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.

PROJECT NARRATIVE OVERALL COMPONENT Relevance statement. An estimated 42 million American suffer from chronic low back pain. Current treatments are only modestly effective and this is likely due to our inability to know which patients will respond to what treatments. As part of the BACPAC initiative our mechanistic research center aims to be a team member in realizing the vision of personalized medicine for individuals with cLBP.