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，并且存在药物毒性和患者不依从率高的问题，这些问题共同导致了耐药菌株的出现。几十年来，结核病药物开发管道首次充满了几种有前途的新药，这些新药将很快准备好进行2期和3期试验。然而，在临床试验中测试这些药物的疗效是一个重大挑战，因为传统的基于肿瘤、基于生长的微生物试验终点具有明显的技术和后勤弱点。对于这一名为TB Surrogate Markers for Assessing Response to Treatment（TB SMART Study）的提案，我们的目标是开发一种基于血液的、定量的、宿主和病原体特异性生物标志物检测，该检测使用经过验证的、高灵敏度的、多路复用的电化学发光（ECL）平台，结合临床数据，可以取代2个月的痰培养，这是目前的二分法II期试验终点。在试验过程早期应用一种非痰、非生长的生物标志物检测方法，可以取代微生物中间终点，同时保留或提高其预测结果的能力，可以改变结核病药物开发和全球结核病控制的步伐和范围。此外，它还可用于监测儿童常见的少杆菌病、肺外结核和HIV/TB的治疗。为了实现这一目标，我们组建了一个由具有结核病药物开发专业知识的学者组成的调查团队;在生物标志物发现的无偏见和定向方法方面具有专业知识的行业合作伙伴;外泌体科学家;以及在生物信息学方法预测和替代标志物鉴定方面具有专业知识的统计学家。我们将利用与临床、影像学、微生物学和PK/PD数据相关的标本，这些标本来自四项研究中入选的经培养确诊的肺结核患者，这些研究包括三项CDC资助的TB试验联盟随机临床试验和一项FDA资助的与III期TB试验相关的储存库。我们将使用现有的临床试验数据和样本集：1）确定血液，宿主 和TB特异性生物标志物的治疗反应2）开发和鉴定多参数分类器，用于使用鉴定的宿主和病原体生物标志物预测杀菌和消毒活性的公认微生物学测量，和3）开发、鉴定和进行基于多路ECL平台构建的最终生物标志物组的验证研究。在完成拟定的全面确认和验证研究后，我们将准备发布多重ECL生物标志物检测试剂盒，作为“合格试剂盒”，用于前瞻性II期和III期试验并进行评价。

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.