International Tuberculosis Clinical Research

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

(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. Data analyses have been slowed by the COVID-19 pandemic. (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 2022. One manuscript was published in press this year. Study enrollment was slowed and follow-up has been made more complicated by the COVID-19 pandemic. (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 2015 at the NIH Clinical Center and the Henan Chest Hospital, Zhengzhou, Henan Province, China. Enrollment completed with 168 participants in 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. Laboratory analysis was to be conducted in China and the US but permission to export laboratory samples from China was denied twice by the China Human Genetic Resource Administration Office. Because we applied for sample export and analysis in one application, the denial applies to both and we are now unable to proceed with sample analysis at Fudan University. We will continue to work with the NIAID China office representative based at the US Embassy Beijing to try to resolve this situation. (4) 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. (5) 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. (6) 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. (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 over the initial 8 weeks of treatment. (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 characterized MDR and XDR TB isolates and their contribution to human disease. 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 linezolid for XDR-TB patients. 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 from 2010-2014 completed 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 6-11 are completed/closed.