale for including radiologic and immunologic analysis in EBA studies of novel drugs to move into phase 2 or 3 trials. The primary objective is 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 is a collaboration with the Gates Foundation (BMGF) and was conducted in Cape Town, South Africa. The study initiated in December 2015 and completed with 160 subjects in September 2017. PET/CT scans collected at baseline and week 2 are being analyzed by readers assisted by a custom-developed automated computer algorithm. Analysis of microbiology data is complete. (2) NIAID 16-I-N133: Using Biomarkers to Predict TB Treatment Duration. The 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 18-month treatment success rate of standard treatment stopped early at week 16 is not inferior to standard treatment stopped at week 24, in participants classified as low 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, the National Natural Science Foundation of China, the China Ministry of Science and Technology, and NIH. Study enrollment began in June 2017 in Cape Town, South Africa (Stellenbosch University and University of Cape Town) and in October 2017 in Henan Province, China (Henan Health and Family Planning Commission, Henan Chest Hospital, and Henan Center for Disease Control and Prevention). The study will enroll 620 participants. It is expected to complete in FY 2022. (3) NIAID 15-I-0187: Sputum Pharmacokinetics of TB Drugs and Bacterial Drug Resistance. The study hypothesizes that sputum drug levels are predictive of drug concentrations in plasma and/or in specific lung lesion compartments. The primary objective is to determine concentrations of TB drugs in plasma and sputum over time. The study began in September 2015 at the NIH Clinical Center and the Henan Chest Hospital, Zhengzhou, Henan Province, China. Enrollment completed with 168 participants in November 2017. Symptomatic subjects already on treatment for TB or non-tuberculous mycobacteria (NTM) provided at least 3 sputa over 2 or more days and blood at 0, 2, 4, and 6 hours after taking their anti-TB or anti-NTM medications on 2 separate days. Sputum was also stored for future testing of an investigational Xpert cartridge being developed for more sensitive diagnosis of XDR TB. Comparison of drug concentrations in sputum with those in plasma and lesions is ongoing. If drug concentrations in sputum correlate as well as or better with those in lung lesion, therapeutic drug monitoring may become easier and more accurate. Sputum and plasma drug concentrations will be analyzed using a specialized assay and the transfer of this technique from our collaborators at Rutgers University to Fudan University is ongoing. We will apply for sample export so testing can be done both in China and outside of China. (4) 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, Johns Hopkins University) 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. (5) DMID Protocol Number 15-0029: Award# N01AI90500C: Multicenter Study of the Accuracy and Feasibility of the Xpert MTB/RIF Ultra Test. This is another NIH-CDRC collaborative study that began in FY2016 evaluating the clinical diagnostic accuracy of another novel Xpert cartridge for detection of M.tb and rifampin resistance that is 10-fold more sensitive than the standard Xpert MTB/RIF. This prospective non-inferiority study was conducted in Brazil, Kenya, Uganda, South Africa and China and found that the Xpert Ultra test was more sensitive than standard Xpert in patients with paucibacillary TB and in patients with HIV but less specific; primary results were published in Lancet Infectious Diseases. (6) Trehalose: Biodistribution and safety of 18F-2-Fluoro-2-deoxytrehalose (FDT) for PET/CT imaging of patients with and without mycobacterial infections. This study is currently in preclinical development (see separate report). A phase 1 clinical trial protocol, an FDA IND application and contract manufacturing are in development. (7) NIAID 10-I-N060: A Natural History Study of TB in China: Correlates of a Successful Response in Treatment. This was a prospective, longitudinal natural history study designed to develop clinical research capacity at the Henan Chest Hospital. The study completed in 2014 and found that interferon- levels decreased significantly in pulmonary TB patients on treatment, largely over the initial 8 weeks of treatment, and thus may offer some value for monitoring treatment response. (8) NIAID 05-I-N069: A Natural History Study of MDR-TB Strains and Host Susceptibility Genes in Korean Patients with Pulmonary TB. This study seeks to characterize MDR and XDR TB isolates and their contribution to human disease. A total of 776 subjects enrolled and the study is now complete. (9) NIAID 07-I-N041: A Randomized, Double-blind, Placebo-controlled Pilot Study of Metronidazole Combined with Anti-TB Chemotherapy vs. Anti-TB Chemotherapy with Placebo in Subjects with Pulmonary MDR-TB. The importance of anaerobic activity in candidate TB drugs was investigated. In 2009, the trial closed enrollment after 35 subjects due to excessive peripheral neuropathies in the metronidazole arm. The study is complete and overall analysis is published. (10) NIAID 08-I-N167: A Phase 2a, Randomized, 2 Arm, Open-label, Clinical Trial of the Efficacy of Linezolid Combined with Anti-TB Therapy in Subjects with Pulmonary XDR-TB. The study evaluated the efficacy, safety and tolerability of one of the drugs of last resort for XDR TB patients, linezolid (Zyvox, Pfizer). The primary analysis, published in 2012, was the first prospective randomized clinical trial of linezolid for drug resistant TB establishing linezolid as a key drug. (11) NIAID 09-I-N061: Pharmacokinetics of Standard First and Second Line Anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery. This multicenter study of the differential penetration of TB drugs into pulmonary TB lesions opened in 2010 and completed in 2014 with 15 subjects. The study further defined the relationship between pathology and drug penetration in the types of lesions commonly seen in TB patients and follow up work we conducted on lesion penetration in rabbits. Lesion penetration properties of TB drugs appear to affect treatment outcomes and should therefore be considered when developing novel treatment regimens. Activities on studies 7-11 are completed/closed.
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