The BEST Trial: Biomarkers for Evaluating Spine Treatments

NCT05396014 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: 21-19721U24AR076730
• Study Type: interventional
• Target: 1,014
• Locations: 1 country
• Sites: 12

Brief Summary

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.

Conditions

Chronic Low-back Pain

Keywords

Pain; Back Pain

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Patient-Reported Outcomes Measurement Information System-Pain Interference

  Baseline, 24 Weeks

• Number of Participants Self-Reporting Taking Opioids

  24 Weeks

• Patient-Reported Outcomes Measurement Information System- Physical Function

  Baseline, 24 Weeks

• Patient-Reported Outcomes Measurement Information System (PROMIS) - Depression Score

  Baseline, 24 Weeks

• Patient-Reported Outcomes Measurement Information System-Emotional Distress-Anxiety

  Baseline, 24 Weeks

Study Arms (4)

Treatment Period 1: Enhanced Self-Care (ESC)

ACTIVE COMPARATOR

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)

Treatment Period 1: Acceptance and Commitment Therapy (ACT)

ACTIVE COMPARATOR

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)

Treatment Period 1: Evidence-Based Exercise and Manual Therapy (EBEM)

ACTIVE COMPARATOR

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)

Treatment Period 1: Duloxetine

ACTIVE COMPARATOR

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

Interventions

Enhanced Self-Care (ESC) BEHAVIORAL

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.

Treatment Period 1: Enhanced Self-Care (ESC)

Acceptance and Commitment Therapy (ACT) BEHAVIORAL

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.

Treatment Period 1: Acceptance and Commitment Therapy (ACT)

Evidence-Based Exercise and Manual Therapy (EBEM) BEHAVIORAL

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.

Treatment Period 1: Evidence-Based Exercise and Manual Therapy (EBEM)

Duloxetine DRUG

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.

Also known as: Cymbalta

Treatment Period 1: Duloxetine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): collaborator

Study Sites (12)

Stanford University

Redwood City, California, 94063, United States

Location

University of California, San Diego

San Diego, California, 92037, United States

Location

University of California, San Francisco

San Francisco, California, 94158, United States

Location

University of Kansas Health System

Kansas City, Kansas, 66160, United States

Location

Massachusetts General Hospital/Brigham Women's Hospital, Harvard Medical School

Boston, Massachusetts, 02114, United States

Location

University of Michigan

Ann Arbor, Michigan, 48189, United States

Location

University of North Carolina Hospital Pain Management Clinic

Chapel Hill, North Carolina, 27599, United States

Location

Atrium Health Wake Forest Baptist

Winston-Salem, North Carolina, 27517, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43203, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15219, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Washington

Seattle, Washington, 98104, United States

Location

Related Publications (3)

• Rowland B, Barth KS, Bell KM, Brooks AK, Chadwick AL, Cleven A, Hurley RW, Mackey S, Patel KV, Piva SR, Schneider MJ, Al-Kadhi F, Asante-Nketiah B, Bagaason S, Batorsky A, Borckardt JJ, Bowden AE, Carey TS, Castellanos J, Chen L, Chidgey B, Dalton D, Dufour JS, Eberting JL, Eller SM, Fields AJ, Fritz JM, Fu A, Ghulamhussain I, Goolsby RW, Greco CM, Grim S, Gunn CA, Hanes L, Harris RE, Harte SE, Hassett AL, Helton K, Hoffmeyer A, Ivanova A, Jones Berkeley S, Kaplan C, Kidwell KM, Knapik GG, Kosorok MR, Kurillo G, Li D, Lobo R, Long J, Lotz JC, Mageswaran P, Majumdar S, Mao J, Marras WS, McCracken LM, McCumber M, McLean SA, McMillan M, Mehling W, Mendoza R, Mitchell UH, Napadow V, O'Neill C, Pearson S, Peltier S, Rundell SD, Ryser S, Schrepf A, Schulze E, Sperger J, Vo N, Wallace MS, Wampler AM, Wasan AD, Weaver TE, Weber KA 2nd, Wilcox L, Williams DA, Wilson L, Woo JE, Zeidan F, Zhao B, Zhou B, Anstrom KJ, Clauw DJ, Sowa GA, Mauck MC. Baseline characteristics of participants in the Biomarkers for Evaluating Spine Treatments clinical trial: a sequential multiple assignment randomized trial for chronic low back paindagger. Pain Med. 2025 Nov 1;26(11):758-772. doi: 10.1093/pm/pnaf073.

  PMID: 40794568 DERIVED

• Jones Berkeley S, Wedin S, Patidar SM, Margolies SO, Goetzinger AM, Mauck MC, Wasan AD, McCracken LM. Design and implementation of online acceptance and commitment therapy with enhanced therapist support for chronic low back pain (ACT for PAIN). Pain Med. 2025 Aug 1;26(8):451-458. doi: 10.1093/pm/pnaf026.

  PMID: 40249098 DERIVED

• Mauck MC, Barth KS, Bell KM, Brooks AK, Chadwick AL, Gunn CA, Hurley RW, Ivanova A, Piva SR, Schneider MJ, Bailey JF, Bagaason S, Batorsky A, Borckardt JJ, Bowden AE, Carey TS, Castellanos J, Chen L, Chidgey B, Dalton D, Dufour JS, Fields AJ, Fritz JM, Goolsby RW, Greco CM, Harris RE, Harte S, Hassett AL, Hoffmeyer A, Jones Berkeley S, Kaplan C, Kidwell KM, Knapik GG, Kosorok MR, Kurillo G, Lobo R, Lotz JC, Mackey S, Mageswaran P, Majumdar S, Mao J, Marras WS, McCumber M, McLean SA, Mehling W, Mitchell UH, Napadow VJ, O'Neill C, Patel KV, Peltier S, Psioda M, Rowland B, Rundell SD, Schrepf A, Sperger J, Vo N, Wallace MS, Wasan AD, Weaver TE, Weber KA 2nd, Williams DA, Wilson L, Zeidan F, Zhao B, Anstrom KJ, Clauw DJ, Sowa GA. The design and rationale of the Biomarkers for Evaluating Spine Treatments trial: a sequential multiple assignment randomized trial. Pain Med. 2025 Sep 1;26(9):538-553. doi: 10.1093/pm/pnaf032.

  PMID: 40205455 DERIVED

MeSH Terms

Conditions

Pain; Back Pain

Interventions

Acceptance and Commitment Therapy; Musculoskeletal Manipulations; Duloxetine Hydrochloride

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cognitive Behavioral Therapy; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities; Complementary Therapies; Therapeutics; Physical Therapy Modalities; Rehabilitation; Thiophenes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

The BEST Trial is a sequential, multiple-assignment randomized trial designed to estimate the optimal treatment (or sequence) for chronic low back pain based on unique biomarkers and response to treatment. As this precision-medicine focus dictates individualized rather than arm-level contrasts, no between-arm comparative-effectiveness analyses are planned as primary analyses. The primary goal of this study was to identify predictive biomarkers for each treatment not comparative effectiveness.

Results Point of Contact

• Title: Matthew Mauck, MD, PhD
• Organization: UNC Chapel Hill

Matt_Mauck@med.unc.edu

(919) 966-5136

Study Officials

• Kevin Anstrom, PhD

  UNC Chapel Hill

  PRINCIPAL INVESTIGATOR

• Matthew Mauck, PhD

  UNC Chapel Hill

  PRINCIPAL INVESTIGATOR

• Gwendolyn Sowa, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

• Daniel Clauw, MD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Sequential Multiple Assignment Randomized Trial (SMART)

Study Record Dates

• First Submitted: May 24, 2022
• First Posted: May 27, 2022
• Study Start: September 12, 2022
• Primary Completion: July 30, 2024
• Study Completion: October 22, 2024
• Last Updated: July 23, 2025
• Results First Posted: July 23, 2025

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• 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.
• 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

Locations

US (12)