International Tuberculosis Clinical Research

国际结核病临床研究

• 批准号: 10927836
• 负责人: Clifton Barry
• 金额: $ 103.41万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927836
• 关键词: Aminoglycosides; Antitubercular Agents; Applied Research; Area; Award; Biological Markers; COVID-19 complications; COVID-19 pandemic; Cause of Death; Characteristics; China; Chinese; Classification; Clinical; Clinical Research; Clinical Trials; Collaborations; Conduct Clinical Trials; Cross-Sectional Studies; Data; Data Analyses; Developing Countries; Diagnosis; Diagnostic tests; Diagnostics Research; Disease; Drug Combinations; Drug resistance; Drug resistant Mycobacteria Tuberculosis; Enrollment; European; Extreme drug resistant tuberculosis; Failure; Fluoroquinolones; Foundations; Funding; Future; Goals; HIV; Immunologic Markers; Infectious Agent; International; Intervention; Isoniazid resistance; Journals; Lesion; Lung; Manuscripts; Measurement; Medical; Medicine; Meropenem; Methodology; Methods; Microbiology; Molecular; Monobactams; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Natural Sciences; New England; PET/CT scan; Participant; Patients; Pattern; Pharmaceutical Preparations; Phase; Protocols documentation; Province; Public Health; Publishing; Radiology Specialty; Regimen; Relapse; Reporting; Research; Research Personnel; Residual state; Resource-limited setting; Resources; Risk; Sampling; Sampling Studies; Science; South Africa; South African; South Carolina; South Korea; Sputum; Technology; Testing; Thoracic Radiography; Translational Research; Treatment Protocols; Tuberculosis; United States National Institutes of Health; Universities; arm; bactericide; clinical candidate; clinical development; clinical diagnostics; cytokine; disease diagnosis; disorder risk; drug candidate; drug testing; drug-sensitive; effective therapy; follow-up; improved; medication compliance; novel; novel diagnostics; novel therapeutics; prospective; radiological imaging; rate of change; secondary analysis; standard care; success; treatment duration; treatment response; treatment strategy; tuberculosis chemotherapy; tuberculosis drugs; tuberculosis treatment; week trial

(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.

(1)NIAID 15-I-N070：用于加强结核病灭菌药物活性的早期杀菌活性(EBA)测量的放射和免疫学生物标记物(NexGen EBA)。这项研究假设，与杀菌活性较低的药物方案相比，与杀菌活性较高的药物方案相比，在EBA期间，某些皮损中具有较高杀菌活性的药物方案显示出不同的细胞因子模式和可量化的PET/CT变化。主要目的是在一项标准的EBA研究的背景下，描述各种抗结核药物对未接受治疗的肺部药物敏感型结核病患者的放射学和免疫学标志物的影响。这项研究是与盖茨基金会(BMGF)合作进行的，于2015-2017年在南非进行。对微生物学、PET/CT和生物标志物数据的初步分析已经完成，并出版了一份手稿。二次分析正在进行中。正在通过EDCTP资助的点击结核病联盟收集关于新药和组合的PET/CT数据。 (2)NIAID 16-I-N133：使用生物标志物预测结核病治疗持续时间。这项研究假设，结合基线的放射学特征、一个月时这些特征的变化率以及治疗结束时残留细菌负荷的标志物，可以确定通过4个月的标准治疗治愈的结核病患者。主要目标是证明在放射学和细菌负荷标记物分类为疾病失败和复发风险较低的参与者中，在第4个月早期停止的标准治疗的18个月治疗成功率不低于在第6个月停止的标准治疗。这是一项由BMGF、欧洲和发展中国家临床试验伙伴关系、中国国家自然科学基金、中国科技部和美国国立卫生研究院共同资助的合作项目。研究招生始于2017年，在南非西开普省和河南省，中国将约310名参与者招募到两个风险较低的分支机构。这项研究预计将于2023财年结束。去年出版了一份手稿。研究招生速度放缓，后续研究因新冠肺炎疫情而变得更加复杂。 (3)抗菌联盟：这是一个由葛兰素史克领导的联盟，成员包括特罗姆索大学、博斯特尔研究中心、开普敦大学、开普敦应用科学任务，以开发和推进新型抗结核病临床候选药物，包括一种新型葛兰素史克化合物美罗培南和其他对抗耐多药结核病的B-内酰胺类抗生素。在为期两周的NexGen EBA研究中，将探索单一药物和药物组合，以及将在未来试验中评估的生物标记物指导的治疗持续时间。这项研究正在TASH进行。这项研究的临床阶段已经结束，数据现在正在分析中。这项研究主要由EDCTP资助。新冠肺炎疫情拖慢了数据分析的速度。 (4)杀死结核病的新临床候选者(Click-TB)联盟：这是一个由葛兰素史克领导的联盟，包括开普敦大学博斯特尔研究中心、开普敦应用科学任务。其目的是确定一种可以进入2b期或3期临床试验的结核病通用治疗方案。三种新化合物和最近批准的药物将包括在内。NexGen EBA研究正在对2种药物组合进行为期两周的研究，随后对3种或4种药物组合进行为期4周的试验。最好的3或4种药物组合将为未来的2b期或3期临床试验做好准备。临床试验目前正在进行中，由TASK进行。这项研究主要由EDCTP资助。试验和数据分析的进行因新冠肺炎疫情而放缓。 (5)DMID协议号13-0029：奖项#N01AI90500C：一种用于快速检测痰中耐药结核分枝杆菌的新型XPERT试剂盒的可行性和准确性。这项前瞻性的横断面研究是与南卡罗来纳医科大学的临床诊断研究联盟(PI：Susan Dorman，南卡罗来纳医科大学)一起在中国和韩国进行的，现已完成。研究中的Xpert XDR试剂盒准确地检测到与异烟肼、氟喹诺酮和氨基糖苷类药物耐药相关的结核分枝杆菌突变；初步结果发表在《新英格兰医学杂志》上。这项研究的样品将用于开发更新的XPERT墨盒。

项目成果

Neurotuberculosis: Control of Steroid-Refractory Paradoxical Inflammatory Reaction With Ruxolitinib.

神经结核：用鲁索替尼控制类固醇难治性矛盾炎症反应。

• DOI: 10.1093/ofid/ofz422
• 发表时间: 2019
• 期刊: Open forum infectious diseases
• 影响因子: 4.2
• 作者: Xie,YingdaL;Ita-Nagy,Fanny;Chen,RayY;Manion,MauraM;Sereti,Irini;Pei,Luxin;Holland,StevenM
• 通讯作者: Holland,StevenM

Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment.

患者体内结核分枝杆菌的微进化与治疗的异质反应相关。

• DOI: 10.1038/srep17507
• 发表时间: 2015-12-01
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Liu Q;Via LE;Luo T;Liang L;Liu X;Wu S;Shen Q;Wei W;Ruan X;Yuan X;Zhang G;Barry CE 3rd;Gao Q
• 通讯作者: Gao Q

A semi-automatic technique to quantify complex tuberculous lung lesions on 18F-fluorodeoxyglucose positron emission tomography/computerised tomography images.

一种半自动技术，用于在 18F-氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描图像上量化复杂的结核性肺部病变。

• DOI: 10.1186/s13550-018-0411-7
• 发表时间: 2018
• 期刊: EJNMMI research
• 影响因子: 3.2
• 作者: Malherbe,StephanusT;Dupont,Patrick;Kant,Ilse;Ahlers,Petri;Kriel,Magdalena;Loxton,AndréG;Chen,RayY;Via,LauraE;Thienemann,Friedrich;Wilkinson,RobertJ;Barry3rd,CliftonE;Griffith-Richards,Stephanie;Ellman,Annare;Ronacher,Kath
• 通讯作者: Ronacher,Kath

The Peripheral Blood Transcriptome Is Correlated With PET Measures of Lung Inflammation During Successful Tuberculosis Treatment.

• DOI: 10.3389/fimmu.2020.596173
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Odia T;Malherbe ST;Meier S;Maasdorp E;Kleynhans L;du Plessis N;Loxton AG;Zak DE;Thompson E;Duffy FJ;Kuivaniemi H;Ronacher K;Winter J;Walzl G;Tromp G;Catalysis TB-Biomarker Consortium
• 通讯作者: Catalysis TB-Biomarker Consortium

Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in monkeys.

• DOI: 10.1016/j.cell.2022.11.006
• 发表时间: 2022-12-08
• 期刊: CELL
• 影响因子: 64.5
• 作者: Le Nouen, Cyril;Nelson, Christine E.;Liu, Xueqiao;Park, Hong-Su;Matsuoka, Yumiko;Luongo, Cindy;Santos, Celia;Yang, Lijuan;Herbert, Richard;Castens, Ashley;Moore, Ian N.;Wilder-Kofie, Temeri;Moore, Rashida;Walker, April;Zhang, Peng;Lusso, Paolo;Johnson, Reed F.;Garza, Nicole L.;Via, Laura E.;Munir, Shirin;Barber, Daniel L.;Buchholz, Ursula J.
• 通讯作者: Buchholz, Ursula J.