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## Study Description

For the NIH BACPAC initiative, this study proposes a single Research Project that will take patients with chronic lower back pain (cLBP) and use a patient-centric, Sequential Multiple Assessment Randomized Trial (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. The study uses 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). The study team 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, 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, the study team 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 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.

**ELIGIBILITY CRITERIA:**

Ages Eligible for Study: 25 Years to 70 Years (Adult, Older Adult)

Sexes Eligible for Study: All

Accepts Healthy Volunteers: No

**Inclusion Criteria (all participants):**
                      - Definition of cLBP described in the NIH Task Force Report on Research Standards for Chronic Low Back Pain (for example (i.e.), low back pain present at least six months, and present more than half of those days.
                      - Individuals must have the eligible protocol pain interference score on PROMIS Pain Interference.
                      - Individuals must be willing to be randomized to receive any of the four proposed treatments.

**Inclusion Criteria for Deep Phenotyping (subset 160 participants):**
                      - Right hand dominant (such as the hand used when writing or throwing/catching a ball)
                      - Normal visual acuity or correctable (with corrective lenses- glasses or contacts) to at least 20/40 for reading instructions in the MRI and visual sensitivity testing
                      - No contraindications to MRI (i.e., metal implants)
                      - Willingness to refrain from taking any "as needed" medications, including pain medications such as Nonsteroidal anti-inflammatory drugs (i.e., Motrin, Advil, Aleve), acetaminophen, and opioids, for 8 hours before undergoing neuroimaging and 10.1 Quantitative Sensory Testing (QST)
                      - Willingness to refrain from alcohol and nicotine on the day of QST and neuroimaging (alcohol and nicotine consumption is allowed after testing is completed)
                      - Willingness to refrain from any unusual physical activity or exercise that would cause muscle and/or joint soreness for 48 hours prior to testing (routine exercise or activity that does not lead to soreness is acceptable)
                      - Able to lie still on back for 2 hours during MRI

 

**Exclusion Criteria (all participants):**
                      - History of discitis osteomyelitis (spine infection) or spine tumor
                      - History of ankylosing spondylitis, rheumatoid arthritis, polymyalgia rheumatica, or psoriatic arthritis, lupus
                      - History of cauda equina syndrome or spinal radiculopathy with functional motor deficit (strength <4/5 on manual motor testing)
                      - Diagnosis of any vertebral fracture in the last 6 months
                      - Osteoporosis requiring treatment other than vitamin D and calcium supplements
                      - Cancer (History of any bone-related cancer or cancer that metastasized to the bone, Currently in treatment for any cancer or plan to start cancer treatment in the next 12 months, History of any cancer treatment in the last 24 months)
                      - Life expectancy less than 2 years
                      - Unable to speak and write English
                      - Visual or hearing difficulties that would preclude participation
                      - Presence of any history that would preclude scanning in magnetic resonance imaging (MRI)
                      - Uncontrolled drug/alcohol addiction
                      - Individuals receiving disability or compensation within the past year, or involved in litigation
                      - Pregnancy or breastfeeding
                      - History of allergy to duloxetine
                      - Individuals on high doses of opioids (over 100 oral morphine equivalents (OME) per day)
                      - Contraindications to receiving duloxetine:                          - certain medications (per protocol)
                        - renal dysfunction (creatinine clearance <30 milliliters per minute (mL/min) or End-Stage Renal Failure)
                        - Hepatic dysfunction: Hepatic impairment defined as having a Child-Pugh score of A-C 
                      - Scheduled back surgery, back surgery within the last year, or more than one back surgery in the past.
                      - Expecting to receive an injection of surgical procedure within the next year for their cLBP
                      - Current/planned (in the next 2 years) enrollment in another study of a device or investigational drug that would interfere with this study, this may include participation in a blinded trial.
                      - Any other diseases or conditions that would make a patient unsuitable for study participation as determined by the site principal investigators. This would include but not be limited to severe psychiatric disorders, active suicidal ideations or history of suicide attempts, and an uncontrolled drug and/or alcohol addiction

**Exclusion Criteria for Deep Phenotyping (subset 160 participants):**
                      - Severe claustrophobia precluding MRI and evoked pain testing during scanning
                      - Diagnosed peripheral neuropathy
                      - Current, recent (within the last 6 months), or habitual use of artificial nails or nail enhancements. (Artificial nails can influence pressure pain sensitivity at the thumbnail)
                      - Body Mass Index greater than 45 or unable to comfortably fit in the bore of the MRI magnet

**Study Design:**

Allocation:       Randomized 

Intervention Model: Sequential Assignment

Masking: Single (Outcomes Assessor)

Primary Purpose: Treatment

**Study Location(s):**

University of Michigan, Ann Arbor, Michigan, United States, 48170

**Study Website:**

https://clinicaltrials.gov/ct2/show/NCT04870957?term=NCT04870957&draw=2&rank=1

December 2021

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