TB Surrogate Markers for Assessing Reponse to Treatment (TB SMART Study)

用于评估治疗反应的结核病替代标志物（结核病 SMART 研究）

• 批准号: 8793680
• 负责人: PAYAM NAHID
• 金额: $ 115.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-12 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793680
• 关键词: Algorithms; Binding; Bioinformatics; Biological Assay; Biological Markers; Blood; Cataloging; Catalogs; Cells; Centers for Disease Control and Prevention (U.S.); Child; Classification; Clinical; Clinical Data; Clinical Trials; Coughing; Culture Media; Data; Data Set; Databases; Detection; Development; Diagnostic; Disease; Dose; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Drug toxicity; Enrollment; Extreme drug resistant tuberculosis; Failure; Funding; Goals; Gold; Growth; HIV; Human; Immunoassay; Intention; Lead; Link; Liquid substance; Measurement; Measures; Membrane; Monitor; Moxifloxacin; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; New Agents; Outcome; Participant; Patient Noncompliance; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Phase II/III Trial; Probability; Proteomics; Pulmonary Tuberculosis; Qualifying; Randomized; Randomized Clinical Trials; Reagent; Recording of previous events; Recovery; Regimen; Relapse; Sample Size; Sampling; Scientist; Serum; Signal Transduction; Specimen; Speed; Sputum; Surrogate Markers; Testing; Time; Treatment Failure; Treatment Protocols; Tuberculosis; Validation; Vesicle; arm; bactericide; base; cost; design; drug development; drug efficacy; efficacy testing; follow-up; improved; industry partner; liquid chromatography mass spectrometry; macromolecule; next generation; novel; pathogen; programs; prospective; prototype; public health relevance; repository; resistant strain; response; rifapentine; success; tool; treatment response; treatment trial; tuberculosis drugs; tuberculosis treatment; validation studies

DESCRIPTION (provided by applicant): The current recommended 6-month treatment regimen for active tuberculosis (TB) is more than 40 years old and suffers from issues with drug toxicity and high rates of patient non-adherence, which combined have contributed to the emergence of drug resistant strains. For the first time in decades, the TB drug development pipeline is filled with several promising new agents that will soon be ready for phase 2 and phase 3 trials. However, testing the efficacy of these agents in clinical trials is a significant challenge because the conventional sputum-based, growth-based, microbiologic trial endpoints have notable technical and logistical weaknesses. For this proposal, entitled TB Surrogate Markers for Assessing Response to Treatment (TB SMART Study), our objective is to develop a blood-based, quantitative, host and pathogen-specific biomarker assay using a proven, high sensitivity, multiplexed electrochemiluminescence (ECL) platform that can, in combination with clinical data, supplant 2-month sputum culture, the current dichotomous Phase 2 trial endpoint. A non-sputum, non-growth based biomarker assay applied early in the course of a trial that could replace microbiologic intermediate endpoints, while retaining or improving upon their ability to predict outcomes, could transform the pace and scope of TB drug development, and of global TB control. It may additionally have utility for monitoring treatment of paucibacillary disease as is often seen in children, extra-pulmonary TB, and HIV/TB. To achieve this goal, we have assembled an investigative team of academics with expertise in TB drug development; industry partners with expertise in both unbiased and directed approaches to biomarker discovery; exosome scientists; and statisticians with expertise in bioinformatic approaches to prediction and surrogate marker identification. We will take advantage of specimens linked to clinical, radiographic, microbiologic, and PK/PD data from well-characterized patients with culture-confirmed pulmonary TB enrolled in four studies: three CDC-funded, TB Trials Consortium randomized, clinical trials, and one FDA-funded repository linked to Phase 3 TB trials. We will use available clinical trial data and sample sets to: 1) Identify blood-based, host and TB-specific biomarkers of treatment response using unbiased, targeted and exosome-enriched approaches 2) develop and qualify multi-parameter classifiers for predicting recognized microbiologic measures of bactericidal and sterilizing activity, using the host and pathogen biomarkers identified, and 3) develop, qualify and conduct validation studies of a finalist biomarker panel built on a multiplexed ECL platform. Upon completion of comprehensive qualification and validation studies proposed, we will be ready to release the multiplexed, ECL biomarker panel assay as "Qualified Kits" to be used and evaluated in prospective Phase 2 and 3 trials.

描述（由申请人提供）：当前的活性结核病（TB）的建议的6个月治疗方案已有40多年的历史，并且患有药物毒性和高患者不遵守率的问题，这些问题综合促成了抗药性菌株的出现。数十年来，结核病药物开发管道首次充满了几种有前途的新代理商，很快就会为第二阶段和第3阶段试验做好准备。但是，测试这些药物在临床试验中的疗效是一个重大挑战，因为常规的基于痰液的基于生长的微生物试验终点具有显着的技术和后勤弱点。 For this proposal, entitled TB Surrogate Markers for Assessing Response to Treatment (TB SMART Study), our objective is to develop a blood-based, quantitative, host and pathogen-specific biomarker assay using a proven, high sensitivity, multiplexed electrochemiluminescence (ECL) platform that can, in combination with clinical data, supplant 2-month sputum culture, the current dichotomous Phase 2 trial endpoint.在试验的早期应用，可以替代微生物中间终点，同时保留或提高预测结果的能力，可以改变结核病药物开发的速度和范围，并通过保留或提高其预测的能力，并改善了微生物中间的终点，并且可以改变TB药物开发的速度和范围。在儿童，肺外结核病和HIV/TB中通常可以看出，它可能还具有监测paucibibacillary疾病的治疗方法。为了实现这一目标，我们组建了一个具有结核病药物开发专业知识的学者的调查团队；行业合作伙伴具有无偏和定向生物标志物发现方法的专业知识；外泌体科学家；以及具有生物信息学方法的专业知识的统计学家，用于预测和替代标记识别。我们将利用与临床，影像学，微生物学和PK/PD相关的标本，来自培养培养确认的肺结核病患者的临床，放射线，微生物和PK/PD数据，其中包括三项研究：三项CDC资助，TB资助的TB试验随机化，随机化，临床试验，一项FDA资助的Repository Repository链接到第3型TB阶段3 TB试验。我们将使用可用的临床试验数据和样本集：1）识别基于血液的宿主 使用公正，有针对性和外泌体的方法2）使用宿主和病原体生物标志物进行验证和进行生物构建的生物构造的替换式构建的替换式研究，并使用型构建生物标准的替换式构建型号的Paner a plodomarker Arkarker Arkarker Arkarker Arkarker Arkarker Arkarker Arkarker Arkarker Arkar aarker sepriper paner，则使用公正，有针对性和外泌体的方法进行治疗反应的生物标志物2）。提出的全面资格和验证研究完成后，我们将准备将多重的，ECL生物标志物小组分析释放为“合格的套件”，将在前瞻性第2阶段和第3阶段试验中使用和评估。