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

描述(由申请人提供)：目前推荐的活动性结核病(TB)6个月治疗方案已有40多年的历史，存在药物毒性和患者高不依从率的问题，这些因素加在一起导致了耐药菌株的出现。几十年来，结核病药物开发管道中第一次充满了几种很有希望的新药物，这些药物很快就会准备好进行第二阶段和第三阶段的试验。然而，在临床试验中测试这些药物的有效性是一个巨大的挑战，因为传统的基于痰、基于生长的微生物学试验终点具有显著的技术和后勤弱点。对于这项名为结核病替代标记物用于评估治疗反应的建议(结核病SMART研究)，我们的目标是开发一种基于血液的、定量的、宿主和病原体特异的生物标记物分析，使用经过验证的、高灵敏度、多路复用的电化学发光(ECL)平台，该平台可以与临床数据相结合，取代2个月痰培养，目前为二分二期试验终点。在一项试验的早期应用一种非痰、非生长的生物标志物分析，可以取代微生物中间终点，同时保留或提高它们预测结果的能力，可能会改变结核病药物开发和全球结核病控制的速度和范围。此外，它还可用于监测少菌病的治疗情况，如儿童、肺外结核病和艾滋病毒/结核病。为了实现这一目标，我们组建了一支调查团队，成员包括具有结核病药物开发专业知识的学者、在无偏见和定向方法发现生物标记物方面具有专业知识的行业合作伙伴、外显体科学家以及在预测和替代标记识别的生物信息学方法方面具有专业知识的统计学家。我们将在四项研究中利用与临床、放射学、微生物学和PK/PD数据相关联的样本，这些样本来自具有良好特征的培养确认的肺结核患者：三项由疾控中心资助的结核病试验联盟随机临床试验，以及一项由FDA资助的与第三阶段结核病试验相关联的资料库。我们将使用可用的临床试验数据和样本集来：1)识别基于血液的宿主 2)开发和鉴定用于预测已识别的杀菌和杀菌活性微生物学措施的多参数分类器，使用已确定的宿主和病原体生物标记物，以及3)开发、鉴定和开展建立在多重ECL平台上的入围生物标志物小组的验证研究。在完成建议的全面鉴定和验证研究后，我们将准备将多路ECL生物标记物小组分析作为“合格试剂盒”发布，以便在预期的第二阶段和第三阶段试验中使用和评估。

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.