The BEST Trial: Biomarkers for Evaluating Spine Treatments

Study Overview
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Brief Summary
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The BEST Trial (Biomarkers for Evaluating Spine Treatments) is a NIAMS-sponsored clinical trial being conducted through the NIH HEAL Initiative's Back Pain Consortium (BACPAC) Research Program. The primary objective of this trial is to inform a precision medicine approach to the treatment of Chronic Low-Back Pain by estimating an algorithm for optimally assigning treatments based on an individual's phenotypic markers and response to treatment. Interventions being evaluated in this trial are: (1) enhanced self-care (ESC), (2) acceptance and commitment therapy (ACT), (3) evidence-based exercise and manual therapy (EBEM), and (4) duloxetine.

Detailed Description
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Each participant will complete an initial screening call and enrollment visit, followed by a 2-week run-in period, two consecutive 12-week treatment periods, and a 12-week post-treatment follow-up period. Upon completion of the run-in period, participant eligibility will be reassessed based on adherence to study protocol. Participants who no longer meet eligibility criteria will be considered screen failures and discontinued from the study. All participants will undergo phenotyping assessments at Visit 0, 1 and 2 corresponding to baseline, the end of the first 12-week intervention period, and the end of the second 12-week intervention period, respectively. A subset of participants will undergo additional phenotyping, consisting of a more comprehensive set of phenotyping assessments, at the same visits. Pain, Enjoyment of Life, and General Activity (PEG) and Patient Global Impressions Scale (PGIC) will be assessed at 6 weeks (midpoint of intervention period one), 12 weeks (Visit 1), 18 weeks (midpoint of intervention period two), 24 weeks (Visit 2), and 36 weeks post-baseline (12 weeks after intervention period two). Basic safety assessments will also be performed at these time points to assess participant tolerability to their current study intervention(s). Patients who are unable to tolerate their assigned study treatment will be educated on how to safely discontinue their current treatment plan but will otherwise remain in the study. The secondary objectives are to (a) estimate Dynamic Treatment Regimes (DTRs) that optimally balance multiple outcomes, taking into account participant preferences for outcomes including pain intensity, pain interference, physical function, opioid use, depression, anxiety, sleep duration and sleep disturbance, (b) estimate DTRs that incorporate additional phenotypic markers (i.e., deep phenotyping) collected on a sub-set of participants, and (c) assess whether effectiveness is sustained based on outcomes collected 24 weeks after randomization to the second treatment.

Official Title
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The BEST Trial: Biomarkers for Evaluating Spine Treatments

Conditions
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Chronic Low-back Pain

Intervention / Treatment
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* Behavioral: Enhanced Self-Care (ESC)
* Behavioral: Acceptance and Commitment Therapy (ACT)
* Behavioral: Evidence-Based Exercise and Manual Therapy (EBEM)
* Drug: Duloxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible, an individual must meet all of the following inclusion criteria: Ability to read and understand English Provision of signed and dated informed consent form(s) Willing and able to receive study-related messages and survey links via email Willing and able to receive study-related phone calls Age 18 years old or older Low-back pain for at least 3 months and occurring on at least half the days in the past 6 months Contraindicated to no more than one of the study interventions at the time of eligibility assessment(s) Eligible to receive at least three of the four study interventions and willing to receive any intervention for which they are eligible A PEG score 4 or higher prior to the Run-in period Willing and able to undergo required phenotyping Regular reliable access to an internet-enabled device such as a smart phone, tablet, or laptop computer Meet Run-in period engagement eligibility criteria: o Completion of two Run-in study information modules prior to period 1 randomization (Visit 0) Low-back pain more severe than pain in other parts of the body Available to complete the full study protocol (approximately 9 months) Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Pregnant at the time of Visit 0 (Baseline) Affirmative participant response to any of the following conditions: Progressive neurodegenerative disease History of discitis osteomyelitis (spine infection) or spine tumor History of ankylosing spondylitis, rheumatoid arthritis, polymyalgia rheumatica, psoriatic arthritis, or 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 pharmacologic treatment other than vitamin D, calcium supplements, or bisphosphonates. History of any bone-related cancer or cancer that metastasized to the bone Currently in treatment for any non-skin cancer or plan to start non-skin cancer treatment in the next 12 months History of any non-skin cancer treatment in the last 24 months Visual or hearing difficulties that would preclude participation Uncontrolled drug/alcohol addiction Individuals actively pursuing disability or workers compensation or involved in active personal injury-related litigation Currently participating in another interventional pain study Any condition that, in the opinion of the investigator, would preclude the patient from being able to safely participate in in the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential Multiple Assignment Randomized Trial (SMART)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Period 1: Enhanced Self-Care (ESC)<br>This arm includes participants who are randomized to ESC in Treatment Period 1. Depending on their response to Treatment 1 measured at 12 Weeks post-initial randomization, participants in this arm will stay on ESC or be randomized to augment ESC with an additional treatment during Treatment Period 2. | Behavioral: Enhanced Self-Care (ESC)<br>* The Enhanced Self-Care intervention will be comprised of educational modules on evidence-based cognitive-behavioral self-management skills for pain. These modules will be provided digitally for self-administration over a period of 12 weeks. There will be no therapist associated with the delivery of these educational materials; however, after the first four modules, email or text messages will be used to make personalized recommendations for accessing additional modules based upon identified problems from the baseline assessment. Additionally, the walking program module will utilize Fitbit step tracking to allow participants to monitor their walking progress.<br>|
| Active Comparator: Treatment Period 1: Acceptance and Commitment Therapy (ACT)<br>This arm includes participants who are randomized to ACT in Treatment Period 1. Depending on their response to Treatment 1 measured at 12 Weeks post-initial randomization, participants in this arm will stay on ACT, augment ACT with an additional treatment, or switch to a new treatment during Treatment Period 2. | Behavioral: Acceptance and Commitment Therapy (ACT)<br>* ACT is a form of cognitive behavioral therapy that is well established for the treatment of chronic pain. The goal of ACT is to build psychological flexibility thereby interrupting pain avoidance behavior patterns. Participants randomized to ACT will take part in 12 sessions over the course of 12 weeks. Sessions will be delivered as a combination of 4 remote face-to-face visits with a therapist and 8 therapist-supported online sessions (self-directed online modules supported by provider coaching). Online sessions will focus on helping participants accept pain, connect with negative thoughts and emotions, develop mindfulness and identify and commit to values and goals that are important to them. During face-to-face sessions with the therapist, participants will be encouraged to share their experience of skills practice and mastery, provide examples of skill use at home, and describe what barriers they encountered.<br>|
| Active Comparator: Treatment Period 1: Evidence-Based Exercise and Manual Therapy (EBEM)<br>This arm includes participants who are randomized to EBEM in Treatment Period 1. Depending on their response to Treatment 1 measured at 12 Weeks post-initial randomization, participants in this arm will stay on EBEM, augment EBEM with an additional treatment, or switch to a new treatment during Treatment Period 2. | Behavioral: Evidence-Based Exercise and Manual Therapy (EBEM)<br>* Licensed physical therapists (PTs) or Doctors of Chiropractic (DCs) will rely on evidence-based guidance to direct decision-making on the particular type of manual and exercise therapy that may be best suited to an individual study participant. Special attention will be paid to the clinician's choice of language in regard to the purpose and expected outcomes of manual therapy in order to avoid enhancing catastrophizing ideations or preference for passive interventions. A total of 10 sessions will be provided over an 8-week treatment period. Two sessions per week are provided in the first two weeks followed by weekly sessions over the next 6 weeks. Treatment sessions will last approximately 60 minutes each.<br>|
| Active Comparator: Treatment Period 1: Duloxetine<br>This arm includes participants who are randomized to Duloxetine in Treatment Period 1. Depending on their response to Treatment 1 measured at 12 Weeks post-initial randomization, participants in this arm will stay on Duloxetine, augment Duloxetine with an additional treatment, or switch to a new treatment during Treatment Period 2. | Drug: Duloxetine<br>* Duloxetine is a serotonin norepinephrine reuptake inhibitor (SNRI) that is FDA-approved for use in Chronic Low-Back Pain, and, as such, is included as a recommended therapy in nearly all current treatment guidelines for low back pain. Study participants will be treated with duloxetine for 12 weeks during the active treatment phase. At the time of randomization, the approved drug pharmacy at each study site will dispense between 185 and 192 duloxetine 30 mg capsules and provide to participants. This will ensure enough capsules to maintain up to a 60 mg dosage through the 12-week intervention phase and to taper the dose in the 13th week if needed.<br>* Other names: Cymbalta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient-Reported Pain Intensity and Interference Score | Patient-reported pain intensity and interference is measured by the Pain, Enjoyment of Life, and General Activity (PEG) scale. The PEG is a series of 3 questions. Results range from -10 to 10, with higher scores indicating increased pain intensity and interference at 24 Weeks compared to Baseline. | Baseline, 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pain Interference | Pain interference is measured by the 4-item PROMIS (Patient-Reported Outcomes Measurement Information System) Pain Interference scale (PROMIS-PI, 4a). The PROMIS-PI, 4a is a series of 4 questions. Results range from -34 to 34 (t-scores range from 41.6 to 75.6), with higher scores indicating increased pain interference at 24 Weeks compared to Baseline. | Baseline, 24 Weeks | 
| Incidence of Any Opioid Use | Incidence of opioid use is measured by a single question, Are you currently taking any opioid pain medication on a daily basis? Participants respond with Yes, No, or Not Sure. | Baseline, 24 Weeks | 
| Change in Physical Function | Physical function is measured by the PROMIS-PF Short Form 6b. The PROMIS-PF Short Form 6b is a series of 6 questions. Results range from -37.1 to 37.1 (t-scores range from 21.6 to 58.7), with higher scores indicating increased physical functioning at 24 Weeks compared to Baseline. | Baseline, 24 Weeks | 
| Change in Depression Score | Depression score is measured by the PROMIS 4-item depression scale from the PROMIS 29 profile. The PROMIS 4-item depression scale from the PROMIS 29 profile is a series of 4 questions. Results range from -38.4 to 38.4 (t-scores range from 41.0 to 79.4), with higher scores indicating increased depression at 24 Weeks compared to Baseline. | Baseline, 24 Weeks | 
| Change in Anxiety Score | Anxiety score is measured by the PROMIS Emotional Distress-Anxiety scale (PROMIS-EDA 4a). The PROMIS-EDA 4a is a series of 4 questions. Results range from -41.3 to 41.3 (t-scores range from 40.3 to 81.6), with higher scores indicating increased anxiety at 24 Weeks compared to Baseline. | Baseline, 24 Weeks | 
| Change in Sleep Disturbance | Sleep disturbance is measured by the PROMIS short form 6a. The PROMIS short form 6a is a series of 6 questions. Results range from -44.4 to 44.4 (t-scores range from 31.7 to 76.1), with higher scores indicating increased sleep disturbance at 24 Weeks compared to Baseline. | Baseline, 24 Weeks | 
| Change in Sleep Duration | Sleep duration is measured by the BACPAC sleep duration question, During the past month, how many hours and minutes of actual sleep did you get at night? (This may be different than the number of hours and minutes you spent in bed). Participants respond with a number of hours and minutes. Results range from -24 to 24 hours, with higher number of hours indicating increased sleep duration at 24 Weeks compared to Baseline. | Baseline, 24 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain, Back Pain