Clinical trial NCT05396014
Conditions: Chronic Low-back Pain
Keywords: Pain Back Pain
Sponsor: University of North Carolina, Chapel Hill
Start date: 2022-09-12; Completion date: 2024-10-22
Enrollment: 1014 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

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.

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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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.
Interventions: intervention 1: Enhanced Self-Care (ESC) intervention 2: Acceptance and Commitment Therapy (ACT) intervention 3: Evidence-Based Exercise and Manual Therapy (EBEM) intervention 4: Duloxetine
Intervention descriptions: intervention 1: 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. intervention 2: 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. intervention 3: 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. intervention 4: 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.

Protocol documents:
ICF_000.pdf: 
The BEST Trial: Biomarkers for Evaluating Spine Treatments 
Study Consent
Protocol Number: 00057948 
National Clinical Trial (NCT) Identified Number: NCT05396014 
Protocol Co-Chairs:  
Daniel Clauw, MD; Gwendolyn Sowa, MD, PhD  
Matthew Mauck, MD, PhD; Kevin Anstrom, PhD 
Sponsor: The Helping to End Addiction Long-termSM Initiative (NIH HEAL 
InitiativeSM) 
Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS) 
Version Date:    February 9, 2023


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Consent to Participate in a Research Study 
Adult Participants 
 
Sponsor / Study Title: 
  
National Institute of Arthritis and Musculoskeletal and Skin 
Diseases (NIAMS) / “The BEST Trial: Biomarkers for 
Evaluating Spine Treatments” 
 
Protocol Number: 
 
00057948 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
CONCISE SUMMARY 
The purpose of this research study is to evaluate four treatments for chronic low back pain and to 
determine whether participant characteristics may predict the effectiveness of different treatment 
options.  
 
Participants will complete:  
• a pre-enrollment screening by telephone,  
• an enrollment visit, during which they will be evaluated for participation in the study, and  
• a 2-week online, self-directed, educational program to learn about the study (the “run-in” 
period).  
 
After the 2-week run-in period, each participant will be re-evaluated to see if they are eligible to 
continue in the study. If participants are still eligible, they will complete:  
• in-person visits to collect data via questionnaires and other assessments, 
• two back-to-back 12-week study treatment periods, and  
• a 12-week follow-up period after the end of the last study treatment.  
 
Participants will be assigned to one of four study treatments for the first 12-week study treatment 
period. For the second 12-week study treatment period, participants will either continue with the 
same treatment as the first period, receive another treatment in addition to their first-period 
treatment, or be assigned to a new treatment. The maximum time participants will be in the study 
is 38 weeks. 
 
Potential benefits to participating in this study include improvement in your chronic low back 
pain. There is no guarantee of this benefit. 


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Potential risks to participating in this study are similar to those encountered in a standard clinical 
practice and are deemed as having no more than a moderate risk level.  Risks include worsening 
of your chronic low back pain, injury, and emotional or physical discomfort. This is not a full list 
of risks.  Refer to the sections below for a more detailed list of risks. 
The information provided in this section is discussed in more detail later in this consent form. 
 
What are some general things you should know about research studies? 
You are being asked to take part in a research study.  Joining the study is voluntary. 
You may choose not to participate, or you may withdraw your consent to be in the study, for any 
reason, without penalty or loss of benefits to which you are otherwise entitled. 
Research studies are designed to obtain new knowledge. This new information may help people 
in the future. You may not receive any direct benefit from being in the research study. There also 
may be risks to being in research studies.  
Deciding not to be in the study or leaving the study before you complete the study activities will 
not affect your relationship with the study investigator, your health care provider, or the study 
site. If you are a patient with an illness, you do not have to be in the research study in order to 
receive health care. 
 
Details about this study are discussed below.  It is important that you understand this information 
so that you can make an informed choice about being in this research study.  
 
You will be given a copy of this consent form.  You should ask the study investigator or staff 
members who may assist them any questions you have about this study at any time. 
 
What is the purpose of this study? 
The purpose of this research study is to study four treatments for chronic low-back pain to learn 
whether or not certain treatments work better for people with certain characteristics. 
The study’s main goal is to find a way to match treatments to low-back pain patients based on 
their characteristics and how they responded to treatments they have used before. 
 
You are being asked to be in the study because you have reported having low-back pain for at 
least 3 months and on at least half the days in the past 6 months. You have also reported that 
your low-back pain is the worst pain you are experiencing.  
 
To participate in this study, you also need to be willing to receive any treatment in this study for 
which you are eligible. 
 
Are there any reasons you should not be in this study? 
You should not be in this study if you are pregnant at the time of the screening phone call or 
enrollment visit. 
 


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In addition, the study investigator can stop you from participating in this study or in certain study 
activities if you have a condition that would mean you cannot safely participate. 
 
How many people will take part in this study? 
Approximately 820 people at up to 15 institutions in the United States will take part in this study. 
 
How long will your part in this study last? 
Participants will be in the study up to 38 weeks. Refer to the table below for the time needed for 
each study activity. This time includes a 2-week run-in period, two 12-week study treatment 
periods, and a final 12-week follow-up period. 
 
What will happen if you take part in the study? 
You will complete several study events before you begin a study treatment. See the table below 
for details about these study events. 
 
Enrollment and Run-in period 
Study Events 
Description 
Approximate 
Time Required 
Activities During Event 
In-person visit If you are eligible to 
participate based on the 
pre-enrollment screening 
phone call, you will 
complete an in-person 
visit to begin the study. 
75 minutes 
• Review of this consent 
form 
• Measurement of waist 
circumference 
• Introduction to study 
website 
• Discussion of your 
current low-back pain 
treatments 
• Questionnaires 
• Scheduling future visits 
Two-week 
run-in period 
During this period, you 
will have access to online 
materials to learn about 
the study and you will 
answer online 
questionnaires. 
 
• Online questionnaires 
• Review of online study 
materials 
• Text messages or e-
mails from study staff 
Check-in 
Phone Call 
After the two-week run-in 
period, study staff will 
call you to discuss your 
eligibility to participate in 
the study.  
10 minutes 
• Questionnaires 
 
After you complete the run-in period, you may no longer be eligible for the study.  
 


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If you are eligible after you complete the run-in period, you will begin the first treatment period 
for the study. The specific events during this period are described below. 
 
You may have the option to participate in additional assessments beyond the required study 
events over three in-person visits if the assessments are supported by the clinic at the time of 
your enrollment.  These additional assessments will provide more information about your 
characteristics and your low-back pain. These additional assessments are in italics in the tables 
below. Please see below for more details about these additional assessments and the time 
required. 
 
Baseline Visit and First Study Treatment Period 
 
Study Events 
Description 
Approximate 
Time Required 
Activities During Event 
Baseline in-
person visit 
You will participate in this 
activity if you are still 
eligible for the study 
based on the above check-
in phone call. You will be 
randomly assigned (like 
flipping a coin) to a 
specific study treatment at 
this visit. 
Approximately 4 
hours 
• Questionnaires*  
• Physical exam 
• Magnetic Resonance 
Imaging (MRI) scan of 
the spine 
• Motion Assessments 
• Collection of blood  
• Take-home stool 
collection kit 
• Assignment to first study 
treatment 
• Scheduling future visits 
Additional 
baseline 
assessments 
You may have the option 
to undergo a set of 
assessments that will 
provide more information 
about your characteristics 
and your low-back pain. 
Approximately 5 
hours for all 
additional 
assessments 
• Motion assessments 
• At-home activity 
monitoring 
• Advanced MRI scan of 
the spine 
• Brain MRI 
• Sensory testing 
(pressure, temperature)  
First study 
treatment 
period 
You will receive a study 
treatment for up to 12 
weeks. 
The time required 
will depend on 
the treatment. 
Activities will depend on 
the treatment.  
Check-in 
phone call 
Study staff will call you to 
check in halfway through 
the 12-week treatment. 
10 minutes 
• Questionnaires 
* Some questionnaires will be available to complete online prior to the visit, and others will be completed 
in-person. 
 
After the completion of the first 12-week treatment, you will begin the second treatment period 
for the study. The events in the second treatment period are described below. Note that if the first 


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treatment is working well for you, you may be asked to continue the same treatment alone or in 
combination with a new treatment. If the first study treatment is not working for you, you will be 
assigned to a different study treatment altogether. 
If you are assigned to a different treatment for the second treatment period, you should not 
continue the first treatment outside of the study. 
 
Second Study Treatment Period 
 
Study Events 
Description 
Approximate 
Time Required 
Activities During Event 
In-person  
visit 
After you complete the 
first period of treatment, 
you will attend another in-
person study visit.  
1 hour 
 
 
 
 
 
 
• Questionnaires* 
• Physical exam 
• Motion Assessment 
• Collection of blood 
• Assignment to second 
treatment 
 
Additional 
assessments  
You may have the option 
to undergo a set of 
assessments that will 
provide more information 
about your characteristics 
and your low-back pain. 
Approximately 4 
hours for all 
additional 
assessments 
• Motion assessments 
• Brain MRI 
• Sensory testing 
(pressure, temperature) 
Second study 
treatment 
period  
You will either continue 
the first treatment, add 
another treatment in 
addition to the first, or be 
assigned to a new 
treatment. 
The time required 
will depend on 
the treatment. 
Activities will depend on 
the treatment.  
Check-in 
Phone Call 
Study staff will call you to 
check in halfway through 
the second treatment 
period. 
10 minutes 
• Questionnaires 
* Some questionnaires will be available to complete online prior to the visit, and others will be completed 
in-person 
 
After completion of the second 12-week period of treatment, you will complete several final 
activities for this study. See the table below for more details about these activities. 
 


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Follow-up Visits 
 
Study 
Events 
Description 
Approximate 
Time Required 
Activities During Event 
In-person 
visit 
After the second 
treatment period, you 
will attend another in-
person study visit. 
40 minutes 
• Questionnaires* 
• Physical exam 
• Motion Assessment 
• Collection of blood 
Additional 
assessments  
You may have the 
option to undergo a set 
of assessments that will 
provide more 
information about your 
characteristics and 
your low-back pain. 
Approximately 4 
hours for all 
additional 
assessments 
• Motion assessments 
• Brain MRI 
• Sensory testing (pressure, 
temperature) 
Check-in 
Phone Call 
Study staff will call 
you to check in 4 
weeks after the end of 
the second treatment 
period. 
10 minutes 
• End of study check-in 
Follow-up 
Texts, 
Emails, 
and/or Phone 
Call 
You will receive texts 
or emails from the 
study staff. 
Study staff will call 
you to follow up 12 
weeks after the end of 
the second treatment 
period. 
10 minutes 
• Questionnaires* 
* Some questionnaires will be available to complete online prior to the visit, and others will be completed 
in-person 
 
How will I be contacted by study staff? 
Portions of the study will involve study staff contacting you by phone and e-mail. You will have 
the option to receive some study information via text messaging. Study-related e-mail and text 
messages will consist of reminders and notifications about study activities or reminders to 
contact the study team. These messages may contain personal information about you and may be 


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sent or received by the study team’s personal electronic devices or in a method that is not able to 
be encrypted (protected).  There is the risk that your information could be shared beyond you and 
the study team. By signing and dating the consent on the last page of this form you are giving 
permission for the study team to contact you by phone, email, and if preferred, text message.  If 
you do not want to receive un-protected communication that may contain personal 
information, then you should not consent to participate in this study. 
After the study is complete and all research activities concluded, or you withdraw from the 
study, you will no longer receive un-encrypted (un-protected) communication specific to this 
study. 
 
Study Treatments 
You will be assigned to one or multiple of the following treatments during your participation in 
this study. Neither you nor the study investigator will choose the treatment.  You will be 
assigned to study treatment(s) by chance (like flipping a coin). Please see below for more details 
about each treatment. 
• Acceptance and Commitment Therapy 
o This treatment consists of 12 sessions designed to help individuals interrupt pain 
avoidance behavior patterns in favor of more open, aware, and engaged behavior. 
Treatment methods include mindfulness exercises, metaphor and identification of 
values. Four of the 12 sessions will occur face-to-face with a therapist online. The 
other eight sessions will be self-directed online with ongoing therapist support 
using an online messaging system. 
• Duloxetine 
o For this treatment, you will be prescribed duloxetine, which is an FDA-approved 
treatment for chronic low-back pain. You will take duloxetine for at least 
11weeks of the 12-week treatment period. 
• Enhanced Self-Care 
o This treatment will involve online “modules” that provide education about 
chronic low-back pain and skills to help you manage your pain. You will also be 
able to monitor your walking activity using a Fitbit that will be provided by the 
study. The program will continue for approximately 12 weeks. After the first four 
weeks of this program, the remaining 8 weeks will be tailored to your 
characteristics and needs. 
• Evidence-based Exercise and Manual Therapy 
o For this treatment, a trained Physical Therapist or Chiropractor will provide 
exercises and hands-on treatment to your joints and muscles. You will complete 
10 sessions during an 8-week period: two sessions per week for the first two 
weeks and 1 session per week for 6 weeks. 
 
If you do not want to receive study-related texts, please initial below. 
 
_____  I do NOT consent to receiving study-related text messages 
 


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At three points during the study, you will be asked to provide blood.  32 mL (about seven tubes) 
of your blood will be drawn by a qualified study staff member.  
 
At one point during the study, you will be asked to provide a stool sample. You will be provided 
with a kit, instructions, and a return shipping label. You will be asked to collect the sample at 
home and send it by mail to the lab. 
 
What are the possible benefits from being in this study? 
Research is designed to benefit society by gaining new knowledge. The information learned from 
this study will assist the researchers and clinicians in learning how to improve treatment for 
chronic low-back pain.  
The benefits to you from being in this study may include improvement in the amount of pain that 
you experience, increased mobility, and/or better ability to perform physical, mental, cognitive, 
emotional, recreational, and social activities as a result of lessened pain. You may also benefit by 
gaining new knowledge about your pain condition or by learning new pain self-management 
techniques. Your mood might improve as a result of interacting with study staff and personnel. 
Your participation may also offer long-term benefits to your general health, such as establishing 
and maintaining healthy habits like exercise. However, there is no guarantee that you will receive 
any direct benefit from being in the study.  
 
What are the possible risks or discomforts involved from being in this study? 
You may experience one or more of the risks listed below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with 
being in this study.    
 
Risks Associated with Study Procedures 
Breach of Confidentiality 
We will make every effort to protect your confidentiality, but there is a small possibility that 
your data could become known to others. Since study data will be transmitted electronically, 
there is always the risk that a transmission could be intercepted and decoded. We will meet or 
exceed all standards of electronic security using only secure servers and encryption. We will 
protect your information, but there is a chance it will be seen by someone not authorized to see it.   
 
Risks Associated with Phenotypic Assessments  
Questionnaires  
You will complete questionnaires regarding your pain, medication use, and history of chronic 
low-back pain and other health conditions. You may find the questions tiring, tedious, or 
embarrassing.  You may choose not to answer a specific question or to decline to complete a 
questionnaire at any time, however there are some questionnaires that are required for study 
participation.   


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Blood Draw  
Taking blood may cause some pain, bleeding or bruising at the spot where the needle enters your 
body. Rarely, taking blood may cause fainting or infection. To minimize these risks, experienced 
medical personnel will perform the blood draws using aseptic (clean) technique.   
 
Stool Collection 
Any stool sample may contain germs that spread disease. It is important to follow the 
instructions included in the stool collection kit and thoroughly wash your hands to avoid 
spreading infection. 
Some people may feel uncomfortable or embarrassed using the stool collection kit. There should 
be no pain while collecting the stool sample. However, if you are constipated, straining to pass 
stool may be painful. 
 
Physical Exam 
There are no physical risks but you might experience momentary embarrassment or discomfort. 
The exam is similar to those that are performed as part of routine medical care. 
 
Biomechanical (Motion) Assessment  
You will receive at least one motion assessment, which requires the use of a wearable device to 
measure your movement and function as related to chronic low-back pain. You may find the 
wearable device uncomfortable and may experience light low-back muscle fatigue or 
soreness similar to a light workout the day following the motion assessment. Less common are 
short-term aggravation of existing low-back symptoms; irritation, pinching, rubbing, or sticking 
of skin from motion harness components; piercings or other wearable materials (for 
example, insulin pump) snagging during the motion testing, and loss of balance while 
performing the motion assessment causing a fall.  
Adhesive may be used to attach wearable sensors during assessments. These adhesives may 
cause short-term, minor skin irritation. Some participants may  participate in additional testing 
by wearing a device on their waist and wrist continuously for seven days, which may be 
burdensome. These additional assessments may also cause minor physical discomfort or 
tiredness but are unlikely to cause long-term physical discomfort.   
 
MRI  
You will undergo one Magnetic Resonance Imaging (MRI) of your spine during your baseline 
visit. This MRI will take approximately 30 minutes.  Some participants may participate in 
additional imaging.  If you participate in the additional imaging, you may undergo one advanced 
spine MRI scan that will take approximately 30 minutes and three brain MRIs. Each of the three 
brain MRIs last approximately 60 minutes and will be given at three separate study visits. During 


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an MRI, you must lie still on your back in the MRI scanner in a tight space. This may make you 
anxious. 
MRI is safe for most participants but is not recommended for certain groups of people, such as 
those with certain medical devices (for example, implanted cardiac devices, cochlear implants, or 
intracranial aneurism clips) or with metal in their body (for example, wire mesh, screws). 
MRI is not safe for pregnant women. While MRI is safe for most participants, the procedure may 
cause some participants to feel emotional discomfort, anxiety, and claustrophobia. The noise of 
MRI requires participants to wear ear protection and may cause peripheral muscle or nerve 
stimulation.  
Quantitative Sensory Testing (QST)  
Some participants may receive QST, a set of assessments that test how sensitive you are to 
pressure and pin prick sensations. These assessments may cause discomfort in the areas of 
testing, but this discomfort is expected to go away a few minutes after the test is done. These 
tests will not cause any tissue injury. 
Participants who receive QST will also be exposed to cold water that is uncomfortable.  The 
water will not be cold enough to cause any tissue damage.  The cold-water part of the QST 
assessment is not recommended for participants with uncontrolled high blood pressure, 
uncontrolled heart conditions, or a history of Raynaud’s Syndrome.  
 
Genetic Analysis & Information 
Genetics and genomics are the study of DNA and RNA.  DNA are substances made of smaller 
pieces called genes. RNA helps uncover the information in the DNA. Your genes influence your 
risk of getting certain diseases and how your disease progresses. As part of this study, the 
investigators would like to use your DNA to look for genes and gene products (for example, 
proteins) that might affect the severity of your chronic low-back pain. DNA and RNA can be 
studied from the blood and stool samples that you provide. Study investigators will not report 
back results found during the course of genetic or genomic analyses. 
The risks related to genetic analyses can be to individuals or groups. These harms include others 
viewing you in a negative way or having trouble getting insurance. To reduce this risk, your 
samples will be stored and labeled with a code. If the results are used for future research, the 
researchers will not be able to identify you. Genetic results from this study will not be recorded 
in your medical record. 
Federal law called the Genetic Information Nondiscrimination Act (GINA) generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. GINA does not protect you against genetic 
discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
genetic condition or disease. 
 


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Risks Associated with Study Interventions and Run-in Activities  
Below are the risks for each type of study treatment. Since you will be assigned to up to two of 
these study treatments, not all of these risks will apply. 
 
Acceptance Commitment Therapy (ACT) 
The ACT behavioral intervention includes discussing your pain experience with a trained 
therapist and may make you feel emotionally uncomfortable. These risks are minimal and are 
sometimes part of the therapeutic process. To reduce the disabling effects of depression, fear or 
other feelings, one may need to first recognize these before identifying healthy goals for 
improvement. You will meet with your assigned study therapist four times and will be able to 
contact them at any time by email. Your study therapist will thoroughly explain study treatment 
and what to expect. They will provide ongoing support over the course of study treatment and, if 
applicable, will monitor you for worsening of depression or anxiety symptoms. You may also 
reach out to your study staff with any questions or concerns throughout the course of the study.   
 
Duloxetine 
Duloxetine is an antidepressant that may be prescribed to you with daily doses ranging from 30 
mg to 60 mg. The most common side effects with this drug include:  
• Nausea  
• Vomiting  
• Dry mouth  
• Constipation  
• Diarrhea  
• Fatigue (tiredness)  
• Difficulty sleeping 
• Dizziness 
Severe liver problems, sometimes fatal, have been seen in patients treated with duloxetine.  
All of these side effects are thought to be less common if your dosage is slowly increased over 
time by your provider and many (especially gastrointestinal intolerance) typically get better.  
The most serious adverse effect associated with duloxetine is the increased risk of 
suicidality when starting this medication, especially in people under age 25. If you have a 
history of bipolar disorder, manic episodes, or suicide attempts you will not be eligible for 
participation in the Duloxetine study intervention. If you are assigned this study treatment, 
you will be regularly monitored for clinical worsening, suicidality, or unusual changes in 
behavior.  
If you are having suicidal thoughts call the study doctor at the telephone number listed on 
the first page of this form. If you feel in crisis, you can call 911 and/or a Nationwide Suicide 
Hotline that is answered 24 hours a day with a skilled, trained counselor. One example is 
the National Suicide Prevention Lifeline at 1-800-273-TALK (8255).  


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If you notice any change in your health or new symptoms after initiating this treatment we would 
like you to notify the study team, and they will provide counseling on how to proceed. 
  
Allergic Reaction Risk 
As with taking any drug, there is a risk of allergic reaction when taking duloxetine.  If you have a 
very serious allergic reaction, you may be at risk of death.  Some symptoms of allergic reactions 
are: 
• Rash 
• Wheezing and difficulty breathing 
• Dizziness and fainting 
• Swelling around the mouth, throat or eyes 
• A fast pulse 
• Sweating 
Please seek treatment immediately and tell the study doctor and study staff if you have any of 
these symptoms. 
 
Enhanced Self-Care (ESC)   
The ESC treatment is an educational and self-care digital intervention. If you are assigned to this 
study treatment, your risks are minimal.  
 
Evidence-Based Exercise and Manual Therapy (EBEM) 
If you are assigned to EBEM Therapy, a trained provider will use manual therapy to reduce pain 
and stiffness, and to improve range of motion. Manual therapy consists of hands-on treatment to 
increase the movement and flexibility of your joints and muscles.  The trained provider will also 
ask you to do specific exercises to improve muscle strength, flexibility and endurance.  Both are 
considered safe for the treatment of low-back pain.  The side effects associated with therapeutic 
exercise, manual therapy to your joints and muscles are common and benign, such as transient 
post-study treatment muscle and/or joint soreness which typically resolve within 24 hours. If you 
receive hands-on study treatment to your muscles, you may have mild muscle soreness at the site 
of the study treatment during and after study treatment. Skin irritation is also possible if massage 
lotions and oils are used.  
You may be asked to discuss your pain experiences and the impact of low-back pain on various 
aspects of your life, which may cause emotional distress. EBEM is not recommended for people 
with high blood pressure or heart conditions.  
Run-In Period 
During the run-in period, you will be asked to read informational materials delivered to you 
electronically. Risks are minimal.  
 


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What are the risks to a pregnancy or to a nursing child? 
If you are pregnant or planning to get pregnant, you should not be in the study.  
If you are currently breastfeeding, you will not be eligible for participation in the Duloxetine 
study intervention. 
 
If you choose not to be in the study, what other treatment options do you have? 
You do not have to be in this research study in order to receive treatment. All of the treatments in 
this study are available outside of this study. If you do not wish to participate in this study, but 
would like to pursue treatment for your chronic low-back pain, contact your physician to discuss 
your options.  
 
What if new findings are made during the study that provides new information?  
You will be given any new information gained during the course of the study that might affect 
your willingness to continue your participation.  
 
Will I receive the results from my MRIs?  
The images we are using in this study will be reviewed for study purposes only.  Images will not 
be reviewed for the purpose of providing individual health information to study participants. As 
a result, you may not be informed of any unexpected findings.  
 
How will information about you be protected? 
Your participation in this study will be kept confidential (private) as permitted by law. This 
includes information you provide in your questionnaire answers and data from your laboratory 
results. You will be assigned a special study code that will be used on the questionnaires and all 
study forms. The list that links your name with this special study code will be kept in a secured, 
private location. Only information needed for this study is recorded.  Staff members involved in 
conducting this study are required to sign a form stating they will protect your information. 
Your coded information from the study will be stored securely by the study team and the data 
coordinating center at the University of North Carolina at Chapel Hill.  The data coordinating 
center provides the study researchers with limited coded information for analysis. All study 
information is grouped together and information will not be linked to any one person. If reports 
or results from that data are shared with the study team and the research staff at your site, no one 
will know what information is yours.  
Once the study is over, the study data will be stored indefinitely at a location approved by the 
National Institutes of Health (NIH). 
Participants will not be identified in any report, presentation, or publication about this study.   
Although every effort will be made to keep research records private, there may be times when 
federal or state law requires the disclosure of such records, including personal information.  This 
is very unlikely, but if disclosure is ever required, the study site will take steps allowable by law 
to protect the privacy of personal information.  In some cases, your information in this research 


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study could be reviewed by representatives of the study site, research sponsors, or government 
agencies (for example, the FDA) for purposes such as quality control or safety. 
Every effort will be made to keep your being in the study and your personal information private 
and confidential; but absolute confidentiality cannot be guaranteed. For example, if we learn 
something that would immediately put you or others in danger, the researchers are required by 
law to take steps to keep you and others safe. This means that we have to report to the authorities 
(hospital, police, or social services) any information you tell us that suggests you might be in 
danger, such as if you tell us that you plan to hurt or kill yourself, hurt or kill someone else, or if 
you tell us that someone is abusing or neglecting you.  
As part of the study, the study team may share the results of your study assessments and parts of 
your medical record with the groups named below. These groups may include people from the 
Back Pain Research Consortium (BACPAC), These groups are required to make sure your 
protected health information (PHI) is kept private.  
In addition, your records may be reviewed, under guidelines of the Federal Privacy Act, by the 
sponsoring agency at the NIH, study monitors acting on behalf of the NIH, investigators and 
research staff from BACPAC, and by Advarra IRB to make sure that the study staff is doing 
what they are supposed to and that study participants are protected. If your study records are 
reviewed, your identity could become known to them. 
Under some state laws, confidentiality does not extend to certain communicable diseases, such as 
TB, HIV, hepatitis, or other illnesses that put others at risk. If the researchers become aware that 
you have such an illness, they may be required to report it to state authorities. 
 
Audio- and Video-Recorded Data 
EBEM sessions, study-related telephone calls, and some ACT face-to-face visits with a therapist 
might be recorded for quality control purposes. This is to ensure that providers are following 
study procedures. 
You will be notified if a study visit, phone call, or telehealth visit is being recorded. Even if you 
consent to be recorded, you may request that any recording be stopped at any point during a visit 
or call.  You do not need to agree to be recorded to be in the study.   
Video tapes, audio recordings, and any transcripts of these recordings will be stored securely up 
to seven years after the study is finished.  After that time, they will be destroyed.  
 
 
Please initial one of the lines below to indicate whether you consent to being recorded during 
this study.  
 
_____ OK to record me during the study 
 
_____ Not OK to record me during the study 


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What is a Certificate of Confidentiality?  
This research is covered by a Certificate of Confidentiality. With this Certificate, the researchers 
may not disclose or use information, documents or biospecimens that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings in the 
United States, for example, if there is a court subpoena, unless you have consented for this use. 
 
The Certificate cannot be used to refuse a request for information from personnel of a federal or 
state agency that is sponsoring the study for auditing or evaluation purposes or for information 
that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA). 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law, such as mandatory reporting requirements for child abuse or neglect, disabled 
adult abuse or neglect, communicable diseases, injuries caused by suspected criminal violence, 
cancer diagnosis or benign brain or central nervous system tumors or other mandatory reporting 
requirement under applicable law. The Certificate of Confidentiality will not be used if 
disclosure is for other scientific research, as allowed by federal regulations protecting research 
participants or for any purpose you have consented to in this informed consent document. 
 
You should understand that a Certificate of Confidentiality does not prevent you from 
voluntarily releasing information about yourself or your involvement in this research. If an 
insurer, employer, or other person obtains your written consent to receive research information, 
then the researchers may not use the Certificate to withhold that information. 
 
Will my study data be included in my medical records? 
By signing and dating this informed consent document, you agree that some of the information 
generated by participating in this study and/or a copy of the consent form may be included in 
your medical record and that this information may be viewed by other physicians or caregivers 
who provide healthcare services to you.  
 
Storage and Sharing of Your Data and Samples 
Your blood and biospecimen-related data will be stored securely at the study site before being 
shipped to the NIH-approved central process laboratory for storage and analysis during the study. 
Participants will collect stool samples at home and ship them to the NIH-approved central 
process laboratory. At the end of the study, all remaining samples will be stored at sites that the 
NIH selects for this study. Your data will also be stored securely at the study site, on data 
servers, and in HIPAA-compliant data management systems. Your data and samples will be 
stored indefinitely. We will do our best to protect your personal information. Your name and 
other personally-identifying information will not be kept with the data or samples. Your data and 
samples will either be stored without a code linking them to you or they will have a code that 
links to your identifying information. If your data has a code, the key to the code will be kept at 
the study site in a separate, secure area and will not be shared outside of the study site.  


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This study is part of the NIH HEAL Initiative focused on understanding and developing new 
treatments for addiction and pain. Research gives us the best information and progresses more 
quickly when data is available from many studies and many individuals, and when many 
researchers can work with the data and samples and analyze them in different ways. Therefore, 
as well as using your data and samples for the purpose of this and other NIH HEAL Initiative 
studies, we would like your permission to make the data and samples collected in the study 
widely available to other researchers. The shared data and samples may be used indefinitely for 
research not related to this study or the HEAL Initiative, without asking you for additional 
consent.  
Your samples collected for this study contain your DNA. Your DNA and genetic information is 
unique to you. With your permission, your genetic information may also be used for research 
unrelated to this study. 
If you withdraw from this research study before it is done, we will keep and continue to use data 
and samples that have already been collected. Your privacy will be protected to the full extent 
possible. 
Please review the information on the potential benefits and risks of storing and sharing your data 
and samples and then indicate your decision in the box below. 
 
Potential benefits of sharing of data and samples 
There is no direct benefit to you from the storage and sharing of data and samples, but sharing 
may help researchers learn more about low-back pain and other diseases, which may help you or 
others in the future.    
 
Risks of sharing data and samples 
Even though we will protect your privacy as much as possible, there is a very small chance that 
the data and samples could be identified as yours. The risk of this happening is very small, but 
may grow in the future as technology changes.   
 
Research using data and samples from this study may lead to new tests, drugs, or devices with 
commercial value. You will not receive any payment for any product developed from research 
using your samples and data. 
 
 
 
Please indicate your choice regarding data and sample sharing by initialing on one of the 
lines below: 
 
I agree to the sharing of my data and samples for use in other research studies.  
 
 
Yes______               No________ 
 


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Will you receive results from research involving your specimens? 
Most research with your specimens is not expected to yield new information that would be 
meaningful to share with you personally. There are no plans to re-contact you or other 
participants with information about research results.   
The use of your samples may result in commercial profit. You will not be compensated for the 
use of your samples other than what is described in this consent form. 
You will be asked to sign a separate form ("HIPAA Authorization") to allow researchers to 
review your medical records. 
 
What will happen if you are injured by this research? 
If you become ill or are injured while you are in the study, get the medical care that you need 
right away. You should inform the healthcare professional treating you that you are participating 
in this study. If you tell the study staff that you think you have been injured then they will help 
you get the care you need.  
 
If you are injured as a result of taking the study drug(s) or from procedures done for the purpose 
of this study, you will have to pay for any medical expenses necessary to treat your injury that 
are not covered by your medical insurance or any other third-party coverage. The study site has 
not set aside funds to pay you for any such injuries, illnesses, or reactions, or for the related 
medical care.  
 
By signing and dating this document, you will not lose any of your legal rights or release anyone 
involved in the research from responsibility for mistakes. 
 
What if you want to stop before your part in the study is complete? 
You can withdraw from this study at any time, without penalty.  The study investigators also 
have the right to stop your participation at any time. This could be because you have had an 
unexpected reaction to a study intervention, you no longer meet the eligibility criteria for the 
study or for the intervention to which you have been assigned, or because the entire study has 
been stopped. 
 
If you withdraw or are withdrawn from this study all data collected up until the point of 
withdrawal will be retained, however no additional information will be collected unless you 
provide additional written permission for further data collection at the time of your withdrawal.  
 
Will it cost you anything to be in this study? 
If you enroll in this study, you will have costs which include travel to/from the clinic and, if 
applicable, child/dependent care needed while participating in study visits. 
The study treatments and assessments will be provided at no cost to you. 
 


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Will you receive compensation for being in this study? 
«Compensation» 
You may receive up to $1,745 for taking part in this study – up to $1,275 for required study 
activities and up to $470 for other study activities. Please see the table below for more detail. 
Any payment provided for participation in this study may be subject to applicable tax 
withholding obligations. 
Your name, address, and U.S. tax payer identification number (SSN or ITIN) are required to 
process payments and/or to report taxable income to the IRS.  You must complete a W-9 (for 
U.S. persons) or W-8BEN and the Foreign Vendor Withholding Assessment with supporting 
documents (for non-resident aliens) in order to receive payment for participation. 
U.S. person participants must complete Form W-9 in order to receive payment for 
participation.  If an individual’s study payment(s) equals or exceeds $600 per calendar year for 
U.S. persons, that amount will be reported to the Internal Revenue Service on Form 
1099.  Nonresident alien participants must complete Form W-8BEN and the Foreign Vendor 
Withholding Assessment with supporting documents in order to receive payment for 
participation.  Payments to nonresident alien participants may be subject to tax withholding and 
are generally reported to the Internal Revenue Service on Form 1042-S.  This information will 
not be linked to any of the study data and will only be used for payment purposes. 
If you do not provide your SSN or ITIN, or complete the appropriate documentation noted 
above, we cannot issue you a payment for participation.  However, you may still choose to 
participate in this study. 
The table below describes the payment by study activity completed. The first table describes 
required activities, and the second table describes additional activities that are not required for 
participation in the study. Not all participants will participate in the additional activities. The cost 
of parking and other costs related to participation in study activities may be covered per your 
study site (if applicable). If you participate in the additional assessments, you will receive 
additional payments, which are detailed in the second table below. If you terminate early from 
the study, you will be reimbursed for those portions of the study you completed. 
 
Payments for Required Study Activities 
 
Study Activity 
Payment per 
activity or day 
Maximum 
number of 
activities/days 
Maximum total for 
activity 
In-person study visits 
$100 
7 
$700 
2-week run-in period 
$20 
1 
$20 
Blood draw 
$20 
3 
$60 
Return stool sample 
$20 
1 
$20 
Spine MRI 
$90 
1 
$90 
Motion assessment 
$20 
3 
$60 
Questionnaires 
$25 
10 
$250 
Completion bonus 
$75 
1 
$75 
 


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Payments for Additional Study Activities 
 
Study Activity 
Payment per 
activity or day 
Maximum 
number of 
activities/days 
Maximum 
total for 
activity 
Brain MRI 
$90 
3 
$270 
Advanced Spine MRI 
$45 
1 
$45 
Return sensors 
$50 
1 
$50 
Additional motion 
assessments 
$20 
3 
$60 
QST 
$15 
3 
$45 
 
If you do not complete the study, for any reason, you will be paid for each study visit you do 
complete.  
 
You will be paid ___________ [“following each completed visit”, “monthly”, “quarterly”, “at 
the end of your participation in the research study”, “following each completed visit or at the 
end of your participation in the research study, whichever you prefer”]. 
 
If you have any questions regarding your compensation for participation, please contact the study 
staff. 
   
 
Who is sponsoring this study? 
This research is funded by the National Institute of Arthritis and Musculoskeletal and Skin 
Diseases (NIAMS).  This means that the research team is being paid by the sponsor for doing the 
study.  The researchers do not, however, have a direct financial interest with the sponsor or in the 
final results of the study. 
 
Whom to Contact About This Study 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study investigator at 
the telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in this 
research study.  


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An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, and/or concerns or complaints regarding this research study, contact: 
 
• By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00057948. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
What if you have questions about your rights as a research participant? 
All research on human volunteers is reviewed by a committee that works to protect your rights 
and welfare.  If you have questions or concerns about your rights as a research subject, or if you 
would like to obtain information or offer input, you may contact the Institutional Review Board 
at 410-884-2900 or by email to adviser@advarra.com. 
 
Required and Optional Study Assessments 
All participants in the study will be required to:  
• answer questionnaires 
• receive a physical exam 
• receive a motion assessment lasting approximately 10 minutes at each of 3 separate 
visits1,2 
• provide blood samples at 3 separate visits 
• receive an at-home stool collection kit to provide a single stool sample 
• receive 1 spine MRI lasting approximately 30 minutes3 
 
Participants who meet additional eligibility requirements may participate in further assessments 
in addition to the required study assessments as the site’s appointment schedule allows.  
Participants participating in additional assessments may: 
• receive additional motion assessments lasting approximately 50 minutes at each of 3 
separate visits1,2 
• receive an advanced spine MRI lasting approximately 30 minutes2,3 
• receive a brain MRI lasting approximately 60 minutes at each of 3 separate visits1,2,3 


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• receive sensory testing (pressure, temperature) lasting approximately 60 minutes at each 
of 3 separate visits1,2 
 
1Participants should not take “as needed” medications for at least 8 hours before these assessments. As 
needed pain medications include NSAIDs (for example, Motrin, Advil, Aleve), acetaminophen (for 
example, Tylenol), certain anti-anxiety medications (for example, Valium, Xanax), certain sedatives (for 
example, Ambien), and opioids.  
 
2Participants should not consume alcohol the day of the assessment. 
 
3Participants must lie flat on their backs for the duration of the MRI. 
 
Access to past and future electronic medical records 
As part of this study, investigators would like to study how chronic low-back pain patients use 
health insurance.  To do this, investigators will need to access your electronic medical records 
and/or your health insurance claims data.   
We are asking your permission to access your electronic medical records and health insurance 
claims data to view claims activity occurring one year prior to your enrollment in this study 
through one year after you complete this study.  This is approximately three years of claims data. 
We are also asking your permission to access the data described above at any point from the time 
of your enrollment in this study through four years after the study ends.  
 
 
Please initial one of the lines below to indicate whether you consent to being considered for 
participating in the additional assessments for this study. Your consent does not guarantee 
participation in the additional assessments.  
 _____ YES, I consent to being considered for participation in the additional assessments 
_____ NO, I do not consent to being considered for participation in the additional assessments 
Please initial one of the lines below to indicate whether you consent to access to your 
electronic medical records. 
 _____ YES, study investigators may access my electronic medical records and claims data 
for this purpose and for the time period described above. 
_____ NO, study investigators may not access my electronic medical records and claims data 
for this purpose or for the time period described above. 


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Participant’s Agreement: 
I have read the information provided above.  I have asked all the questions I have at this 
time.  I voluntarily agree to participate in this research study. 
 
______________________________________________________ 
Signature of Research Participant 
 
_________________ 
Date 
 
______________________________________________________ 
Printed Name of Research Participant  
 
______________________________________________________ 
Signature of Research Team Member Obtaining Consent 
 
____________________ 
Date 
 
______________________________________________________ 
Printed Name of Research Team Member Obtaining Consent   

SAP_002.pdf: 
 
 Back Pain Consortium Research Program (BACPAC)  
  
The BEST Trial: Biomarkers for Evaluating Spine Treatments 
(BEST)   
  
ClinicalTrials.gov Statistical Analysis Plan (SAP)  
 
 SAP Version: 1.0 
SAP Version Date: 05/19/2025 
   
Protocol Number: 00057948  
Protocol Version 7.0  
  
National Clinical Trial (NCT) Number: NCT05396014  
  
Sponsor: The Helping to End Addiction Long-termSM Initiative  
(NIH HEAL InitiativeSM)  
  
Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SAP Approval Page  
Study Title: The BEST Trial: Biomarkers for Evaluating Spine Treatments (BEST)   
SAP Version: 1.0  
SAP Version Date: 05/19/2025  
  
We, the undersigned, have read and approved of this SAP and agree on its content.  
   
_______________________________________________  
BEST Protocol Co-Chair – Daniel Clauw, MD   
  
_______________________________________________  
BEST Protocol Co-Chair – Gwendolyn Sowa, MD, PhD   
  
_______________________________________________  
BEST Protocol Co-Chair – Matthew Mauck, MD, PhD   
  
_______________________________________________  
BEST Protocol Co-Chair – Kevin Anstrom, PhD  
 
_______________________________________________  
BEST Protocol Statistician – Anastasia Ivanova, PhD  
 
_______________________________________________  
BEST Protocol Statistician – Bryce Rowland, PhD  
 
 
 
 


Introduction 
Background and Rationale 
Chronic low-back pain, defined as pain lasting three months or more with pain occurring on most 
days, affects 10-20% of adults in the United States. Those facing chronic low-back pain face physical 
pain, limited mobility, and mental health symptoms. Chronic low-back pain is second only to cancer 
in the number of opioids prescribed, and opioid are the most commonly prescribed class of drugs 
for low-back pain, despite limited evidence of efficacy in chronic pain and the significant risks of 
side effects, addiction, and death. Current treatments, covering a broad range, do not cure chronic 
low-back pain for most patients.1 
Through the NIH Helping to End Addiction Long-termSM Initiative, the NIH seeks an improved 
understanding of the underlying biological mechanism of chronic pain and supports the discovery 
and testing of novel non-addictive pain treatments to stem the ongoing opioid crisis and support 
the translation of scientific findings into clinical practice.  
While a broad range of treatments exists, current treatments do not adequately resolve chronic 
low-back pain for most patients. Systematic reviews of common treatments find small to moderate 
evidence to support many currently used treatments. BACPAC, a funded component of the HEAL 
InitiativeSM, is a multisite consortium that will advance knowledge of the etiology and treatment of 
chronic low-back pain by developing an understanding of the mechanisms contributing to chronic 
low-back pain and identifying specific treatments or combinations of treatments that are most 
effective in identifiable subgroups of participants. The BEST Trial (Biomarkers for Evaluating Spine 
Treatments) is a NIAMS-sponsored clinical trial conducted by the BACPAC research program. The 
multi-site, sequential, multiple assignment randomized trial (SMART) was designed to evaluate 
four evidence-based interventions cLBP and inform a precision medicine approach to treating cLBP.  
Objectives 
The BEST trial was powered for the study’s primary objective of estimating an algorithm to assign 
sequences of two cLBP treatments based on phenotypic markers and an individual patient’s 
response to the initial treatment (i.e., a dynamic treatment regime (DTR)) that optimizes 
effectiveness, as characterized by the primary and secondary endpoints. In this outcome analysis, 
we will report the ITT-least squares adjusted mean of the 24-week outcomes of the BEST Trial and 
associated 95% confidence intervals. It is important to reiterate that the BEST trial was powered 
for biomarker discovery. This analysis describes the primary and secondary outcomes of the study.    
In this analysis, we aim to: 
• 
Report on BEST Trial study flow, baseline characteristics, and adverse events 
• 
Estimate 24-week least squares means for study outcomes by Stage 1 treatment 
assignment. 
 
 


Trial/Study Design 
 
Study data for this analysis will be from the BEST Trial, which has been described elsewhere.1-3 The 
trial follows a two stage sequential multiple assignment random trial SMART trial plan.2  The trial is 
split into two 12-week intervention stages with 3 study visits that occurred at the beginning of 
Stage 1 (Visit 0/Week 0), Stage 2 (Visit 1/Week 12), and the end of Stage 2(Visit 2/Week 24). At 
baseline (Visit 0/Week 0) participants were randomized to one of four interventions. To participate 
in the study participants were required to be eligible for a minimum of 3 of the treatments at 
baseline. A re-randomization happened at Week 12, where participants were assigned to one of 
four responder status categories using a combination of Week 12 Pain, Enjoyment of Life, and 
General Activity (PEG) and Patient Global Impression of Change (PGIC) scores. Participants with 
Week 12 PGIC 1-2 and PEG <= 4 maintained their initial treatment, participant with Week 12 PGIC 
1-2 and PEG > 4 were randomized to augment a second treatment, participants with a Week 12 
PGIC 3-4 were randomized to either augment a second treatment or switch treatments, and 
participants with a Week 12 PGIC of 5-7 or participants who could not tolerate their initial 
treatment were switched to a new treatment. Randomization at the baseline visit was stratified by 
years of cLBP, depression/anxiety, consent to optional phenotyping, and current use of opioids. The 
details of the trial are illustrated in the schema below.  
Schema  
 
 


Sample Size 
The sample size calculation for the BEST Trial is based on the ability to accurately estimate the 
value of the estimated optimal dynamic treatment regime relative to an oracle estimator and is 
described in the study protocol.  
Statistical Principles 
Confidence Levels and p-values 
Level of statistical significance 
Our results will not include any hypothesis testing. All confidence intervals for least squares mean 
outcome estimates will be reported at the 95% confidence level. 
Multiplicity Adjustments 
We will not use a multiplicity adjustment to adjust for the width of the confidence interval because 
the least squares mean is not a primary estimand of interest in the trial's statistical design. The 
primary estimand of interest is the value of the estimated optimal dynamic treatment regime, 
which is outside the scope of the outcome analysis presented here.  
Adherence and Protocol Deviations 
The analysis will summarize results from all randomized participants. Adherence to interventions 
will not be considered in this analysis. 
Analysis Populations 
The population used for statistical analysis consists of the 805 randomized participants to a Stage 1 
treatment.  
Trial Population 
Eligibility 
To be eligible for participation in the BEST Trial 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 as defined in Section 9 


• 
Regular reliable access to an internet-enabled device such as a smart phone, tablet, or 
laptop  
• 
computer 
• 
Meet Run-in period engagement eligibility criteria:  
• 
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 
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: 
o Progressive neurodegenerative disease 
o History of discitis osteomyelitis (spine infection) or spine tumor 
o BEST Trial Protocol v7.0 20 9/1/2023 
o History of ankylosing spondylitis, rheumatoid arthritis, polymyalgia rheumatica, 
psoriatic  
o arthritis, or lupus 
o History of cauda equina syndrome or spinal radiculopathy with functional motor 
deficit  
o (strength <4/5 on manual motor testing) 
o Diagnosis of any vertebral fracture in the last 6 months 
o Osteoporosis requiring pharmacologic treatment other than vitamin D, calcium  
o supplements, or bisphosphonates. 
o History of any bone-related cancer or cancer that metastasized to the bone 
o Currently in treatment for any non-skin cancer or plan to start non-skin cancer  
o treatment in the next 12 months 
o History of any non-skin cancer treatment in the last 24 months 
o Visual or hearing difficulties that would preclude participation 
o Uncontrolled drug/alcohol addiction 
o Individuals actively pursuing disability or workers compensation or involved in 
active  
o personal injury-related litigation 
o 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 
Recruitment 
Recruitment for the BEST Trial has been described extensively in the trial protocol and protocol 
paper.1  
Withdrawal/follow-up 
Study flow reporting is specified in Appendix 1.  
Timing of withdrawal/lost to follow-up data 


Lost to follow-up status was determined at the subsequent study visit at 12-week intervals. Study 
withdrawal was determined as soon as a participant withdrew consent. 
Baseline Characteristics 
List of Baseline Characteristics to be summarized 
The baseline characteristics analyzed are: 
• 
Age 
• 
Sex Assigned at Birth 
• 
Gender Identity 
• 
Ethnicity 
• 
Race 
• 
Highest Level of Education Completed 
• 
Current Employment Status 
• 
Current Relationship Status 
• 
Number of People Living in Household 
• 
Annual household income from all sources 
• 
PEG score (0 to 10) 
• 
Self-Reported low-back pain duration (months) 
• 
Self-reported low-back pain duration (category)   
• 
Low-back Pain Frequency in the Past 6 months 
• 
Low-back Pain Specific Pain Intensity 
• 
Ever had a low back operation? 
• 
When was the last back operation? 
• 
Any back operations involve a spinal fusion? 
• 
Ever unemployed for 1 or more months due to low back pain 
• 
Ever file or awarded worker’s compensation claim related to back problem 
• 
Involved in a lawsuit or legal claim related to back problem 
• 
Ever applied for, or received, disability insurance for pain condition 
• 
BMI  
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Heart Rate (bpm) 
• 
Ever had Hip Replacement surgery? 
• 
Ever had Knee Replacement surgery? 
• 
Observed Gait 
• 
Tobacco Use in Previous 12 Months 
• 
Alcohol Use in Previous 12 Months 
• 
Drug Use in Previous 12 Months 
• 
Prescription Drug Used Not as Intended in Previous 12 Months 
• 
Currently Taking Opioid Medication (daily) 
• 
Previously diagnosed with COVID-19 
• 
Long COVID 
• 
COVID-19 Vaccine 


• 
Fear avoidance beliefs about physical activity raw scoring scale 2 
• 
GAD-2 Raw Score 
• 
Keele STarT Back Screening Tool Risk 
• 
Oswestry Disability Index Percentage 
• 
Pain Catastrophizing Scale SF-6 
• 
Pain Detect Questionnaire Raw Score 
• 
PHQ-2 Raw Score 
• 
HEAL Positive Outlook Raw Score 
• 
PROMIS-Cognitive Function – Abilities 2a Raw Score 
• 
General Sensory Sensitivity Score – External 
• 
General Sensory Sensitivity Score – Interoception 
• 
General Sensory Sensitivity Score – Total 
• 
Self-reported Sleep Duration in the Past Month (hours) 
• 
Symptom Severity Index 
• 
Widespread Pain Raw Score 
• 
Stomach Pain in the Past 4 Weeks 
• 
Headaches in the Past 4 Weeks 
• 
Radiating Pain to Buttock/Thigh, Past 2 Weeks 
• 
Radiating Pain to Below Knee, Past 2 Weeks 
• 
Social Determinants of Health: Transportation Needs 
• 
Social Determinants of Health: Healthcare Needs 
• 
Social Determinants of Health: Food Insecurity 
• 
Social Determinants of Health: Food Money 
• 
Social Determinants of Health: Utilities 
• 
Social Determinants of Health: Stable Housing 
• 
Social Determinants of Health: Emotional Support 
• 
Social Determinants of Health: Number of Close Friends 
• 
Perceived Discrimination: Race/Ethnicity 
• 
Perceived Discrimination: Orientation/Gender Identity 
 
Details of how baseline characteristics will be summarized 
The baseline characteristics are reported as in Appendix 2. Continuous variables are summarized 
with means and standard deviations. Categorical variables are analyzed with counts and 
percentages. More details and analysis of the baseline population are described elsewhere.2  
 
Analysis 
Analysis Methods 
A linear mixed-effect model (LMM) was used to model the least squares mean of the primary and 
secondary outcomes at Visit 2 (Week 24) by the Stage 1 treatment assignment for all continuous 
outcomes. Random intercepts and a linear random slope for time were included to account for 
subject-level variability. The randomization and minimization algorithm variables are included as 


fixed effects. Week indicators as fixed effects were included to model non-linear effects of time. An 
additional fixed effect was included for the number of treatments a participant was eligible for at 
the baseline visit. Estimation was conducted using REML and modern optimization approaches 
with the lme4 package in R. Least squares means were estimated for each Week 24 outcome, along 
with associated 95% confidence intervals, using the emmeans package in R. Due to the small 
number of participants on opioids in the BEST Trial sample, we only report counts of participants 
self-reporting opioid use at Week 24.  
 
Outcome Definitions 
Outcome 
Name 
Outcome Type 
(primary/secondary) 
Specification 
of outcome 
and timing 
Specific 
measurement 
and units 
Calculation to 
derive 
outcome 
Analysis 
Method 
Patient-
Reported 
Pain 
Intensity 
and 
Interference 
Score 
Primary 
PEG Score 
measured at 
the Visit 2 
(Week 24)  
The PEG scale 
is based on a 
participant 
rating of their 
pain in 3 
areas: pain 
intensity, pain 
interference 
with 
enjoyment of 
life, and pain 
interference 
with general 
activities. A 
rating is given 
ranging from -
10 (lowest) to 
10 (highest) 
on each of 
these scales. 
We use the 
average of 
these ratings, 
with higher 
scores 
indicating 
increased 
pain intensity 
and 
interference 
at 24 Weeks 
compared to 
Baseline. 
Calculate the 
PEG Score by 
averaging the 
responses 
from each of 
the 3 scales. 
LMM 
Pain 
Interference 
Secondary 
Pain 
Interference 
Ratings of the 
consequences 
Calculate the 
raw score by 
LMM 


at Visit 2 
(Week 24) 
of pain on 
relevant 
aspects of 
one’s life. This 
includes the 
extent to 
which the 
pain hinders 
engagement 
with social, 
cognitive, 
emotional, 
physical, and 
recreational 
activities.  
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. 
summing all 
appropriate 
responses, 
then translate 
the raw score 
to the 
corresponding 
T-Score 
Physical 
Function 
Secondary 
Physical 
Function at 
Visit 2 
(Week 24) 
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 
Calculate the 
raw score by 
summing all 
appropriate 
responses, 
then translate 
the raw score 
to the 
corresponding 
T-Score 
LMM 


compared to 
Baseline. 
Depression 
Score 
Secondary 
Depression 
at Visit 2 
(Week 24) 
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. A 
rating of 
negative 
mood, views 
of self, as well 
as decreased 
positive affect 
and 
engagement. 
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. 
Calculate the 
raw score by 
summing all 
appropriate 
responses, 
then translate 
the raw score 
to the 
corresponding 
T-Score 
LMM 
Anxiety 
Score 
Secondary 
Anxiety at 
Visit 2 
(Week 24) 
Measured by 
the PROMIS 
Emotional 
Distress-
Anxiety scale 
(PROMIS-EDA 
4a). The 
PROMIS-EDA 
4a is a series 
of 4 questions. 
A rating of 
fear, anxious 
Calculate the 
raw score by 
summing all 
appropriate 
responses, 
then translate 
the raw score 
to the 
corresponding 
T-Score 
LMM 


misery, 
hyperarousal, 
and somatic 
symptoms 
related to 
arousal. 
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. 
Sleep 
Disturbance 
Secondary 
Sleep 
Disturbance 
at Visit 2 
(week 24) 
Measured by 
the PROMIS 
short form 6a. 
The PROMIS 
short form 6a 
is a series of 6 
questions. A 
rating of sleep 
quality, sleep 
depth, and 
restoration 
associated 
with sleep. 
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. 
Calculate the 
raw score by 
summing all 
appropriate 
responses, 
then translate 
the raw score 
to the 
corresponding 
T-Score 
LMM 
Sleep 
Duration 
Secondary 
Response to 
BACPAC 
sleep 
disturbance 
Response to 
“During the 
past month, 
how many 
 
LMM 


question at 
Visit 2 
(Week 24) 
hours and 
minutes of 
actual sleep 
did you get at 
night?” 
measured in 
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. 
Opioid 
Incidence 
Secondary 
Opioid 
incidence 
reported at 
Visit 2 
(Week 24) 
Self-reported 
Yes/No/Not 
Sure response 
to a single 
question, "Are 
you currently 
taking any 
opioid pain 
medication on 
a daily basis?" 
 
Counts 
 
 
Missing Data 
We assume the data are missing at random. We include all subjects randomized at baseline in the 
analysis, regardless of the number of future observations. There is no missingness in model 
covariates because they were required for randomization at the baseline visit.  
 
Additional Analyses 
Additional reporting is included in this submission for adverse events (Appendix 3) 
 


References 
1. 
Mauck MC, Barth KS, Bell KM, et al. The Design and Rationale of the Biomarkers for Evaluating 
Spine Treatments (BEST) Trial: A Sequential Multiple Assignment Randomized Trial. Pain Med. Apr 9 
2025; doi:10.1093/pm/pnaf032. 
2. 
Rowland B, Barth KS, Bell KM, et al. Baseline Characteristics of Participants in the BEST Clinical 
Trial: A Sequential Multiple Assignment Randomized Trial for Chronic Low Back Pain. 2025.  
3. 
Sperger J, Kidwell KM, Mauck MC, et al. Statistical Design and Rationale of the Biomarkers for 
Evaluating Spine Treatments (BEST) Trial. Preprint on arxiv.org, 2025. 
 


 
 
1 
 
Table 1.0. BEST Trial Recruitment Flow Diagram 
All Randomized Participants at Baseline 
 
Arm/Group Title 
Acceptance and 
Commitment Therapy 
(ACT) Alone 
ACT Plus Duloxetine, 
Moderate Treatment 
Response 
ACT Plus Evidence 
Based Exercise and 
Manual Therapy 
(EBEM), Moderate 
Stage 1 Treatment 
Response 
ACT Plus Enhanced 
Self-Care Therapy 
(ESC), Moderate Stage 
1 Treatment Response 
ACT Plus Duloxetine, 
Low Stage 1 Treatment 
Response 
ACT Plus Evidence 
Based Exercise and 
Manual Therapy 
(EBEM), Low Stage 1 
Treatment Response 
ACT Plus Enhanced 
Self-Care Therapy 
(ESC), Low Stage 1 
Treatment Response 
Arm/Group Description 
This arm included both 
participants who had a 
strong response to ACT 
in Stage 1 and 
participants who were 
not assessed for 
response at the end of 
Stage 1. In Stage 1, 
participants randomized 
to ACT took part in 12 
therapy sessions over 
the course of 12 weeks. 
Each participant was 
scheduled for a 
combination of 4 remote 
face-to-face visits and 8 
therapist-supported 
online sessions, which 
included a self-directed 
module combined with 
personalized provider 
coaching delivered via 
an online messaging 
system. In Stage 2, 
strong responders were 
encouraged to continue 
to practice ACT skills at 
home without therapist 
supervision and were 
given access to an 
additional 11 ACT audio 
modules. 
This arm included 
participants who had a 
moderate response to 
ACT in Stage 1 and 
started Duloxetine in 
Stage 2 while continuing 
ACT treatment. 
This arm included 
participants who had a 
moderate response to 
ACT in Stage 1 and 
started EBEM treatment 
in Stage 2 while 
continuing ACT. 
This arm included 
participants who had a 
moderate response to 
ACT in Stage 1 and 
started ESC treatment in 
Stage 2 while continuing 
ACT. 
This arm included 
participants who had a 
low response to ACT in 
Stage 1 and started 
Duloxetine treatment in 
Stage 2 while continuing 
ACT. 
This arm included 
participants who had a 
low response to ACT in 
Stage 1 and started 
EBEM treatment in 
Stage 2 while continuing 
ACT. 
This arm included 
participants who had a 
low response to ACT in 
Stage 1 and started ESC 
treatment in Stage 2 
while continuing ACT. 
Stage 1 Intervention 
(Weeks 0-12) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Screening 
(Week 12 Pre-
Randomization) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Intervention 
(Weeks 12-24) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 


 
 
Arm/Group Title 
ACT Followed by 
Duloxetine, Low Stage 
1 Treatment Response 
ACT Followed by 
Evidence Based 
Exercise and Manual 
Therapy (EBEM), Low 
Stage 1 Treatment 
Response 
ACT Followed by 
Enhanced Self-Care 
Therapy (ESC), Low 
Stage 1 Treatment 
Response 
ACT Followed by 
Duloxetine, Poor Stage 
1 Treatment Response 
ACT Followed by 
Evidence Based 
Exercise and Manual 
Therapy (EBEM), Poor 
Stage 1 Treatment 
Response 
ACT Followed by 
Enhanced Self-Care 
Therapy (ESC), Poor 
Stage 1 Treatment 
Response 
Duloxetine Alone 
Arm/Group Description 
This arm included 
participants who had a 
low response to ACT in 
Stage 1 and started 
Duloxetine treatment in 
Stage 2. ACT treatment 
was discontinued. 
This arm included 
participants who had a 
low response to ACT in 
Stage 1 and started 
EBEM treatment in 
Stage 2. ACT treatment 
was discontinued. 
This arm included 
participants who had a 
low response to ACT in 
Stage 1 and started ESC 
treatment in Stage 2. 
ACT treatment was 
discontinued. 
This arm included 
participants who had a 
poor response to ACT in 
Stage 1 and started 
Duloxetine treatment in 
Stage 2. ACT treatment 
was discontinued. 
This arm included 
participants who had a 
poor response to ACT in 
Stage 1 and started 
EBEM treatment in 
Stage 2. ACT treatment 
was discontinued. 
This arm included 
participants who had a 
poor response to ACT in 
Stage 1 and started ESC 
treatment in Stage 2. 
ACT treatment was 
discontinued. 
This arm included both 
participants who had a 
strong response to 
Duloxetine in Stage 1 
and participants who 
were not assessed for 
response at the end of 
Stage 1. 
Stage 1 Intervention 
(Weeks 0-12) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Screening 
(Week 12 Pre-
Randomization) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Intervention 
(Weeks 12-24) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 


 
 
Arm/Group Title 
Duloxetine Plus 
Acceptance and 
Commitment Therapy 
(ACT), Moderate Stage 
1 Treatment Response 
Duloxetine Plus 
Evidence Based 
Exercise and Manual 
Therapy (EBEM), 
Moderate Stage 1 
Treatment Response 
Duloxetine Plus 
Enhanced Self-Care 
Therapy (ESC), 
Moderate Stage 1 
Treatment Response 
Duloxetine Plus 
Acceptance and 
Commitment Therapy 
(ACT), Low Stage 1 
Treatment Response 
Duloxetine Plus 
Evidence Based 
Exercise and Manual 
Therapy (EBEM), Low 
Stage 1 Treatment 
Response 
Duloxetine Plus 
Enhanced Self-Care 
Therapy (ESC), Low 
Stage 1 Treatment 
Response 
Duloxetine Followed 
by Acceptance and 
Commitment Therapy 
(ACT), Low Stage 1 
Treatment Response 
Arm/Group Description 
This arm included 
participants who had a 
moderate response to 
Duloxetine in Stage 1 
and started ACT 
treatment in Stage 2 
while continuing 
Duloxetine. 
This arm included 
participants who had a 
moderate response to 
Duloxetine in Stage 1 
and started EBEM 
treatment in Stage 2 
while continuing 
Duloxetine. 
This arm included 
participants who had a 
moderate response to 
Duloxetine in Stage 1 
and started ESC 
treatment in Stage 2 
while continuing 
Duloxetine. 
This arm included 
participants who had a 
low response to 
Duloxetine in Stage 1 
and started ACT 
treatment in Stage 2 
while continuing 
Duloxetine. 
This arm included 
participants who had a 
low response to 
Duloxetine in Stage 1 
and started EBEM 
treatment in Stage 2 
while continuing 
Duloxetine. 
This arm included 
participants who had a 
low response to 
Duloxetine in Stage 1 
and started ESC 
treatment in Stage 2 
while continuing 
Duloxetine. 
This arm included 
participants who had a 
low response to 
Duloxetine in Stage 1 
and started ACT 
treatment in Stage 2. 
Duloxetine treatment 
was discontinued. 
Stage 1 Intervention 
(Weeks 0-12) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Screening 
(Week 12 Pre-
Randomization) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Intervention 
(Weeks 12-24) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 


 
 
Arm/Group Title 
Duloxetine Followed by 
Evidence Based 
Exercise and Manual 
Therapy (EBEM), Low 
Stage 1 Treatment 
Response 
Duloxetine Followed 
by Enhanced Self-Care 
Therapy (ESC), Low 
Stage 1 Treatment 
Response 
Duloxetine Followed 
by Acceptance and 
Commitment Therapy 
(ACT), Poor Stage 1 
Treatment Response 
Duloxetine Followed 
by Evidence Based 
Exercise and Manual 
Therapy (EBEM), Poor 
Stage 1 Treatment 
Response 
Duloxetine Followed 
by Enhanced Self-Care 
Therapy (ESC), Poor 
Stage 1 Treatment 
Response 
Evidence Based 
Exercise and Manual 
Therapy (EBEM) Alone 
EBEM Plus Duloxetine, 
Moderate Stage 1 
Treatment Response 
Arm/Group Description 
This arm included 
participants who had a 
low response to 
Duloxetine in Stage 1 
and started EBEM 
treatment in Stage 2. 
Duloxetine treatment 
was discontinued. 
This arm included 
participants who had a 
low response to 
Duloxetine in Stage 1 
and started ESC 
treatment in Stage 2. 
Duloxetine treatment 
was discontinued. 
This arm included 
participants who had a 
poor response to 
Duloxetine in Stage 1 
and started ACT 
treatment in Stage 2. 
Duloxetine treatment 
was discontinued. 
This arm included 
participants who had a 
poor response to 
Duloxetine in Stage 1 
and started EBEM 
treatment in Stage 2. 
Duloxetine treatment 
was discontinued. 
This arm included 
participants who had a 
poor response to 
Duloxetine in Stage 1 
and started ESC 
treatment in Stage 2. 
Duloxetine treatment 
was discontinued. 
This arm included both 
participants who had a 
strong response to 
EBEM in Stage 1 and 
participants who were 
not assessed for 
response at the end of 
Stage 1. 
This arm included 
participants who had a 
moderate response to 
EBEM in Stage 1 and 
started Duloxetine 
treatment in Stage 2 
while continuing EBEM. 
Stage 1 Intervention 
(Weeks 0-12) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Screening 
(Week 12 Pre-
Randomization) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Intervention 
(Weeks 12-24) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 


 
 
Arm/Group Title 
EBEM Plus Acceptance 
and Commitment 
Therapy (ACT), 
Moderate Stage 1 
Treatment Response 
EBEM Plus Enhanced 
Self-Care Therapy 
(ESC), Moderate Stage 
1 Treatment Response 
EBEM Plus Duloxetine, 
Low Stage 1 Treatment 
Response 
EBEM Plus 
Acceptance and 
Commitment Therapy 
(ACT), Low Stage 1 
Treatment Response 
EBEM Plus Enhanced 
Self-Care Therapy 
(ESC), Low Stage 1 
Treatment Response 
EBEM Followed by 
Duloxetine, Low Stage 
1 Treatment Response 
EBEM Followed by 
Acceptance and 
Commitment Therapy 
(ACT), Low Stage 1 
Treatment Response 
Arm/Group Description 
This arm included 
participants who had a 
moderate response to 
EBEM in Stage 1 and 
started ACT treatment in 
Stage 2 while continuing 
EBEM. 
This arm included 
participants who had a 
moderate response to 
EBEM in Stage 1 and 
started ESC treatment in 
Stage 2 while continuing 
EBEM. 
This arm included 
participants who had a 
low response to EBEM 
in Stage 1 and started 
Duloxetine treatment in 
Stage 2 while continuing 
EBEM. 
This arm included 
participants who had a 
low response to EBEM 
in Stage 1 and started 
ACT treatment in Stage 
2 while continuing 
EBEM. 
This arm included 
participants who had a 
low response to EBEM 
in Stage 1 and started 
ESC treatment in Stage 
2 while continuing 
EBEM. 
This arm included 
participants who had a 
low response to EBEM 
in Stage 1 and started 
Duloxetine treatment in 
Stage 2. EBEM 
treatment was 
discontinued. 
This arm included 
participants who had a 
low response to EBEM 
in Stage 1 and started 
ACT treatment in Stage 
2. EBEM treatment was 
discontinued. 
Stage 1 Intervention 
(Weeks 0-12) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Screening 
(Week 12 Pre-
Randomization) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 
Stage 2 Intervention 
(Weeks 12-24) 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
Reason Not Completed 
 
 
 
 
 
 
 


 
 
6 
 
Arm/Group Title 
EBEM Followed by 
Enhanced Self-Care 
Therapy (ESC), Low 
Stage 1 Treatment 
Response 
EBEM Followed by 
Duloxetine, Poor 
Stage 1 Treatment 
Response 
EBEM Followed by 
Acceptance and 
Commitment 
Therapy (ACT), Poor 
Stage 1 Treatment 
Response 
EBEM Followed by 
Enhanced Self-Care 
Therapy (ESC), Poor 
Stage 1 Treatment 
Response 
Enhanced Self-Care 
Therapy (ESC) 
Alone 
ESC Plus 
Duloxetine, 
Moderate to Low 
Stage 1 Treatment 
Response 
ESC Plus 
Acceptance and 
Commitment 
Therapy (ACT), 
Moderate to Low 
Stage 1 Treatment 
Response 
ESC Plus Evidence 
Based Exercise and 
Manual Therapy 
(EBEM), Moderate to 
Low Stage 1 
Treatment 
Response 
Arm/Group 
Description 
This arm included 
participants who had 
a low response to 
ESC in Stage 1 and 
started Duloxetine 
treatment in Stage 2. 
EBEM treatment was 
discontinued. 
This arm included 
participants who had 
a poor response to 
EBEM in Stage 1 and 
started Duloxetine 
treatment in Stage 2. 
EBEM treatment was 
discontinued. 
This arm included 
participants who had 
a poor response to 
EBEM in Stage 1 and 
started ACT 
treatment in Stage 2. 
EBEM treatment was 
discontinued. 
This arm included 
participants who had 
a poor response to 
EBEM in Stage 1 and 
started ESC 
treatment in Stage 2. 
EBEM treatment was 
discontinued. 
This arm included 
both participants who 
had a strong 
response to ESC in 
Stage 1 and 
participants who were 
not assessed for 
response at the end 
of Stage 1. 
This arm included 
participants who had 
a moderate to poor 
response to ESC in 
Stage 1 and started 
Duloxetine treatment 
in Stage 2. ESC 
treatment was 
discontinued. 
This arm included 
participants who had 
a moderate to poor 
response to ESC in 
Stage 1 and started 
ACT treatment in 
Stage 2. ESC 
treatment was 
discontinued. 
This arm included 
participants who had 
a moderate to poor 
response to ESC in 
Stage 1 and started 
EBEM treatment in 
Stage 2. ESC 
treatment was 
discontinued. 
Stage 1 Intervention 
(Weeks 0-12) 
 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
 
Reason Not 
Completed 
 
 
 
 
 
 
 
 
Stage 2 Screening 
(Week 12 Pre-
Randomization) 
 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
 
Reason Not 
Completed 
 
 
 
 
 
 
 
 
Stage 2 Intervention 
(Weeks 12-24) 
 
 
 
 
 
 
 
 
Started 
 
 
 
 
 
 
 
 
Completed 
 
 
 
 
 
 
 
 
Not Completed 
 
 
 
 
 
 
 
 
Reason Not 
Completed 
 
 
 
 
 
 
 
 
 


Table 1: Tabular Characteristics of Randomized Population 
Variable1  
ACT  
(N=203) 
Duloxetine  
(N=198) 
EBEM  
(N=199) 
ESC  
(N=205) 
Total  
(N=805) 
Age  
Age Group 
< 18 years 
18-65 years 
>65 years 
Sex Assigned at 
Birth, n(%)2  
Female  
Male  
Missing  
Gender Identity, 
n(%)  
Female  
Male  
Non-Binary  
Unknown  
Missing  
Ethnicity, n(%)  
Hispanic or Latino 
Not Hispanic or 
Latino  
Unknown/Not 
Reported  
Missing  
Race, n(%)  
White  
Black, African 
American, or  
Black Multiracial  
Asian or Asian 
Multiracial  
Indigenous or 
Indigenous 
Multiracial  
Unknown or Not 
Reported  
Missing  
Highest Level of 
Education 
Completed, n(%)  
Did not complete 
Secondary School 
or High School  
High School or 
Secondary School 
Degree Complete  


Associate's or 
Technical Degree 
Complete  
College or 
Baccalaureate 
Degree Complete  
Doctoral or 
Postgraduate 
Education  
Missing  
Current 
Employment Status, 
n(%)  
Full-time 
employment  
Not employed3  
Part-time 
employment  
Missing  
Current 
Relationship Status, 
n(%)  
Married  
Never married  
Domestic Partner  
Widowed  
Divorced or 
Separated  
Missing  
Number of People 
Living in Household, 
n(%)  
1  
2  
3  
4  
5  
6  
7  
8  
Missing  
Annual household 
income from all 
sources, n(%)  
      Less than 
$10,000  
      $10,000 to 
$24,999  
      $25,000 to 
$34,999  


      $35,000 to 
$49,999  
      $50,000 to 
$74,999  
      $75,000 to 
$99,999  
      $100,000 to 
$149,999  
      $150,000 to 
$199,999  
      $200,000 or more  
      Prefer not to 
answer  
Missing  
PEG score (0 to 10)  
PEG score, 
median 
(range)  
Self-reported low-
back pain duration 
(months)  
Self-reported low-
back pain duration, 
n(%)  
< 1 year  
1-5 years  
> 5 years  
Missing  
Low Back Pain 
Frequency in the 
Past 6 months, 
n(%)  
Every day or 
nearly every day  
At least half the 
days  
Low Back Pain 
Specific Pain 
Intensity, (0 to 10)  
Low Back Pain SPI,
median (range)  
Ever had low back 
operation, n(%)  
No  
Yes, at least one  
Missing  
When was last back 
operation, n(%)4  
Less than 6 
months ago  
More than 6 
months ago but 
less than 1 year 
ago  


Between 1 and 2 
years ago  
More than 2 years 
ago  
Any back operations 
involve a spinal 
fusion, n(%)4  
No  
Yes  
Not Sure  
Ever unemployed 
for 1 or more 
months due to low 
back pain, n(%)  
No  
Yes  
Does not apply  
Missing  
Ever filed or 
awarded worker's 
compensation claim 
related to back 
problem, n(%)  
No  
Yes  
Does not apply  
Missing  
Involved in a 
lawsuit or legal 
claim related to 
back problem, n(%)  
No  
Yes  
Not sure  
Missing  
Ever applied for, or 
received, disability 
insurance for pain 
condition, n(%)  
No  
Yes  
Missing  
BMI  
Systolic Blood 
Pressure (mmHg)  
Diastolic Blood 
Pressure (mmHg)  
Heart Rate (bpm)  


Ever Hip 
Replacement 
Surgery  
Yes  
No  
Missing  
Ever Knee 
Replacement 
Surgery  
Yes  
No  
Missing  
Observed Gait  
 Normal  
 Antalgic  
 Missing  
Tobacco Use in 
Previous 12 Months  
Daily or Almost 
Daily  
Less Than Daily  
Never  
Missing  
Alcohol Use in 
Previous 12 
Months5  
At Least Weekly  
Monthly  
Less Than 
Monthly  
Never  
Missing  
Drug Use in 
Previous 12 Months  
Daily or Almost 
Daily  
Between Monthly 
to Weekly  
Less Than 
Monthly  
Never  
Missing  
Prescription Drug 
Used Not as 
Intended in 
Previous 12 Months  
At Least Once  
Never  
Missing  


Currently Taking 
Opioid Medication 
(daily), n(%)  
Yes  
No  
Not sure  
Previously 
Diagnosed with 
COVID-19  
Yes  
No  
Not Sure  
Prefer not to 
Answer  
Missing  
Long COVID  
Yes  
No  
Not Sure  
Prefer not to 
Answer  
No self-reported 
COVID-19 
Diagnosis  
COVID-19 Vaccine  
Yes  
No  
Not Sure  
Prefer Not to 
Answer  
Fear-avoidance 
beliefs about 
physical activity raw
scoring scale 2  
GAD-2 Raw Score  
Keele STarT Back 
Screening Tool Risk, 
n(%)  
Low Risk  
Medium Risk  
High Risk  
Missing  
Oswestry Disability 
Index Percentage  
ODI Percentage, 
median (range)  
Pain 
Catastrophizing 
Scale SF-6  


PainDetect 
Questionnaire Raw 
Score  
Nociceptive Pain  
Possible 
Neuropathic Pain  
Neuropathic pain  
Missing  
PHQ-2 Raw Score  
HEAL Positive 
Outlook Raw Score  
PROMIS-Cognitive 
Function - Abilities 
2a Raw Score  
General Sensory 
Sensitivity Score - 
External  
General Sensory 
Sensitivity Score - 
Interoception  
General Sensory 
Sensitivity Score - 
Total  
Self-reported Sleep 
Duration in the Past 
Month (hours)  
Symptom Severity 
Index  
Widespread Pain 
Raw Score  
Stomach Pain in the 
Past 4 Weeks   
Not bothered at 
all  
Bothered a little  
Bothered a lot  
Missing  
Headaches in the 
Past 4 Weeks  
Not bothered at 
all  
Bothered a little  
Bothered a lot  
Missing  
Radiating Pain to 
Buttock/Thigh, Past 
2 Weeks  
Yes  
No  
Not Sure  
Missing  


Radiating Pain to 
Below Knee, Past 2 
Weeks  
Yes  
No  
Not Sure  
Missing  
Social Determinants 
of Health: 
Transportation 
Needs  
Yes  
No  
Missing  
Social Determinants 
of Health: 
Healthcare Needs  
Yes  
No  
Missing  
Social Determinants 
of Health: Food 
Insecurity  
Often True  
Sometimes True  
Never True  
Missing  
Social Determinants 
of Health: Food 
Money  
Often True  
Sometimes True  
Never True  
Missing  
Social Determinants 
of Health: Utilities  
Yes  
No  
Missing  
Social Determinants 
of Health: Stable 
Housing  
Yes  
No  
Missing  
Social Determinants 
of Health: Emotional 
Support  


Yes  
No  
Missing  
Social Determinants 
of Health: Number 
of Close Friends  
0  
1-2  
3-5  
6-10  
More than 10  
Missing  
Perceived 
Discrimination: 
Race/Ethnicity  
Never  
Rarely  
Sometimes  
Often to Almost 
Always  
Not sure  
Missing  
Perceived 
Discrimination: 
Orientation/Gender 
Identity  
Never  
Rarely  
Sometimes  
Often to Almost 
Always  
Not sure  
Missing  
 
1Discrete variable rows display count and percent, N (%). Continuous variable rows display mean and standard deviation, XX.X (YY.Y). 
2Sex assigned at birth is defined as the most commonly reported identity collected from a participant across all visits. 
3Counts retired, unemployed, and other participants who are not currently in the labor force. 
4Counts only include respondents who have answered either 'Yes, one operation' or 'Yes, more than one operation' when asked about prior low-back 
operations. 
5Participants who self-reported male sex at birth were asked about the frequency of >4 alcoholic drinks, while participants who self-reported female sex at 
birth were asked about the frequency of >3 alcoholic drinks. 
 


  
Appendix 3 Table 1: Clinical Trials Adverse Event Reporting Table All-Cause Mortality 
Population: All Participants Randomized to Stage 1 (N=805); Including All Participants Randomized to Stage 2 
(N=683) 
 
  All-Cause Mortality 
 
Stage 1 
ACT 
(N=xx) 
Stage 1 
Duloxeti
ne 
(N=xx) 
Stage 1 
EBEM 
(N=xx) 
Stage 1 
ESC 
(N=xx) 
Stage 2 
ACT 
(N=xx) 
Stage 2 
Duloxeti
ne 
(N=xx) 
Stage 2 
EBEM 
(N=xx) 
Stage 2 
ESC 
(N=xx) 
Stage 2 
ACT and 
Duloxeti
ne  
(N=xx) 
Stage 2 
ACT and 
EBEM 
(N=xx) 
Stage 2 
ACT and 
ESC 
(N=xx) 
Stage 2 
Duloxeti
ne  
and 
EBEM  
(N=xx) 
Stage 2 
Duloxeti
ne  
and ESC  
(N=xx) 
Stage 2 
EBEM 
and ESC 
(N=xx) 
 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Affected / 
at Risk 
(%) 
Total 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
x/N 
(x.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
Appendix 3 Table 2: Clinical Trials Adverse Event Reporting Table Serious Adverse 
Events 
Population: All Participants Randomized to Stage 1 (N=805); Including All Participants Randomized to Stage 2 
(N=683) 
 
 
    Serious Adverse Events 
System 
Organ 
Class  
Preferred 
Term 
Stage 1 ACT (N=xx) 
Stage 1 Duloxetine (N=xx) 
 
Stage 1 EBEM (N=xx) 
 
Stage 1 ESC (N=xx) 
 
  
 Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
  
Total 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
  
 
System 
Organ 
Class A  
Preferred 
Term A1
x/N (x.x%) 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
System 
Organ 
Class A  
 
Preferred 
Term A2
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B1
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B2
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
 
 
 
 
 
    Serious Adverse Events 
System 
Organ 
Class  
Preferred 
Term  
Stage 2 ACT (N=xx) 
Stage 2 Duloxetine (N=xx) 
 
Stage 2 EBEM (N=xx) 
 
Stage 2 ESC (N=xx) 
 
  
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
  
Total  
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
  
 
System 
Organ 
Class A  
Preferred 
Term A1  
x/N (x.x%) 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
System 
Organ 
Class A  
 
Preferred 
Term A2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B1  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
 
 
 
 
 
    Serious Adverse Events 
System 
Organ 
Class  
Preferred 
Term  
Stage 2 ACT and 
Duloxetine (N=xx) 
Stage 2 ACT and EBEM (N=xx) 
 
Stage 2 ACT and ESC 
(N=xx) 
 
Stage 2 Duloxetine and EBEM 
(N=xx) 
 
  
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 


  
  
Total  
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
  
 
System 
Organ 
Class A  
Preferred 
Term A1  
x/N (x.x%) 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
System 
Organ 
Class A  
 
Preferred 
Term A2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B1  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
 
 
 
 
    Serious Adverse Events 
System 
Organ 
Class  
Preferred 
Term  
Stage 2 Duloxetine and 
ESC(N=xx) 
Stage 2 EBEM and ESC (N=xx) 
 
  
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
  
Total  
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
  
 
System 
Organ 
Class A  
Preferred 
Term A1  
x/N (x.x%) 
y  
x/N (x.x%) 
 
y  
System 
Organ 
Class A  
 
Preferred 
Term A2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B1  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
 
 


  
Appendix 3 Table 3: Clinical Trials Adverse Event Reporting Table Other (Not 
Including Serious) Adverse Events Over a Threshold of 5% 
Population: All Participants Randomized to Stage 1 (N=805); Including All Participants Randomized to Stage 2 
(N=683) 
 
 
 
    Other (Not Including Serious) Adverse Events 
Frequency Threshold 
for Reporting Other 
Adverse Events 
5% 
System 
Organ 
Class  
Preferred
Term 
Stage 1 ACT (N=xx) 
Stage 1 Duloxetine (N=xx) 
 
Stage 1 EBEM (N=xx) 
 
Stage 1 ESC (N=xx) 
 
  
 Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
  
Total 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
  
 
System 
Organ 
Class A  
Preferred
Term A1
x/N (x.x%) 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
System 
Organ 
Class A  
 
Preferred
Term A2
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred
Term B1
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred
Term B2
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
 
 
 
 
 
    Other (Not Including Serious) Adverse Events 
Frequency 
Threshold for 
Reporting Other 
Adverse Events 
5% 
System 
Organ 
Class  
Preferred 
Term  
Stage 2 ACT (N=xx) 
Stage 2 Duloxetine (N=xx) 
 
Stage 2 EBEM (N=xx) 
 
Stage 2 ESC (N=xx) 
 
  
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
  
Total  
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
  
 
System 
Organ 
Class A  
Preferred 
Term A1  
x/N (x.x%) 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
System 
Organ 
Class A  
 
Preferred 
Term A2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B1  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
 
 
 


  
 
 
    Other (Not Including Serious) Adverse Events 
Frequency 
Threshold for 
Reporting Other 
Adverse Events 
5% 
System 
Organ 
Class  
Preferred 
Term  
Stage 2 ACT and 
Duloxetine (N=xx) 
Stage 2 ACT and EBEM (N=xx) 
 
Stage 2 ACT and ESC 
(N=xx) 
 
Stage 2 Duloxetine and EBEM 
(N=xx) 
 
  
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
  
Total  
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
 
  
 
System 
Organ 
Class A  
Preferred 
Term A1  
x/N (x.x%) 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
x/N (x.x%) 
 
y  
System 
Organ 
Class A  
 
Preferred 
Term A2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B1  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
x/N (x.x%) 
 
y 
 
 
 
 
 
     Other (Not Including Serious) Adverse Events 
Frequency 
Threshold for 
Reporting Other 
Adverse Events 
5% 
System 
Organ 
Class  
Preferred 
Term  
Stage 2 Duloxetine and 
ESC(N=xx) 
Stage 2 EBEM and ESC (N=xx) 
 
  
 
Affected / at 
Risk (%) 
# Events 
 
Affected / at Risk 
(%) 
# Events 
 
  
Total  
x/N (x.x%) 
 
y 
x/N (x.x%) 
 
y 
  
 
System 
Organ 
Class A  
Preferred 
Term A1  
x/N (x.x%) 
y  
x/N (x.x%) 
 
y  
System 
Organ 
Class A  
 
Preferred 
Term A2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B1  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
System 
Organ 
Class B  
 
Preferred 
Term B2  
x/N (x.x%) 
y 
 
x/N (x.x%) 
 
y 
 
 

Prot_001.pdf: 
0The BEST Trial: Biomarkers for Evaluating Spine Treatments 
Study Protocol 
Protocol Number: 00057948 
National Clinical Trial (NCT) Identified Number: NCT05396014 
Protocol Co-Chairs:  
Daniel Clauw, MD; Gwendolyn Sowa, MD, PhD  
Matthew Mauck, MD, PhD; Kevin Anstrom, PhD 
Sponsor: The Helping to End Addiction Long-termSM Initiative (NIH HEAL 
InitiativeSM) 
Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS) 
Version Number:  7.0 
Version Date:    September 1, 2023


 
BEST Trial Protocol v7.0 
ii 
9/1/2023 
Table of Contents 
1. 
SUMMARY OF CHANGES FROM PREVIOUS VERSIONS ................................................... 1 
2. 
STATEMENT OF COMPLIANCE ................................................................................................. 9 
3. 
PROTOCOL CHAIRS AND KEY PERSONNEL ...................................................................... 10 
4. 
PROTOCOL SUMMARY ............................................................................................................... 1 
4.1. 
Synopsis ................................................................................................................................. 1 
4.2. 
Schema ................................................................................................................................... 6 
4.3. 
Schedule of Activities (SoA) ................................................................................................ 7 
5. 
INTRODUCTION ............................................................................................................................ 7 
5.1. 
Study Background and Rationale ....................................................................................... 7 
5.2. 
Risk/Benefit Assessment ..................................................................................................... 8 
5.2.1. 
Known Potential Risks ........................................................................................ 8 
5.2.2. 
Known Potential Benefits ................................................................................. 10 
5.2.3. 
Assessment and Mitigation of Potential Risks .............................................. 11 
5.2.4. 
Risk/Benefit Justification .................................................................................. 14 
6. 
OBJECTIVES AND ENDPOINTS .............................................................................................. 14 
7. 
STUDY DESIGN ........................................................................................................................... 16 
7.1. 
Overall Design ..................................................................................................................... 16 
7.2. 
Scientific Rationale for Study Design ............................................................................... 18 
7.3. 
Justification for Dose/Intervention Regimens ................................................................. 19 
7.4. 
End of Study Definition ....................................................................................................... 19 
8. 
STUDY POPULATION ................................................................................................................. 19 
8.1. 
Study Inclusion Criteria ...................................................................................................... 19 
8.2. 
Study Exclusion Criteria ..................................................................................................... 19 
8.3. 
Study Intervention Contraindications ............................................................................... 20 
8.4. 
Phenotyping Contraindications ......................................................................................... 21 
8.5. 
Lifestyle Considerations ..................................................................................................... 22 
8.6. 
Screen Failures ................................................................................................................... 22 
8.7. 
Strategies for Recruitment and Retention ....................................................................... 22 
9. 
PHENOTYPIC ASSESSMENTS ................................................................................................ 23 
9.1. 
Questionnaires .................................................................................................................... 24 
9.2. 
Blood Draw / Venipuncture ................................................................................................ 24 
9.3. 
Stool Collection .................................................................................................................... 24 
9.4. 
Biomechanical Assessment .............................................................................................. 24 
9.5. 
Imaging ................................................................................................................................. 25 
9.6. 
Quantitative Sensory Testing ............................................................................................ 26 
10. 
STUDY INTERVENTIONS .......................................................................................................... 27 
10.1. 
Study Intervention(s) Administration: Acceptance Commitment Therapy .................. 27 
10.1.1. 
Study Intervention Description ........................................................................ 27 
10.1.2. 
Dosing and Administration ............................................................................... 28 
10.1.3. 
Acquisition and Accountability ......................................................................... 29 
10.1.4. 
Study Intervention Compliance ....................................................................... 29 
10.2. 
Study Intervention(s) Administration: Duloxetine ........................................................... 30 
10.2.1. 
Dosing and Administration ............................................................................... 30 
10.2.2. 
Acquisition and Accountability ......................................................................... 32 
10.2.3. 
Formulation, Appearance, Packaging, and Labeling ................................... 32 
10.2.4. 
Product Storage and Stability .......................................................................... 32 
10.2.5. 
Preparation ......................................................................................................... 32 


 
BEST Trial Protocol v7.0 
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9/1/2023 
10.2.6. 
Study Intervention Compliance ....................................................................... 32 
10.3. 
Study Intervention(s) Administration: Enhanced Self-Care .......................................... 33 
10.3.1. 
Dosing and Administration ............................................................................... 33 
10.3.2. 
Acquisition and Accountability ......................................................................... 35 
10.3.3. 
Study Intervention Compliance ....................................................................... 35 
10.4. 
Study Intervention(s) Administration: Evidence-Based Exercise and Manual 
Therapy 35 
10.4.1. 
Dosing and Administration ............................................................................... 36 
10.4.2. 
Acquisition and Accountability ......................................................................... 37 
10.4.3. 
Study Intervention Compliance ....................................................................... 37 
10.4.4. 
Measures to Minimize Bias: Randomization and Blinding .......................... 37 
11. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................... 39 
11.1. 
Discontinuation of Study Intervention .............................................................................. 39 
11.2. 
Participant Discontinuation/Withdrawal from the Study ................................................ 39 
11.3. 
Lost to Follow-Up ................................................................................................................ 40 
12. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 40 
12.1. 
Efficacy Assessments ........................................................................................................ 40 
12.2. 
Safety Assessments ........................................................................................................... 41 
12.3. 
Adverse Events and Serious Adverse Events ................................................................ 41 
12.3.1. 
Definition of Adverse Events (AE) .................................................................. 42 
12.3.2. 
Definition of Serious Adverse Events (SAE) ................................................. 42 
12.3.3. 
Classification of an Adverse Event ................................................................. 42 
12.3.4. 
Time Period and Frequency for Event Assessment and Follow-Up ......... 43 
12.3.5. 
Adverse Event Reporting ................................................................................. 44 
12.3.6. 
Reporting Events to Participants .................................................................... 44 
12.4. 
Unanticipated Problems ..................................................................................................... 45 
12.4.1. 
Definition of Unanticipated Problems (UP) .................................................... 45 
12.4.2. 
Unanticipated Problem Reporting ................................................................... 45 
13. 
STATISTICAL CONSIDERATIONS ........................................................................................... 45 
13.1. 
Statistical Hypotheses ........................................................................................................ 45 
13.2. 
Sample Size Determination ............................................................................................... 47 
13.3. 
Populations for Analyses ................................................................................................... 50 
13.4. 
Statistical Analyses ............................................................................................................. 50 
13.4.1. 
General Approach ............................................................................................. 50 
13.4.2. 
Analysis of the Primary Efficacy Endpoint(s) ................................................ 51 
13.4.3. 
Analysis of the Secondary Endpoint(s) .......................................................... 51 
13.4.4. 
Safety Analyses ................................................................................................. 51 
13.4.5. 
Baseline Descriptive Statistics ........................................................................ 51 
13.4.6. 
Planned Interim Analyses ................................................................................ 51 
13.4.7. 
Sub-Group Analyses......................................................................................... 51 
13.4.8. 
Tabulation of Individual Participant Data ....................................................... 51 
13.4.9. 
Exploratory Analyses ........................................................................................ 51 
14. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............. 52 
14.1. 
Regulatory, Ethical, and Study Oversight Considerations ............................................ 52 
14.1.1. 
Informed Consent Process .............................................................................. 52 
14.1.2. 
Consent/assent and Other Informational Documents Provided to 
Participants 
53 
14.1.3. 
Consent Procedures and Documentation ..................................................... 54 


 
BEST Trial Protocol v7.0 
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9/1/2023 
14.1.4. 
Study Discontinuation and Closure ................................................................ 54 
14.1.5. 
Confidentiality and Privacy .............................................................................. 55 
14.1.6. 
Future Use of Stored Specimens and Data .................................................. 55 
14.1.7. 
Key Roles and Study Governance ................................................................. 56 
14.1.8. 
Safety Oversight ................................................................................................ 56 
14.1.9. 
Clinical Monitoring ............................................................................................. 58 
14.1.10. 
Quality Assurance and Quality Control .......................................................... 59 
14.1.11. 
Data Handling and Record Keeping ............................................................... 60 
14.1.12. 
Data Collection and Management Responsibilities ..................................... 60 
14.1.13. 
Study Records Retention ................................................................................. 61 
14.1.14. 
Protocol Deviations ........................................................................................... 61 
14.1.15. 
Publication and Data Sharing Policy .............................................................. 61 
14.1.16. 
Conflict of Interest Policy ................................................................................. 62 
14.2. 
Abbreviations ....................................................................................................................... 63 
15. 
REFERENCES .............................................................................................................................. 65 
16. 
SURVEY QUESTIONNAIRES .................................................................................................... 70 
17. 
Appendix A:  Schedule of Activities ........................................................................................... 71 
 
 
 


 
BEST Trial Protocol v7.0 
1 
9/1/2023 
1. 
SUMMARY OF CHANGES FROM PREVIOUS VERSIONS 
 
Version 
Date of 
Revision 
Section(s) 
Summary of Revisions Made 
Rationale 
2.0 
4/20/2022 
Title Page 
Added document title 
  
2.0 
4/20/2022 
Title Page 
Revised protocol chair names 
Kevin Anstrom replaced 
Matt Psioda April 2022 
2.0 
4/20/2022 
Title Page 
Added protocol number 
  
2.0 
4/20/2022 
3 
Updated Protocol Chairs and 
Key Personnel  
Removed Derr per Derr 
request to avoid conflict of 
interest 
Added Rachel Goolsby as 
Project Manager 
2.0 
4/20/2022 
All 
Acronyms added at first 
mention 
  
2.0 
4/20/22022 
4.1 
Objectives clarified 
Per 2/11/22 DSMB request 
2.0 
4/20/22022 
4.1 
Revised duloxetine section  
Revised to reflect 
intervention protocol 
changes, number of sites, 
and revised study launch 
2.0 
4/20/2022 
4.1 
Revised EBEM section 
2.0 
4/20/2022 
4.1 
Revised study length 
2.0 
4/20/2022 
4.2 
Revised schema 
Corrected timing of 
screening call 
2.0 
4/20/2022 
4.3 
Updated Schedule of Activities 
  
2.0 
4/20/2022 
5.2 
 Added duloxetine exclusion 
criteria to risk language 
  
2.0 
4/20/2022 
5.2 
Clarified and corrected risk 
language 
  
2.0 
4/20/2022 
8.1-8.4 
Updated inclusion/exclusion 
criteria and contraindications 
  
2.0 
4/20/2022 
8.7 
Revised recruitment strategies 
Revised to account for site-
specific restrictions 
2.0 
4/20/2022 
9.2 
Updated blood draw protocol 
  
2.0 
4/20/2022 
9.5 
Updated imaging protocol 
  
2.0 
4/20/2022 
10.2 
Updated duloxetine protocol 
  
2.0 
4/20/2022 
10.4 
Updated EBEM protocol 
  
2.0 
4/20/2022 
10.5 
Updated randomization 
methods 
  
2.0 
4/20/2022 
12.2 
Clarified and corrected time 
points at which pregnancy 
status is assessed 
  
 
 


 
BEST Trial Protocol v7.0 
2 
9/1/2023 
Version 
Date of 
Revision 
Section(s) 
Summary of Revisions Made 
Rationale 
2.0 
4/20/2022 
12.3 
Clarified and corrected AE, 
SAE, and UP definitions and 
reporting requirements 
Per 2/11/22 DSMB request 
2.0 
4/20/2022 
13 
Clarified statistical methods 
  
2.0 
4/20/2022 
14.1 
Corrected safety oversight 
language 
Per 2/11/22 DSMB request 
2.0 
4/20/2022 
14.1 
Added data security language 
  
2.0 
4/20/2022 
14.2 
Removed unnecessary listings 
Per 2/11/22 DSMB request 
2.0 
4/26/2022 
All 
Revised “investigational drug 
pharmacy” to “approved 
pharmacy” 
Not all sites will utilize 
Investigational Drug 
Services 
2.0 
4/26/2022 
10.2 
Revised unused pill protocol to 
in-person returns only 
 
3.0 
5/27/2022 
Title Page 
Added National Clinical Trial 
(NCT) Identified Number 
NCT Record created 
3.0 
6/7/2022 
3.0 
Added Anastasia Ivanova, PhD 
as BEST Lead Biostatician 
 
3.0 
6/6/2022 
5.2.1 
Added “MRS of the spine” to 
description of additional 
imaging procedures a subset 
of participants may undergo 
Increased clarity 
3.0 
6/6/2022 
8.3 
Clarified EBEM intervention 
contraindications 
Split two contraindications 
previously combined into 
one bullet into 2 bullets 
3.0 
6/3/2022 
8.4 
Revised Imaging Phenotyping 
Contraindications 
Removed two previous 
contraindications that are 
no longer being assessed 
and identified an additional 
contraindication for the 
spine MRS 
3.0 
6/3/2022 
8.7 
Added more specific 
information about ICD10 
codes and keywords 
coordinators may use to 
identify participants in the 
EMR 
Per site request 
3.0 
6/6/2022 
9 
Changed “more 
comprehensive spin MRI” to 
The additional/deep 
phenotyping spine scan 


 
BEST Trial Protocol v7.0 
3 
9/1/2023 
“spine MRS” and removed 
“longer than the required 
MRI” from the duration 
description 
now only consists of the 
spine MRS 
 3.0 
5/27/2022 
9.2 
Revised list of blood tubes 
collected and which blood 
samples are stored for possible 
future analyses 
Corrected errors 
3.0 
6/6/2022 
9.5 
Changed “additional MRI scans 
of their spine” to “a MRS scan 
of their spine”  
The additional/deep 
phenotyping spine scan 
now only consists of the 
spine MRS 
3.0 
6/7/2022 
13.3 
Added Safety Population and 
Modified Intention to 
Treatment Population 
 
 3.0 
5/27/2022 
14.1.10  
Added information about 
Magnetic Resonance Imaging 
(MRI) Quality Control 
Added extra measures 
taken to ensure QC of MRI 
data 
4.0 
6/30/2022 
4.1, 6, 7.1, 
7.2, 13.1 
Clarified language throughout 
regarding the primary 
outcome of the trial. 
Clarification from statistical 
team 
4.0 
6/30/2022 
4.1, 5.1, 7.1 
Updated ordering of 
interventions 
Clarification from statistical 
team 
4.0 
6/28/2022 
4.1, 10.3, 
10.3.1 
Corrected duration of ESC 
intervention 
Correction from ESC team 
4.0 
6/28/2022 
4.1, 10.3 
Changed information about 
texts and emails received 
during ESC intervention 
Correction from ESC team 
4.0 
6/30/2022 
7.1, 10.5, 
13.2 
Clarified that sample size 
simulations yield approximate 
results 
Clarification from statistical 
team 
4.0 
7/5/2022 
8.3 
Added breastfeeding as a 
contraindication for the 
duloxetine intervention 
ELC decision 7/6/2022 
4.0 
6/28/2022 
10.3 
Added information about 
Walking Program module in 
PainGuide 
Correction from ESC team 
4.0 
6/28/2022 
10.3.1 
Removed information about 
ESC intervention summary 
module 
Correction from ESC team 
4.0 
6/28/2022 
10.3.1 
Updated information about 
FitBit step monitoring 
Correction from ESC team 
4.0 
6/28/2022 
10.3.1 
Updated numbering of ESC 
modules 
Correction from ESC team 
4.0 
6/30/2022 
10.5 
Minimization covariates are 
binary yes/no 
Clarification from statistical 
team 


 
BEST Trial Protocol v7.0 
4 
9/1/2023 
4.0 
6/30/2022 
13.3 
Updated analysis populations 
Clarification from statistical 
team 
4.0 
6/13/2022 
14.1.10 
Changed information about 
Magnetic Resonance Imaging 
(MRI) Quality Control of Brain 
Images 
Planned human scan is not 
required to occur prior to 
scanning research 
participants 
4.0 
7/22/2022 
5.2.1 
Corrected language used and 
timeline specified in Risks 
Associated with Confidential 
Information Disclosure 
 
4.0 
7/22/2022 
9.2 
Updated batch shipping 
schedule and timepoints 
 
4.0 
7/22/2022 
6 
Corrected randomization visits 
specified in description of 
secondary objectives 
 
4.0 
8/1/2022 
9.5 
Added language about imaging 
test scans 
 
4.0 
8/8/2022 
9.6 
Updated information about 
Temporal Summation and 
Conditioned Pain Modulation 
tests 
 
4.0 
9/12/2022 
9 
Corrected time needed for 
required phenotyping activities 
and additional phenotyping 
activities 
Corrected discrepancy 
between Protocol and ICF 
4.0 
9/12/2022 
5.2.1, 8.4, 
9, 9.5 
Changed “a MRS scan of their 
spine” back to “advanced MRI 
scans of their spine” 
Imaging team has decided 
to revert to “advanced 
spine MRI’ terminology 
4.0 
9/13/2022 
8.2 
Updated exclusion criterion 
related to autoimmune 
disorders (increased 
specificity) 
ELC decision 9/13/2022 
4.0 
9/28/2022 
4.2 
Corrected timing of Screening 
Call 2 indicated in Schema 
 
4.0 
10/6/2022 
4.1, 10.2.1 
Corrected number of pills 
dispensed to cover longest 
time between visits 
 
4.0 
10/6/2022 
10.2.4 
Clarified language regarding 
study drug shipments 
 
4.0 
10/6/2022 
4.1, 7.4 
Corrected study duration 
 
4.0 
10/7/2022 
6.0 
Corrected visit # of follow-up 
visit 
 
4.0 
10/7/2022 
8.1 
Revised Run-In eligibility 
requirement to allow more 
time to watch videos and to 
ELC decision 10/5/2022 


 
BEST Trial Protocol v7.0 
5 
9/1/2023 
reduce the # of required 
response to the daily pain 
questions 
4.0 
10/7/2022 
8.3 
Enhanced and clarified 
contraindications to ACT 
 
4.0 
10/12/2022 
9.4 
Clarified language regarding 
additional biomechanical 
assessments 
 
4.0 
10/12/2022 
9.5  
Corrected and clarified 
imaging data flow 
 
4.0 
10/12/2022 
10.1.1 
Deleted incorrect language 
regarding missed ACT 
appointments  
 
4.0 
10/12/2022 
10.2 
Deleted incorrect citation 
 
4.0 
10/12/2022 
10.2.6 
Deleted incorrect language 
regarding duloxetine non-
compliance 
 
4.0 
10/12/2022 
10.4.1 
Clarified number of EBEM 
visits and expectations 
regarding the frequency of 
EBEM fidelity assessments 
 
4.0 
10/12/2022 
11.3 
Corrected definition of Lost to 
Follow-Up 
 
4.0 
10/12/2022 
12.2 
Deleted incorrect information 
regarding tapering duloxetine 
 
4.0 
10/12/2022 
14.1.10 
Corrected timing of 
harmonization scans 
ECL decision 
4.0 
10/12/2022 
14.1.14 
Defined order of phenotyping 
assessments and associated 
protocol deviations 
 
4.0 
10/17/2022 
10.2.1 
Clarified who may conduct the 
physical assessments 
 
4.0 
10/20/22 
5.2.1, 5.2.3, 
8.4, 9, 9.5, 
14.1.14 
Removed clinical spine x-ray 
from phenotypical 
assessments 
Trial leadership/clinicians 
decision 
4.0 
10/20/22 
9 
Changed duration of required 
phenotypical assessments to 
approximately 3 to 5 hours 
 
4.0 
10/20/22 
9 
Table: changed motion 
assessment to 20 minutes and 
changed basic spine MRI to 60 
minutes 
 
4.0 
10/20/22 
10.4.3 
Delete non-compliance 
definition 
 


 
BEST Trial Protocol v7.0 
6 
9/1/2023 
4.0 
10/20/22 
16 
Added footnote regarding 
piloting of NHANES Food 
Frequency Questionnaire 
 
4.0 
10/20/22 
5.2.1 
Changed duloxetine dosage 
increase from gradual to 
increase after seven days, if no 
serious side effects 
 
4.0 
10/20/22 
5.2.1 
Added participants who are 
currently breastfeeding will be 
excluded from duloxetine 
intervention 
 
4.0 
10/20/22 
7.1 
Clarified the timing of the 
PROs and phenotypical 
assessments 
 
4.0 
10/20/22 
9.2 
Changed timing of batch 
sample shipments 
 
4.0 
10/20/22 
9.4 
Changed duration of additional 
biomechanical assessment to 
50-60 minutes 
 
4.0 
10/20/22 
10.2.4 
Removed log of minimum and 
maximum reading as a 
requirement 
 
4.0 
10/20/22 
14.1.3 
Clarified that re-consent is 
allowed remotely with prior 
permission from DAC 
 
4.0 
10/20/22 
14.1.14 
Added incorrect number of 
pills administered to 
participant as a protocol 
deviation 
 
4.0 
10/20/22 
Appendix A 
Updated Schedule of Activities 
 
4.0 
11/4/22 
8.4 
Removed hardware between 
T12 and S1 as a 
contraindication for the MRS  
 
5.0 
2/7/23 
Study 
Description, 
7.1, 8.1, 
10.4.4 
Removed references to post-
Run-In PEG score as an 
eligibility criterion 
 
5.0 
2/7/23 
7.4 
Removed in-person visit 
requirement for 
discontinuation 
 
5.0 
2/7/23 
7.4 
Extended study length 
estimate 
 
5.0 
2/7/23 
8.3 
Clarified EBEM and ACT 
exclusion criteria for treatment 
overlap 
 


 
BEST Trial Protocol v7.0 
7 
9/1/2023 
5.0 
2/7/23 
8.3 
Added to and clarified 
duloxetine contraindications 
 
5.0 
2/7/23 
8.7 
Added recruitment and 
retention referral language 
 
5.0 
2/7/23 
9.4, 9.5, 
9.6, 14.1.1 
Clarified language regarding 
participation in additional 
(deep) phenotyping 
 
5.0 
2/7/23 
10.2.1 
Added Physical Therapists 
 
5.0 
2/8/23 
6.0 
Corrected measurements 
informing stage 2 
randomization 
 
6.0 
4/3/2023 
9, 10.2.1, 
12.2, 12.3.1 
Corrected references to a 
physical exam to instead 
reference the study physical 
assessment 
 
6.0 
5/11/2023 
8.7 
Added online survey as 
recruitment method 
ELC approval 5/10/2023 
6.0 
5/15/2023 
10.2.6 
Added instructions for 
duloxetine dispensation at 
Visit 1 for sites who ship study 
medication 
 
6.0 
5/15/2023 
11.2 
Added safety concerns for staff 
as a reason to discontinue a 
participant 
 
6.0 
5/31/2023 
12.3.4 
Added that AEs followed until 
resolution, stabilization, or 
participant is off study. 
 
6.0 
6/15/2023 
4.1, 7.1, 
7.4, SOA 
Removed “subset of 
participants” from Week 36 
assessment 
 
6.0 
6/15/2023 
7.4 
Removed timeframe for end of 
study 
 
6.0 
6/16/2023 
8.1 
Removed respond to 5 emails 
during Run-in as an inclusion 
criterion 
ELC decision 6/16/2023 
6.0 
6/19/2023 
4.1, 10.2.1 
Added tapering instructions for 
duloxetine  
ELC decision 5/31/2023 
6.0 
6/19/2023 
10.2.1 
Added a reminder that study 
treatment will end in six weeks 
to 18-week phone call, in case 
participant would like to 
schedule an appointment with 
their provider to continue their 
treatment after Visit 2. 
ELC decision 6/7/2023 


 
BEST Trial Protocol v7.0 
8 
9/1/2023 
7.0 
9/1/2023 
4.1, 10.2.1 
Added an additional week to 
the tapering period at the 
investigator or licensed 
designee’s discretion 
ELC decision 8/23/2023 
 
 


 
BEST Trial Protocol v7.0 
9 
9/1/2023 
2. 
STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with the United States (US) Code of Federal Regulations (CFR) 
applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 
CFR Part 812) and NIAMS Terms and Conditions of Award. The study is being conducted under an NIH 
HEAL Initiative application. 
Principal Investigators (PIs) will assure that no deviation from or changes to the protocol will take place 
without prior agreement from the Back Pain Consortium (BACPAC) Research Program and NIAMS (as 
funding agency), and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the 
conduct of this study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the central IRB for review and approval.  Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study.  When changes are 
made to the consent form; a determination will be made regarding whether a new consent needs to be 
obtained from participants who had provided consent earlier using a previously approved consent form. 
 
 


 
BEST Trial Protocol v7.0 
10 
9/1/2023 
3. 
PROTOCOL CHAIRS AND KEY PERSONNEL 
 
Protocol Co-Chair 
Dan Clauw, MD 
University of Michigan at Ann Arbor 
Chronic Pain and Fatigue Research Center 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
734-476-0182 
dclauw@med.umich.edu 
Protocol Co-Chair 
Gwendolyn Sowa, MD, PhD 
University of Pittsburgh 
Departments of Physical Medicine and Rehabilitation 
and Orthopaedic Surgery 
3471 Fifth Avenue, Suite 1103 
Pittsburgh, PA 15213 
412-692-4400 
sowaga@upmc.edu 
Protocol Co-Chair 
Matt Mauck, MD PhD 
UNC Hospitals 
Department of Anesthesiology 
101 Manning Drive, N2198 
Chapel Hill NC 27599-7010 
919-966-5136 
matt_mauck@med.unc.edu 
Protocol Co-Chair  
Kevin Anstrom, PhD 
University of North Carolina at Chapel Hill  
Department of Biostatistics 
123 W. Franklin Street, Suite 450 
Chapel Hill, NC  27516 
919-962-2190 
kevin.anstrom@unc.edu 
BEST Trial Project Manager 
Rachel Goolsby 
University of North Carolina at Chapel Hill  
Collaborative Studies Coordinating Center 
123 W. Franklin Street, Suite 450 
Chapel Hill, NC  27516 
919-843-0685 
rwgoolsby@unc.edu 
 
BACPAC Project Director 
Anna Hoffmeyer, MPH 
University of North Carolina at Chapel Hill  
Collaborative Studies Coordinating Center 
123 W. Franklin Street, Suite 450 
Chapel Hill, NC  27516 
919-962-4390 
ahoffmeyer@unc.edu 
 
BEST Trial Lead Biostatistician 
Anastasia Ivanova, PhD 
University of North Carolina at Chapel Hill 
Department of Biostatistics 
3103-C McGavran-Greenberg Hall CB #7420 
Chapel Hill, NC 27599 
(919) 843-8086 
aivanova@bios.unc.edu 
 
 
 


 
BEST Trial Protocol v7.0 
1 
9/1/2023 
4. 
PROTOCOL SUMMARY 
4.1. SYNOPSIS  
Title: 
The BEST Trial: Biomarkers for Evaluating Spine Treatments 
 
 
Background and 
Rationale: 
Chronic low-back pain lasting three months or more with pain occurring 
on most days affects 10-20% of adults in the United States, and 
contributes to lost employment, disability, and, by some estimates, $100 
billion in US health care expenditures annually1-3. In the 2010 Global 
Burden of Disease Survey, low back pain was ranked highest among 291 
conditions in terms of years lived with disability2,4. Sufferers, who are 
disproportionately women and people with low socioeconomic status, 
contend with physical pain, limited mobility, and mental health 
symptoms2. Chronic low-back pain is second only to cancer in number of 
opioids prescribed, and opioids are the most commonly prescribed class 
of drugs for low-back pain, despite limited evidence of efficacy in chronic 
pain and the significant risks of side effects, addiction, and death.   
While a broad range of treatments exists, current treatments do not 
adequately resolve chronic low-back pain for most patients. Systematic 
reviews of common treatments find small to moderate evidence to 
support many currently used treatments.   
Research into optimum treatment for chronic low-back pain is challenging 
due to the diverse etiology of back pain and the varied phenotypes of 
back pain patients. Additional research priorities include patient 
phenotyping and sub-group stratification and the development of 
pharmacological and non-pharmacological first-line treatments for 
chronic low-back pain. 
Through its Helping to End Addiction Long-termSM Initiative, or NIH HEAL 
InitiativeSM, the NIH seeks an improved understanding of the underlying 
biological mechanisms of chronic pain and supports the discovery and 
testing of novel non-addictive pain treatments to stem the ongoing opioid 
crisis and to support the translation of scientific findings into clinical 
practice2. BACPAC, a funded component of the HEAL InitiativeSM, is a 
multisite consortium which will advance knowledge of the etiology and 
treatment of chronic low-back pain by developing an understanding of the 
mechanisms contributing to chronic low-back pain and identifying specific 
treatments or combinations of treatments that are most effective in 
identifiable subgroups of participants.  
 
 
Study Description: 
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.  Generally, this trial 
will inform a precision medicine approach to the treatment of chronic 


 
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low-back pain (cLBP). BEST is a multi-site, sequential, multiple assignment 
randomized trial (SMART) to evaluate four evidence-based interventions 
for chronic low-back pain. The trial is designed to meet the primary 
objective of 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) duloxetine, and 
(4) evidence-based exercise and manual therapy (EBEM).  
 
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 their adherence to study protocol. Participants who no longer 
meet eligibility criteria will be considered screen failures and discontinued 
from the study. 
 
For the first treatment period, eligible participants will be randomly 
assigned to one of the four study interventions. For the second treatment 
period, depending on response to their initial treatment, participants will 
be randomized to one of the following treatment actions: (1) maintain 
their current intervention, (2) augment their current intervention with 
another study intervention, or (3) switch to a new study intervention. For 
treatment actions (2) and (3), the additional or new intervention will be 
randomly determined independent of participant response to the initial 
treatment. Specific details on these treatment actions are described in 
detail in Section 7. 
 
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.  Section 9 provides a complete description of the 
phenotyping assessments. 
 
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.  
 


 
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Objectives: 
 
The primary objective is to estimate an algorithm to assign sequences of 
two cLBP treatments based on phenotypic markers and an individual 
patient’s response to the initial treatment (i.e., a dynamic treatment 
regime (DTR)) that optimizes effectiveness. as characterized by the 
primary and secondary endpoints. 
The study has the following three secondary objectives: 
 
• 
Estimate 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.  
• 
Estimate DTRs that incorporate additional phenotypic markers 
(i.e., deep phenotyping) collected on a subset of participants. 
• 
Assess whether effectiveness is sustained on outcomes collected 
24 weeks after randomization to the second treatment. 
 
Analyses for secondary objectives will utilize the set of primary and 
secondary endpoints. 
 
The study has the following exploratory objectives:  
• 
Evaluate the comparative effectiveness of individual treatments. 
• 
Evaluate the comparative effectiveness of different treatment 
regimes (i.e., a particular regime with a given set of rules at each 
decision point). 
• 
Evaluate the impact of treatment order on outcomes. 
 
 
 
Analyses for exploratory objectives will utilize the set of primary and 
secondary endpoints. 
Endpoints: 
The primary endpoint for the study is 24-week change from baseline in 
patient-reported pain intensity and interference, measured with the Pain, 
Enjoyment of Life, and General Activity (PEG) scale.  
 
Secondary endpoints are: 
• 
24-week change from baseline in pain interference, measured 
with the 4-item PROMIS Pain Interference scale (PROMIS-PI, 4a) 
• 
Incidence of any opioid use at 24 weeks post baseline. 
• 
24-week change from baseline in physical function, measured 
with the PROMIS-PF Short Form 6b. 
• 
24-week change from baseline in depression score, measured 
with the PROMIS 4-item depression scale from the PROMIS 29 
profile. 
• 
24-week change from baseline in anxiety score, measured with 
the PROMIS Emotional Distress-Anxiety scale (PROMIS-EDA 4a). 
• 
24-week change from baseline in sleep disturbance, measured 
with the PROMIS short form 6a. 
• 
24-week change from baseline in sleep duration, measured with 
the BACPAC sleep duration question.  


 
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Study Population: 
The study will enroll adult participants who report having low-back pain 
for at least 3 months and on at least half the days in the past 6 months. 
Participants must be at least 18 years of age and meet other 
inclusion/exclusion criteria as described in Section 8.  
 
Sample Size: 
The study will enroll approximately 820 participants in order to obtain 
approximately 630 completers (i.e., 10% post-Run-in ineligibility and an 
additional 15% dropout rate over the course of the trial assumed). 
Assuming dropout occurs uniformly across study interventions, the 
sample size of 630 will result in having approximately 80% probability of 
estimating a DTR within 90% of the optimal DTR based on the study’s 
primary endpoint. Based on previous studies, it is estimated that 
approximately 200 participants will consent to undergo comprehensive 
phenotyping (i.e., phenotyping assessments beyond what is required for 
all participants). More details, including assumptions regarding 
intervention effect sizes can be found in Section 13.   
 
 
Interim Analysis: 
Generally, this trial will inform a precision medicine approach to the 
treatment of chronic low-back pain. In order to maintain sufficient power 
for the precision medicine analyses, interim analyses for futility or efficacy 
are not planned. 
 
 
Final Analysis: 
Q-learning5,6 will be used to estimate a two-stage dynamic treatment 
regime that assigns a sequence of cLBP treatments based on phenotypic 
markers and the patient's response to treatment in order to maximize the 
expected reduction in PEG between the beginning and the end of the 
study. Q-learning reduces the reinforcement learning problem of 
optimizing a two-stage dynamic treatment regime to a standard 
regression problem, after which standard regression algorithms can be 
applied. 
 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
Approximately 12 U.S. sites will enroll participants into BEST; all sites are 
clinic settings.  
 
 
 
Description of Study 
Interventions: 
Acceptance Commitment Therapy 
ACT is a form of cognitive behavioral therapy that is well established for 
the treatment of chronic pain7-12. 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 


 
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encouraged to share their experience of skills practice and mastery, 
provide examples of skill use at home, and describe what barriers they 
encountered.  
 
Duloxetine 
Duloxetine is a serotonin norepinephrine reuptake inhibitor (SNRI) that is 
FDA-approved for use in cLBP13, 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. A standard tapering period will occur in the 
13thand 14th weeks, as needed.  At the investigator or licensed designee’s 
discretion, tapering can be extended up to the 15th week. 
 
 
Enhanced Self-Care 
The Enhanced Self-Care intervention will be comprised of educational 
modules on evidence-based cognitive-behavioral self-management skills 
for pain14. 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, automated text or email 
messages will guide participants to specific content.  Everyone receives 
the same ESC materials for weeks 1-4, after which the text/email guidance 
offers personalized recommendations for accessing additional modules 
based upon identified problems from the baseline assessment. 
Additionally, the embedded walking program module will utilize Fitbit 
step tracking to allow participants to monitor their walking progress. 
 
Evidence-Based Exercise and Manual Therapy 
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 participant15. 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.  
Study Duration: 
The BEST trial will run approximately 15 months from first participant 
screened until last participant follow-up. 
 


 
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Participant Duration: 
The study duration for most participants will be 38 weeks. This includes 
the 2-week screening/run-in period, two 12-week intervention periods, 
and the 12-week post-intervention follow-up period.  
 
 
 
4.2. SCHEMA 
 
 
 


 
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4.3. SCHEDULE OF ACTIVITIES (SOA) 
See Appendix A 
5. 
INTRODUCTION 
5.1. STUDY BACKGROUND AND RATIONALE  
Chronic low-back pain is a highly prevalent pain condition among adults that diminishes both physical 
and psychosocial wellbeing4. Chronic low-back pain lasting three months or more with pain occurring on 
most days affects 10-20% of adults1, and 28% report back pain in the past three months4. Chronic low-
back pain contributes to lost employment, disability, and, by some estimates, $100 billion in health care 
expenditures. In the 2010 Global Burden of Disease Survey, low-back pain was ranked highest among 
291 conditions in terms of years lived with disability2. Sufferers, who are disproportionately women and 
people with low socioeconomic status, contend with physical pain, limited mobility, and mental health 
symptoms2. Chronic low-back pain is second only to cancer in number of opioids prescribed, and opioids 
are the most commonly prescribed class of drugs for low-back pain, despite limited evidence of efficacy 
in chronic pain, and the significant risks of side effects, addiction, and death16. While a broad range of 
treatments exists, current treatments do not adequately resolve chronic low-back pain for most 
patients. Systematic reviews of common treatments find small to moderate evidence for efficacy for 
some treatments17-19. In clinical practice, first-line recommendations for chronic low-back pain are often 
non-steroidal anti-inflammatory drugs (NSAIDS) and exercise for patients who experience non-
immobilizing pain, and opioids may still be commonly recommended when other treatments have 
failed20,21.  
Research into optimum treatment for chronic low-back pain is challenged by the diverse etiology of back 
pain, the varied phenotypes of back pain patients, and difficulty assessing both the cause of pain and 
treatment effect. Trial design and retention issues limit our understanding of treatments and their 
effect. While individual trials of single or multi-modal interventions have demonstrated moderate 
treatment effects, heterogeneity of trial design, outcomes, and populations stymie large-scale 
systematic reviews22 as well as reviews of specific treatment approaches19. These methodological factors 
highlight the need for large-scale trials with standardized measures, treatments, and outcome 
measures. Additional research priorities include patient phenotyping and sub-group stratification and 
the development of pharmacological and non-pharmacological first-line treatments for chronic low-back 
pain23. The proposed BEST trial will harmonize recruitment, enrollment, data collection, and retention 
strategies across multiple sites, each of which will recruit from a diverse population of chronic low-back 
pain patients. Drawing on expertise from within and outside of the consortium, sites will adopt 
ambitious recruitment and retention goals. Given historic underrepresentation of minority communities 
in research, the consortium will closely monitor recruitment of underrepresented communities and 
initiate oversampling, as needed. 
The NIH supports the discovery and testing of novel non-addictive pain treatments to stem the ongoing 
opioid crisis and to support the translation of scientific finding into clinical practice2. BACPAC, a funded 
component of the NIH’s Helping End Addiction Long-term (HEAL) initiative, is a multisite consortium 
which will advance treatment of chronic low-back pain by applying a precision medicine approach to 
identify specific treatments or combinations of treatments that are most effective in identifiable 
subgroups of participants.  


 
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In line with these objectives, the BACPAC consortium will conduct a multisite clinical trial, which will 
incorporate four interventions whose components have been studied previously and have been clinically 
proven to be effective for some populations. The interventions to be included in the trial are: enhanced 
self-care (ESC), which incorporates self-management techniques and education, acceptance and 
commitment therapy (ACT), duloxetine, and evidence-based exercise and manual therapy (EBEM)10,13-15. 
The trial will build on this knowledge base by applying a precision medicine approach to these proven 
interventions to determine the optimal treatment for specific participant subgroups.  This precision 
medicine approach is designed to estimate an algorithm to assign sequences of two cLBP treatments 
based on an individual participant’s changing response and phenotypic markers and may help to reduce 
reliance on opioids for many cLBP patients.  
5.2. RISK/BENEFIT ASSESSMENT   
 
 
5.2.1. KNOWN POTENTIAL RISKS  
 
Participants taking part in this study will be exposed to risks that are viewed as similar to those 
encountered in a standard clinical practice and would be deemed as having no more than a moderate 
risk level. The following section describes specific risks associated with undergoing phenotyping 
assessments, receiving study interventions, and disclosure of confidential information (i.e., breaches of 
confidentiality). 
Risks Associated with Phenotypic Assessments 
Questionnaires: Questionnaires pertaining to pain, medication use, and history of chronic low-back pain 
and other pertinent comorbidities will be delivered as part of the study and may be considered 
burdensome and repetitive. Some participants may feel minor discomfort sharing information about 
topics such as physical health, mental health, and substance use.   
Blood Draw / Venipuncture: Collection of blood is occasionally associated with minor bruising, risk of 
infection, discomfort, feeling light-headed, or fainting. 
Stool collection: Participants will be asked to provide a stool sample which will be used to analyze gut 
microbiome. Stool samples may contain germs that may cause or spread infection if proper hygiene 
methods are not followed. 
Biomechanical Assessment: All participants will receive at least one biomechanical assessment, part of 
which requires the use of wearable technology to assess biomechanical factors related to chronic low-
back pain. Participants might find wearable technology uncomfortable and may experience light low 
back muscle fatigue or soreness similar to a light workout the day following the motion assessment.  
Less common are short-term aggravation of existing low back symptoms; irritation, pinching, rubbing, or 
sticking of skin from motion harness components; piercings or other wearable materials (e.g., insulin 
pump) snagging during the motion testing, and loss of balance while performing the motion assessment 
causing a fall. 
Adhesive may be used to affix wearable sensors during assessments. These adhesives may cause short-
term, minor skin irritation in some patients.  A subset of participants will use wearable technology 
continuously for seven days, which participants may find burdensome. These assessments may also 
cause minor physical discomfort or tiredness but are unlikely to cause long-term physical discomfort.  


 
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Imaging: All participants will undergo Magnetic Resonance Imaging (MRI) of the spine. A subset of 
participants may undergo MRI of the brain and an additional spine MRI utilizing magnetic resonance 
spectroscopy.  MRI is safe for most participants but is contraindicated for certain subsets of people, such 
as those with certain medical devices (e.g., implanted cardiac devices, cochlear implants, or intracranial 
aneurism clips) or with ferrous metal in their body (e.g., wire mesh, screws). MRI is not safe for pregnant 
women. While MRI is safe for most participants, the procedure may cause some participants to feel 
emotional discomfort, anxiety, and claustrophobia. The noise of MRI requires participants to wear ear 
protection and may cause peripheral muscle or nerve stimulation.  
Quantitative Sensory Testing (QST): QST may cause minor but temporary physical discomfort.  
Specifically, the manual pressure algometer and pin prick stimulus are commonly used in QST studies 
and will not cause tissue injury at the maximum forces applied in this study. However, these instruments 
may cause minor physical discomfort in the areas of testing; this discomfort is expected to resolve 
within minutes of test completion.  Conditioned Pain Modulation (CPM) assessments using cold stimuli 
are also uncomfortable but will be limited in intensity and duration to prevent tissue damage.  The cold-
water bath component of the QST assessment is contraindicated for certain participants with 
uncontrolled high blood pressure, heart conditions, and a history of Raynaud’s Syndrome. 
Genetic Analysis & Information: The risks related to genetic analyses can be to individuals or groups. 
These harms include stigmatization and impact insurability for life, disability, and long-term care 
insurance. If stored genetic information were re-connected to a participant’s identity, personal 
information about the participant and the participant’s health and risk of disease could become known 
to others. This could present unknown risks.  
Risks Associated with Study Interventions and Run-in Activities 
Acceptance Commitment Therapy (ACT): The ACT behavioral intervention includes discussing one’s pain 
experience with a trained therapist and may make participants feel emotionally uncomfortable. These 
risks are minimal and are sometimes part of the therapeutic process. To reduce the disabling effects of 
depression, fear or other feelings, one may need to first recognize these before identifying healthy goals 
for improvement. Participants will meet with an assigned therapist four times and will be able to contact 
them at any time by email. The therapist will thoroughly explain treatment and what to expect. They will 
provide ongoing support over the course of treatment and, if applicable, will monitor the participant for 
worsening of depression or anxiety symptoms. Study participants may also reach out to study staff with 
any questions or concerns throughout the course of the study. 
Duloxetine: Duloxetine will be administered with daily doses ranging from 30mg to 60mg.  Participants 
will begin with 30 mg and may increase to 60 mg after seven days, if no or only mild side effects are 
experienced. Participants will be warned about the most common side effects with this drug, which 
include nausea, vomiting, nausea, dry mouth, constipation, diarrhea, fatigue, and difficulty sleeping. All 
of these side effects are thought to be less common with slow gradual dose escalation, and many 
(especially gastrointestinal intolerance) typically get better over time. The most serious adverse effect 
associated with duloxetine is the increased risk of suicidality with initiation, especially in individuals 
under age 25. Participants on duloxetine (of all ages) will be monitored appropriately for clinical 
worsening, suicidality, or unusual changes in behavior.  Participants reporting a history of bipolar 
disorder, manic episodes, or suicide attempts and participants who are currently breastfeeding will not 
be eligible for participation in the Duloxetine intervention. 


 
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Enhanced Self Care (ESC):  The ESC intervention is an educational and self-care digital intervention.  
Risks are minimal. 
Evidence-Based Exercise and Manual Therapy (EBEM): Manual therapy may be used to reduce pain and 
stiffness and improve range of motion, and exercises may be used to improve muscle strength, flexibility 
and endurance.  Both are considered safe for the treatment of low-back pain, but side effects associated 
with spinal mobilization/manipulation and therapeutic exercise are common and benign. Approximately 
50% of patients report local post-manipulation or exercise muscle and/or joint soreness which typically 
resolves within 24 hours. Participants may also receive soft-tissue mobilization, and risks associated with 
this procedure are considered to be mild. Mild muscle soreness at the site of soft-tissue treatment 
during and after treatment has been reported. Skin irritation has also been reported when massage 
lotions and oils were used. Exacerbation of any low-back problem is a common risk due to natural 
history of the condition.  Education interventions may ask patients to discuss their pain experiences and 
the impact of their low back pain on various aspects of his or her life possibly resulting in emotional 
distress. EBEM is contraindicated for certain participants with uncontrolled high blood pressure or heart 
conditions. 
Run-in: The Run-in period is comprised of informational materials delivered digitally. Risks are minimal. 
Risks Associated with Confidential Information Disclosure 
Despite significant protections being put in place to protect confidential participant information (e.g., 
protected health information (PHI)), breaches of confidentiality, while very unlikely, are possible. An 
example breach of confidentiality is the disclosure of a participant’s protected health information to a 
party that is not approved to have access to that information. A breach of confidentiality will be 
considered as an unanticipated problem and, as such, will be reported to the IRB of record within 48 
hours of the occurrence, and a remediation plan will be put in place immediately. 
5.2.2. KNOWN POTENTIAL BENEFITS  
The components of each study intervention have been independently shown to clinically improve pain 
intensity10,14,18,24-28 and may improve other outcomes such as function or pain interference; however, 
neither improvement nor direct benefit is guaranteed to study participants. Study participants who 
improve on the treatment to which they are randomized will be allowed to continue that treatment 
either as a single treatment or augmented with an additional treatment. Participants who do not 
improve on the treatment to which they are randomized will be randomized to a new treatment. All 
study treatments will be provided free of charge to participants. Participants may also benefit by gaining 
new knowledge about their pain condition or by learning new pain self-management techniques. 
Participants may experience psychological benefit from interacting with study staff and personnel. 
Participation in the study may be beneficial to participants’ general health, as participants might initiate 
and maintain healthy habits such as exercise. These benefits, if incurred, may be both immediate and 
long-term. 
This research has the potential to benefit society in general by improving treatment for chronic low-back 
pain. Chronic low-back pain is a major cause of disability in the United States and causes both physical 
and emotional suffering. Patients are often unable to find adequate treatment for their condition, given 
the heterogeneity of patient phenotype including biomarkers, pain etiology and mechanism, and 
psychosocial characteristics. The goal of the study is to apply a precision medicine approach to chronic 
low-back pain treatment, which will allow more patients to receive the treatment that is likely to be best 


 
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for them. If providers are better able to target treatments, patients are likelier to improve. Long-term, 
this could reduce the prevalence of chronic low-back pain, improve pain and functional status, reduce 
the duration of symptoms, and reduce long-term opioid use.  
5.2.3. ASSESSMENT AND MITIGATION OF POTENTIAL RISKS 
 
Participant Understanding of Risks and Informed Consent 
All participants enrolled in this study will provide informed consent based on an informed consent 
document that has been approved by the IRB of record for the study. The informed consent process will 
be administered by trained study staff and will include both verbal and written explanation of the study. 
This explanation will include describing the purpose of the study, phenotyping methods to be used, the 
time commitment required, all inclusion/exclusion criteria, potential risks and benefits, monetary and 
non-monetary compensation, study personnel contact information, and information on how study data 
and biospecimens will be shared within the BACPAC Consortium and with NIH approved repositories. All 
participants will be allowed to ask questions on any aspect of the protocol, and study personnel will 
provide answers and confirm there is no residual uncertainty regarding the study procedures prior to 
obtaining informed consent from the participant. 
General Risk Mitigation Procedures 
Protection of subjects from risk is multifaceted and includes monitoring the safety of the research 
participants, putting in place processes for minimizing research-associated risk, maintaining 
confidentiality of study data and participant identification, and reviewing and reporting adverse and 
unanticipated events.  
Study staff at each site will be trained in HIPAA, CITI, and other human subjects research standards as 
required by site’s institutional requirements. The Data Integration, Algorithm Development and 
Operations Management Center (DAC) will hold central training on study procedures and systems for 
clinical personnel prior to the start of the study and record these sessions for use by new staff members 
as needed during the study.  If new procedures or forms are adopted during the study, additional 
training will be conducted via webinars.  New clinical center staff will be trained by experienced staff at 
their site and through the training modules available via webinars.  Each clinical site staff member will 
be certified on study procedures and systems, and certification records will be maintained at the sites 
for auditing. Each intervention arm will be delivered by appropriately trained and licensed personnel. 
The measures taken to minimize risk associated with phenotypic assessments and study interventions 
are described below.   
Risk Assessment & Mitigation for Phenotypic Assessments 
Participants will be screened for contraindications to any of the BEST phenotyping procedures prior to 
enrolling in the study. All phenotyping activities (e.g., quantitative sensory testing, biomechanical 
assessments, blood draws) will be performed by appropriately trained and, where applicable, licensed 
personnel). Participating sites will be staffed by researchers with expertise in the assessment and 
treatment of chronic low-back pain, and the DAC will be responsible for ensuring all staff are trained and 
certified as required by the protocol prior to study launch.  
Questionnaires: To minimize patient burden associated with completing a large number of 
questionnaires, as much as is feasible without sacrificing the validity of the data, participants will be 


 
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allowed to complete most questionnaires online prior to a scheduled visit or phone call assessment. This 
will allow participants to complete the questionnaires at their home or location of choice and to break 
up completion of the questionnaires into multiple sessions at their discretion. Participants will be 
instructed that they can contact study staff if at any point they become distressed while completing a 
questionnaire due to a lack of clarity about one or more questions or general discomfort caused by 
responding. While the completion of questionnaires will be incentivized, all participants will be told that 
they have the option to terminate participation without penalty and/or will be assisted in arranging 
medical/psychiatric help, if necessary. 
Blood Draw / Venipuncture: In order to minimize risk of infection, venipuncture will be performed by 
trained medical personnel using aseptic technique including handwashing before and after the 
procedure and the utilization of sterile kits and gloves.  Alcohol will be swabbed over the region of 
venipuncture prior to the procedure and a sterile bandage will be applied following the procedure. 
Stool collection: Instructions regarding the safe collection of stool will be provided with each stool 
collection kit. 
Biomechanical Assessment: Biomechanical assessments will be supervised by trained staff. Participants 
will be instructed that they can contact study staff if at any point they become distressed while 
completing an assessment.   
Imaging:  The primary established hazard associated with MR imaging is that the magnet exerts a strong 
force on metal objects. For this reason, metal objects are excluded from the vicinity of the magnet so 
that they will not become projectiles. In addition, each subject undergoes a standard screening 
procedure to determine whether they have any implanted materials that may pose a risk.  If there is any 
doubt about the nature of any implanted material, the subject will not be scanned. Participants will be 
instructed to bring or wear clothing without metal fasteners and remove jewelry and any other metal 
objects from their body. Participants will wear foam earplugs or headphones to reduce the loud noises 
made by the scanner. Participants will be able to communicate with the examiner throughout the scan. 
If needed, the participant will be removed immediately from the scanner. MRI sessions will be 
conducted by trained personnel.  Participants will be encouraged to contact the study team if they 
notice any unusual symptoms or untoward side effects. The investigators have extensive prior 
experience in the utilization of MRI for research. The MRI machine is operated within FDA guidelines so 
the potential for inducing peripheral nerve stimulation is low. Participants who report pregnancy will be 
excluded from MRI portion of the protocol. 
Quantitative Sensory Testing (QST): Study personnel will be trained by the investigators to be sensitive 
to participant discomfort and concerns. Participants will be instructed that they can stop any QST 
procedure anytime that the pain or unpleasantness of the task becomes unbearable. All procedures 
have been thoroughly evaluated for reliability and safety, and are well tolerated by individuals with 
chronic pain, causing no more than temporary mild discomfort in the body regions that will be 
evaluated. 
Genetic Analysis: Current federal law will help protect study participants from genetic discrimination in 
health insurance and employment. 
Risk Assessment & Mitigation for Study Interventions 
Participants will be screened for contraindications to any of the BEST study interventions prior to 
enrolling in the study. Participants who have a contraindication to a study intervention and who are 


 
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otherwise eligible for the study will be allowed to participate in the study but will not be randomized to 
the intervention for which they have a contraindication. In Sections 10.1 (Acceptance Commitment 
Therapy), 10.2 (Duloxetine), 10.3 (Enhanced Self Care), and 10.4 (Evidence-Based Exercise and Manual 
Therapy) specific details regarding risk assessment and mitigation are given for each study intervention.  
Participants will be advised that they should contact study staff regarding any side effects or unexpected 
adverse events that occur while enrolled in the study. Prior to the start of a new study intervention, 
participants will be informed that if they are unable to tolerate the intervention, they are permitted to 
cease the intervention.  Specifically for duloxetine, participants will be instructed on how to safely taper 
off the medication. In addition, study staff will conduct a phone call assessment with all participants 
approximately midway into each of the two intervention periods to evaluate pain-related outcomes as 
well as to ascertain how well the participant is tolerating their current study intervention(s). Participants 
who indicate they are unable to tolerate the intervention will be safely transitioned off their current 
intervention but, if in intervention period one, will be allowed to be randomized to a new intervention in 
the second study period. Additionally, all participants will be assessed for unexpected and adverse 
events 4 weeks after the end of the second intervention period (i.e., after completion of all study 
treatment).    
Acceptance Commitment Therapy:   Participants will interact with their therapist at least weekly, and 
the therapist will provide support as well as monitor for worsening of depression or anxiety symptoms 
including suicidal ideation. Participants will be encouraged to contact study staff with questions or 
concerns throughout the course of the study.  
 
Duloxetine: Participants on duloxetine will be monitored appropriately for clinical worsening, suicidality, 
or unusual changes in behavior. Participants may be referred for appropriate treatment including 
emergency services if required. Participation can also be discontinued if there is active suicidal ideation. 
 
Enhanced Self Care:   The ESC intervention is an educational and self-care digital intervention.  Risks are 
minimal; therefore, no intervention-specific risk mitigation is planned. 
 
Evidence-Based Exercise and Manual Therapy:   The EBEM intervention will be delivered by trained 
physical therapists or Doctors of Chiropractic.  Participants who report local post-manipulation or 
exercise muscle and/or joint soreness will be instructed on appropriate self-care. 
 
Run-in:  The Run-in period is comprised of informational materials delivered digitally. Risks are minimal; 
therefore, no intervention-specific risk mitigation is planned. 
 
Risk Assessment & Mitigation for Disclosure of Confidential Information 
Several measures have been taken to minimize the risk of breach of confidentiality via unintended 
disclosure of confidential information. These include the general risk mitigation procedures described 
above (e.g., ensuring study staff have completed HIPAA, CITI, and other human subjects research 
training), providing highly secure electronic data collection systems and procedures (as described in 
Section 14), and collecting only essential identifiable information that is required for the study’s 
scientific objectives and for critical operational reasons (e.g., contact information for scheduling study 
visits and conducting phone call assessments). 
All reasonable steps will be taken to protect the privacy of participants. Each study participant will be 
assigned a unique study ID upon enrollment. All data and other artifacts collected for the study will be 


 
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identified by the participant’s study ID. This includes data collected using the Carolina Data Acquisition 
and Reporting Tool (CDART) data management system, the online survey platforms, biospecimens, and 
web-based applications. Personally identifiable information will be segregated from other data. CDART 
implements a granular authorization model and enforces the principle of lease privilege access. Only a 
restricted set of authorized users will be allowed access to enter or view personal information. To 
further restrict data access, the CDART database is behind a network firewall which is open only to the 
CDART system itself.   
The CDART data management system has robust security features including unique user logins with 
expiration dates and complex password requirements; storage of hashed passwords only; granular 
permissions based on user requirement to enforce the principle of least privilege access; and encrypted 
data transmission. The secure server environment where the systems that host CDART reside is located 
within a hardened data center on the UNC campus and is governed by standard UNC information 
security guidelines. Weekly vulnerability detection scans are performed using third-party vendor 
scanning tools, which include full administrative credentials to perform maximum detection techniques. 
Real-time virus protection software is implemented, and weekly full system virus scans are performed. 
Daily backups of the data are made and stored in an off-site location. CDART is 21 FDA Part 11 
compliant. 
5.2.4. RISK/BENEFIT JUSTIFICATION 
The risks associated with phenotyping procedures are minimal. A greater understanding of the 
biomarkers, biomechanics, and etiology of chronic pain will improve future treatment recommendations 
and enhance quality of life for chronic low-back pain patients.  
The risks associated with study procedures and interventions are generally minimal. The components of 
each of the study interventions have been previously studied and are in current clinical practice. There 
are well-studied side effects associated with duloxetine, but these side effects are generally mild to 
moderate for participants. Moreover, participants will be monitored for side effects and advised to 
discontinue if duloxetine is not well tolerated. These non-invasive treatments may reduce pain intensity, 
improve function, enhance self-management capacity, and increase psychological flexibility. Altogether, 
the potential benefit of these interventions outweighs the potential risk. The screening and monitoring 
of participants by study sites will ensure that risk remains low. 
6. 
OBJECTIVES AND ENDPOINTS 
 
The BEST Trial will inform a precision medicine approach to cLBP and is designed to identify treatments 
that are most effective in identifiable subgroups of patients. Therefore, the study was designed to 
estimate dynamic treatment regimes rather than to test the overall effectiveness of any single 
intervention or combination of interventions. 
 
The primary objective is to estimate an algorithm to assign sequences of two cLBP treatments based 
on phenotypic markers and an individual patient’s response to the initial treatment (i.e., a dynamic 
treatment regime) that optimizes effectiveness. 
 
In this trial, phenotypic markers will not be used to assign treatments, rather participants will be 
randomly assigned to treatment. Response to initial treatment will guide second-stage randomization 
and will be assessed with the Pain, Enjoyment of Life, and General Activity (PEG) scale and the Patient 


 
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Global Impression of Change (PGIC) 12 weeks after the first randomization. The primary analysis will 
then estimate an algorithm that can be applied to cLBP patients that will optimally assign treatments 
based on a patient’s phenotypic markers and changing response (a dynamic treatment regime or DTR). 
Phenotypic markers that will be considered include, for example, preference for treatment and outcome 
priorities, history of depression, and time since diagnosis of chronic back pain. Study participant 
phenotypic markers will be assessed at baseline and a subset will be measured at the end of the first 
intervention period. As part of this analysis, we will compare the estimated best DTR that does not use 
phenotypic variables or participant response with the estimated optimal DTR  A hypothetical example of 
a DTR that we might estimate would involve a sequence of two decision rules: Individuals with chronic 
low-back pain receive physical therapy for 12 weeks and if pain intensity and interference are below a 
given threshold, continue regular follow up with patient; if pain interference is over the threshold, 
provide patient with prescription for duloxetine for 12 weeks. 
 
This procedure will be applied to the following primary and secondary endpoints: 
 
• 
Primary endpoint: 24-week change from baseline in patient-reported pain intensity and 
interference, measured with the Pain, Enjoyment of Life, and General Activity (PEG) scale at 
Visits 0 (baseline) and 2 (24 weeks of treatment)  
• 
24-week change from baseline in pain interference, measured with the 4-item PROMIS Pain 
Interference scale (PROMIS-PI, 4a) at Visits 0 (baseline) and 2 (24 weeks of treatment) 
• 
Incidence of opioid use, measured by self-report at Visit 2 (24 weeks of treatment)  
• 
24-week change from baseline in physical function, measured with the PROMIS-PF Short 
Form 6b at Visits 0 (baseline) and 2 (24 weeks of treatment) 
• 
24-week change from baseline in depression score, measured with the PROMIS 4-item 
depression scale from the PROMIS 29 profile at Visits 0 (baseline) and 2 (24 weeks of 
treatment) 
• 
24-week change from baseline in anxiety score, measured with the PROMIS Emotional 
Distress-Anxiety scale (PROMIS-EDA 4a) at Visits 0 (baseline) and 2 (24 weeks of treatment) 
• 
24-week change from baseline in sleep disturbance, measured with the PROMIS short form 
6a at Visits 0 (baseline) and 2 (24 weeks of treatment) 
• 
24-week change from baseline in sleep duration, measured at Visits 0 (baseline) and 2 (24 
weeks of treatment) 
 
The PEG is a 3-item assessment of pain intensity and interference with enjoyment of life and general 
activity over the past week. This scale is validated, has low participant burden, is responsive to change, 
and captures multiple core outcome domains recommended by the Initiative on Methods, 
Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and that are valued by people who 
experience chronic pain.29-31 In addition, pain intensity was considered the primary outcome of interest 
by the BACPAC Patient Advisory Board. Pain interference with be assessed using PROMIS-PI, which has 
demonstrated reliability and validity across diverse populations for the assessment of the degree to 
which pain interferes with physical, mental, and social activities.32-34 Self-reported opioid use is included 
as a secondary endpoint. Additional secondary endpoints of physical function, depression, anxiety, and 
sleep disturbance are patient-centered and will be assessed using validated instruments from the 
PROMIS measure set. Depression and anxiety, common among individuals who experience chronic pain, 
negatively affect quality of life.35 Finally, PGIC is of key importance in the determination of response to 
treatment following the first randomization because it is valued by patients, integrates both positive and 
negative factors about treatment, and is responsive to change under pharmacologic and 


 
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nonpharmacologic treatment. It has been well validated,36,37 is reliable and is recommended as a global 
outcome measure for chronic pain by the IMMPACT. 
 
The study has the following 3 secondary objectives: 
 
Estimate 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. 
Identification of DTRs that appropriately balance multiple outcomes will be accomplished by collecting 
participant preferences for outcomes at the two randomization points (Visit 0 and Visit 1) as well as 
overall satisfaction of the treatment at 12 and 24 weeks. This participant preference information will not 
be used to assign treatment during the study but will be used to estimate a participant-preference 
based DTR. The participant preference tool, CAPER, has been designed for use in this study and will be  
validated as part of its ongoing development in a BACPAC ancillary study. 
Estimate DTRs that incorporate additional phenotypic markers (i.e., deep phenotyping) collected on a 
sub-set of participants. 
 
A subset of participants (~n=200) will undergo ‘deep’ phenotyping that will include more comprehensive 
biomechanical assessments, functional brain imaging, and qualitative sensory testing. We will apply 
procedures discussed for the primary objective to estimate and identify DTRs to evaluate in future 
studies. While the precision of these estimates will be lower given the reduced sample size, we will learn 
what additional phenotypic measures may predict differential response to treatment. 
 
Assess whether effectiveness is sustained on outcomes collected 24 weeks after randomization to the 
second treatment. 
 
Endpoints will be the same as listed for the primary objective except that they will be measured at the 
final study visit (Visit 3) occurring 24 weeks after the second-stage randomization. Assessment of this 
aim will utilize procedures discussed for the primary objective.  
 
The study has the following 3 exploratory objectives: 
 
Evaluate the comparative effectiveness of individual treatments. 
Evaluate the comparative effectiveness of different treatment regimes (i.e., a particular regime with a 
given set of rules at each decision point). 
Evaluate the impact of treatment order on outcomes. 
 
For these analyses we will estimate average treatment effects. Endpoints will include the primary and 
secondary endpoints identified in the primary objective, measured at 12 and 24 weeks after the first 
randomization. 
 
7. 
STUDY DESIGN  
 
7.1. OVERALL DESIGN 


 
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This study is a multi-site, sequential, multiple assignment randomized trial (SMART) to estimate DTRs 
based on four evidence-based interventions for chronic low-back pain. The trial is designed to meet the 
primary objective of estimating an algorithm for optimally assigning treatments based on an individual 
patient’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) duloxetine, and (4) 
evidence-based exercise and manual therapy (EBEM).  
 
Each participant will complete an initial screening call and enrollment visit, followed by a 2-week run-in 
period, post run-in eligibility screening, two consecutive 12-week treatment periods, and a minimum of 
4 weeks of follow-up. Participants will be screened using a combination of telephone assessments prior 
to, and in-person evaluation during, an initial screening period. Eligible participants who provide consent 
to participate will be enrolled and enter a 2-week run-in period focused on patient engagement. The 
goals of the run-in are to engage individuals from diverse backgrounds, educate potential participants 
about the study, assess adherence and engagement prior to randomization, enhance retention, and 
establish communication between participants and members of the study team. In the first treatment 
period, participants will be randomly assigned at Visit 0 to one of the four study interventions. For the 
second treatment period, depending on response to their initial treatment, participants will be assigned 
to: (1) maintain their current intervention, (2) augment their current intervention with another study 
intervention, or (3) switch to a new study intervention. For treatment actions (2) and (3), the additional 
or new intervention will be randomly determined independent of participant response to the initial 
treatment. Patient Reported Outcome (PRO) assessments will be performed at baseline (Visit 0/Week 0) 
and at Weeks 6, 12, 18, 24, and 36, and phenotyping will be performed at baseline (Visit 0/Week 0) and 
at Weeks 12 and 24 (Visits 1 and 2) 
 
At the end of the run-in period, participants will be re-assessed for eligibility. Those meeting 
requirements for randomization (Section 8) will be randomized to one of the 4 first line treatments. At 
the baseline visit (Visit 0), all participants will undergo baseline data collection and phenotyping. Data 
collected for phenotyping will include patient-reported outcomes, spinal imaging, biomechanical 
assessments, and collection of blood and stool. As described in Section 5.2.2, some of these data will be 
collected at home prior to the in-person portion of the study visit. A subset of eligible and willing 
participants (~n=200) will undergo additional phenotyping. Details of the phenotyping assessments are 
available in Section 9. A subset of phenotypic markers will be re-assessed Week 12 (Visit 1) and Week 24 
(Visit 2). 
 
Participants will be assessed for response to treatment Week 12 (Visit 1) and Week 24 (Visit 2) using the 
PGIC and PEG. Participants will be grouped into one of four responder classes using the PGIC and PEG 
(see Section 7.1) and assigned to the following based on their responses:  
• 
maintain current treatment (PGIC=1-2, PEG <4),  
• 
augment the current treatment with a randomly selected additional treatment (PGIC=1-2, 
PEG ≥4),  
• 
be randomized to augmentation or switching to a new treatment (PGIC=3-4), or  
• 
switch to a randomly selected new treatment (PGIC=5-7)  
  
Since the ESC modules focus on self-care, education and a walking program, requiring participants in this 
intervention arm to cease these activities is not practical; therefore, individuals assigned to ESC at the 
first randomization will maintain ESC if PGIC is 1-2 and PEG<4 else they will augment ESC with a 
randomly selected additional treatment. Participants who wish to discontinue treatment but whose 


 
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PGIC is less than 6 and who are not contraindicated to their current treatment will be asked to continue 
first-line treatment until the end of the 12-week treatment period.  
 
All participants will also receive an assessment 4 weeks after the end of the second treatment period for 
safety purposes (week 28). Participants, whose randomization to the first intervention is at least 36 
weeks prior to the end of data collection, will be assessed for outcomes at 36 weeks.  
 
Participants may need to discontinue treatments prior to the end of the 12-week treatment period (e.g., 
following an adverse reaction to duloxetine; see Section 10.2.1 for list of reasons). Participants needing 
to discontinue first period treatment will be switched to a randomly selected second treatment at Visit 
1.  Participants needing to discontinue second period treatment will remain in the study and undergo all 
future assessments for which they are eligible. 
 
The study will enroll approximately 820 participants in order to randomize approximately 740 
individuals and to have approximately 630 completers (i.e., 15% dropout rate after randomization 
assumed). Assuming dropout occurs uniformly across study interventions, the sample size of 740 
randomized will result in having approximately 80% probability of estimating a DTR within 90% of the 
optimal DTR based on the study’s primary endpoint. See Section 13.2 for additional details on sample 
size needs for precision medicine objectives, including assumptions regarding intervention effect sizes. 
 
The interventions under evaluation are evidence-based, with established efficacy and are standard of 
care. Therefore, we do not expect they will pose safety risks such that these interventions need to be 
stopped before the end of the study. Safety data and adverse events will be monitored. These data will 
be reported to and reviewed by a Data Safety and Monitoring Board. Generally, this trial will inform a 
precision medicine approach to the treatment of chronic low-back pain and therefore we are not 
planning interim analyses for futility or efficacy in order to maintain sufficient power for the precision 
medicine analyses. Blinding is not feasible for study participants or staff involved in the delivery of 
interventions. Investigators involved in the analysis of study data will be blinded to treatment 
assignment. 
 
The study timeline involves approximately 9 months of participant enrollment across 12 sites for a total 
of 820 enrolled. Sites will enroll ~7 participants per month. We anticipate that ~90% of participants who 
consent at the Enrollment Visit will be randomized at the end of the 2-week run-in at Visit 0 and that 
85% of randomized participants will complete all study activities. The total study duration for all 
participants is 38 weeks.To minimize participant burden, where possible, data will be collected 
remotely. 
 
7.2. SCIENTIFIC RATIONALE FOR STUDY DESIGN 
As described above, this trial will inform a precision medicine approach to the treatment of cLBP. This 
goal is motivated by the observation that, while numerous treatments exist for cLBP, all are associated 
with relatively small population average treatment effect sizes. This study seeks to understand how to 
better match future patients to the most appropriate treatment based on their phenotypic measures to 
optimize outcomes. To achieve this goal, we have chosen to conduct a sequential, multiple assignment, 
randomized trial (SMART).  


 
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7.3. JUSTIFICATION FOR DOSE/INTERVENTION REGIMENS 
The justifications for doses for individual treatments are found in Sections 10. 
7.4. END OF STUDY DEFINITION 
For study non-completers, the end of the study will coincide with the point in time when the participant 
notifies study personnel that they wish to discontinue the study. If the reason for study discontinuation 
is related to an incidence adverse event, and if the participant consents to further contact by study staff, 
the participant will be contacted by phone 4 weeks after completion of the study discontinuation visit to 
follow up on adverse events and document their resolution or status. 
The study will end approximately 38 weeks after randomization (at the time of completion of the 12-
week post-intervention follow-up period).  
8. 
STUDY POPULATION 
8.1. STUDY 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 as defined in Section 9 
• 
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) 
8.2. STUDY 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: 
o Progressive neurodegenerative disease 
o History of discitis osteomyelitis (spine infection) or spine tumor 


 
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o History of ankylosing spondylitis, rheumatoid arthritis, polymyalgia rheumatica, psoriatic 
arthritis, or lupus 
o History of cauda equina syndrome or spinal radiculopathy with functional motor deficit 
(strength <4/5 on manual motor testing) 
o Diagnosis of any vertebral fracture in the last 6 months 
o Osteoporosis requiring pharmacologic treatment other than vitamin D, calcium 
supplements, or bisphosphonates. 
o History of any bone-related cancer or cancer that metastasized to the bone 
o Currently in treatment for any non-skin cancer or plan to start non-skin cancer 
treatment in the next 12 months 
o History of any non-skin cancer treatment in the last 24 months 
o Visual or hearing difficulties that would preclude participation 
o Uncontrolled drug/alcohol addiction 
o Individuals actively pursuing disability or workers compensation or involved in active 
personal injury-related litigation 
o 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 
 
8.3. STUDY INTERVENTION CONTRAINDICATIONS 
 
ACT intervention contraindications 
An individual who meets any of the following criteria will be excluded from being randomized to receive 
ACT during the study: 
• 
Currently receiving or intending to receive within the next few months any pain-specific 
psychotherapy, e.g., Cognitive Behavioral Therapy, directed towards pain even if it is only a part 
of the treatment, and delivered by a psychologist or social worker 
 
Duloxetine intervention contraindications 
An individual who meets any of the following criteria will be excluded from being randomized to receive 
duloxetine during the study: 
• 
Pregnant: If the participant becomes pregnant during the study, duloxetine will be rapidly 
tapered.  
• 
Currently taking any of the following: 
Duloxetine 
Lithium 
Tramadol (Ultram, Ultracet) 
St. John’s Wort 
Prochlorperazine (Compazine) 
Thioridazine (a psychiatric medication) 
Propafenone or Flecainide (for heart rhythm problems) 
Ciprofloxacin (Cipro, an antibiotic) 
Linezolid (Zyvox, an antibiotic) 
Methylene Blue 
Cimetidine (Tagamet, for heartburn)  
Bupropion (Wellbutrin) 


 
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SNRIs: 
Venlafaxine 
Milnacipran 
Duloxetine 
Sibutramine 
Atomoxetine 
Desvenlafaxine 
Levomilnacipran 
SSRIs:  
Sertraline 
Paroxetine 
fluoxetine  
escitalopram 
citalopram 
fluvoxamine 
Vortioxetine (Trintellix) 
 
Any other contraindicated SNRIs, SSRIs, and antidepressants 
 
• 
Reporting a current or previous diagnosis of any of the following 
Renal dysfunction 
End-Stage Renal Failure  
Hepatic dysfunction 
• 
Previous allergic or other severe adverse reaction to duloxetine or, as determined by the site PI, 
a medicine with duloxetine cross-reactivity.  
• 
History of bipolar disorder, manic episodes, or suicide attempts 
• 
Currently breastfeeding 
 
EBEM intervention contraindications 
An individual who meets any of the following criteria will be excluded from being randomized to receive 
EBEM during the study: 
• 
Currently receiving or intending to receive within the next few months any type of manual 
therapy or exercise treatment for low-back pain from a licensed provider 
• 
Uncontrolled high blood pressure (≥150 systolic and/or ≥100 diastolic) 
• 
Uncontrolled coronary artery disease 
• 
Inability to walk at least 50 feet unassisted 
• 
Contraindication for manual therapy 
• 
Contraindication for participation in an exercise program 
 
ESC intervention contraindications 
An individual who becomes pregnant during the study will be counseled to stop NSAIDs. 
8.4. PHENOTYPING CONTRAINDICATIONS 
Blood Draw / Venipuncture: 
• 
Active infection over the site of blood draw 
• 
Recent or recurrent history of fainting/vasovagal syncope with previous blood draws 
• 
Lack of vascular access (inability to find venous access) 


 
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Stool collection:  
• 
None 
Biomechanical Assessment:   
• 
Inability to walk at least 50 feet unassisted 
• 
Inability to stand for at least 10 minutes 
• 
Participants with an allergy to adhesives will not have adhesive sensors placed on their body 
Imaging: 
• 
Certain implanted medical devices (e.g., implanted cardiac devices, cochlear implants, or 
intracranial aneurism clips)  
• 
Ferrous metal (e.g., wire mesh, screws) in the body that will cause safety issues (titanium 
implants are acceptable)38  
• 
Waist circumference equal to or greater than the bore diameter of the study site scanner 
• 
Pregnancy 
QST: 
• 
Peripheral neuropathy 
• 
Participants with a history of Raynaud’s Syndrome will not undergo cold-water immersion 
• 
Participants with circulatory or sensory problem in the hands will not undergo cold-water 
immersion 
• 
Participants with SBP  ≥150 and/or DBP  ≥100 will not undergo cold-water immersion 
8.5. LIFESTYLE CONSIDERATIONS 
Not applicable 
 
8.6. SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
8.7. STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Study participants will be recruited from direct contact in clinical settings, screening via electronic health 
records (EHR) for chronic back pain, online surveys, and through community outreach. Sites may also 
choose to compensate current participants who refer others with cLBP that enroll and remain in the 
study.  Site coordinators will generate a programmable phenotype based on the inclusion/exclusion 
criteria to generate a list of medical record numbers/unique patients to be screened. Site coordinators 
will use electronic health records (EHR) to search for ICD10 codes indicating the presence of chronic low 
back pain M54.40, M54.41, M54.42, M54.5, and M54.89 within the past 1 year in order to generate a list 
of medical record numbers/unique potential participants. Progress notes housed within the EHRs may 
also be searched by an algorithm for the presence of “low back pain,” “back pain,” or “lumbago” in 
order to generate a list of medical record numbers/unique potential participants. Site coordinators may 
use additional ICD10 codes and progress note keywords as they develop and identify effective search 


 
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parameters. The list of unique potential participants will be updated as frequently as daily such that new 
patients coming into the system with chronic low back pain or who develop chronic low back pain may 
be screened for eligibility. Patient’s records will be further screened to determine if any exclusion 
criteria are met.  Patients meeting the inclusion/exclusion criteria will be contacted via phone for the 
initial pre-screening call, sent a letter assessing interest in the study, or approached during a scheduled 
clinic visit as allowed by the site’s regulatory guidelines.   
Enrollment of a diverse sample will be monitored in real time to ensure overall enrollment approximates 
the US population experiencing low-back pain.  The DAC will assess subgroup enrollment targets each 
month and instruct sites to adjust recruitment to correct under or overrepresentation of any particular 
subgroup.   
Various approaches will be considered to enhance participant retention including scheduling flexibility, 
phone calls from the coordinators (or electronic messaging), updates on study progress (such as regular 
study newsletter targeted at the participants, celebrating milestones), and invitation to provide input 
into future studies.   
Recruitment and retention throughout the study will be monitored by the DAC, which will oversee 
development of materials to facilitate recruitment and retention, monitor progress of both as the study 
progresses, and develop strategies for addressing recruitment and retention issues as they arise. The 
Data Safety and Monitoring Board (DSMB) will monitor accrual at each clinical center based on periodic 
summary reports provided by the DAC for their review (see Section 14.1.8) and make recommendations 
on proposals to address recruitment or retention challenges, such as adding clinical centers, if needed. 
9. 
PHENOTYPIC ASSESSMENTS 
 
Phenotypic assessments will take place during the study.  Some assessments will be required in order for 
inclusion in the study, therefore, individuals who are contraindicated to any of the required phenotypic 
assessments will not be eligible for study participation.  All participants in the study will be required to 
answer questionnaires, receive a physical assessment, receive a motion assessment lasting 
approximately 10 minutes at each of 3 separate visits, provide blood samples at each of 3 separate 
visits, receive an at-home stool collection kit to provide a single stool sample, and receive 1 spine MRI 
lasting approximately 30 minutes.  Total patient time for required phenotyping assessments is 
approximately 3 to 5 hours at the baseline visit and approximately 1 hour at the 12- and 24-week visits.  
 
Additional assessments are not required to participate in the trial.  It is expected that approximately one 
third of enrolled participants will opt to undergo these additional assessments.  This subset of 
participants will, in addition to the required assessments, receive motion assessments lasting 
approximately 40 minutes at each of 3 separate visits, be asked to wear an actigraphy sensor at home 
continuously for 7 days, receive an advanced spine MRI lasting approximately 30 minutes, receive a 
brain MRI lasting approximately 60 minutes at each of 3 separate visits, and receive Quantitative 
Sensory Testing lasting approximately 60 minutes at each of 3 separate visits. Total patient time for 
additional phenotyping is approximately 4 hours and 40 minutes at the baseline visit, and approximately 
3 hours and 40 minutes at the 12- and 24-week visits. 
 
Required Phenotypic Assessments 
Optional Additional Phenotypic Assessments 
20-minure motion assessment at 3 time points 
60-minute motion assessment at 3 time points 
60-minute basic spine MRI at 1 time point 
7-day continuous at-home activity monitoring via a wearable sensor 
Questionnaires/PROs 
30-minute advanced spine MRI at 1 time point 
Blood draw at 3 time points 
60-minute brain MRI at 3 time points 
Provision of stool sample at 1 time point 
Quantitative Sensory Testing at 3 time points 


 
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9.1. QUESTIONNAIRES 
Questionnaires pertaining to pain, medication use, and history of chronic low-back pain and other 
pertinent comorbidities will be delivered as part of the study.  A complete list is included in Section 16.   
9.2. BLOOD DRAW / VENIPUNCTURE  
All participants will undergo the following blood draws at Baseline (Visit 0) and the 12- and 24-week 
visits (Visits 1 and 2), with the exception of the PAXgene DNA tube which will be collected only at the 
Baseline visit.  At each visit, approximately 32mL of blood will be drawn and collected in the following 
tubes: 
• 
1 TruCulture tube 
• 
1 Sodium Heparin tube 
• 
1 EDTA tube 
• 
1 PAXgene DNA tube 
• 
3 PAXgene RNA tubes 
Blood samples will be minimally processed per protocol at the study site and stored until such 
time as they are shipped to the NYU Langone Health Center for Biospecimen Research and 
Development (CBRD).  Batch sample shipments will occur at a frequency specified by the DAC.  
 
During the study period, Cytokines/MMP, TruCulture, and Genome-wide association study (GWAS) 
analyses will be conducted on the study samples.  Blood samples collected in the Sodium Heparin tube 
and PAXgene RNA tubes will be stored for possible future analyses. 
At the end of the study, the CBRD will ship all remaining samples to the repository(ies) approved by NIH. 
9.3. STOOL COLLECTION  
Study sites will provide participants with stool collection kits to be used at home.  A pre-paid shipping 
label will be provided with each kit.  Participants will be instructed to return their stool sample to the 
CBRD where the sample will be stored for possible future analyses. 
At the end of the study, the CBRD will ship all remaining samples to the repository(ies) approved by NIH. 
9.4. BIOMECHANICAL ASSESSMENT  
All participants will undergo a single biomechanical assessment at Baseline (Visit 0) and the 12- and 24-
week visits (Visits 1 and 2).  At each visit, sensors will be placed on the participant’s pelvis and chest, and 
the participant will be asked to complete a series of motions.  Data from these motions will be uploaded 
from the sensors to the cloud.  This biomechanical assessment requires approximately 10 minutes of 
patient time. 


 
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Study participants who participate in the additional phenotypic assessments will undergo three 
additional biomechanical assessments at Baseline (Visit 0) and the 12- and 24-week visits (Visits 1 and 
2).  These additional assessments require proprietary sensors be placed on the skin of the participants' 
back, waist, and/or hip using adhesive tape, and the participant will be asked to complete a short series 
of motions that include several repetitions of bending, side bending, and twisting as far as remains 
comfortable. Participants will also be asked to complete a series of repeated sit-to-stand 
maneuvers.  Manual palpation of the participant’s spine may be used to ensure correct placement of the 
sensors. Additionally, some of these same motions will be performed in front of a 3D depth 
camera. Data from these motions will be uploaded from these sensors to a secure location on the cloud  
before being securely transferred to the BACPAC Data Portal under the guidelines outlined in the 
BACPAC Data Portal Transfer Standard Operating Procedures (SOP).  The complete set of these 
additional biomechanical assessments will require approximately 50 to 60 minutes of patient time. 
Study participants who participate in the additional phenotypic assessments will also be provided with 
actigraphy sensors to be worn continuously for 7 days at home.  At the end of the 7-day assessment, 
participants will return the sensor to the clinic using the pre-paid label provided.  Data from the sensors 
will be uploaded to a secure location. 
9.5. IMAGING  
 
All participants will undergo a single MRI of their lumbar spine at Baseline (Visit 0).  This scan requires 
approximately 30 minutes of patient time. The following pulse sequences are required:  
• 
Sagittal T2-weighted with fatsat (SAG T2 fs) 
• 
Sagittal T1-weighted without fatsat (SAG T1) 
• 
Axial T2-weighted without fatsat (AX T2) 
• 
Axial T1-weighted without fatsat (AX T1) 
• 
Coronal T1-weighted without fatsat covering both SI joints (COR T1) 
• 
Sagittal T1-weighted without fatsat for SI joints (SAG T1) 
 
Study participants who participate in the additional phenotypic assessments may undergo an advanced 
MRI scan of their spine at Baseline (Visit 0). This scan requires approximately 30 minutes of patient time 
in addition to the required scan, for a total of approximately 60 minutes of patient time. The following 
pulse sequences will be collected on as many participants as is possible given individual site technology: 
• 
MR spectroscopy 
 
Study participants who participate in the additional phenotypic assessments will undergo an MRI of 
their brain at Baseline (Visit 0) and the 12- and 24-week visits (Visits 1 and 2). This scan requires 
approximately 60 minutes of patient time. The following scans are required: 
• 
Tri-Planar Scout 
• 
3D MP-RAGE 
• 
Resting State 
• 
Diffusion Tensor Imaging 
 
Imaging Data 
 
DICOM images will be transferred to the BACPAC Data Portal to allow radiologists or others to analyze 
centrally. Personally identifiable information will be removed from all images prior to uploading the 


 
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image to XNAT.  Stored images will contain only the participant ID, the date of the image, and the scan 
type. 
 
Spine MRIs will be transmitted securely from the BACPAC Data Portal to a central reading center where 
they will be processed for tissue segmentation and measurement prior to the DICOM images being 
transmitted back to the BACPAC Data Portal. 
 
Advanced Spine MRIs (i.e., MR spectroscopy acquisitions) will be transmitted securely from the UNC 
secure OneDrive to a commercial entity where they will be processed.  The resulting reports will then be 
transmitted back to the UNC secure OneDrive. 
 
Scanning a test subject prior to implementing imaging protocols is optional.  Sites choosing to scan a test 
subject must meet their local IRB requirements.  Test subject data will not be included as part of trial 
data. 
 
9.6. QUANTITATIVE SENSORY TESTING  
 
Study participants who participate in the additional phenotypic assessments will undergo quantitative 
sensory testing, which is comprised of the three components below.  QST requires approximately 60 
minutes of patient time.    
 
Pressure pain sensitivity  
Pressure pain sensitivity will be assessed using an analog algometer with a 1-cm2 rubber probe 
(FPK25, Wagner Instruments, Greenwich, CT, USA) to quantify pressure pain thresholds 
(PPT).  The primary test site will be located in the lumbar region by the participant’s response to 
manual over-pressure (springing palpation) performed in the prone position.  The control site 
will be located over the contralateral trapezius muscle (diagonal from lumbar site).  Pressure will 
be manually increased at a rate of rise of 0.5 kgf/cm2/s (10 kg max, metronome guided) until 
participants first report that the pressure sensation becomes painful.  Pressure intensity 
(in kgf/cm2) read from the algometer at that time is considered the PPT.  Measurements will be 
conducted 3x/site with 60-s rest intervals between each pressure application.  Probe placement 
will be varied slightly trial to trial to prevent sensitization from repeated testing of the 
same site.  Mean PPT will be used for analysis.  
 
Temporal Summation 
Temporal Summation measures increases in excitatory pain pathways and is thought to reflect 
the progressive increase in dorsal horn neuronal firing in response to repetitive C-fiber 
stimulation.39-41 Enhanced temporal summation is common in chronic pain and is predictive of 
pain outcomes.43,44 We will evaluate temporal summation using a 
40g Neuropen Neurotip (Owen Mumford, Oxfordshire, United Kingdom) applied to the skin of 
volar forearm and lumbar region, following a train of 10 identical stimuli (1 Hz) using a 
metronome for timing. Participants will report retrospectively the pain intensity of the 1st and 
10th pinprick using a 0-10 numerical rating scale (NRS; 0 = no pain, 10 = worst imaginable 
pain).  The palmer forearm and lumbar region will each be tested three times.  Temporal 
summation for each site will be calculated as the mean difference in pain ratings of the 1st and 


 
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10th stimulus.  Participants will also rate any ongoing pain aftersensations at 15- and 30-
s following each train of stimuli.   
 
Conditioned Pain Modulation  
Immersion of one hand (ipsilateral to the primary lumbar pain site) into a circulating cold-water 
bath (10°C; NESLAB Digital One RTE 7, Thermo Scientific, Newington, NH, USA, or similar) will 
serve as the conditioning-stimulus and PPT at the contralateral trapezius will serve as the test-
stimulus.  This method is consistent with that of Locke45and others.46,47 Baseline measurement 
of the test-stimulus will be acquired during the assessment of pressure pain sensitivity (see 
above).  Conditioning stimulation will begin by immersing the hand to a level approximately 10 
cm above the wrist into the water bath.  The hand will be immersed for 60-s; perceived pain of 
the water will be rated at 30-s after hand immersion, and at 60-s after hand immersion, or 
immediately at hand withdrawal, using a 0-10 NRS to determine the adequacy of conditioning 
pain.48  Trapezius PPT will re-measured 3x after the hand is withdrawn from the cold water.  
CPM magnitude will be calculated as the difference in mean PPT measured prior to and during 
the conditioning stimulus, with increases in PPT during conditioning interpreted as evidence of 
efficient endogenous pain inhibition. 
 
10. 
STUDY INTERVENTIONS 
 
10.1. 
STUDY INTERVENTION(S) ADMINISTRATION: ACCEPTANCE COMMITMENT THERAPY 
 
10.1.1. STUDY INTERVENTION DESCRIPTION 
ACT is a process-based therapy that is among the third-wave cognitive behavioral therapies. It is well 
established for the treatment of chronic pain.7-12 The goal of ACT is to build psychological flexibility 
thereby interrupting pain avoidance behavior patterns. Instead of targeting symptom reduction, ACT 
seeks to help individuals produce more successful responses to symptoms that are aligned with their 
values and goals. The 6 core therapeutic processes are acceptance (embracing unwanted experiences), 
cognitive diffusion (differentiating between thoughts and experience), present-focused attention, self-
as-context (distinguishing between observations and the observer), values, and committed action 
(choosing action based on values). These processes are summarized as ‘open, aware and engaged’ 
behavior.49 Treatment methods are experiential, including mindfulness exercises, metaphor, and 
identification of values. ACT can be delivered in person as well as over the internet. Internet delivery of 
ACT has been demonstrated to be similarly effective as in-person. It is also well-suited for pain patients 
with mobility issues, for individuals residing in rural areas or without transportation, and for areas 
without local qualified providers of ACT.11,49-51, 
Participants randomized to ACT will take part in 12 sessions over the course of a 12-week treatment 
period (Section 10.1.2). There will be a combination of 4 remote face-to-face visits with a therapist and 8 
therapist-supported online sessions (self-directed online modules plus provider coaching via an online 
messaging system). Qualifying therapists will include psychologists or social workers with training in 
chronic pain management and experience delivering ACT. Section 10.1.2 describes each session, delivery 
mode, approximate timing over the course of 12 weeks. Session content is based on ACT interventions 
found to be effective for chronic pain that have been adapted for online delivery.12,52,53 


 
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During the initial session, the therapist will establish rapport, discuss goals of treatment, review the 
online protocol, conduct a brief assessment, and describe the treatment in detail. During subsequent 
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. Online sessions will deliver the ACT content that focuses 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. The online modules will consist of a combination of text, 
audio and video content. In-session exercises are intended to build psychological flexibility and skills in 
the 6 core therapeutic processes (acceptance, cognitive diffusion, present-focused attention, self-as-
context, values, and committed action). After each online session, participant responses are sent to the 
therapist who will provide feedback by way of an online messaging system. All remote face-to-face 
therapy visits will take place virtually via a HIPAA-compliant platform such as Zoom. Access to the online 
content will require log-in via a personal account established at Visit 0. 
Participants are encouraged to practice skills at home daily, repeating exercises from that week’s session 
(as well as those from previous weeks) and to record their progress in a daily diary. Participants provide 
feedback by way of brief questionnaires before and after each session and responses are sent to 
therapists as part of the digital platform. The platform includes an internal messaging service that allows 
for provider coaching throughout the week. This allows for enhanced engagement in the ACT treatment. 
The digital platform will also track progress on Openness, Awareness, and Committed Action for 
participants and providers. Depending on a participant’s progress in these three areas, the provider may 
recommend additional supplemental content as detailed in an ACT manual.  
ACT Protocols for the Second Treatment Period 
Participants who are initially randomized to ACT, depending on their response to treatment, will be 
assigned to either i) maintain ACT, ii) be randomized to ACT plus an augmentation therapy or iii) be 
switched to another treatment for the second treatment period. Participants assigned to maintain ACT 
(with or without a second augmentation treatment) will be encouraged to continue at-home skills and 
will have access to all previously viewed online content. In addition, participants will have access to 11 
additional online ACT audio modules, but without the communications with the therapist. Participants 
assigned to switch will be recommended to stop at-home skills and will no longer have access to the 
online ACT content. 
10.1.2. DOSING AND ADMINISTRATION 
 
Week 
Session Type 
Activity 
1 
Remote face-to-face 
Visit 1: Introduction Familiarize with online treatment 
2 
Therapist-supported online 
Session 1: Shift Your Focus and What Will you Do? 


 
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2 
Therapist-supported online 
Session 2: Drop the Struggle and Act with Openness 
3 
Remote face-to-face 
Visit 2: Review workbook, skills, goals; identify barriers 
3 
Therapist-supported online 
Session 3: Act with Openness to Thoughts 
3 
Therapist-supported online 
Session 4: Clarify Your Values, Define Your Goals, and Act 
4 
Therapist-supported online 
Session 5: Focus on the Present Moment and Take Action  
4 
Therapist-supported online 
Session 6: Build Further Engagement and Incorporate Barriers  
5 
Remote face-to-face 
Visit 3: Review workbook, skills, goals; identify barriers 
5 
Therapist-supported online 
Session 7: Commit, Act, and See You’re the Observer-Self 
6 
Therapist-supported online 
Session 8: Build Wider Patterns of Success 
7 
Remote face-to-face 
Visit 4: Review workbook, skills, goals; close out treatment 
 
Delivery of the online content is standardized given that all participants will view the same content, 
delivered in the same order to all participants. Delivery of the intervention by therapists will also be 
standardized. Therapists will receive a detailed manual covering the goals of the face-to-face sessions (in 
addition to online content) as well as a checklist for activities that should take place at each session. In 
addition, they will receive centralized training and certification, with periodic re-training, and will 
complete self-assessments. A 5% random sample of telehealth sessions per provider will be recorded 
and reviewed and evaluated for adherence and fidelity. At least once per month, and with greater 
frequency at the beginning of the study, all providers will meet with the central ACT provider who will 
support fidelity and competency in an effort to prevent drift. 
10.1.3. ACQUISITION AND ACCOUNTABILITY 
The ACT online platform will be HIPAA and FISMA compliant and will be hosted centrally on a University 
of North Carolina server. Participants assigned to ACT will have secure logins and passwords to access 
the site. 
10.1.4. STUDY INTERVENTION COMPLIANCE 


 
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Adherence to the intervention will be assessed in terms of 1) attendance at each remote face-to-face 
session, 2) access and completion of each online module, 3) completion of exercises as recorded in the 
online platform, and 4) days of at-home skills practice as measured with the online workbook. 
Compliance with ACT treatment is defined as completion of at least half of the prescribed visits and 
modules. Participants completing fewer than 2 face-to-face visits or fewer than 4 online modules will be 
considered non-compliant.  
10.2. 
STUDY INTERVENTION(S) ADMINISTRATION: DULOXETINE 
Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral 
administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine 
hydrochloride. The empirical formula is C18H19NOS0-HCl, which corresponds to a molecular weight of 
333.88. Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in 
water. 
Duloxetine is a serotonin norepinephrine reuptake inhibitor (SNRI) that is FDA-approved for use in cLBP  
and, as such, is included as a recommended therapy in nearly all current treatment guidelines for low-
back pain and was selected by the Interventions Working Group as an evidence-based intervention to be 
included in this precision medicine study. Duloxetine and other drugs that increase both serotonergic 
and noradrenergic activity (e.g. tricyclics) are thought to work as analgesics by increasing activity in 
down descending anti-nociceptive pathways.13 There will not be a placebo arm for this intervention as 
this study is designed to optimize a precision medicine algorithm as opposed to investigate the 
effectiveness of duloxetine versus a placebo. 
10.2.1. DOSING AND ADMINISTRATION 
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral 
administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine 
hydrochloride. The empirical formula is C18H19NOS0-HCl, which corresponds to a molecular weight of 
333.88. Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in 
water. 
Each capsule contains enteric-coated pellets of 33.7 mg of duloxetine hydrochloride equivalent to 30 mg 
of duloxetine. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic 
environment of the stomach. Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, 
hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, 
titanium dioxide, and triethyl citrate.  
Participants randomized to the duloxetine arm will review the dosing schedule for the medication and 
safety information for the medication at the baseline visit with the study coordinator. At the baseline 
visit a physical assessment will be performed. Certain sections must be completed by a licensed medical 
professional (e.g., MD, DO, FNP, PA, PT). Drug contraindications (including allergy to duloxetine, 
concomitant antidepressant use, concomitant tramadol use, liver disease, kidney disease, concomitant 
of St. John’s wort use) will be reviewed with the participant. Participants reporting a history of bipolar 
disorder, manic episodes, or suicide attempts will not be randomized to the duloxetine intervention 
arm. Participants will also be counseled on seeking emergency help if suicidal ideation occurs while on 
duloxetine.   


 
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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 to maintain up to a 60 
mg dosage through the 12-week intervention phase and to taper the dose in through the 14th week if 
needed. 
Duloxetine will be started at 30 mg, orally once per day in the morning for the first 7 days. Study staff 
will conduct an assessment via phone on day 7 (or next business day if falls on a weekend) of the 
intervention phase with participants newly randomized to duloxetine (i.e., day 7 of either the first or 
second intervention period). Study staff will document in the case response forms any adverse events 
and safety concerns the participants may have. 
At the Day 7 assessment: 
Participants tolerating the medication with no side effects (e.g. nausea) will be escalated to 60 mg (two 
30 mg capsules) by mouth once per day in the morning. 
Participants tolerating the medication with mild side effects will have the option to stay at 30 mg or 
discontinue the medication. 
Participants not tolerating the medication will be instructed to discontinue duloxetine. Participants in 
the first period intervention will be instructed to discontinue treatment until the next randomization 
point (Visit 1) at which time they will be randomized to a non-duloxetine second period intervention. 
Participants randomized to duloxetine in the second period intervention and not tolerating the 
medication will be instructed to discontinue duloxetine until their final follow-up of outcomes 24 weeks 
post baseline (Visit 2). 
All participants will be provided with the site phone number and instructed to call if they have new or 
worsening side effects. If any safety or adverse events occur, the medication will be discontinued. 
All participants will be assessed at the midpoint of the intervention treatment period (i.e., either Week 6 
or Week 18) for tolerance, adverse events, and response. At the midpoint phone call: 
Participants tolerating the medication with no side effects will be instructed to increase to 60mg/day (if 
currently taking 30mg/day) or remain on their current dosage (if currently taking 60mg/day). 
Participants tolerating the medication with mild side effects (e.g. nausea) will be given the option of 
continuing their current dosage (30mg/day or 60mg/day), reducing their dosage (from 60mg/day to 
30mg/day), or tapering off their current dosage (if currently taking 30mg/day).  
Participants not tolerating the medication will be instructed to taper off the medication. 
During the Week 18 call, participants will be reminded that their study treatment period is ending in six 
weeks.  If they are tolerating the study medication and would like to continue duloxetine after the end 
of the treatment period, they should schedule an appointment with their provider to discuss continuing 
their duloxetine treatment outside of the study, in order to avoid a lapse in medication. 
Tapering instructions: 
The standard tapering period is up to two weeks.   The following instructions will be provided to 
participants when they end their duloxetine treatment at either Visit 1 or Visit 2, or during the Week 6 


 
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or Week 18 calls.  For participants who are taking 60mg daily, they will be instructed to reduce their 
dosage to 30mg per day for one week, and reduce to 30mg every other day for a week, as needed to 
reduce mild side effects.  Participants taking 30mg per day can reduce their dosage to 30 mg every other 
day for up to 2 weeks, as needed to reduce mild side effects. At the discretion of the site PI or licensed 
designee, tapering can be extended an additional week, with the last dose no later than 21 days after 
Visit 1 or 2. 
10.2.2. ACQUISITION AND ACCOUNTABILITY 
Site staff will be responsible for ensuring study participants are instructed on how to return study 
medications and for tracking returned medication.  
When medication is returned, site staff will count how many capsules are left and this number will be 
reported on the drug accountability log, and the remaining capsules will be disposed according to local, 
institutional policy. 
  
10.2.3. FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral 
administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine 
hydrochloride. The empirical formula is C18H19NOS0-HCl, which corresponds to a molecular weight of 
333.88. Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in 
water.  
10.2.4. PRODUCT STORAGE AND STABILITY 
Medications will be procured from the approved drug pharmacy at each site to retain a supply to recruit 
at least 5 participants at a given time. Temperature in the storage room must be managed between 20 -
25oc (68-77oF); excursions permitted to 15-30oC (59-86oF) – per package insert. Medications may also be 
mailed to participant directly in the event of dispensing challenges (for example as related to the COVID 
pandemic).  Sites must follow the guidelines outlined the Duloxetine Pharmacy Manual for mailing the 
study medication. 
10.2.5. PREPARATION 
30 mg capsule 
10.2.6. STUDY INTERVENTION COMPLIANCE 
Compliance with study protocol will be assessed by participant report and pill count. Participants will be 
required to return remaining medications to the study site at the time of their next in-clinic study visit 
(Visit 1 or Visit 2).  Unused pills will be counted and documented at the site for accountability.  At sites 
that mail the study medication directly to participants, these participants may be permitted to retain 
medication previously dispensed during Visit 0 if the medication is needed to ensure a medically 
appropriate transition.  In these cases, unused study medication must be returned at Visit 2, instead of 
Visit 1, under certain conditions as described in the Duloxetine Pharmacy Manual.  


 
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Adherence to the intervention will be assessed in terms of 1) missed doses as reported by the 
participant and 2) number of capsules left in the returned medication bottle.  
10.3. 
STUDY INTERVENTION(S) ADMINISTRATION: ENHANCED SELF-CARE 
The content of the Enhanced Self-Care intervention is based on interventions which are currently 
available as part of many clinical practices but is formatted and structured in a manner that will provide 
multiple modules over the intervention period.  The intervention is considered ‘enhanced’ in that most 
individuals with chronic pain do not receive an educational and self-care package.  It is self-care given 
there will be no therapist associated with the delivery of these educational materials. The intervention 
will be provided digitally via multiple modules for self-administration over a period of 12 weeks.  Each 
module will consist of evidence-based cognitive-behavioral self-management skills for pain.  While all 
content is available to participants at all times, automated weekly email or text messaging will guide 
participants to specific content. Much of the material is derived from the current University of Michigan 
online self-management program called PainGuide.      
PainGuide (https://PainGuide.com) is an educational website promoting the use of cognitive and 
behavioral self-management skills for chronic pain that is accessible online or by smartphone. PainGuide 
offers (A) education about pain, pain mechanisms, types of pain including chronic overlapping pain 
conditions (COPCs), and education about a wide variety of professionally administered pain treatments, 
(B) rationale and resources for using a variety of self-management approaches for pain, (C) a system for 
monitoring symptoms and self-management activities and (D) external resources supporting pain self-
management.54-57 Multi-media is used in communicating content including videos, text, audio files, apps, 
and downloadable worksheets. PainGuide is an expanded version of its predecessor FibroGuide, a 
similar digital pain self-management program with efficacy supported by clinical trials.58  For the 
purposes of the proposed study, PainGuide has been adapted to the needs of patients with chronic low-
back pain.   
The Enhanced Self Care intervention arm will be comprised of three major components delivered via a 
single platform: 
• 
Behavioral Self-Management– Established education and cognitive-behavior based self-
management skills training and symptoms monitoring.  
• 
Walking Program – a new module contained within PainGuide that offers a structured walking 
program that uses Fitbit devices for monitoring walking (e.g., Steps).  
• 
Personalization and Engagement – ESC uses weekly automated email or text messaging to 
encourage engagement and to personalize the self-management content to be highlighted each 
week based upon participants’ baseline surveys.  
For this study, a customized version of PainGuide will be used. This version of the self-management 
website will include curated education and content targeted to a chronic low-back pain population. Two 
new modules have been added: a Walking Program utilizing Fitbit activity trackers for feedback and an 
over-the-counter (OTC) treatment module (e.g., NSAIDs and topical analgesics). The walking program 
will utilize Fitbit step tracking to allow participants to monitor their walking progress, while the OTC 
medication content will be educational in nature. 
10.3.1. DOSING AND ADMINISTRATION 


 
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During the baseline visit, participants will be given a link for obtaining access to the version of PainGuide 
designed for this study.  Access to this link will be provided after randomization and will require a 
username and password supplied by the study staff. Study staff will help orient the participant to the 
navigation of the site and will aid with login, password creation, and instruct participants to watch the 
overview sections on chronic low-back pain and the rationale for self-management of pain (Education). 
Study participants will be instructed to use this program for a period of 12 weeks. Though participants 
can choose to self-explore the material, there will be specific instructions delivered via text message or 
email that will direct participants to try the first few modules in a prescribed order: (1) Educational 
sections (“What is Pain” “Pain Mechanisms”, and “Approaches to Pain Management,” (2) Goal setting, 
(3) the Fitbit Walking program, and (4) OTC analgesics.  
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 using the PROMIS-29+2. For example, if sleep is identified as a problem at baseline, then the 
sleep module would be recommended for that individual. All materials will be available to the 
participant. This will allow participants to return to the materials for reinforcement or to access 
additional information not previously reviewed.  
Most of the PainGuide modules focus on self-care, education and aerobic exercise (walking program).  
The PainGuide’s educational module on medication has been adapted for BEST to provide a more 
detailed discussion of the use of self-administered over-the-counter (OTC) medications for chronic low-
back pain.  The medication module focuses on NSAIDs, which have been demonstrated to be an 
effective intervention in numerous cLBP trials and systematic reviews. Most of the discussion will be on 
NSAID oral medications such as ibuprofen and naproxen and the importance of consistent dosing. 
However, these medications are not tolerated by all individuals, and oral NSAIDs are contra-indicated 
for some cLBP patients, such as those with a history of gastrointestinal bleeding or who take oral anti-
coagulants.  Materials will stress the importance of the participant talking with their primary care or 
pain management provider in such circumstances.  The module will also provide information on other 
OTC preparations such as oral acetaminophen, topical lidocaine or topical diclofenac.   
The BEST trial’s walking program module will build on PainGuide’s pacing and self-care modules. 
Specifically, this module will provide guidance on the importance of aerobic exercise for cLBP as well as 
specific self-monitoring, goal-setting, and problem-solving education appropriate for cLBP patients. The 
module will provide strategies to counter maladaptive pain beliefs, especially fear avoidance regarding 
movement. All participants will be given a web-connected wearable device, Fitbit, to assist in monitoring 
their step count (a metric of functional status).  
Participants will continue to have access to all of PainGuide modules throughout the trial. Use of the 
website will be captured passively with website utilization metrics. The online platform will also provide 
the participants tools to track their symptoms. 
The Enhanced Self Care arm will be delivered via online self-management modules: 
• 
Week 1:  Educational content  
o What is Pain  
o Pain Mechanisms 
o Approaches to Pain Management  
• 
Week 2: Goal setting 
• 
Week 3: Fitbit walking program 
• 
Week 4: OTC analgesics 


 
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• 
Weeks 5-12: Personalized recommendations (based on baseline, e.g., PROMIS 29+2, modules: 
(e.g., Sleep, Mood, Reframing) 
 
ESC Protocol for Second Randomization Period 
Participants randomized to continue receiving ESC in the second period intervention will receive 
personalized recommendations based on the most recently completed PROMIS 29+2.  
10.3.2. ACQUISITION AND ACCOUNTABILITY 
PainGuide is hosted centrally on a University of Michigan Server. Study staff at each participating site 
will be given the ability to establish personal accounts for each participant who is randomized to the ESC 
arm of the study. 
10.3.3. STUDY INTERVENTION COMPLIANCE 
Adherence to the intervention will be assessed in terms of 1) which modules were accessed by the 
participant over the course of the intervention period, 2) how long the participant spent on each 
module, 3) a questionnaire asking participants to provide feedback on their experience with the 
materials, and 4) number of days with login/activity. 
10.4. 
STUDY INTERVENTION(S) ADMINISTRATION: EVIDENCE-BASED EXERCISE AND 
MANUAL THERAPY 
Evidence-Based Exercise and Manual Therapy (EBEM) is provided by a licensed physical therapist or 
Doctor of Chiropractic. Evidence-based guidelines, including those from the American College of 
Physicians, the Agency for Healthcare Research and Quality, and the Departments of Defense and 
Veterans’ Affairs, indicate that exercise and manual therapy are beneficial for persons with chronic back 
pain. Practice Guidelines and Systematic Reviews support benefits of exercise and manual therapy for 
persons with chronic LBP.59,60 
Exercise and manual therapy interventions are most commonly provided to persons with LBP by physical 
therapists and Doctors of Chiropractic. Exercise helps patients with chronic LBP recover and avoid 
recurrence. Exercise has positive impact on both mental and physical well-being and will be included in 
every EBEM session. Evidence-based guidance is provided to direct decision-making on tailoring the 
particular type of exercise that is best-suited to each individual study participant.  
Although systematic reviews have not found any specific type of manual therapy or exercise superior to 
another for all patients with LBP, there is support for decision-making strategies that describe how 
exercise and manual therapy interventions should be personalized to individual patients with LBP.   
Evidence supports a multimodal approach combining exercise with manual therapy. Manual therapy is 
therefore included in each EBEM session. Evidence-based guidance is provided to direct decision-making 
on the particular type of manual therapy that may be best suited to an individual study participant. 
Special attention is 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 
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The EBEM intervention will train licensed physical therapists and Doctors of Chiropractic to personalize 
care to individual participants and enhance their effectiveness. These strategies are outlined below: 
Risk Stratification  
Risk stratification involves identifying physical and psychological factors associated with developing 
prolonged disability and providing treatments to address the specific risk factors present in an 
individual patient. The type and dosage of the EBEM treatment components (exercise, manual 
therapy and education) will be based on the participant’s degree of risk. Training will provide 
guidance on how each of the treatment components can be tailored to participant’s risk based on 
the results of the STarT Back Screening Tool collected at the baseline visit. 
Intervention Tailoring  
The core components of EBEM (exercise and manual therapy) will be tailored to address the unique 
needs of an individual participant. Training will focus on Treatment-Based Classification (TBC) as a 
decision-making framework with evidence to support its effectiveness. The TBC decision-making 
framework trains clinicians to tailor the particular selection of exercise and manual therapy 
techniques to individual patients with back pain. 
Education Strategies  
All participants will be helped to understand the biopsychosocial model of pain, which places 
emphasis on the important role of thoughts and attitudes as well as environmental factors on the 
pain experience. Key messages include the importance of remaining active and maintaining a 
positive outlook towards recovery. Education strategies are also designed to enhance participants’ 
self-efficacy through motivation-enhancing communication and shared-goal setting procedures. 
Training will emphasize recommended communication strategies for establishing an optimal 
supportive and collaborative relationship with participants.   
10.4.1. DOSING AND ADMINISTRATION 
The EBEM intervention will be provided in face-to-face, one-on-one, sessions with a licensed physical 
therapist or Doctor of Chiropractic who has been trained in the intervention protocol. 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. If visits are missed and/or need to be 
rescheduled, visits may be scheduled for up to 12 weeks. No more than 10 visits will be scheduled for 
participants newly randomized to EBEM in either the first or second intervention period. For participants 
maintaining EBEM in the second treatment period, no more than 4 visits will be scheduled. Treatment 
sessions will last approximately 60 minutes each. 
Providers will be licensed PTs or DCs with at least 1 year experience working with patients with cLBP.  
Providers are required to attend 12 hours of training covering performance of specific techniques, 
adaptations to telehealth, risk stratification, tailoring, and participant education procedures. Some 
training content will be online.  
Study providers will have their intervention visits monitored for fidelity via a video recording or in-
person observation once they are certified to deliver the intervention. Fidelity assessments will be 
conducted with greater frequency during the early stages of enrollment and then as needed. Video 
recordings/observations will be reviewed/performed by investigators or designee and evaluated for the 


 
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criteria on a fidelity checklist. Fidelity assessments will focus on verifying that the exercise and manual 
therapy components were delivered as outlined in the protocol, and that no prohibited interventions 
were delivered. Individual providers will receive additional or remedial training in the intervention 
protocol whenever deficiencies in fidelity are observed. 
EBEM Protocol for Second Randomization Period 
Participants randomized to continue receiving EBEM in the second period intervention will receive 4 
additional in-person EBEM sessions during weeks 1-4 of this period. If visits are missed and/or need to 
be rescheduled, visits may be scheduled up to 5 weeks from the date of the first 
augmenting/maintenance visit. 
10.4.2. ACQUISITION AND ACCOUNTABILITY 
Licensed Doctors of Chiropractic and physical therapists are eligible to be trained in the EBEM study 
protocol. Training will consist of a total of 12 hours of content covering the performance of specific 
exercise and manual therapy techniques as well as instruction in procedures for risk stratification, 
intervention tailoring using the TBC decision-making framework, and communication and motivation.  
10.4.3. STUDY INTERVENTION COMPLIANCE 
Adherence to the intervention will be assessed in terms of attendance to in-person sessions. Compliance 
with the first period EBEM treatment is defined as completion of at least 8 of the 10 prescribed visits.  
Compliance with the second period EBEM treatment is defined as completion of at least 3 of the 4 
prescribed visits 
10.4.4. MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
The first-stage randomization will use a randomized version61 of the Minimization method62,63 to 
maintain marginal covariate balance. Minimization is an alternative to stratified permuted block 
randomization for maintaining (marginal) covariate balance across treatments that is better equipped to 
handle a larger number of factors to balance on. When a participant is randomized, a measure of the 
marginal discrepancy between treatments is calculated and the patient is randomized using a biased 
coin method where whichever treatment would make the discrepancy smallest has a higher probability 
and the other treatments have equal, smaller probabilities. Covariates included in minimization 
algorithm: 
• 
Willingness to participate in deep phenotyping (yes/no) 
• 
Depressive or anxiety symptoms (yes/no) 
• 
Duration of pain symptoms (<5 years/≥5 years) 
• 
Current use of opioid treatment (yes/no) 
 
A total of approximately 740 participants will be randomized to ACT (n=185), duloxetine (n=185), ESC 
(n=185), and EBEM (n=185) and which will require recruitment of approximately 820 participants, 
anticipating that 10% will not be randomized due to failure to meet eligibility criteria at the end of the 
run-in phase and an estimated 15% will be lost to follow-up over the course of the study. Participants 
who did not complete required run-in procedures will not be randomized. In order to assign equal 
numbers of participants to each of the 4 study interventions, randomization probabilities will account 


 
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for the fact that certain participants, e.g., because of a contraindication, may be eligible for only 3 of the 
4 treatments.  
 
Second-stage randomization will occur at the end of the first treatment period. Response to treatment 
will be assessed using the PEG and PGIC. Based on these scores, individuals will be grouped into 4 
response classes. 
• 
Group 1 participants (PGIC 1-2 and PEG <4) are assigned to maintain the first-line treatment.  
• 
Group 2 participants (PGIC 1-2, PEG ≥4) are assigned to maintain the current treatment and 
augment with a randomly selected additional treatment.  
• 
Group 3 participants (PGIC 3-4) are randomized to an augmentation treatment or to switch to a 
new treatment.  
• 
Group 4 participants (PGIC 5-7) are randomly assigned to switch to a second-line treatment.  
 
 
Table 10.1 provides a list of all possible augmentations (combinations of the initial treatment with a 
second study intervention) and treatment switches for each of the initial treatment assignments. This 
randomization will be performed within initial treatment by using the minimization method62,63 to 
achieve study-wide balance across treatments. Over the course of the study, the number and proportion 
of participants assigned to augmentation and switching overall, blinded to initial treatment assignment, 
will be monitored. If the proportions in each group differ meaningfully from the underlying assumptions 
used in the estimation of sample size, the proportion randomized to augment vs switch within Group 3 
will be adapted to maintain power. 
 
Table 10.1. List of all possible augmentations and treatment switching based on first-stage intervention. 
First Stage Treatment 
All Potential Second Stage 
Augmentations  
All Potential Switches to Second 
Treatments 
ESC 
ESC + ACT 
ESC + Duloxetine 
ESC + EBEM 
N/A 
ACT 
ESC + ACT 
ACT + Duloxetine 
ACT + EBEM 
ESC 
Duloxetine 
EBEM 
Duloxetine 
ESC + Duloxetine 
ACT + Duloxetine 
ESC 
ACT 


 
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Participants who must discontinue first-stage treatment early, regardless of their PGIC or PEG score, will 
be randomized to switch to a second treatment. These individuals will discontinue treatment and will be 
randomized to switch to a second-line treatment 12 weeks post baseline (Visit 1).  
 
Randomization will be performed using the Carolina Data Acquisition and Reporting Tool (CDART), 
developed by the Collaborative Studies Coordinating Center at the University of North Carolina. CDART 
is designed and implemented as a centrally hosted, web-based, customizable and scalable data 
management system. Randomization algorithms will be developed by a biostatistician and custom-
written in Java, which provides a full set of libraries and tools capable of complex algorithm 
implementation. This data management system will provide a means for implementing treatment 
allocation protocols, masking allocation of future participants, and for study staff to obtain allocation 
information immediately following randomization. Study staff and participants will not be blinded to 
treatment allocation given the nature of the interventions. Study investigators and staff involved in data 
analysis will be blinded to assignment. 
 
Although patients and providers cannot be blinded with respect to study interventions, during the study 
data summaries produced for review by the study team that involve primary and secondary endpoint 
data will be blinded (e.g., treatment groups randomly permuted). Unblinded summaries may be 
required for review by the DSMB. Study team members involved in producing DSMB reports and/or 
presenting unblinded data to the DSMB will have no role in development of the study’s statistical 
analysis plan. 
 
11. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
11.1. 
DISCONTINUATION OF STUDY INTERVENTION 
 
Early discontinuation of treatment is anticipated to be rare. Examples include a broken leg, precluding 
continuation of EBEM, or adverse reaction to duloxetine, necessitating discontinuation of duloxetine 
treatment. 
11.2. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
A participant may be discontinued from the study if he/she is shown to not meet the inclusion criteria 
based on new information that was not available at the time of initial enrollment and continuing in the 
study poses a safety risk (e.g., pregnancy or development of liver failure if on duloxetine).  Participants 
should not be discontinued for reasons other than new information that constitutes a safety risk.  For 
example, if new information indicates that a participant meets one of the exclusion criteria for an 
intervention, but the criteria does not pose a safety risk to the participant, then the participant should 
not be discontinued.  In this case, the participant will be considered in violation of the protocol for that 
Duloxetine + EBEM 
EBEM 
EBEM 
ESC + EBEM 
ACT + EBEM 
Duloxetine + EBEM 
ESC 
ACT 
Duloxetine 


 
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period and excluded from the per protocol analysis (see Sections 10.1.4, 10.2.4, 10.3.4, and 10.4.4).  In 
general, participants with poor compliance but at no increased risk will continue in the study to 
complete all study assessments and minimize attrition.   
Other criteria for participant discontinuation at any point in the study: 
• 
Participant meets one or more of the safety exclusion criteria defined in Section 8. 
• 
Study physician determines that continuation in the study is not in the best interest of the 
participant. 
• 
Participants can withdraw consent from the protocol at any point, and that will lead to 
discontinuation from the study.  At that point, the investigator will make reasonable effort to 
ensure participant’s well-being and safety and provide a termination visit with appropriate 
documentation. 
• 
The site investigator may decide to stop a participant’s treatment due to side effects or other 
safety concerns for the participant and/or site staff.  If the participant is participating in the 
duloxetine intervention arm at the time of discontinuation from the entire study, the participant 
will be advised to taper their dose as outlined in Section 10.2. or obtain a prescription for 
duloxetine from their primary care physician or other provider. 
11.3. 
LOST TO FOLLOW-UP 
Participants who do not show up for a scheduled non-intervention study visit will be contacted by 
available means (calling, email, text). If an emergency number is provided, it can be used to contact the 
participant, at least to ensure they are doing well. Participants who fail to respond to voice and written 
requests to contact the clinical site and who miss the Baseline Visit or 12-Week Visit will be considered 
lost to follow-up.  Participants who miss their 24-Week Visit will not be considered lost to follow-up and 
will be sent the 36-Week timepoint questionnaires.  A termination form should be completed by the 
investigator to record the exit of any participant deemed lost to follow-up. 
12. 
STUDY ASSESSMENTS AND PROCEDURES 
 
12.1. 
EFFICACY ASSESSMENTS  
Study outcomes will be assessed by self-report using a series of validated instruments to measure pain 
intensity and interference, physical function, depression, anxiety, sleep disturbance and duration, and 
opioid use. Patient-reported outcome measures will be administered at study baseline as well as at 12- 
and 24-weeks following first-stage randomization using a web-based survey platform. The primary 
endpoint is based on the Pain, Enjoyment of Life, and General Activity (PEG) scale, a 3-item assessment 
of pain intensity and interference with enjoyment of life and general activity over the past week. 
Response values for each item range from 0 to 10 and the average score across the three items will be 
used as the outcome value. 
Secondary outcome assessments include: 
• 
PROMIS Pain interference scale (PROMIS-PI, 4a) 
• 
Current use of opioid medication on a daily basis 
• 
PROMIS Physical Function (PROMIS-PF Short Form 6b) 
• 
PROMIS 4-item Depression scale (from the PROMIS 29 profile) 
• 
PROMIS Emotional Distress-Anxiety scale (PROMIS-EDA 4a) 


 
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• 
PROMIS Sleep disturbance (PROMIS short form 6a) 
• 
Sleep duration (reported number of minutes asleep per night over the past month) 
 
Primary and secondary endpoints 
• 
Primary endpoint: 24-week change from baseline in patient-reported pain intensity and 
interference, measured with the Pain, Enjoyment of Life, and General Activity (PEG) scale at 
Visits 0 (baseline) and 2 (24 weeks of treatment)  
• 
24-week change from baseline in pain interference, measured with the 4-item PROMIS Pain 
Interference scale (PROMIS-PI, 4a) at Visits 0 (baseline) and 2 (24 weeks of treatment) 
• 
Incidence of opioid use, measured by self-report at Visit 2 (24 weeks of treatment)  
• 
24-week change from baseline in physical function, measured with the PROMIS-PF Short Form 
6b at Visits 0 (baseline) and 2 (24 weeks of treatment) 
• 
24-week change from baseline in depression score, measured with the PROMIS 4-item 
depression scale from the PROMIS 29 profile at Visits 0 (baseline) and 2 (24 weeks of treatment) 
• 
24-week change from baseline in anxiety score, measured with the PROMIS Emotional Distress-
Anxiety scale (PROMIS-EDA 4a) at Visits 0 (baseline) and 2 (24 weeks of treatment) 
• 
24-week change from baseline in sleep disturbance, measured with the PROMIS short form 6a 
at Visits 0 (baseline) and 2 (24 weeks of treatment) 
• 
24-week change from baseline in sleep duration, measured at Visits 0 (baseline) and 2 (24 
weeks of treatment) 
 
12.2. 
SAFETY ASSESSMENTS 
 
Participants will be screened for contraindications to any of the BEST study interventions and 
phenotyping procedures prior to enrolling in the study.  At the baseline visit, participant medical history 
will be obtained by the clinical coordinator and a physical assessment will be performed by a qualified 
medical professional. Basic safety assessments will be performed 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) 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 staff will conduct an additional assessment of participants randomized to duloxetine 
via phone on day 7 (or next business day if falls on a weekend) of the intervention phase with 
participants newly randomized to duloxetine (i.e., day 7 of either the first or second intervention 
period). 
 
Participants will be asked to report pregnancy status at multiple time points:  prior to enrollment at Pre-
screening and Screening, and prior to randomization at the Baseline and 12-Week visits. Participants 
who report pregnancy prior to randomization to the first period intervention are excluded from the 
study.  If the participant becomes pregnant during the study, duloxetine will be rapidly tapered.  
Participants who become pregnant during the study will not undergo study MRIs. 
12.3. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 


 
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12.3.1. DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event (AE) is defined as any untoward or unfavorable medical occurrence in a human patient 
or research subject, including any abnormal sign (for example, abnormal physical assessment or 
laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the research.  Adverse 
events occurring after the participant provides informed consent will be recorded. 
 
12.3.2. DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
• 
death 
• 
a life-threatening adverse event 
• 
inpatient hospitalization ≥ 24 hours or prolongation of existing hospitalization 
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• 
a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant and may require intervention to prevent one 
of the other outcomes listed in the definition above.  
This definition permits either the sponsor or the investigator to decide whether an event is serious. 
Serious adverse events are critically important for the identification of significant safety problems. 
Therefore, if either the investigator believes that the event is serious, the event must be considered 
serious and evaluated by the sponsor for expedited reporting (21 CFR 312.32(a) and 312.32(c)(1)). 
 
12.3.3. CLASSIFICATION OF AN ADVERSE EVENT 
 
Severity of Event 
For adverse events (AEs), the following guidelines will be used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
Relationship to study intervention 
The site investigator is responsible for assessing the relationship between the AE and the study agent(s). 
Site investigators must provide the initial assessment as to whether there is a reasonable possibility that 
the study agent(s) caused or contributed to a SAE. The relationship assessment, based on clinical 
judgment, often relies on the following:  
• 
A temporal relationship between the event and administration of the study agent(s),  
• 
A plausible biological mechanism for the agent to cause the AE,  


 
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• 
Another possible etiology for the AE,  
• 
Previous reports of similar AEs associated with the study agent or other agents in the same 
class, and  
• 
Recurrence of the AE after re-challenge or resolution after de-challenge, if applicable.  
Further assessment of causality is provided by the DSMB based on accumulating safety reports between 
treatment groups. 
The terms used to assess the relationship of an event to study agent are:  
• 
Related – There is a reasonable possibility that the AE may be related to the study agent(s).  
• 
Not Related – There is not a reasonable possibility that the AE is related to the study 
agent(s).  
 
Expectedness  
Expected AEs are AEs that have been previously observed with the study intervention or procedures. An 
adverse event is considered “unexpected” if its nature, severity, or frequency is not consistent with 
either of the following:  
• 
the known or foreseeable risk of adverse events associated with the procedures involved in 
the research that are described in (a) the protocol-related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and (b) other relevant sources of information, such 
as product labeling and package inserts; or  
• 
the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile 
for the adverse event.  
 
12.3.4. TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study intervention (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
A site physician investigator or sub-investigator will record all reportable events between the time the 
participant provides informed consent through 4 weeks after their last treatment. At each study visit, 


 
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the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed 
for outcome information until resolution,stabilization, or participant is off-study. 
 
12.3.5. ADVERSE EVENT REPORTING  
 
Serious Adverse Event Reporting  
Study investigators will immediately notify the DAC of any serious adverse event, whether or not 
considered test treatment-related, including those listed in the protocol or investigator brochure.  The 
report must include an assessment of whether there is a reasonable possibility that the treatment 
caused the event.  
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the DAC and should be provided as soon as possible. 
• 
All AEs will be reported in aggregate to the NIAMS and the DSMB (through the NIAMS 
Executive Secretary) as part of the routine DSM report.  
• 
All SAEs (regardless of relatedness or expectedness) will be reported to the NIAMS and the 
DSMB (through the NIAMS Executive Secretary) within 48 hours of the investigator 
becoming aware of the event.  
 
12.3.6. REPORTING EVENTS TO PARTICIPANTS  
Participants will be informed of any adverse events or serious adverse events if risk-benefit profile is 
impacted. Events significantly impacting the study integrity will require a change in protocol and 
additionally require re-consenting of participants. All active study participants would then be notified.  
An abnormal finding may occur whenever imaging, conducting assessments, performing interventions, 
or completing study tasks. The purpose of imaging, assessments, and interventions are for research 
purposes only and are not intended to be used for clinical care (i.e., images will not be read by a 
radiologist). The imaging will not be read for clinical purposes and will not be reported to the patient 
(e.g., findings of spinal stenosis, neuroforaminal stenosis, lipomatosis, arachnoiditis will not be reported 
to the patient as the purpose is not for clinical care). During the course of the study, any gross abnormal 
finding noted in imaging or other assessment may be disclosed to the participant by the site investigator 
and the patient would be asked to follow-up with their Primary Care Physician (PCP). If the patient does 
not have a primary care provider, they will be instructed to establish care with a PCP to discuss further 
clinical management of the abnormal finding.  Site investigators will work with DAC staff to notify 
participants and ensure that the patients are informed to follow-up with their PCP. 
Examples of findings of clear clinical significance include:  
• 
Abnormal blood pressure 
• 
Intracranial abnormalities (e.g., hematoma, tumor) 
• 
Intraspinal abnormalities (e.g., intraspinal tumors) 
• 
Syncope during blood draws 
• 
Pathological reflexes 
Any other condition/finding in the discretion of the investigator that needs to be reported to the patient 
and assessed by a clinician/PCP. 


 
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12.4. 
UNANTICIPATED PROBLEMS 
 
12.4.1. DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
Unanticipated Problem Involving Risk to Participants or Others (UPIRSO): Any incident, experience, or 
outcome that: 
Is unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the participant population being studied; 
Is related or possibly related to a participant’s participation in the research; and 
Is serious or suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
12.4.2. UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing IRB, as required, and to the 
DAC. The UP will be entered into the DMS and will include the following information: 
A detailed description of the event, incident, experience, or outcome;  
An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP;  
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP.  
All UPs will be reported to the NIAMS and the DSMB (through the NIAMS Executive Secretary) within 48 
hours of the investigator becoming aware of the event.  
13. 
STATISTICAL CONSIDERATIONS  
 
13.1. 
STATISTICAL HYPOTHESES 
 
The general objective of this study is to inform a precision medicine approach to cLBP. The statistical 
focus is on the estimation of a dynamic treatment regime (DTR) rather than to test the overall 
effectiveness of any single intervention or combination of interventions. The DTR will be estimated after 
the trial is completed, and it will use a panel of features, i.e. phenotypic markers, collected at baseline to 
recommend a first-line treatment, and then, depending on the response to treatment and any changes 
in participant covariates, recommend a second treatment (which may be a continuation of the first-line 
treatment). The performance will be measured by the estimated mean improvement in a given outcome 
(i.e. the PEG for the primary analysis) after two stages of treatment relative to baseline if the DTR were 
used to select treatments (called the value of the DTR). It is important to note that this goal 


 
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encapsulates discovering phenotypic markers that are associated with improved treatment response 
because the outcome is a function of the treatment received and a participant’s covariates. 
This section is intended to give an overview of the estimation targets for each study objective for the 
primary efficacy endpoint: the 24-week change from baseline in the PEG composite score. The PEG is a 
three-item scale with each item rated on a 0-10 scale. The mean response on these items will be used as 
the outcome. 
The primary objective is to estimate an algorithm to assign sequences of two cLBP treatments based on 
phenotypic markers and an individual patient’s response to the initial treatment (i.e., a dynamic 
treatment regime) that optimizes effectiveness. 
 
The goal is to estimate a DTR that maximizes the expected improvement in PEG after two stages of 
treatment relative to baseline. The estimation targets for this goal are 1) the parameters of the DTR and 
2) the value of the estimated DTR. 
 
To specify this formally, we will introduce notation from precision medicine (for a detailed review of this 
literature see Kosorok & Laber 2019).65 Let 𝑋𝑋1 denote the participant’s covariates at the time of the first 
randomization, and 𝑋𝑋2denote the interim data collected before the second randomization. 𝐴𝐴𝑡𝑡 denotes 
the assigned treatment at the 𝑡𝑡-th stage randomization, and 𝑌𝑌𝑡𝑡 the difference between the PEG 
measured after completing the 𝑡𝑡-th stage course of treatment and the participant’s baseline PEG score 
coded so that higher is better. Define 𝐻𝐻𝑡𝑡 as the participant history available at the t-th stage 
randomization, so that 𝐻𝐻1 = (𝑋𝑋1) and 𝐻𝐻2 = (𝑋𝑋1, 𝐴𝐴1, 𝑌𝑌1, 𝑋𝑋2), 𝑎𝑎𝑎𝑎𝑎𝑎 𝑯𝑯 = (𝐻𝐻1, 𝐻𝐻2). A dynamic treatment 
regime (DTR) is a sequence of functions  𝒅𝒅= (𝑑𝑑1, 𝑑𝑑2) that maps participants to treatments based on the 
available history. An optimal DTR maximizes the expectation of a prespecified cumulative outcome 𝑌𝑌=
𝑓𝑓(𝑌𝑌1, 𝑌𝑌2). In our case the outcome of interest is the 24-week change from baseline in PEG so 𝑌𝑌= 𝑌𝑌2. The 
potential outcome under a regime 𝒅𝒅 is given by 
𝑌𝑌∗(𝐝𝐝) =
෍𝑌𝑌∗(𝑎𝑎1, 𝑎𝑎2)𝟏𝟏(𝑑𝑑1(𝐻𝐻1) = 𝑎𝑎1)𝟏𝟏(d2(𝐻𝐻2) = 𝑎𝑎2)
(𝑎𝑎1,𝑎𝑎2)
 
where 𝟏𝟏 is the indicator function that is equal to one when the condition is met and zero 
otherwise. The goal is to estimate 𝐝𝐝opt, the DTR that maximizes the value function 𝑉𝑉(𝐝𝐝) =
𝐸𝐸[𝑌𝑌∗(𝐝𝐝)]. The efficacy will be assessed in terms of the estimated value of the DTR 𝑉𝑉෠൫𝐝𝐝̂൯. The optimal 
DTR, 𝐝𝐝opt, is fundamentally unknowable in the same way that regression parameters are.  
 
Secondary objective 1: Estimate 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. 
 
A utility-based combination of multiple outcomes will be used Aim 2. These outcomes include level of 
pain, physical abilities, fatigue, anxiety, depressive symptoms, cognitive function, and overall enjoyment 
of life. Three combinations will be considered: 1) a combination of pain and physical abilities; 2) a 
combination of pain, physical abilities, and cognitive function; 3) a combination of all seven outcomes. 
By eliciting participant preferences between different outcomes, we can construct an optimal DTR that 
balances multiple competing outcomes and respects the relative importance of these outcomes to each 
participant (Butler et al). Future treatment decisions could be informed by administering the preference 


 
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elicitation tool in combination with the estimated DTR to guide treatment decisions. Participant 
preferences will be elicited at baseline through a series of discrete choice tasks, and participant 
satisfaction with treatment will be measured after each stage of treatment to help calibrate the 
preference estimation. The efficacy will be assessed in terms of the estimated value, or expected 
patient-tailored combination of outcomes, of the DTR. 𝑉𝑉෠൫𝐝𝐝̂൯. 
 
Secondary objective 2: Estimate DTRs that incorporate additional phenotypic markers (i.e., deep 
phenotyping) collected on a sub-set of participants. 
 
Secondary objective 3: Assess whether effectiveness is sustained based on outcomes collected 24 
weeks after randomization to the second treatment. 
 
The change in the PEG composite score collected 24 weeks after the start of the second treatment 
relative to baseline will the efficacy endpoint for Secondary objective 3. This is identical to the primary 
efficacy endpoint except with a longer follow-up time. The efficacy will be assessed in terms of the 
estimated value of the DTR 𝑉𝑉෠൫𝐝𝐝̂൯. 
 
Exploratory objectives: Evaluate the (1) comparative effectiveness of individual treatments; (2) 
comparative effectiveness of different treatment regimes (i.e., a particular regime with a given set of 
rules at each decision point); and (3) impact of treatment order on outcomes. 
We can test the null hypothesis that the value of two different DTRs are equal. Let 𝐝𝐝0 denote the best 
DTR that does not consider a participant’s phenotype (the best zero-order DTR). This DTR assigns every 
participant the treatment with the best population average treatment effect. Let 𝐝𝐝opt denote the 
optimal DTR that considers participant phenotype. We can conduct two-sided tests of superiority of the 
hypothesis 
𝐻𝐻0: 𝐕𝐕(𝐝𝐝0) = 𝐕𝐕(𝐝𝐝opt)  
𝐻𝐻1: 𝐕𝐕(𝐝𝐝0) ≠𝐕𝐕(𝐝𝐝opt)  
For the other interventions that are not the best, we can analogously define a DTR that always 
recommends each of these treatments and compare them to each other and to the optimal DTR.  
13.2. 
SAMPLE SIZE DETERMINATION 
 
Simulation Methodology Overview 
 
Simulation studies were used to determine the sample size for the trial using a grid search over 
potentially feasible sample sizes. The outcome measure was the difference in PEG at 24 weeks relative 
to baseline. The performance metric of interest in the simulation studies was how close the value of the 
estimated dynamic treatment regime, 𝑉𝑉൫d𝑛𝑛
෢൯, was to the value of the optimal dynamic treatment 
regime 𝑉𝑉(dopt) for the difference. The percentage of optimal value is equal to 𝑉𝑉൫d𝑛𝑛
෢൯/𝑉𝑉(dopt) (assuming  
𝑉𝑉൫d𝑛𝑛
෢൯ is non-negative and 𝑉𝑉(dopt) is strictly positive). Note that this is not a hypothesis test but a 
performance criterion that evaluates how close the estimated treatment regime is to the optimal 
treatment regime 
 
The estimated value of the estimated dynamic treatment regime for each replicate was obtained using 
Monte-Carlo methods and an independent out-of-sample data set. First, an out-of-sample data set was 


 
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generated using the same data generating distribution as the one used to generate the trial data for a 
given simulation scenario. A dynamic treatment regime is estimated on the replicate study data using Q-
learning.5,6  Then for every dynamic treatment regime, the estimated DTR is used to assign the out-of-
sample participants to treatment sequences, and the estimated value of the DTR calculated (the 
expected outcome under each treatment is known for all out-of-sample participants). Finally, the ratio 
of the value from estimated DTR to the optimal DTR is calculated. 
 
The analog to power in this setting is the probability that the ratio of the value from a DTR estimated on 
a trial with sample size 𝑛𝑛 relative to the value of the optimal DTR is greater than or equal to a fixed 
performance cutoff δ. 
𝑃𝑃൫𝑉𝑉൫d𝑛𝑛
෢൯÷ 𝑉𝑉(dopt) ≥𝛿𝛿൯ 
We chose a performance cut-off δ of 0.9, so that for a simulated trial to be considered a success the 
value of the DTR estimated on that simulation replicate’s data must be within 90% of the optimal DTR’s 
value. 
 
There is no analog to Type-I error for this because a null scenario would imply that all treatments are 
equally ineffective and no biomarkers matter, and in this situation any dynamic treatment regime is 
trivially optimal. 
 
Simulations were conducted using R version 4.0.4 
 
Simulation Data Generation 
The outcome after each stage, 𝑌𝑌𝑡𝑡 the outcome is defined as the difference in PEG between the follow-up 
visit at the end of the stage and the baseline PEG. The simulation outcomes are on the standardized 
effect size scale instead of the 0-10 scale. The outcome of interest, 𝑌𝑌,  is the difference in PEG at 24 
weeks relative to baseline 𝑌𝑌= 𝑌𝑌2,.  
Let 𝐴𝐴𝑡𝑡,𝑘𝑘 denote the indicator function 𝟏𝟏(Intervention 𝑘𝑘 given for stage 𝑡𝑡) that is one whenever 
intervention 𝑘𝑘 is given for stage 𝑡𝑡 and zero otherwise. For the outcome after each stage, 𝑌𝑌𝑡𝑡 , denote 
the conditional expectation of 𝑌𝑌𝑡𝑡  given the history and intervention by  𝑄𝑄𝑡𝑡(𝐻𝐻𝑡𝑡, 𝐴𝐴𝑡𝑡) = 𝐸𝐸[𝑌𝑌𝑡𝑡|𝐻𝐻𝑡𝑡, 𝐴𝐴𝑡𝑡]. Then 
the data generating model for one of the simulation scenarios with a single covariate associated with 
the outcome is: 
𝑄𝑄1(𝐻𝐻1, 𝐴𝐴1) = .1𝐴𝐴1,0 + .25𝐴𝐴1,1 + .3𝐴𝐴1,2 + .4𝐴𝐴1,3 + .3𝑋𝑋1𝐴𝐴1,3 + .25𝑋𝑋2 −.25𝑋𝑋3  
𝑄𝑄2(𝐻𝐻2, 𝐴𝐴2) = .1𝐴𝐴2,0 + .25𝐴𝐴2,1 + .3𝐴𝐴2,2 + .4𝐴𝐴2,3 + .3𝑋𝑋1𝐴𝐴2,3 −.1𝐴𝐴2,1𝐴𝐴2,2  − 1𝐴𝐴2,1𝐴𝐴2,3
− .1𝐴𝐴2,2𝐴𝐴2,3         + .25𝑋𝑋2 −.25𝑋𝑋3 
𝑌𝑌1 = 𝑄𝑄1(𝐻𝐻1, 𝐴𝐴1) + ϵ1,      ϵ1 ∼𝑁𝑁(0,1) 
𝑌𝑌2 = 𝑄𝑄2(𝐻𝐻2, 𝐴𝐴2) + ϵ2, 
ϵ2 ∼𝑁𝑁(0,1) 
𝑌𝑌= 𝑌𝑌2 
Recall that in the first stage exactly one intervention can be given, while in the second stage one or two 
interventions may be given.  
The covariates were generated independently with 𝑋𝑋1 ∼Bern(. 5), 𝑋𝑋𝑙𝑙∼Bern(𝑝𝑝𝑙𝑙), l = 2, ..., 5 where and 
𝑝𝑝𝑙𝑙 ranges from 0.5 to 0.9 and 𝑋𝑋𝑙𝑙 are coded to take values {−1, 1} instead of {0, 1} and an additional five 
normally distributed covariates 𝑁𝑁(0, .5).  There were a total of ten covariates, one of which was 


 
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associated with the outcome through a treatment interaction, and two prognostic covariates that 
influence the outcome but was not associated with response to treatment. The  𝑄𝑄-functions were 
estimated using mis-specified models that included interaction terms for every treatment by covariate 
pair, and the models were fit by the Lasso.  
These settings give rise to the following optimal rule: 
𝑋𝑋1 
𝐴𝐴1
opt 
𝐴𝐴2
opt 
Response to treatment at 24 weeks 
compared to baseline 
𝑋𝑋1  = −1 
Any intervention 
𝐴𝐴2,1 and 𝐴𝐴2,2 in 
combination 
0.45 
𝑋𝑋1 =  1 
Any intervention 
𝐴𝐴2,2 and 𝐴𝐴2,3 in 
combination 
0.9 
 
The optimal rule above, 𝐝𝐝opt, has an average (over the values of X1) response of (0.45+0.9) = 0.675. An 
example DTR with a value that is within 90% of the optimal value is: 
𝑋𝑋1 
𝐴𝐴1
opt 
𝐴𝐴2
opt 
Response to treatment at 24 weeks 
compared to baseline 
𝑋𝑋1  = −1 
Any intervention 
𝐴𝐴2,1 and 𝐴𝐴2,2 in 
combination 
0.45 
𝑋𝑋1 =  1 
Any intervention 
𝐴𝐴2,1 and 𝐴𝐴2,3 in 
combination 
0.85 
Which assigns 𝐴𝐴2,1instead of 𝐴𝐴2,2  as part of the combination for biomarker positive patients in stage 
two. The average response (over the values of biomarker X1) is 0.65. 
 
The table below shows 𝐝𝐝optand other treatment rules for comparison.  
 
Treatment Regime 
Average response to treatment 
at 24 weeks compared to 
baseline 
𝐝𝐝opt (incorporates phenotypic markers) 
0.675 
Assign 𝐴𝐴0 in both stages 
0.1 
Assign 𝐴𝐴1 in both stages 
0.25 
Assign 𝐴𝐴2 in both stages 
0.3 
Assign 𝐴𝐴3 in both stages 
0.4 
Assign 𝐴𝐴3 in the first stage and 𝐴𝐴2,2 and 𝐴𝐴2,3 in combination in the second 
stage (no phenotypic markers) 
0.6 
 
The probability of attaining a value within at least 90% of the optimal value for this scenario is 81% 
based on 5,000 replicates (Monte Carlo standard error ≈ 0.009 ) 
The treatment effect sizes were based on systematic review by the Agency for Healthcare Research and 
Quality18,59 and an internal review conducted by the experts on BACPAC’s Interventions Working Group. 
The standardized treatment effect sizes were assumed to be 0.25 for ACT, 0.3 for Duloxetine, and 0.4 for 
EEMT. The effect size for enhanced standard of care was assumed to be 0.1. Subgroup-specific effects 
were constrained so that the population average treatment effect was equal to the effect sizes from the 
systematic review.  
 


 
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Simulation Results 
A total of 630 complete cases yields 80% probability to attain a value within at least 90% of the optimal 
value. Assuming ~15% of participants fail to complete the study through the primary efficacy endpoint, a 
total sample size of approximately 740 randomized would be sufficient to achieve at least 90% of the 
possible reduction in PEG 80% of the time. The 15% drop-out is intended as an upper-bound, not the 
actual anticipated drop-out, and is based on a threshold provided by experts in this area where they 
would have serious concerns about any study having above this rate of drop-out. 
 
13.3. 
POPULATIONS FOR ANALYSES 
 
All participants 
The “All participants” population will consist of all participants consented to the study. 
 
All Randomized Population 
The All Randomized population will consist of all participants randomized and statistical analyses will 
follow the intention to treat approach as much as possible. The All Randomized population will be used 
in primary, secondary, and exploratory analyses. 
 
13.4. 
STATISTICAL ANALYSES 
 
13.4.1. GENERAL APPROACH 
Below we provide an overview of the general statistical approach planned for this trial. A complete and 
detailed statistical analysis plan (SAP) will be completed prior to any evaluation of primary or secondary 
outcome data stratified by treatment group or sequence. 
The primary goal will be to estimate a two-stage dynamic treatment regime that maximizes the 
expected reduction in PEG between the beginning and the end of the study. We will use Q-learning for 
this approach.5 Q-learning reduces the reinforcement learning problem of optimizing a two-stage 
dynamic treatment regime to a standard regression problem, after which standard regression 
algorithms can be applied. A secondary interest will be to estimate a two-stage DTR that minimizes 
some combination of multiple outcomes, where the ideal trade-off is estimated using participant 
preferences. Here we will use a latent variable approach: We will assume that that the optimal 
combination, or preferred trade-off, of outcomes for each individual can be represented as a simple 
convex combination of outcomes, where the participant-specific weights of the convex combination are 
unobserved and depend on the participant’s covariates and responses to questionnaires. To estimate 
and make inferences on these weights, we will estimate the posterior distribution of these 
latent weights conditional on the covariates and questionnaire responses. This is what was proposed, 
for example, in Butler 2016.67 Other objectives include assessing long-term effectiveness of embedded 
and estimated treatment regimes and conducting hypothesis tests to compare the effectiveness of 
individual treatments and nested treatment regimes. Comparisons of first-stage treatments and of 
second-stage treatments adjusted for first-stage treatments can be conducted using standard t-tests. 
Comparisons of nested DTRs can be conducted using the methodology discussed in Kosorok and Moodie 


 
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2016.68 Estimation and assessment of DTRs based on longer-term outcomes can be conducted using Q-
learning. The methods used for conducting inference and variable importance analysis of the Q-
functions will depend on the data at hand and the regression procedures chosen. However, one possible 
contender is the bootstrapping method of Chakraborty, Laber and Zhao 2013.69  
We expect missing data to be minimal because of study procedures discussed previously to enhance 
retention such as incentives, incorporation of patient stakeholder feedback in the development of study 
materials, and efforts to minimize participant burden. In addition, there will be ongoing participant 
engagement through a study website, contact with research staff and regular patient engagement 
efforts. Finally, protocols for discontinuation of study treatment that are not tolerated are planned to 
enhance retention. We will continue to follow all participants until the end of the study and will utilize 
alternative forms of data collection for those who do not attend planned study visits (e.g., telephone 
administration or online data collection). Despite these efforts, missing data will arise and, as needed 
and appropriate, will be addressed using non-parametric multiple imputation procedures. Sensitivity 
analyses will be presented in detail as part of the SAP. 
13.4.2. ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Complete details will be provided in the formal Statistical Analysis Plan for the study. 
 
13.4.3. ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Complete details will be provided in the formal Statistical Analysis Plan for the study. 
 
13.4.4. SAFETY ANALYSES 
No safety analyses are planned other than descriptive summaries and data listings of reported adverse 
events. 
 
13.4.5. BASELINE DESCRIPTIVE STATISTICS 
Complete details will be provided in the formal Statistical Analysis Plan for the study. 
 
13.4.6. PLANNED INTERIM ANALYSES  
 
No interim analyses are planned for the study. Adaptation to the design, i.e. the second stage 
randomization probabilities, is planned and details will be included in a future Statistical Analysis Plan. 
Briefly, overall proportions of participants assigned to augment or switch will be monitored. If 
proportions deviate meaningfully from assumptions, we will consider shifting randomization 
probabilities within Group 3 (e.g., from 50/50 to 60/40 augment/switch). 
 
13.4.7. SUB-GROUP ANALYSES 
N/A 
 
13.4.8. TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Complete details will be provided in the formal Statistical Analysis Plan for the study. 
 
13.4.9. EXPLORATORY ANALYSES 
Complete details will be provided in the formal Statistical Analysis Plan for the study. 


 
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14. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
14.1. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
14.1.1. INFORMED CONSENT PROCESS 
Potential participants will be asked to provide consent to the protocol at the Enrollment Visit through a 
master consent document.  Our general approach to the consent process is to explain the design of the 
master protocol to each potential participant, why this design will assist with  understanding how to 
better match future cLBP patients to the most appropriate treatment(s) based on their individual 
characteristics, lifestyle, and environment and optimize their outcomes, how participation in the 
protocol will allow participants to receive treatment(s) that have been independently shown to clinically 
improve pain intensity and interference and may improve other outcomes such as function, why their 
participation is important, and how their data will contribute to the research. The goal is to obtain buy-
in from potential participants on the study expectations and requirements as a whole and explain clearly 
what they can expect from participation in the study (e.g., expected study duration given their 
enrollment date, possibilities of participating in two different treatments or remaining in one treatment 
assignment throughout the study, etc.).  The master consent form provides details about the possible 
treatment(s) each potential participant may receive. 
The master consent document describes the intervention process and procedures involved in the BEST 
trial. Participants will be informed that their consent will allow them to be assigned to a treatment, 
which may be augmented or changed during the intervention period. If they are not willing to provide 
consent, they are not eligible for the study.   
Note that participants will also be asked to consent to storage of and future use of their data and 
biospecimens separately from their consent to study participation.  Participants will be able to consent 
to the study (including use of biospecimens in BEST) but opt out of having their data and biospecimens 
stored for future use. Participants will also have the option to be considered for participation in more 
comprehensive phenotyping procedures, which include brain MRI, quantitative sensory testing, and an 
advanced spine MRI.   
Each consented participant will receive a signed copy of the study consent. The site's signed consent 
form copy is to be filed with other confidential participant information. Upon completion of the 
consenting process, each participant’s informed consent information is entered into the data 
management system for study tracking purposes.  During the study, consent information is updated in 
the data management system when the participant notifies the study that they would like to modify 
their consent or withdraw from the study. After study completion, participants may not be able to 
modify their consent for biospecimen use because all remaining biospecimens will be transferred the 
NIH biospecimen repository which will control access to the biospecimens. 
This study will be reviewed under a single institutional review board (IRB) at Advarra®.  All sites will rely 
on the Advarra® IRB, and a reliance agreement, either an IRB Authorization Agreement (IAA) or SMART 
IRB agreement, will be established for each site institution.  If an institution has a master service 
agreement established with Advarra®, a study-specific IAA will not need to be established.  Once fully 
executed, a copy of the IAA, SMART IRB agreement, will be submitted to the DAC, with the original 
agreement filed on site. If the institution is under a master service agreement with Advarra®, the site 
will need to supply a copy to the DAC.  The DAC will ensure that every consent form meets federal 


 
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requirements and presents accurate information, as determined by the protocol team and NIH 
regulatory officials, and the current consent form will be kept on file and available for review. 
In obtaining and documenting informed consent, BEST study investigators and study teams will comply 
with applicable regulatory requirements, namely, ICH, GCP and other regulatory requirements including 
Title 45 Part 46 of the Code of Federal Regulations (45 CFR 46), 21 CFR 11 (Electronic Records), 21 CFR 
50 (Protection of Human Subjects), 21 CFR 54 (Financial Disclosure of Clinical Investigators), 21 CFR 56 
(Institutional Review Boards), and 21 CFR 312 (Investigational New Drug Application).  
14.1.2. CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting administration 
of the study intervention.  The following consent materials are submitted with this protocol: 
• 
Adult Consent Form_English 
Basic consent elements and appropriate additional elements as outlined in 45 CFR §46.116 and 21 CFR 
§50.25 include: 
• 
Statement that the study involves research; 
• 
Explanation of the purposes of the research, the expected duration of the subject’s 
participation, and a description of the procedures to be followed; 
• 
A statement of the conditions and period of time under which the participant’s data will be 
stored and will be accessible; 
• 
A description of any foreseeable risks or discomforts to the participant; 
• 
Reasonably expected benefits to participant or others; 
• 
Disclosure of alternative procedures; 
• 
Confidentiality measures; 
• 
Explanation of compensation and medical treatment, if any, for injury; 
• 
A statement that participation is voluntary, refusal to participate will involve no penalty or loss 
of benefits and that the participant may discontinue participation in any time without penalty or 
loss of benefits; and 
• 
An explanation of whom to contact for answers to pertinent questions about the research and 
research participant’s rights, and whom to contact in the event of a research-related injury to 
the participant, for research questions, or for questions about rights. 
Additional elements include:  
• 
Unforeseeable risks to the participant and/or to the fetus or embryo in case of pregnancy; 
• 
Circumstances under which participation may be terminated without regard to participant’s 
consent; 
• 
Additional costs to participant resulting from study participation; 
• 
Consequences of the decision to withdraw and procedures for orderly termination of 
participation by the participant; 
• 
New study findings which may affect the participant’s decision to continue; and 
• 
Approximate number of study participants. 
Informed consent form requirement for clinical trials: 


 
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The FDA and NIH have mandated that all informed consent documents inform participant volunteers 
that trial data will be added to the national clinical trial registry databank at ClinicalTrials.Gov.  The exact 
wording to be included in the documents reads: “A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that 
can identify you. At most, the Web site will include a summary of the results. You can search this Web 
site at any time.” 
 
14.1.3. CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be IRB-approved, and 
the participant will be asked to read and review the document. The investigator or study coordinator 
will explain the research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants.  Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to signing. 
The participants should have the opportunity to discuss the study with their family or surrogates or think 
about it prior to agreeing to participate. The participant will sign the informed consent document prior 
to any procedures being done specifically for the study. Participants must be informed that participation 
is voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the 
informed consent document will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the form 
signed, before the participant undergoes any study-specific procedures. In cases where a participant is 
required to be re-consented, re-consent may also be obtained remotely with prior permission from the 
DAC. In this case, the consent form will be provided to the participant. It will be reviewed with the 
participant over the phone or during a video call. The participant may sign the consent form and return 
it to the site, or the form may be signed electronically, provided a software tool that is compliant with 
the Code of Federal Regulations (CFR) 21 Part 11 concerning electronic signatures is available at the site. 
The rights and welfare of the participants will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
14.1.4. STUDY DISCONTINUATION AND CLOSURE 
The trial may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause (see examples below). Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, investigators, 
the NIAMS, the Food and Drug Administration and other relevant regulatory authorities. If the study is 
prematurely terminated or suspended, the Principal Investigator at each study site will promptly inform 
study participants, the IRB, and the sponsor and will provide the reason(s) for the termination or 
suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.  Please refer to Section 11, Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal, for handling of enrolled study participants. 
Circumstances that may warrant termination or suspension of the study include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 


 
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The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy NIAMS, the IRB and/or other regulatory agencies.  
14.1.5. CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study 
documentation, data, and all other information generated will be held in strict confidence.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, or 
regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
records for the participants in this study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data used for purposes of statistical analysis and scientific reporting will be 
securely transmitted to and stored at the DAC. The study data entry and study management systems 
used by clinical sites and by the DAC will be secured and password protected (see Sections 5.2.3. and 
14.1.11.). At the end of the study, data will be de-identified and sent to an NIH data repository. 
Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality (COC) has been 
automatically issued by the National Institutes of Health (NIH).  This certificate protects identifiable 
research information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By 
protecting researchers and institutions from being compelled to disclose information that would identify 
research participants, Certificates of Confidentiality help achieve the research objectives and promote 
participation in studies by helping assure confidentiality and privacy to participants. 
 
14.1.6. FUTURE USE OF STORED SPECIMENS AND DATA  
 
BEST will be collecting specimens on all participants. Strict confidentially standards are in place and will 
be maintained to protect the privacy of study participants. Biospecimen samples will be labeled with a 
unique identifier that does not contain any protected health information or otherwise identify a 
participant. Biospecimens collected will not be stored long-term at the clinical sites but rather will be 
deposited in batches at the NYU Langone Health Center for Biospecimen Research and Development 
(CBRD).  These specimens will not be individually identifiable by the laboratories, clinical centers, or DAC 
personnel. The DAC will develop and maintain a tracking system whereby study participants can modify 
their level of consent for their use of any stored samples for future studies. Participants can ask that any 
specimens still in storage be destroyed and not included in future analyses.  


 
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Genetic studies utilizing the participant’s DNA will be conducted in BEST. Other “omics” studies will also 
be conducted in BEST.  These may include studies to evaluate the RNA transcriptome and the 
microbiome, and they could potentially include studies involving the metabolome, the epigenome, and 
the proteome.  Data collected for this study will be analyzed and stored in the secure servers at the DAC 
and submitted to the secure cloud-based data portal at the DAC per the schedule defined in the BACPAC 
Data Transfer SOP.  After the study is completed, the de-identified data will be transmitted to and 
stored at an NIH-approved repository for use by other researchers including those outside of the study. 
Permission to transmit data to the NIH repository will be included in the informed consent.  
With the participant’s approval and as approved by the study’s single IRB, de-identified biological 
samples will also be stored at a NIH’s HEAL repository after the study is completed. These samples could 
be used for future research.  
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed. When the study is completed, 
access to study data and/or samples will be provided through the NIH data and biospecimen 
repositories. 
14.1.7. KEY ROLES AND STUDY GOVERNANCE 
 
The BEST Executive Leadership Committee (ELC) will provide leadership for the implementation of the 
BEST trial and will serve as the primary decision-making body regarding actions taken in response to 
challenges that arise implementing the study protocol.  Membership will include the BEST Protocol Co-
Chairs, the BEST Project Manager, the NIAMS BACPAC Program Coordinator, and two BEST site PIs 
(serving on a rotating basis).  Primary duties of the ELC will include interacting with NIH regarding the 
progress of the trial towards key milestones, facilitating the BEST Operations Committee (OC) meetings, 
and providing high-level reporting on the trial to the BACPAC Steering Committee at regular intervals. 
The ELC will also be responsible for determining whether protocol modifications are needed and for 
seeking input/approval from the BACPAC Steering Committee as needed. 
The BEST OC will provide feedback to the ELC regarding the conduct of the study. OC bi-weekly meetings 
will provide a forum for site PIs to share implementation successes and challenges with the broader set 
of OC members to foster refinement of best practices regarding conduct of the study.  Membership will 
include ELC members, BEST site PIs, NIH/NIAMS representatives, and BEST intervention experts, as well 
as experts from the BACPAC Adaptive Design Expert Group, Intervention Working Group, Deep 
Phenotyping Working Group, and Theoretical Model Working Group. 
 
14.1.8. SAFETY OVERSIGHT 
NIAMS will establish an independent Data and Safety Monitoring Board (DSMB) charged with oversight 
of data quality, study integrity, and safety of participants. Per NIAMS requirements, all SAEs regardless 
of the expectedness and relatedness must be reported to the NIAMS and the DSMB through the NIAMS 
Executive Secretary within 48 hours of the investigator becoming aware of the event. 
AEs are reported in aggregate and presented at the semi-annual DSMB meetings.  The DSMB will review 
unblinded data reports semi-annually and make recommendations to the NIAMS to ensure that 


 
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participants are not exposed to undue risks.  The DAC will submit a summary report of 
recommendations after each DSMB meeting to the central IRB.  After IRB review, the summary of 
recommendations will be distributed to the site investigators to store with study documentation. 
The DSMB will make recommendations as to whether an intervention or the entire study should be 
stopped for safety reasons based on periodic monitoring of adverse events and other safety parameters.  
Regularly scheduled DSMB meetings will be held to review safety data reports prepared by the DAC that 
include summary statistics by treatment group for adverse events, laboratory parameters, and other 
safety outcomes.  Ad hoc DSMB meetings to review safety data can also occur if triggered by unusually 
high or unexpected SAE reporting. 
Once a determination is made to recommend discontinuation of the study or a specific intervention for 
safety reasons, the DSMB’s deliberations and rationale for arriving at the recommendation will be 
shared with the PI and key personnel. The DAC will prepare a report for the NIAMS Project Officer and 
the Operations Committee that summarizes the results of analyses supporting the recommendations, 
the stopping boundaries or rules used, and the DSMB’s summary of their deliberations to arrive at the 
decision.  The DAC will then work with the Operations Committee to develop an appropriate 
communication plan for the various stakeholders.   
DSMB Members 
Members of the DSMB are independent experts chosen by NIAMS on the basis of their expertise and 
scientific rigor. They are not associated with the trial or with the pharmaceutical companies that supply 
the study agents. Committee members’ areas of expertise span the disciplines relevant to the conduct 
of this clinical trial, including clinical trials, pharmacology, biostatistics, and clinical care of participants 
with cLBP. 
DSMB Mandates 
The DSMB has the responsibility to review the research protocol and other study materials and to 
evaluate the progress of the trial overall and at each participating clinical center. This includes accrual, 
data quality and completeness, episodes of exacerbations, hospitalizations, mortality, other toxicities, 
and protocol violations. NIAMS expects expedited reporting of SAEs, Unanticipated Problems, and 
Protocol deviations that impact participant safety to occur within 48 hours of the investigator becoming 
aware of the event.  Protocol deviations that occur but do not affect participant safety are submitted in 
aggregate as part of the routine DSMB meeting report. 
Concurrently, the DSMB will evaluate the safety of the interventions studied under the Protocol as the 
trial progresses, considering evolving scientific discoveries or treatment options that may affect the 
desirability of continued treatment with any one of the interventions. At the conclusion of each 
meeting, the DSMB will recommend whether the study or specific interventions be continued. If the 
intervention proves to be more harmful than expected in terms of mortality or severe morbidity, the 
treatment of all participants will be stopped and the intervention arm closed to study enrollment. This 
decision will be made by NIAMS on recommendation of the DSMB. 
Frequency of DSMB Meetings 
The DSMB will meet via webinar approximately every 6 months to review study progress and safety. The 
schedule of meetings will be determined during the first meeting. These meetings will likely take place 
via webinars, due to the need to schedule them at different times for different interventions.  Ad hoc 


 
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meetings may also be scheduled via webinar if particular safety issues for any of the interventions arises 
in between the regularly scheduled meetings. 
DSMB Meeting Structure 
The BEST principal investigators, the DAC statisticians (blinded and unblinded), NIAMS representatives, 
and, on occasion, other key personnel will participate in the meetings’ open sessions.  Open sessions will 
include but not be limited to consideration of recruitment, retention, and general scientific issues. The 
DSMB’s voting members will discuss the unblinded by-treatment data for each intervention in a closed 
session.  These data include but are not limited to adverse events, and material that should be kept 
confidential from the investigators. 
Frequency and content of reports to the DSMB 
In advance of each meeting, the unblinded statistician at the DAC will prepare a report for DSMB review. 
The report will contain the following categories of information aggregated by treatment group, where 
applicable, as well as any additional information required by the DSMB: 
• 
Current enrollment status and timeline for completion of follow-up 
• 
Adverse events reported, both serious and non-serious, including hospitalizations and any 
mortality 
• 
Major and minor protocol violations and deviations 
• 
Numbers of participants whose study medication is discontinued 
Decisions on the labeling of treatment groups in the safety reports and other considerations to lessen 
the chance of accidental unmasking will be determined at the first meeting of the DSMB.  The unblinded 
DAC statistician will provide the treatment for each code to DSMB members as needed, and the same 
code mapping will be used for all meetings. 
Serious events are reported to the NIAMS within 48 hours of the investigator becoming aware of the 
event.  
Frequency, content, and distribution of meeting reports 
Following each meeting of the DSMB, the meeting recommendations and open meeting minutes are 
drafted by the NIAMS Executive Secretary and include, but are not limited to, questions raised by the 
DSMB, monitoring recommendations, and recommendations for the continuation of treatments or the 
study as a whole. These minutes are reviewed and approved by the DSMB and NIAMS.  The NIAMS 
executive secretary will prepare a summary of the questions raised by committee members, monitoring 
recommendations, and recommendations for the continuation of treatments. The meeting 
recommendations and minutes will be distributed confidentially to meeting participants. The NIAMS 
executive secretary also prepares a closed session minutes (if applicable) for distribution to BEST 
investigators and their IRBs. 
14.1.9. CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of study participants are 
protected, that the reported study data are accurate, complete, and verifiable, and that the conduct of 
the study is in compliance with the currently approved protocol/amendment(s), with International 


 
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Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).   Monitoring for this study will be performed by the DAC. 
Areas of Focus 
• 
Staff training  
• 
Human subjects protection 
• 
Protocol compliance 
• 
Regulatory compliance 
• 
Laboratory SOPs and compliance 
• 
Quality assurance (QA) 
• 
Safety 
• 
Adverse event reporting 
• 
Integrity of research data and samples 
Two types of data monitoring will be conducted during the study: on-site monitoring and central 
monitoring.  On-site monitoring refers to a review of the data that takes place at the clinical site 
whereas central monitoring refers to activities that can be conducted at the data coordinating center. 
Monitoring Activities will include: 
• 
Review of credentials, training records, and delegation of duties logs 
• 
Review of 100% of Consent Forms 
• 
Review of reports on missed events, missing data, protocol deviations, and unanticipated 
problems 
• 
Comparison of CRFs to source documentation to ensure data are accurate and complete  
• 
Review of documentation for AEs, SAEs, and UPs 
• 
Review of critical fields such as eligibility, study endpoints, and SAEs 
• 
Regulatory Files: Limited reviews at interim visits, e.g., IRB annual reviews, safety reporting, IRB 
submissions of protocol deviations, and updated essential documents 
• 
Laboratory Review: Full laboratory review of processing and storage of specimens at first and 
close-out visits and at least biannually.  Assessment of laboratory specimens stored at the 
clinical site 
 
The DAC will provide copies of on-site monitoring reports within 10 business days of the visit.  
Details of clinical site monitoring will be documented in the BEST Clinical Monitoring Plan (CMP). The 
CMP will describe in detail who will conduct the monitoring, at what frequency monitoring will be done, 
at what level of detail monitoring will be performed, and the distribution of monitoring reports.   
 
14.1.10. 
QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system. The 
database will include real-time data QC checks.  Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 


 
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Following written SOPs, the monitors will verify that the clinical trial is conducted, data are generated, 
and biological specimens are collected, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonization Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the DAC, and inspection by local and regulatory 
authorities. 
Magnetic Resonance Imaging (MRI) Quality Control of Brain Images 
Even when comparable hardware and experimental procedures are employed in brain imaging studies 
with functional magnetic brain imaging (fMRI) and structural MRI, between-site variability may arise.  
This may come from a number of sources including: small flaws in data collection equipment/software, 
subtle differences in experimenters’ administration of standardized protocols, and differences between 
scanner brands.  It is not possible to quantify these variables using non-human models (e.g., brain MRI 
phantoms).  To control for these variables, the same member of the BEST Trial MRI domain expert’s 
research team will travel to each trial site.  This study member will undergo MRI scan protocols that are 
identical to the phantom scans.  These scans include: structural T1 brain image, resting state brain 
image, and diffusion tensor structural brain image.  Performing these scans on the same human at each 
trial site will allow researchers to identify, measure, and minimize inter-site variability among MRI 
scanners.  Data from these scans will not be included in the BEST Trial dataset. 
 
14.1.11. 
DATA HANDLING AND RECORD KEEPING  
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the DAC. The study data entry and study management systems used by 
clinical sites and by the DAC will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at an NIH-approved data repository. 
Risk of disclosure will be minimized through the use of several procedures.  The DAC operates under 
FISMA (Federal Information Security Management Act) guidelines, and the data management system 
used in BEST is compliant with FDA 21 CFR Part 11, which establish security policies for the study 
databases, such as requiring use of strong passwords, limiting access to data based on study role, and 
the use of secure sockets layer encryption during data transmission.  The data management system 
database is encrypted at rest using a FIPS 140-2 certified cryptographic system. Within the data 
management system, data elements are persisted in a format which isolates personal identifying 
information from other data elements. 
 
14.1.12. 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the study staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   


 
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Data recorded in the electronic case report form (eCRF) derived from source documents should be 
consistent with the data recorded on the source documents.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MEDDRA) and 
concomitant medications will be coded using the National Drug Code (NDC) Directory. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into CDART, a 21 CFR Part 11-compliant data capture 
system managed by the DAC. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 
14.1.13. 
STUDY RECORDS RETENTION 
Study documents should be retained for a minimum of 3 years after the completion of research in 
accordance with HHS regulations.   These documents will be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of NIAMS. It is 
the responsibility of the study sponsor to inform the investigators when these documents no longer 
need to be retained. 
14.1.14. 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the study protocol, International Conference on 
Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff.  As 
a result of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, Section 5.1.1  
• 
5.20 Noncompliance, Sections 5.20.1, and 5.20.2.  
Protocol deviations require reporting to the DAC, and to the oversight IRB, and additional 
source/supporting documents may be requested and should be kept in the participant’s record.  Sites 
should notify the DAC in accordance with the Manual of Procedures.   
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 48 hours of identification of the protocol deviation, or within 15 working days of the 
scheduled protocol-required activity.  All deviations must be addressed in study source documents and 
reported to the DAC. Protocol deviations must be sent to the reviewing IRB per their policies, as 
applicable. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. Further details about the handling of protocol deviations will be included in the MOP. 
 
14.1.15. 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the BACPAC DAC Data Portal Protocol, Data Transfer 
SOP, BACPAC Data Access and Publications Policy, and the following publication and data sharing 
policies and regulations: 


 
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National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH-funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this study will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers at the 
discontinuation of BACPAC by contacting the NIH-approved HEAL repository.    
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of 
these data for subsequent research. Large-scale data include genome-wide association studies (GWAS), 
SNP arrays, and genome sequence, transcriptomic, epigenomic, and gene expression data. 
The BACPAC Data Access and Publications Committee will be responsible for developing publication 
procedures and resolving authorship issues.   
14.1.16. 
CONFLICT OF INTEREST POLICY 
The independence of the BEST study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of investigators who have a 
role in the design, conduct, analysis, publication, or any aspect of this study will be disclosed and 
managed. Furthermore, investigators who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct of 
this trial.  The study leadership in conjunction with the NIAMS has established policies and procedures 
for investigators to disclose all conflicts of interest and has established a mechanism for the 
management of all reported dualities of interest.   
 


 
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14.2. 
ABBREVIATIONS 
 
ACT 
Acceptance and Commitment Therapy 
AE 
Adverse Event 
BACPAC 
Back Pain Consortium Research Program 
CBRD 
Center for Biospecimen Research and Development 
CDART 
Carolina Data Acquisition and Reporting Tool 
CFR 
Code of Federal Regulations 
cLBP 
Chronic Low-Back Pain 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CPM 
Conditioned Pain Modulation 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAC 
Data Integration, Algorithm Development and Operations Management Center  
DC 
Doctor of Chiropractic 
DSMB 
Data Safety Monitoring Board 
DTR 
Dynamic Treatment Regime 
EBEM 
Evidence-Based Exercise and Manual Therapy 
eCRF 
Electronic Case Report Forms 
EHR 
Electronic Health Record 
ESC 
Enhanced Self Care 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HEAL 
Helping to End Addiction Long Term Initiative 
HIPAA 
Health Insurance Portability and Accountability Act  
IAA 
IRB Authorization Agreement 
ICH 
International Conference on Harmonisation  
IMMPACT 
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MRI 
Magnetic Resonance Imaging 
NCT 
National Clinical Trial 
NDC 
National Drug Code 
NIAMS 
National Institute of Arthritis and Musculoskeletal and Skin Diseases 
NIH  
National Institutes of Health 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OC 
Operations Committee 
PEG 
Pain, Enjoyment of Life, and General Activity 
PGIC 
Patient Global Impressions Scale 


 
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PHI 
Protected Health Information 
PI 
Principal Investigator 
PRO 
Patient Reported Outcome 
PT 
Physical Therapist 
QA 
Quality Assurance 
QC 
Quality Control 
QST 
Quantitative Sensory Testing 
RSS 
Radiation Safety Sub-committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMART 
Sequential, Multiple Assignment Randomized Trial 
SNRI 
Serotonin Norepinephrine Reuptake Inhibitor 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
UPIRSO 
Unanticipated Problem Involving Risk to Participants or Others 
 
 
 


 
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16. 
SURVEY QUESTIONNAIRES  
 
Abbreviated Pain Somatization  
Current Opioid Use  
Daily Pain Question 
Demographics  
FABQ-PA scale  
NHANES Food Frequency*  
GAD-2  
GSS-8  
HEAL Resilience  
Hip/Knee replacement  
Low-Back Pain Duration  
Low-Back Pain Frequency  
Low-Back Pain Specific Pain Intensity  
Michigan Body Map  
Oswestry Disability Index  
Pain Catastrophizing Scale SF 6  
Pain, Enjoyment of Life, and General Activity (PEG) 
PainDETECT  
Patient Global Impressions Scale (PGIC)  
Patient Preference for Outcome  
Patient Preference for Treatment  
Patient Satisfaction with Outcomes  
PHQ-2  
PROMIS 29+2 / PROPr  
Radicular Pain  
Sleep duration  
Social Determinants of Health  
SSI (symptom severity index)  
StartBack Tool 
TAPS 1  
Treatment Categorization  
Widespread Pain Inventory  
 
*Will be piloted and may be removed from study protocol if it is determined to cause excessive participant burden  


 
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17. 
APPENDIX A:  SCHEDULE OF ACTIVITIES 


 
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Pre-Screening
Enrollment Visit
Run-in  Week 1
Run-in  Week 2
Post Run-In Screening
Visit 0 (Baseline)
Visit 0 (Baseline optional day 2)
Week1
Week2
Week3
Week4
Week5
Phone Call1 (week 6)
Week7
Week8
Week9
Week10
Week11
Visit 1 (Week 12)
Visit 1 (Week 12 optional day 2)
Week 13
Week 14 
Week 15 
Week 16 
Week 17 
Phone Call 2 (week 18)
Week 19 
Week 20 
Week 21 
Week 22 
Week 23 
Visit 2 (Week 24)
Visit 2 (Week 24 optional day 2)
Phone Call 3: Safety follow-up (week 28)
Phone Call 4: Observational follow-up for 
subset (week 36)**
EMR Review/ Interview/ Pre-screen eligibility 
X
Low-Back Pain Duration Q'naire
X
Low-Back Pain Frequency Q'naire
X
Low-Back Pain Intensity
X
X
X
X
X
X
X
Low-Back Pain Severity Q'naire
X
X
X
X
X
PEG
X
X
X
X
X
X
X
Eligibility Assessment Questions
X
X
X
X
X
X
X
Demographics
X
X
Informed Consent
X
Contact Information Form
X
X
Schedule study visits
X
X
X
X
Review of study informational materials
X
X
X
Introduction/ Onboarding to patient website
X
Introduction/ Onboarding to Run-In
X
Daily Pain Questions
X
X
Post run-in assessment
X
Sleep duration Question
X
X
X
X
Abbreviated Pain Somatization
X
X
X
X
Radicular Pain Questions
X
X
X
X
FABQ-PA scale
X
X
X
X
GSS-8 
X
Pain Catastrophizing Scale SF 6
X
X
X
X
PHQ-2
X
X
X
X
GAD-2
X
X
X
X
TAPS 1
X
X
X
X
Social Determinants of Health
X
Perceived Discrimination
X
HEAL Positive Outlook
X
X
X
X
PROMIS 29+2 / PROPr
X
X
X
X
Treatment Categorization Q’naire
X
X
X
X
StartBack Tool
X
SSI (symptom severity index)
X
Widespread Pain Inventory
X
X
X
X
Current Opioid Use
X
X
X
X
ODI
X
Satisfaction overall ranking
X
X
Satisfaction with treatment
X
X
X
COVID vaccination status question
X
X
X
X
COVID previous diagnosis question
X
X
X
X
Michigan Body Map
X
PainDETECT
X
Patient Preference Tool 
X
X
X
X
Food Frequency Questionnaire
X
Physical Assessment
X
X
X
Randomization to 1st period Intervention
X
Blood collection
X
X
X
Stool collection
X
x*
Biomechanical assessment (light)
X
x*
X
x*
X
x*
Basic Spine MRI
X
x*
Activity monitoring (deep)
X
x*
Biomechanical assessment (deep)
X
x*
X
x*
X
x*
Advanced Spine MRI
X
x*
Brain MRI
X
x*
X
x*
X
x*
Quantitative Sensory Testing
X
x*
X
x*
X
x*
PGIC
X
X
X
X
X
Intervention tolerance assessment/ Adverse Events
X
X
X
X
End-of-study safety assessment
X
Randomization to 2nd period Intervention
X
Scheduling/Introduction/Onboarding to 2nd period Activities
X
Schedule of Activities: National Institute of Arthritis and Musculoskeletal and Skin Diseases, (NIAMS) - BACPAC - 21-1972, The BEST Trial: Biomarkers for Evaluating, Spine Treatments (Pro00057948)***


 
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Schedule of Activities: The BEST Trial: Biomarkers for Evaluating, Spine Treatments (Pro00057948)*** 
 
* If not completed on day 1 of the visit 
 
 
 
 
 
 
 
 
 
** Participants who are enrolled early enough to complete the 36-week assessments 
 
 
 
 
 
 
*** Refer to Manual of Procedures for Visit Windows 
ACT intervention-specific contact points
X
X
X
X
Duloxetine intervention-specific contact points
X
X
EBEM intervention-specific contact points
X
X
X
X
X
X
X
X
X
X
X
X
ESC intervention-specific contact points
First treatment period
Second treatment period (maintenance subset)
Intervention-specific contact points