University of Michigan BACPAC Mechanistic Research Center

项目总结/摘要 总体组件 NIH BACPAC计划旨在“产生关于表型，内型， 机制、诊断、试验结果和治疗反应。. .慢性腰痛（CLBP） 我们认为我们在密歇根大学（UM）的团队非常适合领导一项机械研究， 中心（MRC）作为更广泛的BACPAC倡议的一部分，因为我们一直在沿着所有这些路线工作 二十多年了我们提出了一个单一的研究项目，将采取患者与cLBP和使用 一项以患者为中心的SMART设计研究，纵向跟踪这些人，因为他们尝试了几种不同的方法， 循证疗法，而机制研究覆盖，以得出关键的推论， 治疗将在什么样的患者内型中起作用。我们使用术语“干预反应表型”来 描述在任何精准医学倡议中，对参与者进行表型的需要， 做和不响应-以便稍后可以将不同的疾病内在表型与 那些优先对针对这些机制的治疗做出反应的人。UM的第一个具体目标 BACPAC MRC将在cLBP患者队列（n=500）中进行干预反应表型分析。我们 将使用一个成熟的cLBP患者队列进行一项长期的务实试验，这些患者将接受 已知对cLBP有效的干预序列。所有cLBP参与者将在前6周接受 一个基于网络的病人疼痛自我管理项目。第一个治疗期不是测试机制 假设，而是将减少或消除回归的平均值，以及安慰剂效应， 在随后的随机化治疗之前与工作人员互动。然后那些仍然有症状的参与者 将入组一项适应性、序贯多重评估随机试验（SMART）， 个人两个额外的治疗给予12周，从一个列表，包括：a）正念为基础的 认知疗法（MBCT）; B）物理疗法和锻炼; c）度洛沙汀，d）加巴喷丁和e）自我治疗。 进行穴位按摩。在研究期间的任何时间点，参与者（作为持续护理的一部分）还可以 接受硬膜外类固醇或小关节注射，或腰椎手术。虽然参与者不会 随机接受这些介入治疗，我们可以评估不同的预测因素， 响应能力。该提案的第二个具体目标是证明目前可用的临床- 衍生的测量可以预测对上述疗法的不同反应性（n=500）。第三特定 目的是确定新的实验措施（功能性神经成像，定量感觉测试，血浆 炎症，自主神经张力的测量），预测对每种药物的不同反应性。 治疗，以及推断治疗的作用机制（n=200）。第四个具体目标是 通过提供有关MRC参与者的数据，为更广泛的BACPAC计划做出贡献， 科学专业知识，研究方法和领导BACPAC。

PROJECT SUMMARY / ABSTRACT OVERALL COMPONENT The NIH BACPAC initiative is designed to “generate new knowledge regarding phenotypes, endotypes, mechanisms, diagnostics, trial outcomes, and therapeutic responsiveness . . . in chronic low back pain (cLBP). We feel that our group at the University of Michigan (UM) is ideally suited to lead a Mechanistic Research Center (MRC) as part of the broader BACPAC initiative, because we have been working along all of these lines for over twenty years. We propose a single Research Project that will take patients with cLBP and use a patient-centric, SMART design study to follow these individuals longitudinally as they try several different evidence-based therapies, while mechanistic studies are overlaid to draw crucial inferences about what treatments will work in what patient endotypes. We use the term Interventional Response Phenotyping to describe the need in any precision medicine initiative to phenotype participants regarding what therapies they do and do not respond to - so that one can later link mechanistically distinct disease endophenotypes with those who preferentially respond to therapies targeting those mechanisms. The first Specific Aim of the UM BACPAC MRC is to perform Interventional Response Phenotyping in a cohort of cLBP patients (n=500). We will perform a long-term pragmatic trial using a well-established cohort of cLBP patients, who will receive a sequence of interventions known to be effective in cLBP. All cLBP participants will for the first 6 weeks receive a web-based patient self-management program for pain. This first treatment period is not testing mechanistic hypotheses, but instead will reduce or eliminate regression to the mean, as well as the placebo effect of interacting with staff, prior to subsequent randomized treatments. Then participants who remain symptomatic will be enrolled in an adaptive, Sequential Multiple Assessment Randomized Trial (SMART) to randomize individuals to two additional treatments given for 12 weeks each, from a list including: a) mindfulness-based cognitive therapy (MBCT); b) physical therapy and exercise; c) duloxetine, d) gabapentin and e) self- administered acupressure. At any point during the study, participants (as part of ongoing care) may also undergo an epidural steroid or facet joint injection, or lumbar surgery. Although participants will not be randomized to receive these interventional therapies, we can assess for predictors of differential responsiveness. The second Specific Aim of this proposal is to demonstrate that currently available, clinically- derived measures, can predict differential responsiveness to the above therapies (n=500). The third Specific Aim is to identify new experimental measures (functional neuroimaging, quantitative sensory testing, plasma measures of inflammation, autonomic tone) that predict differential responsiveness to the each of the therapies, as well as to infer mechanisms of action of treatments (n=200). The fourth Specific Aim is to contribute to the broader BACPAC initiative by providing data on our MRC participants, as well as contributing scientific expertise, research methods, and leadership to BACPAC.