Clinical trial NCT04395001
Conditions: Chronic Pain
Keywords: non-opioid pain medication psychoeducational treatments chronic musculoskeletal pain
Sponsor: Wake Forest University Health Sciences
Start date: 2021-02-24; Completion date: 2024-07-18
Enrollment: 280 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research is is to determine if the combination of non-opioid medication (duloxetine) and web-based pain-coping skills training (PCST) is beneficial for individuals with chronic musculoskeletal pain (CMP).

Detailed description:
With this study, the study team hopes to address two important unanswered questions: (1) Does combination treatment consisting of duloxetine and web-based Cognitive Behavioral Therapy (CBT) optimize treatment outcomes? (2) Would adherence-focused guidance delivered by nurse clinician using motivational interviewing (MI) techniques enhance treatment effectiveness? This study is significant because the study team aims to optimize pain-related treatment outcomes at the primary care level where most patients with pain are managed. Importantly, the use of nurse clinician providing adherence-focused guidance (as opposed to content-focused guidance) on the continued practice (or use) of pain coping skills increases the likelihood that the study's intervention is scalable in the future. Effective, accessible and scalable psychoeducational treatments are needed to manage CMP in real world clinic settings.

Arms: arm 1: Subjects randomized to this arm will receive duloxetine, web-based Cognitive Behavioral Therapy (CBT) and nurse support. arm 2: Subjects randomized to this arm will receive duloxetine and web-based Cognitive Behavioral Therapy (CBT). arm 3: Subjects randomized to this arm will receive duloxetine only.
Interventions: intervention 1: duloxetine intervention 2: Web-based Cognitive Behavioral Therapy (CBT) intervention 3: Nurse-delivered Motivational Interviewing
Intervention descriptions: intervention 1: All participants will receive duloxetine 30 mg once daily for one week and 60 mg once daily for 24 weeks. intervention 2: The web-based CBT program is an automated program (i.e., users learn skills with interactive, personalized training without any therapist contact) that includes 8, 35- to 45-minute training sessions, each of which provides an educational rationale and training in cognitive or behavioral pain coping skill drawn from face-to-face CBT. intervention 3: Subjects randomized to the duloxetine and web-based Cognitive Behavioral Therapy (CBT) with nurse support will receive 6 phone calls from MI trained nurse at week 3, 6, 10, 14, 18 and 22. Telephone sessions may run for 20 minutes on the average.

Protocol documents:
Prot_SAP_001.pdf: 
Official Title:  Pain Response Evaluation of a Combined Intervention to Cope Effectively
NCT04395001
IRB Approval Date:  10/21/2022


Pain Response Evaluation of a Combined 
Intervention to Cope Effectively (PRECICE) 
Protocol Number*: 1
National Clinical Trial (NCT) Identified Number:  NCT04395001 
Principal Investigator*: Dennis C Ang, MD 
Sponsor: Wake Forest Health Sciences (WFHS) 
Grant Title: Pain Response Evaluation of a Combined Intervention to Cope 
Effectively (PRECICE) 
Grant Number*: 1UG3NR019196-01 
Funded by: NIH NINR 
Version Number:  8 
October 21, 2022 
Statement of Changes: 
See Section 10.4, Protocol Amendment History, for a list of changes. 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the 
NIH terms of award.  


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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 2 
1 
PROTOCOL SUMMARY ............................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................ 3 
1.2 
Schema ................................................................................................................................................. 6 
1.3 
Schedule of Activities .......................................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................................ 7 
2.1 
Study Rationale .................................................................................................................................... 7 
2.2 
Background........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................. 11 
2.3.1 
Known Potential Risks ................................................................................................... 11 
2.3.2 
Known Potential Benefits .............................................................................................. 12 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 12 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 12 
4 
STUDY DESIGN ........................................................................................................................................... 16 
4.1 
Overall Design .................................................................................................................................... 16 
4.2 
Scientific Rationale for Study Design.............................................................................................. 16 
4.3 
Justification for Intervention ............................................................................................................. 16 
4.4 
End-of-Study Definition ..................................................................................................................... 16 
5 
STUDY POPULATION ................................................................................................................................ 17 
5.1 
Inclusion Criteria ................................................................................................................................ 17 
5.2 
Exclusion Criteria ............................................................................................................................... 17 
5.3 
Lifestyle Considerations .................................................................................................................... 17 
5.4 
Screen Failures .................................................................................................................................. 18 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 18 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ............................................ 18 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ...................................... 18 
6.1.1 
Study Intervention or Experimental Manipulation Description ................................. 18 
6.1.2 
Administration and/or Dosing ....................................................................................... 20 
6.2 
Fidelity ................................................................................................................................................. 20 
6.2.1 
Interventionist Training and Tracking .......................................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 20 
6.4 
Study Intervention/Experimental Manipulation Adherence.......................................................... 21 
6.5 
Concomitant Therapy ........................................................................................................................ 22 
6.5.1 
Rescue Therapy ............................................................................................................. 22 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................... 22 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................. 22 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 22 
7.3 
Lost to Follow-Up ............................................................................................................................... 23 


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STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 23 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 23 
8.2 
Safety Assessments .......................................................................................................................... 24 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 26 
8.3.1 
Definition of Adverse Events ........................................................................................ 26 
8.3.2 
Definition of Serious Adverse Events .......................................................................... 26 
8.3.3 
Classification of an Adverse Event .............................................................................. 26 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 27 
8.3.5 
Adverse Event Reporting .............................................................................................. 28 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 28 
8.3.7 
Reporting Events to Participants ................................................................................. 28 
8.3.8 
Events of Special Interest ............................................................................................. 28 
8.3.9 
Reporting of Pregnancy ................................................................................................ 28 
8.4 
Unanticipated Problems .................................................................................................................... 28 
8.4.1 
Definition of Unanticipated Problems .......................................................................... 28 
8.4.2 
Unanticipated Problems Reporting .............................................................................. 29 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 29 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 29 
9.1 
Statistical Hypotheses ....................................................................................................................... 29 
9.2 
Sample Size Determination .............................................................................................................. 30 
9.3 
Populations for Analyses .................................................................................................................. 30 
9.4 
Statistical Analyses............................................................................................................................ 30 
9.4.1 
General Approach .......................................................................................................... 30 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 30 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 31 
9.4.4 
Safety Analyses .............................................................................................................. 31 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 31 
9.4.6 
Planned Interim Analyses ............................................................................................. 31 
9.4.7 
Sub-Group Analyses ..................................................................................................... 32 
9.4.8 
Tabulation of Individual Participant Data .................................................................... 32 
9.4.9 
Exploratory Analyses ..................................................................................................... 32 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 34 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 34 
10.1.1 
Informed Consent Process ........................................................................................... 34 
10.1.2 
Study Discontinuation and Closure ............................................................................. 35 
10.1.3 
Confidentiality and Privacy ........................................................................................... 36 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 36 
10.1.5 
Key Roles and Study Governance .............................................................................. 37 
10.1.6 
Safety Oversight ............................................................................................................. 38 
10.1.7 
Clinical Monitoring .......................................................................................................... 39 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 39 


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10.1.9 
Data Handling and Record Keeping ............................................................................ 40 
10.1.10 
Protocol Deviations ........................................................................................................ 40 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 41 
10.1.12 
Conflict of Interest Policy .............................................................................................. 41 
10.2 
Additional Considerations ................................................................................................................. 42 
10.3 
Abbreviations and Special Terms ................................................................................................... 42 
10.4 
Protocol Amendment History ........................................................................................................... 44 
11 
REFERENCES ............................................................................................................................................. 45 
 


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STATEMENT OF COMPLIANCE 
PRECICE will be carried out in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
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).  
 
NIH funded investigators and clinical trial site staff who are responsible for the conduct, management, or 
oversight of NIH funded clinical trials 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 IRB for review and approval. Approval of both the protocol and the consent form(s) must 
be obtained before any participant is consented. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form(s) 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 


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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines, as described in the Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name*:  Dennis C. Ang, MD, MS 
 
Title*: Principal Investigator (PI), Chief of Rheumatology and Immunology 
 
Investigator Contact Information 
Affiliation*: Wake Forest Baptist Medical Center 
Address: Medical Center Blvd., Winston-Salem, NC 27157 
Telephone: 336-713-4504 
Email: dang@wakehealth.edu 
 
 
 
 
 


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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Pain Response Evaluation of a Combined Intervention to Cope 
Effectively (PRECICE) 
Grant Number: 
1UG3NR019196-01 
Study Description: 
The purpose of this research is to determine if the combination of non-
opioid medication (duloxetine) and web-based pain-coping skills 
training (PCST), with or without health care professional support, is 
beneficial for individuals with chronic musculoskeletal pain (CMP). 
 
Objectives*: 
 
The objective of this study is to conduct a 24-week randomized clinical 
trial of primary care patients with CMP. 280 participants will be 
randomized to one of three treatments: (1) combination treatment 
[duloxetine + web-based cognitive behavioral therapy CBT] with health 
care professional support, (2) combination treatment without health care 
professional support, and (3) duloxetine monotherapy. 
Endpoints*: 
Primary Endpoint: Brief Pain Inventory (BPI)-Global Pain Severity 
(GPS) 
 
Subgroup Analyses: We will conduct subgroup analysis using linear 
mixed effects models (LMMs) to test the interactions between 
intervention arm (with and without health care professional support vs. 
monotherapy) and baseline characteristics. 
 
Secondary Endpoints:  
The secondary outcomes will include the two individual components of 
the BPI GPS: BPI pain severity and BPI pain interference. 
 
Tertiary Endpoints: 
1. Global Rating of Change (GRC)  
2. PROMIS pain intensity 
3. PROMIS pain interference 
4. Chronic Pain Coping Inventory (CPCI) 
 
Exploratory Endpoints: 
1. Generalized Anxiety Disorder 7-item scale (GAD-7)  
2. Patient Health Questionnaire 8-Item Depression Scale (PHQ-8) 
3. Pain catastrophizing scale (PCS) 
4. SF-36 physical function (SF-36) 
4. PROMIS Adult measures: physical function, fatigue, social health, 
sleep disturbance, pain behavior 
5. Opioid Morphine Equivalent (OME) 
6. Health care service utilization 
7. PHQ Anxiety-Depression Scale (PHQ-ADS)  
8. Frequency of Practicing Pain Coping Skills  
9. Others. Medication use and co-intervention effect. 
 
For a full description of these endpoints see section 8.1. 


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Study Population: 
(1) patients at the primary care clinic with daily pain for 3 months or 
longer affecting the low back, neck, hip, knee or widespread pain; 2) at 
least moderate in BPI GPS, defined as a GPS score of 5 or greater1,2; 
and (3) at least age 18 years old or older. We are restricting our age 
criteria because of the risk of poly-pharmacy from centrally-acting 
medications in older adults.  All sexes who meet these criteria are 
eligible for the study. (n=280) 
Phase* or Stage: 
Phase 4  
Description of 
Sites/Facilities Enrolling 
Participants: 
We will recruit participants from the 271 primary care clinics within the 
Atrium Health - Wake Forest (WF) Baptist Health System as well as 
surrounding providers outside of Atrium Health in North Carolina .    
 


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Description of Study 
Intervention/Experimental 
Manipulation: 
PRECICE is a 24-week randomized controlled clinical trial (RCT) of 
patients in the primary care clinics. During the study, participants will 
be randomized to one of three treatments: (1) [duloxetine + web-based 
CBT] with health care professional support, vs. (2) [duloxetine + web-
based CBT] without health care professional support, vs. (3) duloxetine 
only. 
 
Web-based Cognitive Behavioral Therapy (web-based CBT). The web-
based CBT program is an automated program (i.e., users learn skills 
with interactive, personalized training without any therapist contact) that 
includes 8, 35- to 45-minute training sessions, each of which provides 
an educational rationale and training in cognitive or behavioral pain 
coping skill drawn from face-to-face CBT 3.  
 
Health care professional-delivered Motivational Interviewing (MI). The 
primary purpose of health care professional contact is to enhance 
participant’s motivation to engage in web-based CBT by encouraging 
participant’s continued use and practice of pain coping skills. Subjects 
randomized to the [duloxetine + web-based CBT] with health care 
professional support will receive 6 phone calls from a MI trained health 
care professional at week 3, 6, 10, 14, 18 and 22. Telephone sessions 
may run for 20 minutes on the average.  
 
Duloxetine. We chose duloxetine as the first line drug because: (1) it has 
established efficacy for CMP and Food and Drug Administration (FDA) 
approval for that indication; and (2) it is available in generic form, 
which makes it more readily available. At study entry, all participants 
will receive duloxetine 30 mg once daily for one week; subjects who are 
able to tolerate 30 mg and do not have chronic kidney disease III (CKD-
3) will increase to 60 mg once daily for 24 weeks. At week 25, 
participants will return to the research clinic for outcome assessments. 
At the last study visit (week 25), participants who would like to stop the 
medication, will be provided duloxetine 30 mg once daily for 7 days and 
medication treatment will then stop (tapering regimen). Subjects already 
taking 30 mg daily will stop dosing at their week 25 visit. Those who 
would like to continue duloxetine will be prescribed a 2-week supply of 
duloxetine and will be instructed to talk to their primary care provider 
(PCP). In addition, the investigator  will send a Wake One message to 
the PCP to consider continuation of duloxetine. 
 
Other treatments. The use of over-the-counter analgesic medications 
will be permitted and assessed to adjust for co-intervention differences 
between groups in the analyses.  
 
For further details, see Section 6, Study Interventions or Experimental 
Manipulations. 
Study Duration*: 
The estimated time from when the study opens to enrollment until 
completion of data collection is 45 months. 
Participant Duration: 
The time it will take for each individual participant to complete all 
study-related tasks is 25 weeks. 


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1.2 
SCHEMA  
 
 
Flow Diagram 
 
Pre-Screening 
 
 
 
 
  
IPV, 
Week 0 
 
 
 
IPV, 
Week 1 
 
 
 
3 Treatment 
Arms  
 
 
 
Weeks 
2 - 12 
 
 
 
 
IPV, 
Week 13  
 
 
 
Weeks 
14 - 24 
 
 
IPV, 
Week 25 
 
 
 
Total N: 300 
Pre-screen potential participants by inclusion and exclusion criteria; schedule in-person 
visit (IPV). 
Conduct informed consent process. Perform baseline assessments. 
See Table 1 in Section 1.3 for a list of all forms and measures to occur at Week 0. 
Medication Symptom Monitoring Form, Health care professional Counselling for 
treatment 1. 
Close-out, Data analyses, 
Manuscript Writing 
 
  
 
Medication Modification, Medication Symptom Monitoring Form, Web-based CBT for 
treatments 1 & 2.  Health care professional Counselling for treatment 1.  See Table 1 in 
Section 1.3 for timing of activities in Weeks 2 – 12. 
 
N: 280 
Randomization 
Duloxetine prescription 
See Table 1 in Section 1.3 for all Week 1 activities. 
Physical measures, Questionnaires, Medication forms. 
See Table 1 in Section 1.3 for Week 13 activities. 
 
N: 93 
Arm 1: Duloxetine + 
Web-based CBT + 
Health care 
N: 93 
Arm 2: Duloxetine + 
Web-based CBT 
N: 93 
Arm 3: Duloxetine 
monotherapy 
Final visit.  Physical measures, Questionnaires, Medication forms. 
See Table 1 in Section 1.3 for all Week 25 activities. 


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1.3 
SCHEDULE OF ACTIVITIES  
 
 
2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
 
Significance 
With our proposed work, we hope to address two important unanswered questions: (1) Does 
combination treatment consisting of duloxetine and web-based CBT optimize treatment outcomes? (2) 
Would adherence-focused guidance delivered by health care professional clinician using MI techniques 
enhance treatment effectiveness? Our proposed work is significant because we aim to optimize pain-
related treatment outcomes at the primary care level where most patients with pain are managed. 
Importantly, the use of health care professional clinician providing adherence-focused guidance (as 
opposed to content-focused guidance) on the continued practice (or use) of pain coping skills increases 
the likelihood that our proposed intervention is scalable in the future. Effective, accessible and scalable 
psychoeducational treatments are needed to manage CMP in real world clinic settings 4. 
 
Objectives 
The objective of this UH3 application is to conduct a 24-week randomized clinical trial of primary care 
patients with CMP. In the UH3 trial, 280 participants will be randomized to one of three treatments: (1) 


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combination treatment [duloxetine + web-based CBT] with health care professional support, (2) 
combination treatment without health care professional support, and (3) duloxetine monotherapy.  
 
Specific Aim 1. To compare combination treatment (with and without health care professional support) 
and duloxetine monotherapy in improving GPS (as measured by BPI pain severity and interference).  
H1: Combination treatment with and without health care professional support is more effective than 
duloxetine monotherapy in improving GPS.  
 
Specific Aim 2. To examine if health care professional support to increase participants’ motivation on 
continued practice of pain coping skills will enhance treatment outcomes among those who receive 
combination treatment. 
H2: Combination treatment with health care professional support is more effective than combination 
treatment without health care professional support in improving GPS. 
2.2 
BACKGROUND  
Abnormal Endogenous Pain Modulation: Shared Biology among CMP Conditions 
A major problem in designing new therapies to treat CMP is that the underlying mechanisms driving 
musculoskeletal pain are not fully understood 5,6. In fact, physical findings in patients with CMP are poor 
predictors for self-reported pain severity and dysfunction 7. Moreover, the extent of tissue abnormalities 
appears to be poorly correlated with self-reported pain intensity 8. For example, minor radiographic 
abnormalities of the spine or knee may be painless in some individuals but may be associated with 
severe chronic pain in others 9. The poor correlation of patients’ peripheral tissue abnormalities with 
chronic pain intensity has shifted research to focus on central pain processing abnormalities as the 
primary causal factors of chronic pain 10. Augmented central nervous system (CNS) processing of 
nociceptive signals and dysfunctional endogenous pain inhibition have been identified as characteristics 
of many musculoskeletal pain conditions 7,10-12 including low back pain, neck pain, temporomandibular 
disorder (TMD), osteoarthritis, and fibromyalgia 13-18.  
Duloxetine: Efficacious in CMP Conditions 
Augmented CNS processing of nociceptive signals and dysfunctional endogenous pain inhibition 
contribute to central sensitization. Central sensitization manifests as pain hypersensitivity, particularly 
tactile allodynia (painful response to a normally innocuous touch), pressure hyperalgesia, and enhanced 
temporal summation 19. In preclinical studies of pain, duloxetine, a selective serotonin norepinephrine 
reuptake inhibitor, reduces central sensitization 20-22. In clinical studies, the efficacy of duloxetine is well 
documented in many of the musculoskeletal pain conditions including fibromyalgia 23,24, osteoarthritis, 
and chronic low back pain 25.   
Psychological Factors in Chronic Pain 
Two key factors that have important clinical implications for pain management are pain-related 
appraisals and beliefs (including catastrophizing), and pain coping 26.  
Pain-related appraisals and beliefs about pain can affect an individual’s affective and behavioral 
response to pain27,28. People are less able to adjust to pain when they believe that pain is a signal of 
damage, activity should be avoided when one has pain, pain leads to disability, pain is uncontrollable, 
and pain is a permanent condition 27,29. For example, patients with low back pain believed that a wrong 
movement could have serious negative consequences for their back 2. Moreover, this belief was 


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associated with reduced activity levels and increased disability. Among patients with fibromyalgia, 
positive outcomes were most closely related to: (1) an increased sense of control over pain, (2) a belief 
that one is not necessarily disabled by pain, and (3) a belief that pain is not necessarily a sign of  
damage 30.   
One pain-related appraisal, catastrophizing (defined as an exaggerated negative orientation toward 
actual or anticipated pain experience and effects), has been an important therapeutic target in 
managing chronic pain 31-33. 
Pain coping. Coping is the use of behavioral and cognitive techniques to manage demands perceived as 
stressful 34. Variations in pain coping are significantly related to pain, physical function and pain behavior 
35-37. Both active and passive coping dimensions are significantly related to chronic pain adjustment 38. In 
patients with osteoarthritis, greater self-control and increased rational thinking were associated with 
lower pain ratings and less self-reported physical disability 39. Among chronic pain patients, both poor 
coping skills and maladaptive pain related beliefs predicted physical disability27. These findings suggest 
the importance of targeting specific pain-related beliefs and coping strategies for modification to reduce 
physical disability.   
Cognitive Behavioral Therapy (CBT) 
  
Modification of cognition (pain-related appraisals and beliefs) and behavior can positively or negatively 
affect the course of an individual’s chronic pain condition. The goal of CBT is to aid the patient in re-
conceptualizing his or her personal view of pain and role (from passive to a more proactive role) in the 
process of healing. CBT is effective in the management of low back pain, neck pain, temporomandibular 
joint pain, knee osteoarthritis, and fibromyalgia 40.      
Scientific Premise 
i. 
Optimizing Treatment Outcome: Combining Duloxetine and CBT   
The bio-psychosocial model is particularly useful for understanding chronic painful conditions even 
when etiologies are vague 41,42. This model suggests that coping with illness involves a complex 
interaction of biological factors (central sensitization), psychological factors (mood and thoughts) 
and the social context (interpersonal relationships) 43. Along with drug management, a treatment 
approach based on the bio-psychosocial model involves addressing the psychosocial issues relevant 
to chronic pain. Unfortunately, only a few trials have tested medications plus non-pharmacologic 
treatments. In migraine headaches, the combination of beta blockers and behavioral migraine 
management was more effective than either therapy alone in reducing headache severity 44. In 
chronic tension headaches, tricyclic antidepressant plus stress management notably reduced the 
severity of headaches over 1 month, compared to either intervention alone 45. In non-cardiac chest 
pain, the combination of pain coping skills training and sertraline significantly reduced pain intensity 
and pain unpleasantness 46. In CMP, a collaborative care team approach that delivered multi-
component treatment program (medication and pain self-management training) improved pain-
related outcomes compared to usual care 47. 
Preliminary Data:  In our feasibility study 48, 58 patients with chronic widespread pain (fibromyalgia) 
were randomized to: (1) combination milnacipran (100 mg/day) + CBT (n=20), (2) milnacipran (100 
mg/day) + education control (n=19), or (3) placebo medication + CBT (n=19). Participants received 


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either milnacipran (100 mg/day) or placebo. They also received 8 sessions of phone-delivered CBT or 
educational instructions. One of the primary endpoints was a composite responder rate; responders 
were defined as participants who reported a ≥30% reduction from baseline in the weekly average 
pain severity, and ≥10-point improvement from baseline in the SF-36 physical function score. We 
found a 41% composite responder rate for combination treatment versus 24% for milnacipran and 
7% for CBT. We concluded that a therapeutic approach that combines CBT and milnacipran (a 
medication closely related to duloxetine) was feasible and acceptable 48. The observed effect sizes 
indicated that a full clinical trial was warranted.         
While the reasons why medicine has not moved beyond the biomedical model are complex (e.g., 
inadequate economic incentives, continued focus on biomedical models in medical school 
education), the scarcity of comparative effectiveness studies to support the use of the bio-
psychosocial model in CMP is another important factor. 
 
ii. Web-based CBT to Improve Access 
Despite the proven efficacy of traditional face-to-face CBT 49, access to care is one major limitation. 
Barriers to accessing face-to-face programs are numerous and include cost, stigma, and availability 
of psychologists that are trained in pain management. Consequently, the use of CBT in primary care 
where most patients with CMP are seen, is rare.  
Web-delivered CBT is one innovative approach to increase access to pain management programs. 
Web-based programs use the same principles, content, and components as face-to-face programs 
but can be provided with varying levels of clinician support ranging from regular clinician contact to 
no clinician support at all.  
Systematic reviews have reported small but clinically significant improvements in pain severity 
(effect size/ES= 0.33) and disability (ES= 0.39) 50,51.  
 
iii. Importance of Maintaining and Enhancing Treatment Outcome of Web-based CBT 
As in the in-person CBT protocol, participants in a web-based CBT program are typically asked to 
practice each new cognitive or behavioral pain coping skill after learning it. Fundamental to the long 
term effectiveness of CBT is the requirement that pain coping skills are applied or practiced on a 
regular basis. In a study of traditional CBT for chronic pain, pre- to post-treatment changes in pain 
control and catastrophizing mediated the effects of CBT on pain and activity interference52. In 
fibromyalgia, treatment outcomes were most closely related to 5 coping strategies or skills: 
decreased guarding, increased use of exercise, seeking support from others, activity pacing, and use 
of coping self-statements 30. Unfortunately, as with face-to-face CBT programs, maintenance of 
clinical improvements from web-based CBT has not been consistently observed 50 partly due to 
reduced use of cognitive and behavioral pain coping skills over time.  
Rini C, Keefe F et al. evaluated the effectiveness of web-based CBT (+ physiotherapist-guided home 
exercise delivered through Skype) to 148 persons with chronic knee pain. Improvements in pain and 
function with the intervention were large at 3 months (immediate post-intervention) and were 
greater than those in the control group3. Benefits were apparent at follow-up, although between 
group differences were reduced. Further, 64% of the CBT practice exercises (i.e., relaxation, coping 
thoughts, pleasant imagery, distraction, problem solving, activity-rest cycling, pleasant activity 


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scheduling) were completed at 3 months with numbers decreasing during follow-up to 41%. Based 
on these findings, treatment strategies are needed to motivate continuous use or practice of pain 
coping skills to achieve long term success.    
 
iv. MI to Enhance Benefits of Web-based CBT  
MI is an effective counseling approach to elicit behavior change (e.g., from sedentary lifestyle to 
physically active lifestyle, from poor food choices to healthier food choices to achieve weight loss, 
etc.) 53-57.  In contrast to delivering simple advice, a MI-trained health care professional helps a 
patient discuss the pros and cons, and the barriers and solutions to behavior change; consequently, 
enhancing self-efficacy. Self-efficacy determines whether an individual attempts a given task, the 
degree of persistence when difficulty is encountered and ultimate success or failure of the behavior.  
Preliminary Data: In our RCT study 58, 216 participants with fibromyalgia were randomized to MI to 
increase physical activity vs. education (attention) control. Over a 12-week period, participants 
received either six telephone-delivered MI or educational (attention control) instructions. Post 
intervention, MI was superior to control in increasing the number of weekly hours of self-report 
physical activity. At follow up, more MI participants than controls exhibited meaningful 
improvement in global severity. Additionally, participants in the MI group had a significantly greater 
improvement (i.e., walked longer distance) in the 6-minute walk test compared to controls. 
      
Given our success on the use of telephone-delivered MI, it is reasonable to hypothesize that six 
sessions of telephone-delivered MI to increase participant’s continued practice of pain coping skills 
will enhance treatment outcomes. 
2.3 
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
The risks primarily involve direct adverse effects of duloxetine which are well-described and minimal 
(i.e., sedation, nausea, headache, and dizziness that are typically transient in nature) in most individuals.  
For those who do not tolerate the side effects, the medication will be reduced or discontinued with an 
appropriate 7-day tapering regimen to prevent discontinuation syndrome.  Side effects of these 
medications resolve shortly after stopping them.   
 
Pregnant women are excluded from participation in this study. Because NO method of birth control is 
100% reliable, a pregnancy test is required at baseline and at week 13.  For subjects who become 
pregnant while in the study, duloxetine will be discontinued (with appropriate tapering regimen), and 
subjects will be allowed to continue with the study. 
 
If a participant happens to become pregnant while in the study, the rare side effects of duloxetine for 
the fetus late in the third trimester include breathing difficulties, seizures, temperature instability, 
feeding difficulty, vomiting, low blood sugar, jitteriness, irritability, and tremor. To avoid unnecessary 
exposure to duloxetine, participants will get a repeat urine pregnancy test mid-way (week 13) during the 
24 week study period.   The enumerated side effects are side effects for the newborn. 
 
Other potential risks include emotional distress related to the web-based pain coping skills training, 
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side effects, will be able to ask about emotional distress, with an agreed upon approach to refer 
participants to the medical safety officer if any concerns are present. Participants should discuss the risk 
of being in this study with the study staff. 
 
There are no additional tests performed while enrolled in this study; however, a participant’s study doctor 
may capture results of testing performed for normal clinical care. 
 
Taking part in this research study may involve providing information that a participant considers 
confidential or private.  Efforts, such as coding research records, keeping research records secure and 
allowing only authorized people to have access to research records, will be made to keep information 
safe. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Participants may experience relief of pain and improvement in quality of life. It is possible; the information 
learned from this study will benefit other people in the future. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
See Section 2.3.1, Known Potential Risks, and Manual of Procedures (MOP) chapter 05, Informed Consent 
for more details regarding potential risks and benefits.   
 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
The primary outcome of the 
study is BPI GPS score 
collected at Weeks 13 and 25. 
BPI GPS is a self-report 
measure of pain severity and 
interference with proven 
reliability and validity across 
different pain conditions. It is 
defined as the average of BPI 
pain severity and BPI pain 
interference. BPI pain 
severity is the average of 4 
items asking about current 
pain and worse, least, and 
average pain in the past week. 
BPI pain interference is the 
average of 7 items that rate 
how pain interferes with 
various activities (higher 
score indicate greater pain 
interference). We have two 
Brief Pain 
Inventory-Global 
Pain Severity.   
BPI GPS is a self-report measure of pain 
severity and interference with proven reliability 
and validity across different pain conditions 1,2. 
In this application, BPI GPS is defined as the 
average of BPI pain severity and BPI pain 
interference. BPI pain severity is the average of 
4 items asking about current pain and worse, 
least, and average pain in the past week. BPI 
pain interference is the average of 7 items that 
rate how pain interferes with various activities 
(higher score indicate greater pain 
interference) 59. 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
primary hypotheses (H1 and 
H2): 
 
H1: Combination treatment 
with and without health care 
professional support is more 
effective than duloxetine 
monotherapy in improving 
GPS.   
 
H2: Combination treatment 
with health care professional 
support is more effective than 
combination treatment 
without health care 
professional support in 
improving GPS.   
        
For further details, see section 
9.4.2, Analysis of the Primary 
Endpoint(s) 
Secondary 
 
 
The secondary outcomes will 
include the two individual 
components of the BPI GPS: 
BPI pain severity and BPI 
pain interference.  
BPI pain severity 
and  
BPI pain 
interference 
The BPI assesses pain at its “worst,” “least,” 
“average,” and “now”.  The BPI measures how 
much pain has interfered with seven daily 
activities, including general activity, walking, 
work, mood, enjoyment of life, relations with 
others, and sleep. 
Tertiary 
 
 
We propose 4 tertiary 
outcomes to further assess the 
effect of the interventions on 
pain.  
 
 
Global Rating of 
Change 
GRC assesses overall clinical response. It is 
consistent with the IMMPACT 
recommendations for a 7-item patient global 
change scale 59. Modified to detect finer 
gradations of improvement, this scale is 
sensitive to treatment-related improvements 60.  
 
PROMIS pain 
intensity  
& 
PROMIS pain 
interference 
 
PROMIS Adult Self-Reported Measures on 
physical health (fatigue, pain intensity, pain 
interference, physical function, sleep 
disturbance, pain behavior and sleep-related 
impairment) and social health (ability to 
participate in social roles and activities) 
(http://www.healthmeasures.net/explore-
measurement-systems/promis/intro-to-promis). 
PROMIS measures were developed and 
validated with state of the science methods to 
be psychometrically sound 
(http://www.healthmeasures.net/explore-
measurement-systems/promis/measure-
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
 
Chronic Pain 
Coping Inventory 
(CPCI) 
Designed to assess the use of coping strategies 
that are typically targeted for change in 
multidisciplinary pain treatment programs, 
the CPCI can be used as a treatment outcome 
measure, as a screening measure, and to 
document the necessity of treatment. 
Exploratory 
 
 
 
Generalized 
Anxiety Disorder 
7-item scale (GAD-
7)  
GAD-7 is a validated screening and severity 
measure for the most common anxiety 
disorders in primary care (i.e., generalized 
anxiety, panic, social anxiety, and post-
traumatic stress disorder) 61,62. Higher scores on 
GAD-7 represent more severe anxiety 
symptoms. Clinical anxiety is defined as GAD-
7 score of ≥10, a cut point validated in previous 
studies 61,62.   
 
Patient Health 
Questionnaire 8-
Item Depression 
Scale (PHQ-8) 
PHQ-8 is a brief self-administered scale that 
assesses major depressive disorder core 
symptoms and allows a score (range: 0 to 24) 
based on the total number and severity of 
depressive symptoms noted over the previous 
two-week period. Its validity (including 
telephone mode of delivery), feasibility and 
capacity to detect changes of depressive 
symptoms over time are well established 63-66. 
Clinical depression is defined as PHQ-8 score 
of ≥10, a cut point validated in prior studies 
65,67-69.  
 
The Pain 
Catastrophizing 
Scale (PCS)  
PCS is a 13-item scale that describes the 
catastrophic thoughts and feelings that people 
may have in response to pain. The 
psychometric properties of PCS are well 
established 70-72 including sensitivity to change 
73,74. The total score ranges 0 (no 
catastrophizing) to 52 (severe catastrophizing).  
 
SF-36 physical 
function * 
The Short Form 36 Health Survey 
Questionnaire (SF-36) is used to indicate the 
health status of particular populations, to help 
with service planning and to measure the 
impact of clinical and social interventions. 
 
PROMIS Adult 
measures: physical 
function, fatigue, 
social health, sleep 
disturbance, pain 
behavior 
 
PROMIS Adult Self-Reported Measures on 
physical health (fatigue, pain intensity, pain 
interference, physical function, sleep 
disturbance, pain behavior and sleep-related 
impairment) and social health (ability to 
participate in social roles and activities) 
(http://www.healthmeasures.net/explore-
measurement-systems/promis/intro-to-promis). 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
validated with state of the science methods to 
be psychometrically sound 
(http://www.healthmeasures.net/explore-
measurement-systems/promis/measure-
development-research).  
 
Opioid Morphine 
Equivalent (OME) 
OME is a measure of daily dose of opioid use. 
We will use self-reported opioid type75,76, 
medical record-based dosage and self-reported 
daily frequency to calculate the OME, reported 
in milligrams per day. The OME is calculated 
by multiplying dosage by daily frequency by a 
conversion factor for each opioid based on 
opioid strength77.  
 
Health care service 
utilization 
 
We will extract data on use of different allied 
health care services from date of enrollment 
until the one-year anniversary utilizing EMR. 
The general approach will include models for 
count data. Length of follow-up will be used as 
an offset. Poisson models will be used to 
estimate the mean number of events for each 
intervention group. Alternatively, negative 
binomial (NB) models will used if there is 
evidence of over-dispersion in model 
diagnostics. The specific health care utilization 
measures include the following. 
 
PHQ Anxiety-
Depression Scale 
(PHQ-ADS) 
PHQ-ADS is a composite of PHQ-8 and GAD-
7 scores. PHQ-ADS is a single measure for 
assessing psychological distress in clinical 
practice and research 78. This is especially 
salient given the frequent co-occurrence of 
depression and anxiety. PHQ-ADS cut points 
of 10, 20 and 30 were shown to represent mild, 
moderate, and severe levels of psychological 
distress, respectively.  We are using cut point of 
≥20 to represent moderate level of 
psychological distress. 
 
Frequency of 
Practicing Pain 
Coping Skills  
Frequency of Practicing Pain Coping Skills. 
During the outcome data collection at weeks 13 
and 25 we will ask participants how many days 
they practiced pain coping skills in the past 2 
weeks (maximum of 14)3.  
 
 
 
. 
Others. 
The study will 
track medication 
use but will not 
control or restrict 
medication use as 
part of the study.  
To assess co-intervention effect, a treatment 
survey will inquire about specific treatments 
the patient has received (opiates and other 
analgesics, psychotropic medications and use of 
complementary and integrative health 
modalities such as acupuncture) for pain since 
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*We realize that the PROMIS Pain Interference and Pain Intensity are similar to BPI measures. However, the PROMIS 
measures are required of all NIH HEAL related projects. To reduce participant burden, we will drop SF-36 physical 
function (given that we already have PROMIS physical function). 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
PRECICE is a 24-week RCT of patients in the primary care clinics. During the study, participants will be 
randomized to one of three treatments: (1) [duloxetine + web-based CBT] with health care professional 
support, vs. (2) [duloxetine + web-based CBT] without health care professional support, vs. (3) 
duloxetine only. The primary purpose of the phone-based health care professional support is to enhance 
participant’s motivation to engage in the web-based CBT program with regular practice of newly learned 
pain coping skills during and after the study.  See section 9 for the analytical plan including sub-group 
analyses.    
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
We initially thought of a 3-arm study that compares combination treatment [duloxetine and web-based 
CBT] vs. duloxetine only vs. web-based CBT only. Such a design would allow us to also compare drug vs. 
web based CBT. We discarded the idea because it would be unethical to randomize participants with 
coexisting depression to a treatment arm (i.e., web-based CBT alone) without targeted treatment for 
depression. In addition, given the general tendency for practicing clinicians to prescribe medication, a 
more clinically relevant question would be, “What is the additional benefits of web-based CBT when 
offered concurrently with duloxetine?”       Alternatively, a 2-arm RCT (duloxetine only vs. web-based CBT) 
would be a reasonable design, with combination treatment reserved for those who are non-responders 
to either duloxetine or CBT alone. However, we rejected this alternative for two reasons: (1) our primary 
goal is to optimize treatment outcome and a single agent would only yield minimal pain relief; and (2) 
initiating CBT earlier during treatment may prevent disability and further pain chronicity.   
4.3 
JUSTIFICATION FOR INTERVENTION 
We realized that there are a few disadvantages in using a global endpoint: (1) they generally permit only 
global, not component-specific, conclusions and are subject to misinterpretation 93; and (2) treatment 
effects may be qualitatively different for different components of the composite 93, 94. Such an endpoint 
can thus mask a beneficial effect, or lack of effect for one or more of the components of the global 
endpoint. For this reason, the committee on the Initiative on Methods, Measurement, and Pain 
Assessment in Clinical Trials (IMMPACT) has recommended that analyses of each component of the BPI 
GPS should be reported as well 95. Thus, in the current application, we have put forth secondary 
hypotheses to examine the effects of combination treatment (duloxetine + web-based CBT) on the 
individual component of BPI pain severity and BPI pain interference as secondary endpoints. 
4.4 
END-OF-STUDY DEFINITION 
 


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A participant is considered to have completed the study if he or she has completed the baseline 
assessment at Week 0, activities associated with the randomized treatment arm, and assessments at 
Week 1, Week 13, and Week 25.  We would consider a participant as having “complete” data if the BPI 
global pain severity (BPI-GPS) measure is collected at week 25. For further details, see Table 1 in section 
1.3 Schedule of Activities. For a description of how we will handle missing data, see Section 9.4.2, “Analysis 
of the Primary Endpoint(s)”. 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. patients at the primary care clinic with daily pain for 3 months or longer affecting the low back, 
neck, hip, knee or widespread pain;  
2. at least moderate in BPI GPS, defined as a GPS score of 5 or greater1,2; and  
3. at least age 18 years old or older.  
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. uncontrolled hypertension - sitting systolic blood pressure >170 mmHg or diastolic blood pressure 
>100 mmHg at screening - (because duloxetine rarely increases blood pressure);   
2. active suicidal ideation; 
3. planned elective surgery during the study period (to avoid the confounding effect of possible 
complicated post-surgery recovery course on the primary outcome); 
4. ongoing unresolved disability claims; 
5. inflammatory arthritis (e.g., lupus and ankylosing spondylitis); 
6. cancer-related musculoskeletal pain; 
7. pregnancy; 
8. history of bipolar disorder or schizophrenia; 
9. narrow angle glaucoma;  
10. participant reported chronic kidney disease stage 4, eGFR <30 and/or severe renal impairment 
(creatinine clearance <30);  
11. current use of duloxetine;  
12. current use of any of the following medications (to avoid adverse drug-to-drug interactions): tricyclic 
antidepressant > 25 mg daily dose, monoamine oxidase inhibitors, fluoxetine, sertraline, 
paroxetine, citalopram, escitalopram, venlafaxine, milnacipran, mirtazapine, , or aripiprazole, 
serotonin precursors (e.g., tryptophan), and strong CYP1A2 inhibitors (e.g., ciprofloxacin, other 
fluoroquinolones, fluvoxamine and verapamil); 
13. poly-pharmacy (defined as concurrent daily use of 4 or more centrally acting medications for anxiety 
(anxiolytics), insomnia (hypnotics), anti-psychotic and anticonvulsants (gabapentin and pregabalin 
are permitted, if subject on a stable dose for at least 4 weeks). 
5.3 
LIFESTYLE CONSIDERATIONS 


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N/A  
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently assigned to the study intervention or entered in the study. This includes those who fall out 
during the run in phase prior to randomization. Individuals who do not meet the criteria for participation 
in this trial (screen failure) because of meeting one or more exclusion criteria that are likely to change 
over time may be rescreened. Rescreened participants will be assigned the same participant number as 
for the initial screening. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION  
Setting and Recruitment 
We will recruit participants from the 271 primary care clinics within the Wake Forest (WF) Baptist Health 
System, as well as surrounding providers outside of Atrium Health  in North Carolina .    
Subjects Selection Criteria 
See sections 5.1 Inclusion Criteria and 5.2 Exclusions Criteria for details. 
See MOP chapter 02 for more Recruitment and Retention information. 
 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
Web-based Cognitive Behavioral Therapy (web-based CBT). The web-based CBT program is an 
automated program (i.e., users learn skills with interactive, personalized training without any therapist 
contact) that includes 8, 35- to 45-minute training sessions, each of which provides an educational 
rationale and training in cognitive or behavioral pain coping skill drawn from face-to-face CBT 3. The 
sessions and features are controlled by a programming component that applies an “expert systems” 
approach. That is, it pairs decision rules (in the form of computerized tailoring algorithms) with a 
knowledge database to simulate the behavior and judgment of an expert – in this case, a highly trained 
therapist experienced in delivering face-to-face CBT. The decision rules customize (tailor) participants’ 
experience in the program based on their responses and progress through the program. In other words, 
our web-based CBT retains the therapeutic components and processes (e.g., knowledge, collaborative 
skills training, self-monitoring, reinforcement, motivational enhancement, and working alliance) 
underlying the benefits of the face-to-face interventions on which they are based 79.  
Participants will complete one session per week (on average) over 12 weeks; this timing offers flexibility 
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sessions, which we have found users prefer). Session 1 starts with an overview of the CBT program, and 
the intervention’s therapeutic rationale. This overview is followed by training in the first pain coping 
skill: progressive muscle relaxation. Sessions 2-7 teach, respectively, brief relaxation skills (i.e., “mini-
practices”), activity-rest cycling, pleasant activity scheduling, cognitive restructuring (“coping thoughts”), 
pleasant imagery, and problem solving. Session 8 reviews each skill to consolidate learning and teaches 
strategies for long-term skill use. Between sessions, participants are asked to practice their newly 
learned skill and any skills they learned in past sessions. The program also includes a feature to enhance 
engagement and facilitate practice. This feature is a section of the program that participants access to 
self-monitor their progress by reviewing and changing practice goals, recording practices and “coping 
confidence” (self-efficacy for managing pain), viewing graphic summaries of progress over time, and 
managing automated practice reminders.  
Health care professional-delivered MI. The primary purpose of health care professional contact is to 
enhance participant’s motivation to engage in web-based CBT by encouraging participant’s continued 
use and practice of pain coping skills. Subjects randomized to the [duloxetine + web-based CBT] with 
health care professional support will receive 6 phone calls from MI trained health care professional at 
week 3, 6, 10, 14, 18 and 22. Telephone sessions may run for 20 minutes on the average. Similar to our 
previously tested MI protocol to encourage exercise, the MI intervention has 3 phases: 
1. First phase: The first two calls will focus on strategies that enhance motivation to practice newly 
learned pain coping skills. It involves eliciting from the patient statements (i.e. self-motivational 
statements) that support the following: a) The patient’s recognition of the full nature and extent 
of the problem, b) The patient’s concern about how he or she is currently managing the 
problem, c) The patient’s intention of changing in the direction of adaptive pain management, 
and d) The patient’s optimism that changes are possible.  
2. Second phase: This phase is devoted to strategies that strengthen commitment to practice 
newly learned pain coping skills regularly and consistently. Specifically, the third call would 
include helping the patient develop a plan for change (i.e. shift from why the patient should 
consider change to how the patient will make changes) communicating free choice, and 
reviewing consequences of adaptive vs. maladaptive pain-related behaviors. The fourth phone 
call would involve asking for a commitment to practice new skills and a plan worksheet.  
3. Third phase: The last 2 calls are for follow-through strategies to prevent relapse. To review the 
changes that have occurred since the last session, the MI-trained health care professional will 
praise and reinforce any and all approximations of progress. He or she will also review 
behavioral indicators of motivation, patient’s responses to questions concerning reasons for 
making or maintaining changes, and barriers to adherence. He or she will again obtain a 
commitment to follow through on the new plan.  
Duloxetine. We chose duloxetine as the first line drug because: (1) it has established efficacy for CMP 
and FDA approval for that indication; and (2) it is available in generic form, which makes it more readily 
available.   
At study entry, all participants will receive duloxetine 30 mg once daily for one week. At Week 1, 
subjects who tolerate the 30 mg daily dose and do not have chronic kidney disease stage 3 will begin 60 
mg once daily for 24 weeks. Subjects with CKD-3 tolerating 30mg daily, will continue on 30mg for 24 
weeks. At week 25, participants will return to the research clinic for outcome assessments.  
To assure safety of study participants, subjects will complete a symptom monitoring form (formerly 
labeled as medication side effects checklist) at week 1, week2, week 4, week 13 and week 25. The 
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monitoring at weeks 2 and 4 and for appointment reminders.  The medical safety officer will be 
informed of any AEs (at week 1, week 2, week 4, week 13 and week 25) that require medical attention. 
For AEs that require medical attention, the study Medical Safety Officer will directly contact the 
participant to provide immediate care and guidance.  
At the last study visit (week 25), participants who would like to stop the medication will be provided 
duloxetine 30 mg once daily for 7 days and medication treatment will then stop (tapering regimen). 
Subjects already taking 30 mg daily will stop dosing at their week 25 visit. Those who would like to 
continue duloxetine will be prescribed a 2-week supply of duloxetine and will be instructed to talk to 
their primary care provider (PCP). In addition, the investigator will send a Wake One message to the PCP 
to consider continuation of duloxetine.   
Other treatments. The use of over-the-counter analgesic medications will be permitted and assessed to 
adjust for co-intervention differences between groups in the analyses.  
 
6.1.2 ADMINISTRATION AND/OR DOSING 
See Duloxetine dosing information under Section 6.1.1.  
 
See MOP chapter 09, Intervention, for more details. 
 
6.2 
FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
 
Health care professional-delivered MI. 
To assess treatment fidelity, 10% of all audiotaped MI sessions will be reviewed. A qualified MI 
consultant , will use the MITI 4 method in evaluating treatment integrity80. The MITI method represents 
a focused tool for evaluating competence in the use of MI.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
The PI and the analysis team  at the clinical site will remain blinded to group assignment throughout the 
study.  Randomization will be stratified by number of pain sites (≤2 vs. ≥3 sites) and opioid use. Number 
of pain sites is included as a stratification variable, since it has been associated with worse outcomes 81-83. 
 
The data team , who is blinded of treatment group assignment, has the primary responsibility of analyzing 
outcome data throughout the study. 
 
Randomization will be accomplished through the REDCap Randomization Module.  REDCap helps 
implement a defined randomization model within the study project, by allowing users to 1) Define all of 
the randomization parameters; 2) Create and upload a custom randomization table (i.e., allocation list). 
The table serves as a lookup table for deciding how to randomize subjects/records. The module also 
monitors the overall allocation progress and assignment of randomized subjects. 
 


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For more randomization details, see MOP chapter 07, Randomization. 
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
Importance of Maintaining and Enhancing Treatment Outcome of Web-based CBT 
As in the in-person CBT protocol, participants in a web-based CBT program are typically asked to 
practice each new cognitive or behavioral pain coping skills after learning it. Fundamental to the long 
term effectiveness of CBT is the requirement that pain coping skills are applied or practiced on a regular 
basis. In a study of traditional CBT for chronic pain, pre- to post-treatment changes in pain control and 
catastrophizing mediated the effects of CBT on pain and activity interference52. In fibromyalgia, 
treatment outcomes were most closely related to 5 coping strategies or skills: decreased guarding, 
increased use of exercise, seeking support from others, activity pacing, and use of coping self-
statements 30. Unfortunately, as with face-to-face CBT programs, maintenance of clinical improvements 
from web-based CBT has not been consistently observed 50 partly due to reduced use of cognitive and 
behavioral pain coping skills over time.  
Rini C, Keefe F et al. evaluated the effectiveness of web-based CBT (+ physiotherapist-guided home 
exercise delivered through Skype) to 148 persons with chronic knee pain. Improvements in pain and 
function with the intervention were large at 3 months (immediate post-intervention) and were greater 
than those in the control group3. Benefits were apparent at follow-up, although between group 
differences were reduced. Further, 64% of the CBT practice exercises (i.e., relaxation, coping thoughts, 
pleasant imagery, distraction, problem solving, activity-rest cycling, pleasant activity scheduling) were 
completed at 3 months with numbers decreasing during follow-up to 41%. Based on these findings, 
treatment strategies are needed to motivate continuous use or practice of pain coping skills to achieve 
long term success.    
 
MI to Enhance Benefits of Web-based CBT  
MI is an effective counseling approach to elicit behavior change (e.g., from sedentary lifestyle to 
physically active lifestyle, from poor food choices to healthier food choices to achieve weight loss, etc.) 
53-57. In contrast to delivering simple advice, a MI-trained health care professional helps a patient discuss 
the pros and cons, and the barriers and solutions to behavior change; consequently, enhancing self-
efficacy. Self-efficacy determines whether an individual attempts a given task, the degree of persistence 
when difficulty is encountered and ultimate success or failure of the behavior.  
Preliminary Data: In our RCT study 58, 216 participants with fibromyalgia were randomized to MI to 
increase physical activity vs. education (attention) control. Over a 12-week period, participants received 
either six telephone-delivered MI or educational (attention control) instructions. Post intervention, MI 
was superior to control in increasing the number of weekly hours of self-report physical activity. At 
follow up, more MI participants than controls exhibited meaningful improvement in global severity. 
Additionally, participants in the MI group had a significantly greater improvement (i.e., walked longer 
distance) in the 6-minute walk test compared to controls. 
Given our success on the use of telephone-delivered MI, it is reasonable to hypothesize that six sessions 
of telephone-delivered MI to increase participant’s continued practice of pain coping skills will enhance 
treatment outcomes.  


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The web-based CBT program (painTRAINER) utilizes online tools as well as a workbook to help 
participants track goals for completing pain coping modules and practicing coping skills, log practices, 
log coping confidence, and view progress. 
See Table 1 in Section 1.3, Schedule of Activities, for a list of study measures and time points for data 
collection. 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, participants may use the medications that they were on at study entry including opioid 
and non-opioid analgesics for pain control, including over-the-counter medications and dietary 
supplements, and prescribed medications. Medication usage will be assessed at each IPV and documented 
in the relevant Case Report Form (CRF). 
6.5.1 RESCUE THERAPY 
N/A 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
When a subject discontinues from the study intervention but not from the study, remaining study 
procedures will be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods for 
determining the need to discontinue 
• 
If the participant is due to complete assessments within 2 weeks of being discontinued from the 
study intervention, those assessments will be administered at the time of discontinuation; if the 
next scheduled assessments are more than 2 weeks from the discontinuation date, the 
discontinued participant will wait for the next scheduled assessment. Thereafter, the participant 
will be included in all future scheduled assessments, even though not participating in the 
intervention. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 


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• 
Significant study intervention non-compliance, unless varying compliance is an aspect of the study 
objectives  
• 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up  
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Participant Status form. Subjects who sign the informed consent form and are randomized but do not 
receive the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, will not be replaced. 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for one IPV and study staff are 
unable to contact the participant after at least 3 attempts.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
 
• 
The staff will attempt to contact the participant, reschedule the missed visit, counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
 
• 
Study staff will utilize a participant provided alternate contact list, if necessary, to reach the 
participant. 
 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts will be documented in the participant’s medical record or study file.  
 
• 
We will use multiple methods to contact participants who drop out, including text messaging 
and/or email.  
 
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
The specific timing of procedures/evaluations to be done at each study visit are captured in Section 1.3, 
Schedule of Activities (SoA) including physical examination-based assessments, administration of 


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questionnaires and interviews, and collection of health care utilization data from the participant’s EMR.  
Health Insurance Portability and Accountability Act (HIPAA) rules, other relevant federal or state laws, and 
local institutional requirements will be followed, as applicable. 
 
Also, see Section 3 for a full list of Objectives and Endpoints. 
8.2 
SAFETY ASSESSMENTS 
1. A Safety Monitoring Committee (SMC) will be formed to assure human subject safety and study 
integrity.  
2. The PI and the study team will meet monthly to review all serious, unexpected and on-site AEs and 
make recommendations for any changes in reporting, consent or study activities.  
3. A site visit program will 1) include an experienced data  auditor who will review data to ensure that 
study procedures are understood and carried out correctly and 2) provide a mechanism to 
encourage the effective and standardized delivery of recruitment efforts, intervention programs, 
and the collection of appropriate and valid data. See MOP Chapter 14, Quality Control (QC), for 
additional information  
4. We will minimize duloxetine-related risks by doing the following: 
a. Study staff will administer a study medication Symptom Monitoring Form at five different 
occasions (weeks 1, 2, 4, 13 and 25) and will report every adverse effect (AE) to the medical 
safety officer (an internal medicine physician with active primary care clinic practice). For 
AEs that require medical attention, the medical safety officer will directly contact the 
participant to assess the need for adjustment or discontinuation of the study medication.  
b. Participants will be assessed for suicidal ideation. The medical safety officer will be notified 
of low and moderate risk individuals and will direct study personnel how to proceed.  
Emergency procedures will be employed if a participant is considered high risk. 
c. Urine pregnancy test will be performed at baseline (week 0) and at week 13 for all females 
of childbearing potential. We will ask pregnancy status at each study visit. We will ask 
subjects who become pregnant while in the study to discontinue duloxetine.  These subjects 
will not be withdrawn from the study. Importantly, in the informed consent, we will include 
the rare side effects of Serotonin–norepinephrine reuptake inhibitor (e.g., duloxetine) 
exposure late in the third trimester.  
d. The medical safety officer or the investigator will review AEs and determine likelihood that 
AEs are related to study drug.    
5. Our trained study staff will ask about emotional distress related to the web-based CBT and report 
any concerning issues to the medical safety officer.    
6. Data monitoring plan  
a. Web-based scripted data entry forms will be utilized to guide staff through the 
administration of screening instruments administered via phone.  
b. Once a subject passes screening and is formally enrolled in the study, study staff will use a 
custom data collection and randomization engine to collect demographic information, 
receive the randomization by stratum, and validate that inclusion and exclusion criteria have 
been appropriately tested.  
c. Only the following people or organizations will be granted access to study records and data: 
study investigators, research team, Institutional Review Boards, the FDA, and the NIH 
(NINR).  
d. Electronic case report forms (eCRFs) will be used for all data collection procedures. The data 
security measures will encompass the following functions: 


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i) 
Data Tracking – will be used to provide the status of enrollment, number of complete 
data collection forms and number of forms. 
ii) Data Entry – systems will be in place to allow easy-to-use interfaces to minimize errors. 
iii) Data Editing – The need for data editing will be minimal because systems will be in 
place to prevent erroneous data entry.  
iv) Reporting – The study website will generate reports on a weekly basis of the number of 
patients enrolled, the number of missing data fields and the number of missing phone-
delivered intervention sessions for the combination group (duloxetine + web-based 
CBT) with health care professional support. Periodic and ad-hoc reporting will be 
utilized to show subject recruitment and retention data.   
v) Statistical Analysis – The data management team will perform data analysis with SAS. 
f. Quality assurance (data integrity and validity) measures will be as follows:  
i) 
Real-time data validation will be utilized to ensure data quality at the time of entry.  
ii) Data and form checks will be completed by the WFDM team.  
iii) Missing data will be monitored on a regular basis and the project manager on the 
study team side will be informed of missing data daily via “red flag” reminders in the 
database.  
iv) The PI will discuss the rate and type of missing data during the bi-monthly 
teleconferences.  
v) Data entry safeguards will prevent the erroneous entry of data that would fall outside 
the bounds of data that would be acceptable for a particular field.  
vi) Dr. Ang will review weekly updates generated by the data management team to 
monitor missing data rates, and response times to red flag reminders.  
g. Data confidentiality will be ensured in the following ways:  
i) 
Data will be used only in aggregate and no identifying characteristics of individuals will 
be published or presented.  
ii) Alert values for medically relevant procedures (e.g., blood pressure, pulse rate, and 
suicidal ideation) will be developed, and a system will be in place to alert the medical 
study officer, depending on the urgency of the values.  
iii) Confidentiality of data will be maintained by using research identification numbers 
that uniquely identify each individual.  
iv) Safeguards will be established to ensure the security and privacy of participants’ study 
records.  
v) Appropriate measures will be taken to prevent unauthorized use of study information. 
Data other than demographic information will not use names as an identifier.  
vi) Research records will be kept in a locked room at the research office.  
vii) The files matching participants' names and demographic information with research ID 
numbers will be kept in a locked computer file (password protected) that uses a 
different key from that of all other files. Only trained and certified study personnel will 
have access to these files, and they will be asked to sign a document that they agree 
to maintain the confidentiality of the information.  
viii) After the study is completed, local data will be stored with other completed research 
studies in a secured storage vault.  
ix) In compliance with HIPAA and the Standards for Privacy of Individually Identifiable 
Health Information of the Department of Health and Human Services, we access 
personal health information and medical records only after receiving signed informed 
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See MOP chapter 12, Safety Monitoring and Serious Adverse Events, for more details of the monitoring 
entity, monitoring procedures, and data monitoring plan.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
 
An adverse event is any undesirable experience that occurs during  the study, whether or not it is 
associated with the interventions in a participant. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
An AE is serious if it results in death, is life-threatening, requires inpatient hospitalization or prolongs an 
existing hospitalization, results in a persistent or significant disability/incapacity, or might require 
medical or surgical intervention to prevent one of the outcomes, such as treatment in the emergency 
room for severe injurious falls.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
As part of the safety monitoring system, AEs reported to study staff at any time will be reviewed by the 
medical safety officer, who will identify,  assess severity and relatedness to study drug, and if needed, 
manage the event. The study staff will report AEs and/or any unanticipated problems, to the medical 
safety officer. For AEs that require medical attention, the medical safety officer will directly contact the 
subject. 
Safety related events will be reported within 10 days, as required by the SMC and the IRB that are 
responsible for study oversight.  
For ongoing participant safety, events are assessed by the medical safety officer or Investigator to 
determine if they are Serious, Unexpected, or Related to study participation. If the event is  reportable 
to the IRB, an event evaluation form will be completed that will include a description of the event, a 
classification of seriousness, assessment of potential relationship to the intervention, assessment of 
need for change in the consent or the study activities, a summary of known prior health issues, event 
outcome and a classification of the main organ system involved.  The classification of potential 
relationship to the intervention is as follows. 
Definite - Temporal pattern + Known or expected AE response pattern + Confirmed by stopping the 
intervention + Reappearance of AE on re-challenge 
Probable - Temporal pattern + Known or expected AE response pattern + Confirmed by stopping the 
intervention + could not be explained by participant’s clinical state 
Possible - Temporal pattern + Known or expected AE response pattern + could have been produced 
by a number of other factors 
Unknown -  Relationship for which no evaluation can be made. 


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Not related - AE for which sufficient information exists to indicate that the cause is unrelated to the 
study intervention 
 
The medical safety officer or the Investigator  will determine the attribution/relatedness of each AE. The 
PI will report AEs to NINR every 6 months,  including actions taken by the IRB as a result of such AEs.  
 
See MOP chapter 12, Safety Monitoring and Serious Adverse Events, for more details of adverse and 
serious adverse events (SAEs) including the Study Medication Symptom Monitoring Form, the Adverse 
Event Form, and the Suicide Algorithm. 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
See section 8.3.3.1 above for classification of potential relationship to the intervention.  
 
8.3.3.3 EXPECTEDNESS  
 
 The medical monitor or Investigator  will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study procedures. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the AE Form (included in MOP 
chapter 12, Safety Monitoring and Serious Adverse Events). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study procedures, and time 
of resolution/stabilization of the event. All AEs occurring while on study will be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution or stabilization. 
 
Any medical or psychiatric 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. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 
Clinic staff and the study safety officer will record events with start dates occurring any time after 
informed consent is obtained.  At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until resolution or 
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8.3.5 ADVERSE EVENT REPORTING  
 
See section 8.3.3.1 above and MOP chapter 12, Safety Monitoring and Serious Adverse Events, for 
additional information on AE reporting. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
In consultation with the PI, study team members will be responsible for reporting AEs, SAEs and 
unanticipated events that meet IRB reporting criteria, as soon as possible, but no  later than 10 working 
days after the investigator first learns of the event. 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
See section 8.2 Safety Assessments for pregnancy related policy. 
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
 
An unanticipated problem is any event, incident, experience, or outcome (including, but not limited to, 
adverse events and serious adverse events) which occurs in a research study and meets ALL of the 
following criteria:  
 
• Unexpected in nature, frequency, or severity (not articulated in the study protocol, informed 
consent or Investigator’s Brochure or not expected as a consequence of the natural history of a 
disease under study)  
 
• Related or possibly related to participation in the research (there is a reasonable possibility the 
that the event, incident, experience, or outcome may have been caused by the drug/device, 
procedures or interventions involved in the research) 
 
• Places subjects or others at a greater risk of harm than was previously known or recognized 
(causes physical, psychological, economic, or social harm to a human subject; increases the risk 
of harm of any kind; or otherwise compromises subject's safety, rights, welfare, or privacy).  
 


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Reportable events are not limited to physical injury, but also include psychological, economic, and social 
harm. Reportable events may arise as a result of the use of drugs, biological agents, devices, procedures 
or other interventions, or as a result of the use of questionnaires, surveys, observations or other 
interactions with research subjects. All breaches of confidentiality are reportable events. Reporting to 
the IRB is required regardless of the funding source or study sponsor. 
 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing IRB and to the Data 
Coordinating Center (DCC). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• 
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 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are SAEs will be reported to the IRB, the DCC, and the NINR Program Officer within 48 
hours of the investigator becoming aware of the event  
• 
Any other UP will be reported to the IRB, the DCC, and the NINR Program Officer within 7 calendar 
days of the investigator becoming aware of the problem  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures) and the supporting agency head (or designee) 
• 
OHRP reporting is made by the IRB in accordance with federal and institutional requirements 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Any unanticipated problem resulting in a change to the protocol that might affect participant’s 
participation in the study will be reported to the participant should the IRB require this and the IRB will 
make the decision if re-consenting is needed.  
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
We have two primary hypotheses (H1 and H2): 
 
H1: Combination treatment with and without health care professional support is more effective than 
duloxetine monotherapy in improving BPI GPS.   
 
The primary comparison will be the combination treated groups (with and without health care 
professional support) vs. duloxetine group.  


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H2: Combination treatment with health care professional support is more effective than combination 
treatment without health care professional support in improving BPI GPS.          
   
The primary comparison will be combination group with health care professional support vs. without 
health care professional group.   
      
Exploratory hypothesis: Compared to those without comorbid psychological distress, participants with 
comorbid psychological distress are more likely to respond to combination therapy (with and without 
health care professional support) than to duloxetine monotherapy. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
With 280 participants and 20% loss to follow-up, we will have 75 evaluable participants in each treatment 
group.  Based on published literature (Kroenke K et. al JAMA July 2014), the estimated standard deviation 
(SD) for BPI GPS score is 2.2. Assuming a moderate correlation of 0.5 between baseline and follow-up 
measures, we estimate that the SD in an analysis of covariance (ANCOVA) will be approximately 1.9. 
Therefore, we will have 90% power to detect a difference of -1 in BPI GPS score between combination 
groups (n= 150) and drug only group (n=75) for Aim 1. The power will be 83% power for comparison 
between combination with health care professional (n=75) and combination without health care 
professional (n=75) for Aim 2. All power calculations are based on two-sided t tests with alpha level of 
0.025 to adjust for Bonferroni correction of testing two main hypotheses. 
9.3 
POPULATIONS FOR ANALYSES 
 
WF Baptist Health. We have identified 9,243 unique individuals in the age range of at least 18 years old or 
older; seen at the primary care clinic over the past 12 months; and who received one of the relevant ICD 
10 codes. The pool of potentially eligible participants (N=9,243) is large enough to get us to our target 
sample size of 250 at WF Baptist Health. This pool of 9,243 individuals has the following characteristics: 
Gender: 62% females and 38% males; Race:  21% African Americans, 2.8% Hispanics, 1% Asians and 72.2% 
Whites.      Over the past 4 months we surveyed 86 patients with CMP (48% females; mean age= 51 years 
old) who were seen in one of WF Baptist Health primary care centers. We found that 58 (67%) patients 
continue to have a significant amount of pain despite current treatments, and also reported that pain 
prevented them from working or doing the things they enjoy almost every day. From these 58 patients, 
50 (86%) have expressed willingness to participate in clinical studies to help reduce their pain and improve 
their quality of life. 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
See the following sections for details. 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
Primary Outcome  


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The primary outcome of the study is BPI GPS score collected at Weeks 13 and 25. BPI GPS is a self-report 
measure of pain severity and interference with proven reliability and validity across different pain 
conditions. The overall score is defined as the average of 11 items. Two subscales are also defined: BPI 
pain severity and BPI pain interference. BPI pain severity is the average of 4 items asking about current 
pain and worse, least, and average pain in the past week. BPI pain interference is the average of 7 items 
that rate how pain interferes with various activities (higher score indicate greater pain interference). All 
study participants will be analyzed according to randomized treatment assignment regardless of 
adherence to the treatment protocols. We have two primary hypotheses (H1 and H2): 
 
H1: Combination treatment with and without health care professional support is more effective than 
duloxetine monotherapy in improving BPI GPS.   
H2: Combination treatment with health care professional support is more effective than combination 
treatment without health care professional support in improving BPI GPS.          
 
Research has shown that the use of ANCOVA with baseline measure as a covariate is an optimal method 
in both design and analysis of trials with a continuous primary outcome. Compared to the use of change 
score as the primary outcome, ANCOVA is generally superior in terms of efficiency, precision, and 
power. Therefore, the primary analysis will be Week 13 and 25 BPI scores as a primary outcome while 
adjusting for baseline measurement.  
 
In primary analysis, we will fit a LMM to account for the correlation among the repeated measures. The 
model will include indicator variables for intervention arms, visit, and the interaction term. Covariates 
will include the pre-randomized measure of BPI global score, the stratification factor opioid use, and the 
number of pain sites. Average follow-up BPI global pain scores for the 3 intervention groups will be 
estimated using least square means. Two different contrasts will be constructed to test H1 and H2 
separately, each at the significance level of 0.025.  
 
We will conduct several sensitivity analyses to evaluate the robustness of the results. First, we will use 
inverse probability weighting (IPW) to account for missing data. We will identify the baseline 
characteristics that may be associated with lost to follow-up and derive weights for use in IPW analysis. 
Additional sensitivity analysis will include indicators of new pain related medication taken, and any use of 
complementary treatment. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary Outcomes 
The secondary outcomes will include the two individual components of the BPI GPS: BPI pain severity and 
BPI pain interference. We will use similar LMMs described for the primary outcome analysis. 
9.4.4 SAFETY ANALYSES 
N/A 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
N/A 
 
9.4.6 PLANNED INTERIM ANALYSES  
N/A 


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9.4.7 SUB-GROUP ANALYSES 
Subgroup Analyses  
We will conduct subgroup analysis using LMMs to test the interactions between intervention arm (with 
and without health care professional support vs. monotherapy) and baseline characteristics. The 
subgroups include comorbid psychological distress, use of opioid, and number of painful body sites 
(dichotomized at the median value). The interaction will be tested at the 0.10 level of significance. A 
significant interaction is indicative of potential moderating effect of baseline characteristic such as 
psychological distress for predicting the mean BPI GPS score under combination therapy. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
N/A 
 
9.4.9 EXPLORATORY ANALYSES 
Tertiary outcomes 
We propose the following 4 tertiary outcomes to further assess the effect of the interventions on pain. 
We will use similar LMMs described for the primary outcome analysis. 
1. GRC  
GRC assesses overall clinical response. It is consistent with the IMMPACT recommendations for a 
7-item patient global change scale 59. Modified to detect finer gradations of improvement, this 
scale is sensitive to treatment-related improvements 
2. PROMIS pain intensity 
3. PROMIS pain interference 
PROMIS (http://www.healthmeasures.net/explore-measurement-systems/promis/intro-to-
promis) Adult Self-Reported Measures on physical health (fatigue, pain intensity, pain 
interference, physical function, sleep disturbance, pain behavior and sleep-related impairment) 
and social health (ability to participate in social roles and activities). PROMIS measures were 
developed and validated with state of the science methods to be psychometrically sound 
(http://www.healthmeasures.net/explore-measurement-systems/promis/measure-
development-research). 
4. CPCI 
 
Exploratory outcomes 
1. GAD-7  
GAD-7 is a validated screening and severity measure for the most common anxiety disorders in 
primary care (i.e., generalized anxiety, panic, social anxiety, and post-traumatic stress disorder) 
61,62. Higher scores on GAD-7 represent more severe anxiety symptoms. Clinical anxiety is 
defined as GAD-7 score of ≥10, a cut point validated in previous studies 61,62.   
2. PHQ-8 
 PHQ-8 is a brief self-administered scale that assesses major depressive disorder core symptoms 
and allows a score (range: 0 to 24) based on the total number and severity of depressive 
symptoms noted over the previous two-week period. Its validity (including telephone mode of 
delivery), feasibility and capacity to detect changes of depressive symptoms over time are well 
established 63-66. Clinical depression is defined as PHQ-8 score of ≥10, a cut point validated in 
prior studies 
3. PCS 


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PCS is a 13-item scale that describes the catastrophic thoughts and feelings that people may 
have in response to pain. The psychometric properties of PCS are well established 70-72 including 
sensitivity to change 73,74. The total score ranges 0 (no catastrophizing) to 52 (severe 
catastrophizing). 
4. SF-36 physical function  
This 10-item scale inquires about the subject’s perception of their limitations in the 
performance of various types of physical activities. Scale scores can range from 0 to 100, with 
higher scores indicating better functioning. 
4. PROMIS Adult measures: The weight of evidence supports the appropriateness of using PROMIS 
measures across different medical conditions including various CMP conditions 85.   
Physical function  
Fatigue 
Social health 
Sleep disturbance  
Pain behavior 
5. OME 
OME is a measure of daily dose of opioid use. We will use self-reported opioid type75,76, medical 
record-based dosage and self-reported daily frequency to calculate the OME, reported in 
milligrams per day. The OME is calculated by multiplying dosage by daily frequency by a 
conversion factor for each opioid based on opioid strength77.  
6. Health care service utilization 
We will extract data on use of different allied health care services from date of enrollment until 
the one-year anniversary utilizing EMR. The general approach will include models for count 
data. Length of follow-up will be used as an offset. Poisson models will be used to estimate the 
mean number of events for each intervention group. Alternatively, negative binomial (NB) 
models will used if there is evidence of over-dispersion in model diagnostics. The specific health 
care utilization measures include the following. 
7.1 Number of new referrals to other specialties or allied health services from enrollment date 
to the one-year anniversary 
 
a. Orthopedic surgery 
b. Spine center 
c. Neurosurgery 
d. Pain specialty 
e. Physical Medicine/Rehabilitation (PMR) 
f. Rheumatology 
g. Integrative Medicine  
h. Psychiatry 
i. Medication  
ii. Counseling 
iii. Medication + counseling 
i. 
Quartet system for PCP – psychiatry/psychology referral (not currently link with Wake 
One) 
j. 
Physical therapy 
k. Occupational therapy 
7.2 Number of visits to each specialty or allied health services from enrollment date to the one-
year anniversary  
l. 
Orthopedic surgery 
m. Spine center 


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n. Neurosurgery 
o. Pain specialty 
p. Physical Medicine/Rehabilitation (PMR) 
q. Rheumatology 
r. Integrative Medicine  
s. Psychiatry 
i. Medication  
ii. Counseling 
iii. Medication + counseling 
t. Quartet system for PCP – psychiatry/psychology referral (not currently link with Wake 
One) 
u. Physical therapy 
v. Occupational therapy 
7.3 Number of orthopedic or musculoskeletal surgeries from enrollment date to the one-year 
anniversary. See attached relevant CPT codes. 
8 
PHQ-ADS is a composite of PHQ-8 and GAD-7 scores. PHQ-ADS is a single measure for assessing 
psychological distress in clinical practice and research 78. This is especially salient given the 
frequent co-occurrence of depression and anxiety. PHQ-ADS cut points of 10, 20 and 30 were 
shown to represent mild, moderate, and severe levels of psychological distress, respectively.  
We are using cut point of ≥20 to represent moderate level of psychological distress. 
9 
Frequency of Practicing Pain Coping Skills. During the outcome data collection at weeks 13 and 
25 we will ask participants how many days they practiced pain coping skills in the past 2 weeks 
(maximum of 14)3.  
10 Others. The study will track medication use but will not control or restrict medication use as part 
of the study. To assess co-intervention effect, a treatment survey will inquire about specific 
treatments the patient has received (opiates and other analgesics, psychotropic medications 
and use of complementary and integrative health modalities such as acupuncture) for pain since 
the last follow-up 69. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to the 
participant and written documentation of informed consent will be completed prior to starting the study 
intervention.  We will make every attempt to send (via regular mail or email) the informed consent to 
participants before the first study visit to allow participants to carefully review the informed consent 
document.  
 
See MOP chapter 05, Informed Consent, for consent materials.  


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10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
To be eligible for participation in the PRECICE study, participants must have the capacity to give their 
own informed consent. To avoid pressuring the participant, only one person associated with the study 
should be present when the participant reviews the consent forms.  The setting in which consent is 
obtained will be as private as possible so participants can freely ask questions without embarrassment. 
 
The participant should be fully informed and be given ample time to consider the pros and cons of 
participation in the study.  The participant should be encouraged to discuss the study with anyone they 
wish. 
 
The participant should be given a copy of the informed consent forms after they are signed and dated by 
the participant and study team member obtaining informed consent.  Even though participants are free 
to withdraw from the study at any time, the consent form spells out our obligations to the participant 
and the participant's obligations to the study while he or she is a subject.    
 
Participants should be encouraged to keep the consent forms. The consent forms contain useful 
information about the study which participants may want to review from time to time.  After the 
participant has signed the consent form, forward the consent form to the PI for his signature. 
 
Anyone who signs a consent form should personally date it.  If consent is obtained the same day that the 
participant's involvement in the study begins, the participant's study record should document that 
consent was obtained prior to participation in the research. A general statement for source 
documentation should be included, such as, "All the required elements of informed consent were 
presented to the patient. Voluntary consent was obtained, and the patient's questions were answered 
prior to initiation of any research procedures." 
 
For further details, see MOP chapter 05, Informed Consent. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending, or terminating party to study participants, investigator, funding agency, and regulatory 
authorities. If the study is prematurely terminated or suspended, the PI will promptly inform study 
participants, the IRB, and sponsor/funding agency 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. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance of study staff to the protocol (i.e., significant protocol violations) 
• 
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 the funding agency, sponsor, IRB, FDA, or other relevant regulatory or oversight bodies (OHRP, 
SMC). 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a specific 
study participant will be held in strict confidence within the research team. No personally identifiable 
information from the study will be released to any unauthorized third party without prior written approval 
of the sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor or funding agency, representatives of 
the IRB, regulatory agencies or representatives from companies or organizations supplying the product, 
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 the 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/funding agency 
requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the WFHS DCC. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by the clinical site and 
by WFHS DCC research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the WFHS DCC. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should be made available 
to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms used to 
share data will include proper plans and safeguards for the protection of privacy, confidentiality, and 
security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not be 
traceable to a specific study participant). Plans for archiving and long-term preservation of the data will 
be implemented, as appropriate.  
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  


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Data collected for this study will be analyzed and stored at WFHS DCC. After the study is completed, the 
de-identified, archived data will be transmitted to and stored at the NIH Data Repository, for use by other 
researchers including those outside of the study. Permission to transmit data to the NIH Data Repository 
will be included in the informed consent.   
 
When the study is completed, access to study data will be provided through the NIH Data Repository. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor  
Dennis Ang, MD, MS   
Principal Investigator 
Chief of Rheumatology and Immunology 
William Y. Rice, III  
Co-Investigator,  
Associate Professor, General Internal Medicine 
Wake Forest Baptist Medical Center 
Wake Forest Baptist Medical Center 
Medical Center Blvd. 
Winston-Salem, NC 27157 
Medical Center Blvd. 
Winston-Salem, NC 27157 
336.716.4209 (work)   
336.716.3787 (work)   
dang@wakehealth.edu  
wrice@wakehealth.edu  
 
 
 


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Study leadership includes a Statistical/Data Management team, a Wake Forest Baptist Research team, and 
Study Intervention teams for Psycho-education and Study Medication.  See MOP chapter 16, Publications 
and Other Study Policies, for a list of study team roles and responsibilities of those involved in the conduct, 
management, or oversight of the trial. 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a SMC composed of individuals with the appropriate 
expertise, including two clinical investigators (one with expertise in clinical trials and the second with 
expertise in behavioral-based intervention) and one PHD level biostatistician. Members of the SMC will 
be independent from the study conduct and free of conflict of interest.  
 
The SMC will meet twice a year and will be provided with a report that will contain safety data summaries, 
patient demographics and compliance data, recruitment, visit schedules, missed visits, outcomes and 
Medical Event Forms and any other AEs. Each member of the SMC will be given a detailed progress report 
at least two weeks before the meeting.  The SMC will be able to request specific information and analyses 
from the PI’s research team for monitoring purposes at any time during the study. Finally, the SMC will 
make recommendations to the PI regarding continuation, termination, or other modifications to the study 
based on observed AEs of the treatment under study. The PI will inform the NINR (National Institute of 
Nursing Research) project officer of any recommendations from the SMC.  The NIH program officer will 
attend the SMC meeting on as needed basis.  
 
 
 


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10.1.7 CLINICAL MONITORING 
 
Data monitoring will be conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with ICH GCP, and with 
applicable regulatory requirement(s). Monitoring activities will be as follows: 
 
• 
The data team  will oversee the data integrity of the current study. 
o Participant forms will be reviewed throughout the study. Initially, all forms from the first 
ten randomized participants will be reviewed.  This will include all forms entered in the 
data entry system, the consent forms, and the informed consent tracking form.   This set 
of ten forms will be sent to for review as they are completed.    
o Ten percent of informed consent forms will be reviewed on a periodic basis,  to verify 
that the forms are legible and that they have been filled out correctly and completely. 
• 
Study staff will be trained to administer and review all questionnaires and data collection forms  
before the participant leaves the clinical research unit. Additionally, the study staff will perform 
monthly QC checks in the data entry system.  
• 
Site study team meetings may also be conducted, if consistent departures from the Protocol and 
MOP are detected.  Retraining may be done as needed during these visits, depending on the 
availability of staff.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Study-wide QC is the ultimate responsibility of the PRECICE clinical center and the DCC.  The PRECICE 
Project Coordinator at the clinical research site must become familiar with PRECICE requirements and 
schedule clinic activities so that there is adequate time for clinic staff to carry out their responsibilities 
while meeting quality standards. 
The clinical research site will perform internal quality management of study conduct, and data collection, 
documentation, and completion.  The clinical research site will follow a common quality management 
plan. 
 
QC procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process as well as 
a percentage of the completed consent documents.  This review will evaluate compliance with GCP, 
accuracy, and completeness.  Feedback will be provided to the study team to ensure proper consenting 
procedures are followed.  
 
Source documents and the electronic data --- Study data will be captured in RedCap(see Section 10.1.9, 
Data Handling and Record Keeping) 


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Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and will 
implement corrective actions when the quantity or nature of deviations are deemed to be at a level of 
concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all trial related 
sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities. 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection will be the responsibility of the clinical trial staff at the site under the supervision of the 
investigator. The investigator will be responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
 
  
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into a REDCap secure web platform for building and managing online 
databases and surveys.  REDCap is a 21 CFR Part 11-compliant data capture system available through the 
Wake Forest School of Medicine Clinical and Translational Science Institute. 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. 
10.1.9.2 STUDY RECORDS RETENTION  
 
As required for NIH grantees, PRECICE study documents will be retained for a period of three years from 
the date of the Federal Financial Report (FFR) submission. 
10.1.10 
PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, ICH GCP, 
or MOP requirements. The noncompliance may be either on the part of the participant, the investigator, 


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or the study site staff. As a result of deviations, corrective actions will be developed by the site and 
implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
 
It will be the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation.  All deviations will be 
addressed in study source documents, reported to the NINR Program Official and WFHS sponsor.  Protocol 
deviations will be sent to the reviewing IRB per their policies. The site investigator will be responsible for 
knowing and adhering to the reviewing IRB requirements. Further details about the handling of protocol 
deviations will be included in the MOP.  
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
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. 
 
The project will comply with all NIH HEAL Initiative Data Sharing policies. 
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 trial 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.   
 
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 is not 
applicable for this study. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons 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. WFHS has established 


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policies and procedures for all study group members to disclose all conflicts of interest and will establish 
a mechanism for the management of all reported dualities of interest. 
10.2 ADDITIONAL CONSIDERATIONS 
 
In case of complete shutdown of all clinical research activities, 
 
1. Participants will complete the questionnaires online.  
2. We will mail the medication (and urine pregnancy test if relevant) to the participant’s home 
address. Participant will take a picture of the result of the pregnancy test and email it to the 
research staff.  
 
In case of partial shutdown of all clinical research activities,  
 
1. Participants will complete the questionnaires online. 
3. Participants will pick up the medication (and urine pregnancy test if relevant) on a designated 
pick up area within the medical center. Participant will take a picture of the result of the 
pregnancy test and email it to the research staff.  
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BPI 
Brief Pain Inventory 
CBT 
Cognitive Behavioral Therapy 
CFR 
Code of Federal Regulations 
CMP 
Chronic Musculoskeletal Pain 
CPCI 
Chronic Pain Coping Inventory 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
eCRF 
Electronic Case Report Forms 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
GAD-7 
Generalized Anxiety Disorder 7-item scale 
GCP 
Good Clinical Practice 
GPS 
Global Pain Severity 
GRC 
Global Rating of Change 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Council on Harmonisation  
IPV 
In-person Visit 
IRB 
Institutional Review Board 
LMM 
Linear Mixed Effects Model 
MI 
Motivational Interviewing 
MITI 4 
Motivational Interviewing Treatment Integrity Code 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 


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OHRP 
Office for Human Research Protections 
OME 
Opioid Morphine Equivalent 
PCP 
Primary Care Provider 
PCS 
Pain catastrophizing scale 
PCST 
Pain-coping Skills Training 
PHQ-8 
Patient Health Questionnaire 8-Item Depression Scale 
PHQ-ADS PHQ Anxiety-Depression Scale 
PI 
Principal Investigator 
PRECICE 
Pain Response Evaluation of a Combined Intervention to Cope Effectively 
PROMIS® 
Patient-Reported Outcomes Measurement Information System 
QC 
Quality Control 
RCT 
Randomized Clinical Trial 
SAE 
Serious Adverse Event 
SF-36 
The Short Form 36 Health Survey Questionnaire 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
UP 
Unanticipated Problem 
US 
United States 
WFDM 
Wake Forest Data Management 
WFHS 
Wake Forest Health Sciences 
 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
Version 
Date 
Description of Change  
Brief Rationale 
1 
05/13/2020 
IRB approved  
Original version 
2 
12/08/2020 
Protocol modified to NIH preferred 
format  
NIH provided “NIH Protocol 
Template for Behavioral and 
Social Sciences Research 
Involving Humans” 
3 
12/17/2020 
Protocol modified to include NIH 
suggested changes. 
Response to NIH reviewers’ 
feedback. 
4 
01/14/2021 
At week 25, participants who would 
like to continue duloxetine will be 
prescribed a 2-week supply of 
duloxetine. Modified Table 1 to 
indicate Pre-Screening. 
The 2-week supply will give 
participants enough time to ask 
their PCP for a refill. Modified 
Table 1 to indicate Pre-
Screening. 
5 
03/11/2021 
Change to the calculation of our 
primary outcome on Page 30. 
Compared to the use of change 
score as the primary outcome, 
ANCOVA is generally superior in 
terms of efficiency, precision, 
and power. Therefore, the 
primary analysis will be Week 
13 and 25 BPI scores as a 
primary outcome while 
adjusting for baseline 
measurement. 
 
04/14/2021 
Changed “nurse” to “coach” 
throughout the protocol. 
It was determined by speaking 
with the hiring department and 
nursing management that the 
coaching did not have to be 
done by a nurse. The Informed 
Consent document indicates 
“coach”. 
 
04/19/2021 
Updated Table 1, footnote. 
Made correction to footnote 
“e”: “At week 1, participants 
will receive duloxetine 60 mg 
once daily for 24 weeks”. 
6 
07/19/2021 
Added footnote “i” to Table 1.  
Added text to Section 6.1.1. 
Added using text messaging as an 
adjunct to our phone calls to assess 
duloxetine symptoms monitoring at 
weeks 2 and 4 and for appointment 
reminders. 
We have observed that a 
substantial proportion of 
participants perceive the phone 
calls as “burdensome”. This is 
manifested by not answering or 
not returning our calls. To 
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added the option of using text 
messaging as an adjunct to our 
phone calls. 
7 
03/28/2022 
Changed “coach” to “health care 
professional” throughout the 
protocol and updated the analysis 
plan text regarding painful body sites 
stratification. 
Changed “coach” to reflect a 
more generic term.  The health 
care professionals trained in MI 
may range from a coach to PhD 
level.  Updated the analysis 
plan based on decisions we 
made about the painful body 
sites stratification. 
8 
11/01/2022 
Updated description of site 
enrollment facilities to add providers 
outside of the Atrium Health system 
Enhance recruitment 
 
 
5.2 Eligibility criteria: revised to add 
inclusion of CKD-3 patients 
Enhance recruitment 
 
 
5.2 Eligibility criteria: clarified 
criteria for uncontrolled 
hypertension 
Safety 
 
 
5.2 Eligibility criteria: clarified use of 
gabapentin and pregabalin 
Safety 
 
 
6.1.1 Revised to include drug dosing 
for subjects with CKD -3; text 
messaging may be used to contact 
subjects; clarified end of study drug 
discontinuation procedure 
Safety 
 
 
10.1.7 Revised to reflect data 
collection oversight process 
Clarification 
 
 
Editorial revisions and administrative 
changes throughout 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Jensen MP, Turner JA, Romano JM, Lawler BK. Relationship of pain-specific beliefs to chronic 
pain adjustment. Pain. 1994;57(3):301-309. 
30. 
Nielson WR, Jensen MP. Relationship between changes in coping and treatment outcome in 
patients with Fibromyalgia Syndrome. Pain. 2004;109(3):233-241. 
31. 
Wertli MM, Burgstaller JM, Weiser S, Steurer J, Kofmehl R, Held U. Influence of catastrophizing 
on treatment outcome in patients with nonspecific low back pain: a systematic review. Spine 
(Phila Pa 1976 ). 2014;39(3):263-273. 
32. 
Miles CL, Pincus T, Carnes D, et al. Can we identify how programmes aimed at promoting self-
management in musculoskeletal pain work and who benefits? A systematic review of sub-group 
analysis within RCTs. Eur J Pain. 2011;15(8):775-711. 
33. 
Edwards RR, Bingham CO, III, Bathon J, Haythornthwaite JA. Catastrophizing and pain in arthritis, 
fibromyalgia, and other rheumatic diseases. Arthritis Rheum. 2006;55(2):325-332. 
34. 
RS L, S F. Stress, appraisal and coping. New York: Springer; 1984. 
35. 
N L, FJ K. Coping with chronic pain. Cambridge UK: Cambridge University Press; 1997. 
36. 
Jensen MP, Turner JA, Romano JM, Karoly P. Coping with chronic pain: a critical review of the 
literature. Pain. 1991;47(3):249-283. 
37. 
Tan G, Jensen MP, Robinson-Whelen S, Thornby JI, Monga TN. Coping with chronic pain: a 
comparison of two measures. Pain. 2001;90(1-2):127-133. 
38. 
Snow-Turek AL, Norris MP, Tan G. Active and passive coping strategies in chronic pain patients. 
Pain. 1996;64(3):455-462. 
39. 
Keefe FJ, Caldwell DS, Baucom D, et al. Spouse-assisted coping skills training in the management 
of knee pain in osteoarthritis: long-term followup results. Arthritis Care Res. 1999;12(2):101-
111. 
40. 
Williams AC, Eccleston C, Morley S. Psychological therapies for the management of chronic pain 
(excluding headache) in adults. Cochrane Database Syst Rev. 2012;11:CD007407. 
41. 
Ferrari R. The biopsychosocial model--a tool for rheumatologists. Baillieres Best Pract Res Clin 
Rheumatol. 2000;14(4):787-795. 


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42. 
Keefe FJ, Smith SJ, Buffington AL, Gibson J, Studts JL, Caldwell DS. Recent advances and future 
directions in the biopsychosocial assessment and treatment of arthritis. J Consult Clin Psychol. 
2002;70(3):640-655. 
43. 
Gallagher RM. Biopsychosocial pain medicine and mind-brain-body science. Phys Med Rehabil 
Clin N Am. 2004;15(4):855-882, vii. 
44. 
Holroyd KA, Cottrell CK, O'Donnell FJ, et al. Effect of preventive (beta blocker) treatment, 
behavioural migraine management, or their combination on outcomes of optimised acute 
treatment in frequent migraine: randomised controlled trial. BMJ. 2010;341:c4871. 
45. 
Holroyd KA, O'Donnell FJ, Stensland M, Lipchik GL, Cordingley GE, Carlson BW. Management of 
chronic tension-type headache with tricyclic antidepressant medication, stress management 
therapy, and their combination: a randomized controlled trial. JAMA. 2001;285(17):2208-2215. 
46. 
Keefe FJ, Shelby RA, Somers TJ, et al. Effects of coping skills training and sertraline in patients 
with non-cardiac chest pain: a randomized controlled study. Pain. 2011;152(4):730-741. 
47. 
Kroenke K, Bair MJ, Damush TM, et al. Optimized antidepressant therapy and pain self-
management in primary care patients with depression and musculoskeletal pain: a randomized 
controlled trial. JAMA. 2009;301(20):2099-2110. 
48. 
Ang DC, Jensen MP, Steiner JL, Hilligoss J, Gracely RH, Saha C. Combining Cognitive-Behavioral 
Therapy and Milnacipran for Fibromyalgia: A Feasibility Randomized-controlled Trial. Clin J Pain. 
2013. 
49. 
Dixon KE, Keefe FJ, Scipio CD, Perri LM, Abernethy AP. Psychological interventions for arthritis 
pain management in adults: a meta-analysis. Health Psychol. 2007;26(3):241-250. 
50. 
Buhrman M, Gordh T, Andersson G. Internet interventions for chronic pain including headache: 
A systematic review. Internet Interv. 2016;4:17-34. 
51. 
Macea DD, Gajos K, Daglia Calil YA, Fregni F. The efficacy of Web-based cognitive behavioral 
interventions for chronic pain: a systematic review and meta-analysis. J Pain. 2010;11(10):917-
929. 
52. 
Turner JA, Holtzman S, Mancl L. Mediators, moderators, and predictors of therapeutic change in 
cognitive-behavioral therapy for chronic pain. Pain. 2007;127(3):276-286. 
53. 
Keeley R, Engel M, Reed A, Brody D, Burke BL. Toward an Emerging Role for Motivational 
Interviewing in Primary Care. Curr Psychiatry Rep. 2018;20(6):41. 
54. 
Barnes RD, Ivezaj V. A systematic review of motivational interviewing for weight loss among 
adults in primary care. Obes Rev. 2015;16(4):304-318. 
55. 
Stonerock GL, Blumenthal JA. Role of Counseling to Promote Adherence in Healthy Lifestyle 
Medicine: Strategies to Improve Exercise Adherence and Enhance Physical Activity. Prog 
Cardiovasc Dis. 2017;59(5):455-462. 
56. 
Jiang S, Wu L, Gao X. Beyond face-to-face individual counseling: A systematic review on 
alternative modes of motivational interviewing in substance abuse treatment and prevention. 
Addict Behav. 2017;73:216-235. 
57. 
Palacio A, Garay D, Langer B, Taylor J, Wood BA, Tamariz L. Motivational Interviewing Improves 
Medication Adherence: a Systematic Review and Meta-analysis. J Gen Intern Med. 
2016;31(8):929-940. 
58. 
Ang DC, Kaleth AS, Bigatti S, et al. Research to encourage exercise for fibromyalgia (REEF): use of 
motivational interviewing, outcomes from a randomized-controlled trial. Clin J Pain. 
2013;29(4):296-304. 
59. 
Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: 
IMMPACT recommendations. Pain. 2005;113(1-2):9-19. 


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60. 
Geisser ME, Palmer RH, Gendreau RM, Wang Y, Clauw DJ. A pooled analysis of two randomized, 
double-blind, placebo-controlled trials of milnacipran monotherapy in the treatment of 
fibromyalgia. Pain Pract. 2011;11(2):120-131. 
61. 
Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety 
disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-1097. 
62. 
Kroenke K, Spitzer RL, Williams JB, Monahan PO, Lowe B. Anxiety disorders in primary care: 
prevalence, impairment, comorbidity, and detection. Ann Intern Med. 2007;146(5):317-325. 
63. 
Lowe B, Unutzer J, Callahan CM, Perkins AJ, Kroenke K. Monitoring depression treatment 
outcomes with the patient health questionnaire-9. Med Care. 2004;42(12):1194-1201. 
64. 
Lowe B, Kroenke K, Herzog W, Grafe K. Measuring depression outcome with a brief self-report 
instrument: sensitivity to change of the Patient Health Questionnaire (PHQ-9). J Affect Disord. 
2004;81(1):61-66. 
65. 
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J 
Gen Intern Med. 2001;16(9):606-613. 
66. 
Lowe B, Spitzer RL, Grafe K, et al. Comparative validity of three screening questionnaires for 
DSM-IV depressive disorders and physicians' diagnoses. J Affect Disord. 2004;78(2):131-140. 
67. 
Kroenke K, Strine TW, Spitzer RL, Williams JB, Berry JT, Mokdad AH. The PHQ-8 as a measure of 
current depression in the general population. J Affect Disord. 2009;114(1-3):163-173. 
68. 
Kroenke K, West SL, Swindle R, et al. Similar effectiveness of paroxetine, fluoxetine, and 
sertraline in primary care: a randomized trial. JAMA. 2001;286(23):2947-2955. 
69. 
Kroenke K, Bair M, Damush T, et al. Stepped Care for Affective Disorders and Musculoskeletal 
Pain (SCAMP) study: design and practical implications of an intervention for comorbid pain and 
depression. Gen Hosp Psychiatry. 2007;29(6):506-517. 
70. 
MJ S, SR B, J P. The Pain Catastrophizing Scale: Development and validation. Psychological 
assessment. 1995;7:524-532. 
71. 
Chibnall JT, Tait RC. Confirmatory factor analysis of the Pain Catastrophizing Scale in African 
American and Caucasian Workers' Compensation claimants with low back injuries. Pain. 
2005;113(3):369-375. 
72. 
Osman A, Barrios FX, Gutierrez PM, Kopper BA, Merrifield T, Grittmann L. The Pain 
Catastrophizing Scale: further psychometric evaluation with adult samples. J Behav Med. 
2000;23(4):351-365. 
73. 
Keogh E, McCracken LM, Eccleston C. Do men and women differ in their response to 
interdisciplinary chronic pain management? Pain. 2005;114(1-2):37-46. 
74. 
Moseley GL, Nicholas MK, Hodges PW. A randomized controlled trial of intensive 
neurophysiology education in chronic low back pain. Clin J Pain. 2004;20(5):324-330. 
75. 
Pit S, Byles J. Older Australians' medication use: self-report by phone showed good agreement 
and accuracy compared with home visit. J Clin Epidemiol. 2010;63(4):428-434. 
76. 
Lacasse A, Ware MA, Bourgault P, et al. Accuracy of Self-reported Prescribed Analgesic 
Medication Use: Linkage Between the Quebec Pain Registry and the Quebec Administrative 
Prescription Claims Databases. Clin J Pain. 2016;32(2):95-102. 
77. 
Nielsen S, Degenhardt L, Hoban B, Gisev N. A synthesis of oral morphine equivalents (OME) for 
opioid utilisation studies. Pharmacoepidemiol Drug Saf. 2016;25(6):733-737. 
78. 
K K, Jingwei W, Zhangsheng Y, et al. The Patient Health Questionnaire Anxiety and Depression 
Scale (PHQ-ADS): Initial Validation Using Data from Three Clinical Trials. In:2014. 
79. 
Rini C, Porter LS, Somers TJ, McKee DC, Keefe FJ. Retaining critical therapeutic elements of 
behavioral interventions translated for delivery via the Internet: recommendations and an 
example using pain coping skills training. J Med Internet Res. 2014;16(12):e245. 


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80. 
Moyers TB, Rowell LN, Manuel JK, Ernst D, Houck JM. The Motivational Interviewing Treatment 
Integrity Code (MITI 4): Rationale, Preliminary Reliability and Validity. J Subst Abuse Treat. 
2016;65:36-42. 
81. 
DC A, J W, SD O, Z Y, M B. Increased number of painful body sites is associated wtih worse pain 
and disability-assoicated outcomes among returning OEF/OIF service members. Arthritis & 
Rheumatism. 2012;64(10):S418. 
82. 
Forseth KO, Forre O, Gran JT. A 5.5 year prospective study of self-reported musculoskeletal pain 
and of fibromyalgia in a female population: significance and natural history. Clin Rheumatol. 
1999;18(2):114-121. 
83. 
Andersson HI. The course of non-malignant chronic pain: a 12-year follow-up of a cohort from 
the general population. Eur J Pain. 2004;8(1):47-53. 
85. 
Cook KF, Jensen SE, Schalet BD, Beaumont JL, Amtmann D, Czajkowski S, Dewalt DA, Fries JF, 
Pilkonis PA, Reeve BB, Stone AA, Weinfurt KP, Cella D. PROMIS measures of pain, fatigue, 
negative affect, physical function, and social function demonstrated clinical validity across a 
range of chronic conditions. J Clin Epidemiol. 2016 May;73:89-102. 

ICF_000.pdf: 
PRECICE
NCT04395001
IRB Approved Date:  05MAR2024


Page 1 of 10
PRECICE ICF V08 12.12.2023
Pain Response Evaluation of a Combined Intervention to Cope 
Effectively (PRECICE)
Informed Consent Form to Participate in Research 
Dennis Ang, M.D., Principal Investigator
SUMMARY
You are invited to participate in a research study. The purpose of this research is to 
determine if the combination of non-opioid medication (duloxetine) and web-based pain- 
coping skills training (PCST) is beneficial for individuals with chronic musculoskeletal pain 
(CMP). You are invited to be in this study because you have chronic musculoskeletal pain in 
different body parts. Your participation in this research will involve 4 in person visits and 
several phone calls. 
Participation in this study will involve completing symptom questionnaires, web modules, 
and daily intake of an FDA-approved non-addicting medication (duloxetine) for chronic 
musculoskeletal pain. All research studies involve some risks. A risk to this study that you 
should be aware of is that you may (or may not) experience self-limiting duloxetine side 
effects, such as nausea and sweating; and feeling anxious about talking to us over the 
phone. There is the possibility that you may benefit from participation in this study.
Your participation in this study is voluntary. You do not have to participate in this study if 
you do not want to. There may be other choices available to you. Some other choices may 
include follow-up with your primary care doctor for pain management. You will not lose any 
services, benefits, or rights you would normally have if you choose not to participate.
The remainder of this form contains a more complete description of this study. Please read 
this form carefully. You can ask any questions if you need help deciding whether to join the 
study. The person in charge of this study is Dennis Ang, M.D. If you have questions, 
suggestions, or concerns regarding this study or you want to withdraw from the study, his 
contact information is: 
.
If you have any questions, suggestions, or concerns about your rights as a volunteer in this 
research, contact the Institutional Review Board at 
 or the Research Subject 
Advocate at Wake Forest at 
.
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have chronic musculoskeletal pain in different body parts. Please take 
your time in making your decision as to whether or not you wish to participate. Ask your 
study doctor or the study staff to explain any words or information contained in this informed 
consent document that you do not understand. You may also discuss the study with your 
friends and family.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00065428
Meeting Date Approved 3/5/2024          
Version Valid Until: 3/4/2025


Page 2 of 10
PRECICE ICF V08 12.12.2023
WHY IS THIS STUDY BEING DONE?
The primary purpose of the study is to determine if the combination of non-opioid medication 
(duloxetine) and web-based pain-coping skills training (PCST) is beneficial for individuals 
with chronic musculoskeletal pain (CMP). The secondary purpose is to determine if phone 
support delivered by a health care professional is more effective than no phone call in 
reducing pain and improving physical function therapy.
While you take part in this study, you may not take part in any other medical research 
studies, however observational studies can be allowed. If you want to take part in another 
study, please inform the study staff.
HOW MANY PEOPLE WILL TAKE PART IN the STUDY?
        280 people at Wake Forest Baptist Health will take part in this study, 
        although up to 375 persons may be consented. 
WHAT IS INVOLVED IN THE STUDY?
Your primary care doctor will continue to make treatment decisions. This study will not 
influence how your primary care doctor chooses to treat your condition.
If you agree to participate, before any study information is collected, you will be asked to 
review and sign this informed consent document.
After you have been informed about the study and signed this form, the study team will 
collect information concerning your health, medical diagnoses and medications you are 
taking at each visit.
Baseline Visit:
You will come to the research clinic to provide information on your medical health and all the 
medications you are taking. You will be asked to complete baseline questionnaires about 
your activities of daily living and your pain levels; we will collect your height, weight, blood 
pressure, and if you are a woman of child bearing potential, a urine pregnancy test. 
You will receive a medication packet of duloxetine (30 mg per capsule) with the instruction 
to take one capsule once daily for one week. After one week, you will return to the research 
clinic.
Week 1 Visit:
You will be randomly assigned to one of  3 treatment arms:
(1) Duloxetine and web based pain-coping skills training (PCST) with health care 
professional support,
(2) Duloxetine and web based pain-coping skills training (PCST) without health care 
professional support,
(3) Duloxetine only
The study doctor will not know which of the treatments you are receiving; however, this 
information can be made available if medically necessary.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00065428
Meeting Date Approved 3/5/2024          
Version Valid Until: 3/4/2025


Page 3 of 10
PRECICE ICF V08 12.12.2023
(1) Duloxetine and web based PCST with health care professional support
If you are randomized to this treatment arm, you will receive a medication packet with 90 
capsules of duloxetine 60 mg with the instruction to take one capsule once daily for 12 
weeks. If you are unable to tolerate the 60mg dose, you will be able to continue in the 
study at the 30mg dose. If you have chronic kidney disease, you may continue in the study 
on duloxetine 30 mg daily. You will also be enrolled in an automated web-based PCST 
program that includes eight 35- to 45-minute training sessions over a 12-week period, as 
well as daily practice sessions, to help you better manage your pain. In addition, you will 
receive six phone calls from our research health care professional to motivate you to apply 
the newly learned pain coping skills in your daily life.
(2) Duloxetine and web-based pain-coping skills training without health care professional 
support
If you are randomized to this treatment arm, you will receive a medication packet with 90 
capsules of duloxetine 60 mg with the instruction to take one capsule once daily for 12 
weeks. If you are unable to tolerate the 60mg dose, you will be able to continue in the 
study at the 30mg dose. If you have chronic kidney disease, you may continue in the study 
on duloxetine 30 mg daily. You will also be enrolled in an automated web-based PCST 
program that includes eight 35- to 45-minute training sessions over a 12-week period, as 
well as daily practice sessions, to help you better manage your pain. You will not receive 
phone calls from a health care professional.
(3) Duloxetine only
If you are randomized to this treatment arm, you will receive a medication packet with 90 
capsules of duloxetine 60 mg with the instruction to take one capsule once daily for 12 
weeks. If you are unable to tolerate the 60mg dose, you will be able to continue in the 
study at the 30mg dose. If you have chronic kidney disease, you may continue in the study 
on duloxetine 30 mg daily. You will not be enrolled in the web-based PCST program. You 
will not receive phone calls from our health care professional. In addition, if you are 
assigned to this treatment arm, you will have access to the web based PCST modules, but 
you agree to wait to access the program until study participation is complete. 
Week 2
You will be contacted by a study team member to see how you are feeling, and if 
applicable, to see if you have any questions about accessing the web modules.
     
Week 4
You will be contacted by a study team member to see how you are feeling, and if 
applicable, to see if you have any questions about accessing the web modules.
Week 13
You will return to the research clinic to complete symptom-based questionnaires including: 
brief pain inventory/pain severity and physical function scales, pain catastrophizing scale, 
global rating of change, and anxiety and depression scales. We will collect your weight, 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00065428
Meeting Date Approved 3/5/2024          
Version Valid Until: 3/4/2025


Page 4 of 10
PRECICE ICF V08 12.12.2023
blood pressure, and if you are a female of childbearing potential, a urine pregnancy test.  
You will also be asked about any changes to your health since you last visit and we will 
review your medications.
All participants will continue duloxetine (60 mg per capsule) one capsule once daily for the 
next 12 weeks unless you were on 30 mg following your Week 1 visit, which you will take 
once daily for the next 12 weeks.
If you were previously assigned to the treatment group with access to the web-based PCST 
program, you will maintain access to that website for the next 12 weeks to allow you to 
review and practice those newly learned pain coping skills.
Week 25 (final outcome assessment)
You will come to the research clinic and complete another set of symptom-based 
questionnaires. You will have your weight, and blood pressure checked.
If you want to continue with duloxetine, you will be prescribed a 2-week supply of 
duloxetine. The 2 week supply will give you enough time to ask your primary care 
provider (PCP) to request a refill. In addition, the study team will send a note to your 
PCP with a short summary about the research study including a statement that you 
tolerated your current duloxetine dose.
If you do not want to continue with duloxetine, you will be provided with seven duloxetine (30 
mg per capsule) capsules you will take one capsule once daily for one week, and then 
discontinue the medication. Stopping duloxetine abruptly may result in one or more of the 
following withdrawal symptoms: irritability, nausea, feeling dizzy, vomiting, nightmares, 
headache, and/or paresthesia’s (prickling, tingling sensation on the skin). If you were on 30 
mg of duloxetine, you will stop the medication at this visit.
The study does not require any specific testing. This study does not change the way in 
which your doctor delivers your care.
As part of this research study, if you are randomized to the arm of the study that includes 
calls from a healthcare professional, you will be audiotaped. This is being done for 
training and quality assurance purposes. You may request the recording be stopped at 
any time during the course of the research study. You can also withdraw your consent to 
use and disclose the audiotapes before they are used. You should also understand that 
you will not be able to inspect, review, or approve the audiotapes or other media 
(including articles containing such) before they are used in this study.
Please choose one of the following regarding the use and disclosure of the audiotapes used 
in this research study:
 
I would like the audiotapes of me to be destroyed once their use in this study is 
finished.
 
The audiotapes of me can be kept for use in future studies provided they are kept 
secure and any future study will be reviewed by an IRB. I understand that I will not be able 
to inspect, review or approve their future use.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00065428
Meeting Date Approved 3/5/2024          
Version Valid Until: 3/4/2025


Page 5 of 10
PRECICE ICF V08 12.12.2023
Communication and Reminders Opt-in
As part of your ongoing research care, you will receive a call/ or text message from a 
research staff member at week 2 and week 4. Please choose one of the following:
 
No, I do not want to be contacted by text messaging.
 
Yes, I agree to be contacted by text messaging.
If you agree, standard messaging and data rate may apply. You will receive text messages 
about study related visits and procedures. If you prefer not to receive text messages, you 
will receive these communications by email, mail, or phone. If you share your phone number 
with another person, there is a chance they will receive your messages instead of you.
You can opt-out of text communications through contacting study staff at 
or 
.
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for about 25 weeks. You can stop participating at any time. If you 
decide to stop participating in the study, we encourage you to talk to the study doctor or 
study staff first to learn about any potential health or safety concerns and how to taper your 
medication. There are no serious consequences if you should suddenly withdraw from the 
study.
WHAT ARE THE RISKS OF THE STUDY?
The risks primarily involve direct adverse effects of duloxetine which are well-described and 
minimal (i.e., sedation, nausea, headache, dizziness, and constipation that are typically 
transient in nature) in most individuals. For those who do not tolerate the side effects, the 
medication will be discontinued with an appropriate 7-day tapering regimen to prevent 
discontinuation syndrome. Side effects of this medication resolve shortly after stopping it.
Reproductive Risks and other Issues to Participating in Research
Pregnant women are excluded from participation in this study. Because NO method of birth 
control is 100% reliable, and to avoid unnecessary fetal exposure to duloxetine, a pregnancy 
test is required at baseline and at your third study visit (week 13), if relevant.
If you happen to get pregnant while in the study, the rare side effects of duloxetine for the 
fetus late in the third trimester include breathing difficulties, seizures, temperature instability, 
feeding difficulty, vomiting, low blood sugar, jitteriness, irritability, and tremor.
Other potential risks include emotional distress related to the web-based PCST, which is 
typically a minor issue. Our trained study team, who collects information on medication 
side effects, will be able to ask about emotional distress, with an agreed upon approach to 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00065428
Meeting Date Approved 3/5/2024          
Version Valid Until: 3/4/2025


Page 6 of 10
PRECICE ICF V08 12.12.2023
refer you to the medical safety officer if any concerns are present. You should discuss the 
risk of being in this study with the study staff.
There are no additional laboratory tests performed while enrolled in this study; however, your 
study doctor may capture results of testing performed for your normal clinical care.
Taking part in this research study may involve providing information that you consider 
confidential or private. Efforts, such as coding research records, keeping research records 
secure and allowing only authorized people to have access to research records, will be 
made to keep your information safe.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
You may experience relief of pain and improvement in quality of life. The information learned 
from this study may also benefit other people in the future.
WHAT OTHER CHOICES ARE THERE?
Your alternative is to not participate in this study.
WHAT ARE THE COSTS?
All study costs related directly to the study will be paid for by the study. Costs for your 
regular medical care, which are not related to this study, will be your own responsibility.
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals. Your identity and/or your personal health information will not 
be disclosed unless it is authorized by you, required by law, or necessary to protect the 
safety of yourself or others. There is always some risk that even de-identified information 
might be re-identified.
The information collected by the study doctor or study staff as part of the study may be sent 
to other contractors and consultants working for the Sponsor and to regulatory authorities.
Participant information may be provided to Federal and other regulatory agencies as 
required. The Food and Drug Administration (FDA), for example, may inspect research 
records and learn your identity if this study falls within its jurisdiction.
If you choose to participate in this study, your medical record at Wake Forest University 
Baptist Medical Center will indicate that you are enrolled in a research study. Information 
about the research may be included in your medical record. This part of the medical record 
will only be available to people who have authorized access to your medical record. If you 
are not a patient at this Medical Center, a medical record will be created for you to ensure 
that this important information is available to doctors in case of an emergency.
WILL YOU BE PAID FOR PARTICIPATING?
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00065428
Meeting Date Approved 3/5/2024          
Version Valid Until: 3/4/2025


Page 7 of 10
PRECICE ICF V08 12.12.2023
You will be paid $25 for each completed in-person study visit. If you complete all study 
visits you will be paid a total of $100. If you withdraw for any reason from the study before 
completion, you will receive $25 for each study visit you have completed. 
Costs for your regular medical care, which are not related to this study, will be your own 
responsibility
To receive payment, you must provide your social security number, name and address so 
that we can comply with IRS (Internal Revenue Service) reporting requirements. When 
payments are reported to the IRS we do not let them know what the payment is for, only that 
you have been paid. If you do not wish to provide this information you can still take part in 
this study, but you will not be paid.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by the National Institutes of Health National Institute of 
Nursing Research (NINR). The sponsor is providing money or other support to Wake Forest
University Health Sciences to help conduct this study. The researchers do not, however, 
hold a direct financial interest in the sponsor or the product being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A RESULT OF PARTICIPATING IN 
THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest School of Medicine maintains limited research insurance coverage for the 
usual and customary medical fees for reasonable and necessary treatment of such injuries or 
illnesses. To the extent research insurance coverage is available under this policy, the 
reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total 
of $250,000 for all claims in any one year. The Wake Forest School of Medicine, and the North 
Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these medical 
services or to provide any other compensation for such injury or illness. Additional information 
may be obtained from the Medical Center’s Director of Risk and Insurance Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care. This is because the insurer is required 
by law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. 
For more information on medical treatment for research related injuries or to report a study 
related illness, adverse event, or injury you should call Dr. Dennis Ang at 
 
during normal business hours or 
 on nights and weekends.
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or information we get 
from your medical records or other facilities about your health or behaviors is considered 
Protected Health Information. The information we will collect for this research study 
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Institutional Review Board 
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includes: your health information, diseases you have been diagnosed with, and medications 
you are taking.
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer.
Your personal health information and information that identifies you (“your health 
information”) may be given to others during and after the study. Monitors, auditors, IRB or 
other regulatory agencies will be granted direct access to the participant’s original medical 
record for verification of clinical trial procedures or data, without violating confidentiality of 
the participant and to the extent permitted by other applicable laws. This is for reasons such 
as to carry out the study, to determine the results of the study, to make sure the study is 
being done correctly, to provide required reports, and to get approval for new products.
Some of the people, agencies, and businesses that may receive and use your health 
information are the research sponsor; representatives of the sponsor assisting with 
theresearch; investigators at other sites who are assisting with the research; central 
laboratories, reading centers or analysis centers; the Institutional Review Board; 
representatives of Wake Forest University Health Sciences and North Carolina Baptist 
Hospital; representatives from government agencies such as the Food and Drug 
Administration (FDA), the Department of Health and Human Services (DHHS) and similar 
agencies in other countries.
Some of these people, agencies, and businesses may further disclose your health 
information. If disclosed by them, your health information may no longer be covered by 
federal or state privacy regulations. Your health information may be disclosed if required by 
law. Your health information may be used to create information that does not directly identify 
you. This information may be used by other researchers. You will not be directly identified in 
any publication or presentation that may result from this study unless there are photographs 
or recorded media which are identifiable.
If required by law or court order, we might also have to share your Protected Health 
Information with a judge, law enforcement officer, government agencies, or others. If your 
Protected Health Information is shared with any of these groups, it may no longer be 
protected by federal or state privacy rules.
If you choose to participate in this study, your medical record at Wake Forest University 
Baptist Medical Center will indicate that you are enrolled in a clinical trial. Information about 
the research and any medications or devices you are being given as a participant may also 
be included in your medical record. This part of the medical record will only be available to 
people who have authorized access to your medical record. If you are not a patient at this 
Medical Center, a medical record will be created for you to ensure that this important 
information is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this Web site at any time.
Data collected for this study will be analyzed and stored at Wake Forest Health Sciences 
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Institutional Review Board 
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Meeting Date Approved 3/5/2024          
Version Valid Until: 3/4/2025


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Data Coordinating Center. After the study is completed, the de-identified, archived data will 
be transmitted to and stored at the NIH Data 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. When the study is completed, access to study data will 
be provided through the NIH Data Repository.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for at least 15 years. This authorization does not expire and/or 
any research information entered into your medical record will be kept for as long as your 
medical record is kept by the Medical Center. You will not be able to obtain a copy of your 
Protected Health Information in the research records until all activities in the study are 
completely finished.
You can tell Dennis Ang, M.D. that you want to take away your permission to use and share 
your Protected Health Information at any time by sending a letter to this address:
Dennis Ang
 
However, if you take away permission to use your Protected Health Information you will not 
be able to be in the study any longer. We will stop collecting any more information about 
you, but any information we have already collected can still be used for the purposes of the 
research study.
By signing this form, you give us permission to use your Protected Health Information for 
this study.
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study, we 
encourage you to talk to the investigators or study staff first to learn about any potential health 
or safety consequences. The investigators also have the right to stop your participation in the 
study at any time. This could be because the study is canceled. Your primary therapy will be 
stopped if your study doctor believes it is in your best interest to stop treatment for safety or 
tolerability reasons, such as a side effect.
You will be given any new information we become aware of that would affect your 
willingness to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Dennis Ang at 
.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
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Institutional Review Board 
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Meeting Date Approved 3/5/2024          
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your rights. If you have a question about your rights as a research participant, or you would 
like to discuss problems or concerns, have questions or want to offer input, or you want to 
obtain additional information, you should contact the Chairman of the IRB at 
 
I have been informed that my study doctor will inform my other doctors, if any, about my 
participation in this study, and I agree to this.
Yes/No/ NA, I have no other doctors
 
 
(Please check yes, no, or NA)
You will be given a copy of this signed consent form.
I agree to have my de-identified data transferred to the NIH Data Repository at the end of 
the study.
Yes
No
 
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information 
as described in this consent and authorization form. If I have not already received a copy of 
the Privacy Notice, I may request one or one will be made available to me. I have had a 
chance to ask questions about being in this study and have those questions answered. By 
signing this consent and authorization form, I am not releasing or agreeing to release the 
investigator, the sponsor, the institution, or its agents from liability for negligence.
Subject Name (Printed):  
Subject Signature: 
Date: 
Time: 
am pm
Person Obtaining
Consent : 
Date: 
Time: 
am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00065428
Meeting Date Approved 3/5/2024          
Version Valid Until: 3/4/2025