The BEST Trial: Biomarkers for Evaluating Spine Treatments (BEST)

The BEST Trial (Biomarkers for Evaluating Spine Treatments) is a National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)-sponsored clinical trial being conducted through the NIH Helping to End Addiction Long-term (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 the optimal treatment or combination of treatments based on patient features and response to the initial 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.

Study Overview

• Status: Completed
• Conditions: Chronic Low-back Pain
• Intervention / Treatment: Behavioral: Enhanced Self-Care (ESC); Behavioral: Acceptance and Commitment Therapy (ACT); Behavioral: Evidence-Based Exercise and Manual Therapy (EBEM); Drug: Duloxetine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1014
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Redwood City, California, United States, 94063
      • Stanford University
    • San Diego, California, United States, 92037
      • University of California, San Diego
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Health System
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital/Brigham Women's Hospital, Harvard Medical School
  • Michigan
    • Ann Arbor, Michigan, United States, 48189
      • University of Michigan
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospital Pain Management Clinic
    • Winston-Salem, North Carolina, United States, 27517
      • Atrium Health Wake Forest Baptist
  • Ohio
    • Columbus, Ohio, United States, 43203
      • The Ohio State University Wexner Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15219
      • University of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment Period 1: Enhanced Self-Care (ESC); 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); 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.
Active Comparator: Treatment Period 1: Acceptance and Commitment Therapy (ACT); 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); 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.
Active Comparator: Treatment Period 1: Evidence-Based Exercise and Manual Therapy (EBEM); 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); 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.
Active Comparator: Treatment Period 1: Duloxetine; 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; 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.; Other Names: Cymbalta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Patient-Reported Outcomes Measurement Information System-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, and measures self-reported consequences of pain on relevant aspects of one's life. Results range from -34 to 34 (t-scores range from 41.6 to 75.6). For each t-score, 50 indicates the population mean with a standard deviation of 10. Lower scores indicate lower pain interference and a better outcome. PROMIS measures are not used for clinical decision making but to describe participant symptoms.	Baseline, 24 Weeks
Number of Participants Self-Reporting Taking Opioids	The number of participants self-reporting taking opioids ("Yes" response) is measured by a single question, "Are you currently taking any opioid pain medication on a daily basis?".	24 Weeks
Patient-Reported Outcomes Measurement Information System- Physical Function	Physical function is measured by the Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF) Short Form 6b. The PROMIS-PF Short Form 6b is a series of 6 questions. T-scores range from 21.6 to 58.7 and for each t-score, 50 indicates the population mean with a standard deviation of 10. Results range from -37.1 to 37.1, with higher physical function scores indicating a better outcome and increased physical functioning at 24 Weeks compared to Baseline. A higher physical function is the better outcome. PROMIS measures are not used for clinical decision making but to describe participant symptoms.	Baseline, 24 Weeks
Patient-Reported Outcomes Measurement Information System (PROMIS) - Depression Score	Depression score is measured by the Patient-Reported Outcomes Measurement Information System (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. T-scores range from 41.0 to 79.4), and for each t-score, 50 indicates the population mean with a standard deviation of 10. Results range from -38.4 to 38.4, with higher scores indicating increased depression at 24 Weeks compared to Baseline. A lower depression score is the better outcome. PROMIS measures are not used for clinical decision making but to describe participant symptoms.	Baseline, 24 Weeks
Patient-Reported Outcomes Measurement Information System-Emotional Distress-Anxiety	Anxiety score is measured by the Patient-Reported Outcomes Measurement Information System-Emotional Distress-Anxiety (PROMIS-EDA) scale 4a. The PROMIS-EDA 4a is a series of 4 questions. T-scores range from 40.3 to 81.6, and for each t-score, 50 indicates the population mean with a standard deviation of 10. Results range from -41.3 to 41.3, with higher scores indicating increased anxiety at 24 Weeks compared to Baseline. A lower anxiety score is the better outcome. PROMIS measures are not used for clinical decision making but to describe participant symptoms.	Baseline, 24 Weeks
Patient-Reported Outcomes Measurement Information System - Sleep Disturbance	Sleep disturbance is measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) short form 6a. The PROMIS short form 6a is a series of 6 questions. T-scores range from 31.7 to 76.1 and for each t-score, 50 indicates the population mean with a standard deviation of 10). Results range from -44.4 to 44.4, with higher scores indicating increased sleep disturbance at 24 Weeks compared to Baseline. A lower sleep disturbance score is the better outcome. PPROMIS measures are not used for clinical decision making but to describe participant symptoms.	Baseline, 24 Weeks
Sleep Duration	Sleep duration is measured by the Back Pain Consortium (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

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: Daniel Clauw, MD, University of Michigan; Principal Investigator: Kevin Anstrom, PhD, UNC Chapel Hill; Principal Investigator: Matthew Mauck, PhD, UNC Chapel Hill; Principal Investigator: Gwendolyn Sowa, PhD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2022
• Primary Completion (Actual): July 30, 2024
• Study Completion (Actual): October 22, 2024

Study Registration Dates

• First Submitted: May 24, 2022
• First Submitted That Met QC Criteria: May 24, 2022
• First Posted (Actual): May 27, 2022

Study Record Updates

• Last Update Posted (Actual): July 23, 2025
• Last Update Submitted That Met QC Criteria: July 2, 2025
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Pain; Back Pain
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Back Pain; Low Back Pain; Serotonin and Noradrenaline Reuptake Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Sensory System Agents; Analgesics; Neurotransmitter Agents; Membrane Transport Modulators; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Dopamine Agents; Antidepressive Agents; Duloxetine Hydrochloride
• Other Study ID Numbers: 21-1972; 1U24AR076730 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All relevant study data will be shared through NIH portals as required.
• IPD Sharing Time Frame: Data will be made publicly available on the NIH HEAL Platform or other NIH repositories after acceptance of publication for the primary results per NIH HEAL Data Sharing Policy and will remain available for a minimum of 10 years.

IPD Sharing Access Criteria

BACPAC Data Access and Publications Policy:

https://sites.cscc.unc.edu/cscc/sites/default/files/bacpac/qxq/BACPAC_Data_Access_and_Publications_Policy.pdf

Data from this study may be requested by other researchers by using the HEAL Data Platform: https://heal.nih.gov/data/heal-data-ecosystem

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No