Integrated Health Services to Reduce Opioid Use While Managing Chronic Pain
Phase: NA
Conditions: Chronic Pain
Sponsor: RTI International

Integrated Health Services to Reduce Opioid Use 
While Managing Chronic Pain: The INSPIRE Trial 
STUDY PROTOCOL 
 
IRB Number: 18-0703 
PI: Lauren McCormack, PhD, MSPH 
National Clinical Trial (NCT) Identifier Number: NCT03454555 
Sponsor: RTI International 
Funded by: Patient-Centered Outcomes Research Institute (PCORI) 
Version Date: 03/30/2022 
Version number: 16 
 
CHANGE LOG* 
Version date 
Version 
Number 
Changes 
07/27/2018 
0.1 
Initial version submitted to UNC Scientific Review Committee 
08/01/2018 
0.2 
Version sent to PCORI.  
• 
Added cover page and IRB number 
• 
Wording revisions for clarity and to reduce redundancy 
09/06/2018 
1.0 
First version submitted to UNC IRB.  
• 
Added contact information for PIs 
• 
Added CBT as an exclusion 
• 
Added active suicidal ideation as exclusion 
• 
Added screening items to protocol 
• 
Added information about qualitative data component 
• 
Revised Efficacy Evaluation section and Statistical Analysis section to 
respond to SRC comments  
• 
Added revised SDM materials 
• 
Added safety protocol as an appendix and added references to protocol 

Integrated Health Services to Reduce Opioid Use While Managing Chronic Pain: The INSPIRE Trial  
(IRB Number: 18-0703) 
Study Protocol, v16, 03/30/2022 
 
Front Matter 
Page 2 of 81 
CHANGE LOG* 
Version date 
Version 
Number 
Changes 
10/30/2018 
2.0 
Version re-submitted to IRB to respond to stipulations: 
• 
Added recruitment manual, recruitment script, FAQ, voicemail/message 
script, screening and consent script, screening informed consent form, 
study informed consent form, HIPAA authorization form, SDM patient 
handouts, MI-CBT patient handouts, MI-CBT therapist manual, T2/T3 
follow-up survey, alternate contact script, and DSMB charter as appendices 
and added references throughout the protocol 
• 
Clarified the study phase  
• 
Clarified the roles and responsibilities of the study team 
• 
Changed consent to screen from verbal to written 
• 
Added DSMB description 
• 
Added rationale for interventions 
• 
Revised description of recruitment targets across sites 
• 
Added English language inclusion criterion 
• 
Clarified which exclusion criteria relate to past medical history 
• 
Revised description of policy regarding blanket permission to contact 
• 
Added rationale for excluding patients for other reasons at investigator’s 
discretion 
• 
Clarified factors that are not exclusion criteria 
• 
Added information about UDTs 
• 
Clarified recruitment staff roles 
• 
Added recruitment plan information 
• 
Added measures to reduce coercion; removed language about emphasizing 
the importance of follow-up to patients 
• 
Added that total compensation is under $200 
• 
Changed extraction of EHR data from opt-out to opt-in consent if patient 
withdraws from study 
• 
Added expectations for qualitative data collection; removed incentive 
amount for qualitative activities 
• 
Added satisfaction with care as an outcome measure and removed 
knowledge check 
• 
Removed interim analysis 
• 
Added information about MI-CBT provider training/qualifications 
• 
Added potential for risk for opioid tapering and loss of confidentiality 
11/29/2018 
3.0 
Version re-submitted to IRB to respond to stipulations: 
• 
Added information about study rationale to study overview and to 
introduction 
• 
Revised cancer-related exclusion criterion 
• 
Added information about the additional costs of participating in the study 
• 
Added Withdrawal Consent Addendum to seek permission to extract EHR 
data if patient withdraws from study 
• 
Clarified opioid management procedures for Arm 1 

Integrated Health Services to Reduce Opioid Use While Managing Chronic Pain: The INSPIRE Trial  
(IRB Number: 18-0703) 
Study Protocol, v16, 03/30/2022 
 
Front Matter 
Page 3 of 81 
CHANGE LOG* 
Version date 
Version 
Number 
Changes 
12/06/2018 
4.0 
Version submitted to PCORI with changes to reflect contract modification 
• 
Changed opioid dose cutoff from 50 mg MED to 40 mg MED. This change 
will enhance enrollment and have no impact on study sample size or 
power. We also made administrative updates to power calculations in the 
protocol 
• 
Added clarifications regarding the cost of the intervention 
• 
Revised the number of contact attempts  
02/21/2019 
5.0 
Version submitted to IRB for study amendment: 
• 
Clarified inclusion criteria that patient must be on opioids for chronic non-
cancer pain (CNCP) 
• 
Added that we will confirm in the EHR that the actual dosage prescribed is 
at least 40 mg daily MED.  
• 
Clarified that patients taking opioids for maintenance treatment of an 
opioid use disorder (OUD) will be excluded from the study 
• 
Updated CONSORT diagram and Figure 5 to match the above clarifications 
• 
Clarified that lack of insurance is not an exclusion criterion  
• 
Added patient-centered communication measure to surveys 
• 
Added text messaging as a recruitment method 
• 
Changed length of MI session to 30 to 60 minutes  
• 
Removed language about sites obtaining a Certificate of Confidentiality; RTI 
will request the Certificate.  
• 
Removed language about participants in CBT not being asked to share full 
names 
• 
Removed reference to using pain contract as a proxy for cognitive status 
• 
Participating clinicians will affirm relevant training but will not be required 
to produce documentation 
• 
Clarified the process evaluation plan 
• 
Fixed reference to CBT-MI providers to include licensed professional 
counselors and other licensed clinicians. 
• 
Minor administrative revisions to data management section 
• 
Added change log, revised cover page 
3/26/2019 
6.0 
• 
Removed text messaging as a recruitment method after receiving IRB 
guidance that text messaging is not allowable for recruitment purposes. 
07/03/2019 
7.0 
• 
Added brochure as a recruitment method.  
• 
Added patient incentive receipt.  
11/07/2019 
8.0 
• 
Updated the T2/T3 follow-up survey protocol 
• 
Changed the upper age limit for exclusion criteria from 75 to 85 years 
• 
Removed current CBT exclusion criterion 
• 
Clarified cancer exclusion criterion 
• 
Updated the name of Mid-South CDRN to STAR CRN 
• 
Updated the plans for data management for T2 and T3 follow-up surveys 
• 
Removed the exclusion criterion about visit scheduled within next 90 days. 
This criterion is not clinically meaningful.  
• 
Revised the post-CBT group session form 

Integrated Health Services to Reduce Opioid Use While Managing Chronic Pain: The INSPIRE Trial  
(IRB Number: 18-0703) 
Study Protocol, v16, 03/30/2022 
 
Front Matter 
Page 4 of 81 
CHANGE LOG* 
Version date 
Version 
Number 
Changes 
12/13/2019 
9.0 
• 
Changed opioid dose cutoff from 40 mg MED to 20 mg MED. This change 
will enhance enrollment and have no impact on study sample size or 
power. We also made administrative updates to power calculations in the 
protocol. 
• 
Removed current CBT exclusion criterion as per PCORI request 
4/16/2020 
10.0 
• 
Described remote intervention delivery measures  
• 
Clarified enrollment procedures for Arm 1  
07/08/2020 
11 
• 
Described remote enrollment procedures 
06/30/2021 
12 
• 
Decreased the target sample size from 1,060 to 608. Updated power 
calculations.  
• 
Revised the study timeline and duration.  
• 
Described qualitative research activities for focus groups and individual 
interviews with enrolled participants, 
• 
Updated recruitment and retention procedures (removed contacting 
alternate contacts; added option to contact participants during telehealth 
appointments; added option to send text message reminders to enrolled 
participant about follow-up surveys; added option to mail follow-up surveys 
to participants). 
• 
Updated study safety reporting procedures.  
• 
Updated background information about opioid use trends. 
• 
Made minor clarifications regarding remote enrollment and remote 
intervention delivery.  
08/09/2021 
13 
Revised to respond to IRB stipulations: 
• 
In section 3.6, removed collection of participant alternate information. 
• 
In section 3.9.2, replaced “Stakeholder Advisory Committee” with “SAC” 
which is a reference to the Study Advisory Committee as defined in the 
Abbreviations section.  
• 
In section 3.9.2, in reference to planned periodic newsletter, deleted “if 
required” which followed “newsletter content will be submitted to IRB for 
approval.” 
Corrected minor errors: 
• 
Replaced reference to “section X” with “section 3.9.3” in Table 2, reference 
to “Table 7” with “Table 9” in section 6.3.1; reference to “Table 8” with 
“Table 10” in section 7.2, and reference to “Table 9” with “Table 11” in 
section 8.3.1.  
• 
Updated headers and footers in Sections 4-12.  
10/07/2021 
14 
Corrected version numbers and dates in the list of attachments.  
12/23/2021 
15 
Revised to include publicly available data as a data source.  
 
3/30/2022 
16 
Revised to describe procedures related to requesting death certificates: maintaining 
the confidentiality of the data, procedures for ensuring the privacy of subjects, and 
how these data will be used.  
*Version numbers will be updated upon subsequent final versions submitted to IRB with additions, modifications, 
and deletions described.

Integrated Health Services to Reduce Opioid Use While Managing Chronic Pain: The INSPIRE Trial  
(IRB Number: 18-0703) 
Study Protocol, v16, 03/30/2022 
 
 
Front Matter 
Page 5 of 81 
Principal Investigators 
Study Principal Investigator (PI) 
RTI International 
Lauren McCormack, PhD, MSPH 
3040 E. Cornwallis Road, PO Box 12194 
Research Triangle Park, NC 27709-2194 USA 
Phone: 919-541-6277 
email: Lmac@rti.org 
 
Duke University Institution PI 
Li-Tzy Wu, RN, ScD, MA 
Duke South Hospital, Rm 3521, Box 3903 
Durham, NC 27710 USA 
Phone: 919-889-9369 
Email: litzy.wu@duke.edu 
 
University of North Carolina at Chapel Hill Institution PI 
Paul Chelminski, MD, MPH, FACP 
5034 Old Clinic Building, CB# 7110 
Chapel Hill, NC 27599 USA 
Phone: 984-974-4462 
Email: paul_chelminski@med.unc.edu  
 
Vanderbilt University Institution PI 
Kristin Archer, PhD, DPT 
1211 Medical Center Drive 
Nashville, TN 37232 USA 
Phone: 615-322-2732 
Email: Kristin.archer@vumc.edu  
 
 

Integrated Health Services to Reduce Opioid Use While Managing Chronic Pain: The INSPIRE Trial  
(IRB Number: 18-0703) 
Study Protocol, v16, 03/30/2022 
 
 
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Table of Contents 
Abbreviations ................................................................................................................................................ x 
Protocol Synopsis ........................................................................................................................................xiii 
1 
Background and Rationale ................................................................................................................ 16 
1.1 
Introduction ............................................................................................................................. 16 
1.2 
Name and Description of Investigational Product or Intervention ......................................... 17 
1.3 
Nonclinical and Clinical Study Findings ................................................................................... 19 
2 
Study Objectives and Design ............................................................................................................. 22 
2.1 
Primary Objective .................................................................................................................... 22 
2.2 
Secondary Objectives .............................................................................................................. 22 
2.3 
Study Design ............................................................................................................................ 22 
2.4 
Random Allocation to Treatment Groups and Blinding .......................................................... 22 
2.5 
Study Duration......................................................................................................................... 24 
2.6 
Study Enrollment and Number of Subjects ............................................................................. 24 
2.7 
Study Population ..................................................................................................................... 24 
2.8 
Inclusion and Exclusion Criteria ............................................................................................... 25 
3 
Study Procedures .............................................................................................................................. 28 
3.1 
Identification of Potential Participants ................................................................................... 29 
3.2 
Eligibility Screening .................................................................................................................. 31 
3.3 
Recruitment ............................................................................................................................. 31 
3.4 
Screening ................................................................................................................................. 35 
3.5 
Informed Consent .................................................................................................................... 36 
3.6 
Enrollment and Baseline Data Collection ................................................................................ 37 
3.7 
Screen Failures ........................................................................................................................ 38 
3.8 
Randomization and Intervention Delivery .............................................................................. 38 
3.9 
Follow-up Assessment Procedures.......................................................................................... 38 
3.10 Incentives for Study Participation ........................................................................................... 41 
3.11 Study Completion .................................................................................................................... 42 
3.12 Withdrawal from the Study ..................................................................................................... 42 
3.13 Loss to Follow-up ..................................................................................................................... 42 
4 
Study Evaluations and Measurements .............................................................................................. 43 
4.1 
Efficacy Evaluation ................................................................................................................... 43 

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4.1.1 Primary Outcome .................................................................................................................... 43 
4.1.2 Secondary Outcomes .............................................................................................................. 43 
4.1.3 Other Self-Reported Outcomes ............................................................................................... 44 
4.1.4 Other EHR-Derived Outcomes ................................................................................................. 45 
4.2 
Safety Evaluations ................................................................................................................... 46 
4.3 
Process Evaluation ................................................................................................................... 46 
5 
STATISTICAL CONSIDERATIONS ......................................................................................................... 48 
5.1 
Summary of Statistical Analysis ............................................................................................... 48 
5.2 
Study Endpoints ....................................................................................................................... 49 
5.3 
Statistical Analysis Methods .................................................................................................... 50 
5.4 
Sample Size and Power ........................................................................................................... 53 
5.5 
Interim Analysis ....................................................................................................................... 55 
6 
Study Intervention ............................................................................................................................ 56 
6.1 
Guideline Concordant Care Intervention ................................................................................ 56 
6.2 
SDM Intervention .................................................................................................................... 57 
6.3 
MI+CBT-CP Intervention .......................................................................................................... 59 
7 
Study Intervention Training and Documentation ............................................................................. 62 
7.1 
CDC Guidelines Training Material Content for Providers ........................................................ 62 
7.2 
SDM Provider Training............................................................................................................. 62 
7.3 
MI+CBT-CP Provider Training .................................................................................................. 62 
7.4 
Research Coordinator Training ................................................................................................ 62 
8 
Safety Management .......................................................................................................................... 63 
8.1 
Potential for Risk ..................................................................................................................... 63 
8.2 
Risk Monitoring ....................................................................................................................... 65 
8.3 
Adverse Event/Serious Adverse Event monitoring and reporting procedures ....................... 65 
9 
Data Management ............................................................................................................................ 69 
9.1 
Pre-Enrollment Data Management ......................................................................................... 69 
9.2 
Enrolled Participant Data Management .................................................................................. 69 
9.3 
Follow-Up Survey Data Management ..................................................................................... 70 
9.4 
Qualitative Data Management ................................................................................................ 70 
9.5 
Quality Assurance .................................................................................................................... 70 
10 
Confidentiality of the Data ................................................................................................................ 71 

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10.1 Procedures for Maintaining Confidentiality ............................................................................ 71 
10.2 Procedures for Data Transmission .......................................................................................... 72 
10.3 Collection of Sensitive Information ......................................................................................... 73 
10.4 Post-study disposition of identifiable data ............................................................................. 73 
11 
Plans for Publication ......................................................................................................................... 74 
12 
References ......................................................................................................................................... 75 
 
List of Tables  
Table 1. Pre-enrollment Study Phases, Procedures, and Materials ............................................................ 28 
Table 2. Study Phases, Procedures, and Materials for Enrolled Participants ............................................. 29 
Table 3. Primary and Secondary Outcomes ................................................................................................ 44 
Table 4. Additional Self-Reported Outcome Measures .............................................................................. 45 
Table 5. Process Evaluation......................................................................................................................... 46 
Table 6. Schedule of Assessments .............................................................................................................. 47 
Table 7. Sample Size Required to Obtain 80% Power for Primary and Key Secondary Outcomes ............ 55 
Table 8. Power for Primary and Key Secondary Outcomes with N=608 Randomized Participants ........... 55 
Table 9. Motivational Interviewing Processes ............................................................................................ 60 
Table 10. SHARE Approach to Shared Decision Making ............................................................................. 62 
Table 11. Reportable Events and Assessment Methods ............................................................................. 66 
 
List of Figures 
Figure 1. Study Design ................................................................................................................................. 22 
Figure 2. CONSORT 2010 Flow Diagram Shell ............................................................................................. 23 
Figure 3. Study Timeline.............................................................................................................................. 24 
Figure 4. Study Phases Flow Diagram ......................................................................................................... 28 
Figure 5. Recruitment Diagram ................................................................................................................... 33 
 
 
 

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Study Protocol, v16, 03/30/2022 
 
 
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Appendix (List of Attachments) 
A. Consent Forms 
Document Type 
File Name 
Adult Consent form 
• 
INSPIRE Study Informed Consent Form_2019-02-21.docx 
• 
INSPIRE Informed Consent for Duke 2019-11-05.docx 
• 
INSPIRE Study Consent Form for VUMC - clean.docx 
Consent addendum for 
current subjects 
• 
INSPIRE Withdrawal Consent Addendum.docx 
• 
INSPIRE Withdrawal Consent Addendum Duke 2019-11-05.docx 
• 
INSPIRE Withdrawal Consent Addendum-VUMC - Tracked.docx 
HIPAA Authorization 
• 
INSPIRE Study HIPAA Authorization_2021-12-23.docx 
• 
INSPIRE Study VUMC Consent Form_2018-12-21 Subject Injury and HIPAA Included 
- Clean_final.docx 
Other Consent Materials 
• 
INSPIRE Informed Consent for Screening_2019-02-12.docx 
• 
INSPIRE Informed Consent for Screening_Duke_2019-11-05.docx 
• 
INSPIRE VUMC Informed Consent for Screening_2019-06-12.docx 
• 
INSPIRE Informed Consent for CBT Participant Focus Group 2021-06-28.docx 
• 
INSPIRE Informed Consent for SDM Participant Interview 2021-08-09.docx 
 
B. Other Attachments 
Document Type 
File Name 
Master Protocol 
• 
INSPIRE Study Protocol v16 2022-03-30 
Other Study Protocol 
• 
INSPIRE Combined MI+CBT Patient Packet_FINAL_2020-06-25.pdf 
• 
INSPIRE Combined SDM Patient Packet_2020-04-16.pdf 
• 
INSPIRE Safety Protocol v3 2020-07-08.docx  
• 
MI and CBT for Chronic Pain Manual v4 2020-06-24.docx 
DSMB Charter or 
Stopping Rules 
• 
INSPIRE B4 DSMB Charter V4 2020-final version_signed.pdf 
DSMB/DSMC Report 
• 
DSMB Recommendation letter_for signature_2020-11-17--signed by TK 11-29-
20.pdf  
• 
INSPIREStudyDSMBReport(2019.09.17)_OPEN_Final.pdf 
• 
INSPIREStudyDSMBReport_Open_FINAL_2021-07-16.pdf 
• 
DSMB Recommendation letter_for signature_2021-08-03 signed 2021-08-06.pdf 
Email or Listserv 
Recruitment 
• 
INSPIRE Email Recruitment Announcement 2020-07-08.docx 
• 
INSPIRE Remote Enrollment Forms Email 2020-07-10.docx 
Recruitment Listing PDF – 
Research for Me @ UNC 
• 
RFM_ResearchStudy_18-0703_2020-07-16_1527_to submit with 
modification_Reviewed by NC TRacs_1.pdf 
Recruitment Follow-Up 
• 
INSPIRE Appointment and Survey Reminders Handout 2021-06-25.docx 
• 
INSPIRE T1 Emails 2020-07-10.docx 
Script for In-Person 
Recruitment 
• 
INSPIRE Participant Screening and Consent Script 2020-07-14.docx 
Flyer for Recruitment 
• 
13343_INSPIRE Poster_DUKE_Printer.pdf 
• 
13343_INSPIRE Poster_UNC_v2.pdf 
• 
13343_INSPIRE Poster_v3.pdf 
• 
13343_INSPIRE Poster_VUMC_v2.pdf 
• 
INSPIRE Study Recruitment Ad 2018-11-28.docx 
Letter for Recruitment 
• 
INSPIRE Recruitment Letter v2 2020-07-05.docx 

Integrated Health Services to Reduce Opioid Use While Managing Chronic Pain: The INSPIRE Trial  
(IRB Number: 18-0703) 
Study Protocol, v16, 03/30/2022 
 
 
Front Matter 
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Document Type 
File Name 
Other Materials for 
Recruitment 
• 
INSPIRE Baseline Receipt_2019-06-25.doc 
• 
INSPIRE Brochure 2019-05-22.pdf 
• 
INSPIRE Provider Talking Points 2020-07-08.docx 
• 
INSPIRE Recruitment Manual v5 2020-07-09.docx 
• 
INSPIRE Thank You Letter with Incentive 2020-07-10.docx 
• 
Summary_Sheet_UNC.pdf 
Telephone Script for 
Recruitment 
• 
INSPIRE Messages Script_2019-03-26_final.docx 
• 
INSPIRE Recruitment Script_2019-05-22.docx 
Electronic Questionnaire 
Survey 
• 
INSPIRE T1 Baseline Survey_2019_02-21.docx 
Interview Questionnaire 
Survey 
• 
INSPIRE Qualitative Research CBT Focus Group Guide 2021-06-28.docx 
• 
INSPIRE Qualitative Research SDM Interview Guide 2021-08-09.docx 
Other Questionnaire 
Survey 
• 
INSPIRE T2 and T3 Follow-Up Survey_2019-10-21.docx 
Certificate of 
confidentiality 
• 
18-0703 Chelminski CoC Assurance Page ex'd 4-1-19.pdf 
Data Use Agreement 
• 
68331 DUA FE.pdf 
• 
Data Use Agreement for Carolina Data Warehouse (Patient Authorization or IRB 
Waiver) (00056536-6)_Version2.0 _06282019-FullyExecuted.pdf 
Scientific Review 
Committee Approval 
Letter 
• 
18-SRC057_Chelminski_IRB Documents_(2018-07-30).pdf 
Other 
• 
INSPIRE FAQ script 2020-07-08.docx 
• 
Figure 1_Recruitment Process Flowchart.pdf 
• 
INSPIRE Qualitative Research Recruitment Materials 2021-06-28.docx 
• 
INSPIRE Qualitative Research Thank You Letter 2021-06-28.docx 
• 
INSPIRE participant newsletter content 2021-10-07.docx 
Scientific Review 
Documentation 
• 
18-SRC057_Chelminski_SRC review_clean_compilation_(2018-07-26).pdf 
 
Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AHRQ 
Agency for Healthcare Research and Quality 
CBT-CP 
Cognitive Behavioral Therapy for Chronic Pain 
GCC 
guideline-concordant care 
CATI 
Computer-Assisted Telephone Interviewing 
CDC 
Centers for Disease Control and Prevention 
CDM 
common data model 
CFR 
Code of Federal Regulations 
CI 
confidence interval  
CITI 
Collaborative Institutional Training Initiative 
CME 
Continuing Medical Education 
CNCP 
chronic noncancer pain 

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Abbreviation 
Definition 
CONSORT 
Consolidated Standards of Reporting Trials 
COT 
chronic opioid therapy 
CRF 
case report form 
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data and Safety Monitoring Plan 
DUA 
Data Use Agreement 
ED 
emergency department 
EHR 
electronic health record 
ESN 
Enhanced Security Network 
FAQ 
frequently asked question 
FIPS 
Federal Information Processing Standards 
FISMA 
Federal Information Security Management Act 
FTP 
File Transfer Protocol 
FWA 
Federal-Wide Assurance  
GCC  
guideline-concordant care 
GUID 
global unique identifier 
HIPAA 
Health Insurance Portability and Accountability Act 
ICD-9 
International Classification of Diseases, 9th Revision 
ICD-10 
International Classification of Diseases, 10th Revision 
INSPIRE 
Integrated Services for Pain: Interventions to Reduce pain Effectively 
IOM 
Institute of Medicine 
IRB 
Institutional Review Board 
ITT 
intent to treat 
LTF 
loss to follow-up 
MAR 
missing at random 
MCID 
minimal clinically important differences 
MED 
morphine-equivalent dose 
MI 
motivational interviewing 
MID 
minimally important difference 
NCT 
National Clinical Trials 
NIH 
National Institutes of Health 
NPS 
National Pain Strategy 
OHRP 
Office for Human Research Protection 
OUD 
Opioid Use Disorder 
PCORI 
Patient-Centered Outcomes Research Institute 
PCORNet 
National Patient-Centered Clinical Research Network 
PCP  
primary care provider 
PDMP 
Prescription Drug Monitoring Program 
PHI 
Protected Health Information 
PI 
Principal investigator 
PII 
Personally Identifiable Information 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PROMIS-PF 
Patient-Reported Outcomes Measurement Information System—Physical Functioning 
PROMIS-PI 
Patient-Reported Outcomes Measurement Information System—Pain Interference 

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Abbreviation 
Definition 
REDCap 
Research Electronic Data Capture 
RTI 
RTI International 
SAC 
Study Advisory Committee 
SAE 
serious adverse event 
SD 
standard deviation 
SDM 
Shared Decision Making 
SFTP 
Secure File Transfer Protocol 
STAR CRN 
Stakeholders, Technology and Research Clinical Research Network  
SUD 
substance use disorder 
UNC 
University of North Carolina  
UDT 
urine drug testing 
VUMC 
Vanderbilt University Medical Center 
 

Integrated Health Services to Reduce Opioid Use While Managing Chronic Pain: The INSPIRE Trial  
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Protocol Synopsis 
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Protocol Synopsis 
PROTOCOL SYNOPSIS 
Title 
Integrated Health Services to Reduce Opioid Use While Managing Chronic Pain 
(Short title: Integrated Services for Pain: Interventions to Reduce pain Effectively 
(INSPIRE)) 
Clinical Phase 
The research is a pragmatic trial and does not fit within the usual framework of the 
clinical trial rubric of phase I-IV phases 
Study Team 
RTI International (RTI) was awarded funding from the Patient-Centered Outcomes 
Research Institute (PCORI) and is the data coordinating center. To the extent 
permitted under applicable law, RTI has full responsibility and liability for the conduct 
of the study and for the results reported. Three sites will be enrolling participants for 
the INSPIRE study: 
• 
Duke University  
• 
The University of North Carolina at Chapel Hill (UNC) 
• 
Vanderbilt University Medical Center (VUMC) 
Study Rationale 
• 
Up to one-third of Americans suffer from chronic noncancer pain (CNCP). 
• 
Opioids are often used to treat CNCP. Once on chronic opioid therapy (COT), 
individuals often continue with this class of medication for years. 
• 
Evidence for the effectiveness of COT to treat CNCP is limited, exposing 
individuals to known risks. 
• 
Modified or novel pharmacological and nonpharmacological strategies are 
needed to improve pain management and promote informed decision making 
regarding possible opioid dose reduction. 
• 
This project will evaluate two nonpharmacologic approaches to pain management 
and opioid reduction in primary care and specialty pain clinics. 
• 
The approaches are designed to educate medical care providers and patients 
currently being treated for CNCP, help patients address pain and pain coping 
skills, and enhance patient motivation to reduce or discontinue opioid use  
• 
This study will determine the feasibility, effectiveness, and potential scalability of 
these interventions in reducing opioid use in patients who are using at least 20 
morphine equivalent doses [MED]).  
• 
The study will also assess patient acceptability of the interventions including 
involvement in their implementation and willingness to incur out-of-pocket costs 
associated with the visits. 
Objective 
To conduct a multisite pragmatic trial of two active interventions: shared decision 
making (SDM) as compared with cognitive behavioral therapy for chronic pain with 
motivational interviewing (MI+CBT-CP). 
Primary Objective 
• 
To assess if the interventions result in opioid dose reduction and compare their 
effectiveness. 
Secondary Objectives 
• 
To examine the impact of the interventions on physical function. 
• 
To examine the impact of the interventions on pain interference.  

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Protocol Synopsis 
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PROTOCOL SYNOPSIS 
Description of Study 
Intervention 
Intervention 1 (Arm 1) 
• 
The Shared Decision-Making intervention is patient-provider communication 
intervention to explore and compare treatment options for chronic pain, assess a 
patient’s values and preferences, and reach a shared decision about chronic pain 
treatment. 
• 
Patients randomized to Arm 1 will have their study visits and opioid use managed 
by an SDM-trained provider at their practice. 
Intervention 2 (Arm 2) 
• 
The Motivational Interviewing Plus Cognitive Behavioral Therapy (CBT) for 
Chronic Pain intervention is an empirically based behavioral pain management 
intervention that includes MI to enhance motivation for active participation in the 
CBT-CP, and the use of CBT-CP to enhance pain coping skills. 
• 
One individual MI session that will focus on patient engagement and enhancing a 
patient’s own intrinsic motivation for CBT-CP participation. MI will also be woven 
into the group CBT-CP sessions. 
Participants in each study arm will receive guideline-concordant pharmacotherapy 
treatment, based on clinical guidelines for opioid therapy for CNCP. 
Study Design 
This study is a multisite, randomized pragmatic trial to examine the comparative 
effectiveness of 2 interventions: 
1. A guideline-concordant pharmacotherapy approach with SDM (Arm 1) 
2. A guideline-concordant pharmacotherapy approach with CBT-CP and MI (Arm 2) 
Subject Population 
Key Criteria for Inclusion 
and Exclusion 
Inclusion Criteria 
• 
Ages 18 to 85 years 
• 
History of CNCP 
• 
Average daily dose of at least 20 mg morphine-equivalent dose (MED) for CNCP 
according to most recent prescription 
• 
Receiving care at a participating clinic from a participating provider as evidenced 
by at least 1 in-person visit within the past 12 months 
Exclusion Criteria 
• 
Opioid use is for pain directly related to a cancer diagnosis 
• 
Opioid use is for maintenance treatment of an opioid use disorder (OUD) 
• 
Suicide attempt within the past 3 years  
• 
Active suicidal ideation 
• 
Currently receiving CBT  
• 
Non-English speaking 
• 
Other reason at the discretion of the investigator 
Number of Subjects  
608  
Study Duration 
The entire study is expected to last 72 months, from February 2018 to January 2024.  

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Protocol Synopsis 
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PROTOCOL SYNOPSIS 
Study Phases 
Prescreening 
Screening 
Enrollment 
Randomization 
Intervention 
Follow-up  
Prescreening: Potentially eligible participants will be identified through electronic 
health records (EHRs) and invited to participate. 
Screening: The Research Coordinator will explain the study to the potential 
participant. Potential participants will provide written or electronic consent to 
complete screening. The Research Coordinator will screen the participant.  
Enrollment: Eligible participants will be asked to provide written or electronic consent 
to take part in the study and written or electronic HIPAA authorization. Once 
consented, they will take a baseline survey to complete enrollment. 
Randomization/Allocation: Once enrolled, participants will be randomized to either 
Arm 1 or Arm 2 of the intervention using a 1:1 ratio.  
Intervention: In Arm 1, participants and providers will engage in SDM. In Arm 2, 
participants will attend MI+CBT-CP sessions. Participants in both study arms will 
receive guideline-concordant pharmacotherapy treatment, based on Center for 
Disease Control and Prevention (CDC) clinical guidelines for COT for CNCP. 
Follow-up: A comprehensive, multimode data collection method will be used that 
includes collecting patient-reported outcomes through Web-based and telephone 
approaches and leveraging existing harmonized EHR data maintained by the PCORnet 
STAR CRN. Considering the pragmatic nature of the trial, we will track loss to follow-
up (LTF) and intervention fidelity. 
Efficacy Evaluations 
• The primary outcome, opioid dose reduction from baseline, will be assessed using 
prescribing information from the EHRs. This outcome will be assessed at 6, 12, and 
18 months after enrollment. 
• Patient self-reported outcomes, including physical function and pain interference, 
will be measured via patient survey at 3 timepoints: baseline, 6 months, and 12 
months.  
Safety Evaluations 
The study team and the Data and Safety Monitoring Board (DSMB) will monitor for 
potential adverse events (AEs) and serious adverse events (SAEs). This DSMB consists 
of three individuals who are not participating investigators in this trial, who were 
nominated by the participating clinical institutions, and appointed by the study 
sponsor, RTI. The board includes a primary care clinician, a psychiatry researcher, and 
a biostatistician. 
Statistical and Analytic 
Plan 
Clinical and patient-reported outcomes will be evaluated using cross-sectional and 
longitudinal intent-to-treat analyses. These analyses will use mixed effects models to 
compare opioid dose between the two study arms over an 18-month period. We also 
will explore differences in the intervention effect according to participant 
characteristics, such as age, sex, baseline pain level, baseline opioid dose, and the 
presence of physical comorbidities, mental health comorbidities, or a history of 
substance misuse or abuse. 
Data and Safety 
Monitoring Plan 
(Cross-reference: UNC IRBIS 
application section 1.7.1)  
The study PI and the institution PIs will be responsible for data quality management 
and ongoing assessment of safety. They will be aided by the Data and Safety 
Monitoring Board (DSMB), which will review cumulative study data to evaluate 
intervention safety, study conduct, scientific validity, and data integrity to ensure that 
the study is operating in a safe and ethical manner.  

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Background and Rationale 
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1 BACKGROUND AND RATIONALE 
Cross-reference: UNC IRBIS Application section A.1.1. 
1.1 Introduction 
Chronic noncancer pain (CNCP) is common, and the societal and clinical burden is high. A recent 
Institute of Medicine (IOM) report estimated that up to one-third of Americans suffer from CNCP.1,2 
With current treatment approaches, 13% of headache patients and 18% of back pain patients remain 
unable to work full time because of pain.3 CNCP costs the United States up to $635 billion annually, 
more than the cost for cancer or diabetes or heart disease.4 The etiology of a patient’s CNCP is often 
poorly understood, and no physiological test can objectively identify its presence or intensity. Mental 
health disorders and substance use disorders (SUDs) are often comorbid with CNCP.5-10 Complete 
resolution of CNCP symptoms is uncommon. 
Primary care and specialty pain clinics have relied disproportionately on pharmacologic approaches, 
typically opioids, to treat pain. Prescribed opioid use increased threefold in the 1990s and 2000s, 
peaking around 2011, 11-18 and has decreased 60% since that time.18 (However, due to data lags, this 
peak did not become apparent until around 2015). Whereas 50% of all the prescriptions written by pain 
specialists are for opioids, only 6% of the prescriptions written by primary care physicians (PCPs) are for 
opioids. However, PCPs write 56% of all opioid prescriptions.19 For some patients, opioids may be the 
most effective, or only effective, analgesic for pain management. Most prescription opioid use is chronic 
opioid therapy (COT) for CNCP. Patients initiating COT remain on this treatment for years. 20,21 A large 
body of anecdotal evidence suggests that discontinuation has become more common in the past 5 
years, but empirical studies quantifying this are lacking. Individuals on high-dose COT are the least likely 
to discontinue COT. 
Despite the dramatic increase in use, opioids are a challenging treatment modality for CNCP. Their 
efficacy is incomplete, and some individuals may receive little or no pain relief from COT. A recent 
Agency for Healthcare Research and Quality (AHRQ) systematic review concluded that evidence for the 
effectiveness of COT is insufficient.22  
No studies have evaluated the effects of discontinuing opioids on pain level, function, quality of life, or 
withdrawal symptoms. Despite the lack of evidence for the effectiveness of COT for chronic pain, it is 
commonly used in practice. 
Further, COT has substantial potential for harm. Opioid overdose deaths continue to be an 
“epidemic,”16,23-26 with over 46,000 deaths in 2018.26-29  Men have almost twice the mortality rate from 
opioid use than women.22 In one study, most prescription opioid overdose deaths were attributed to 
diversion,23 illustrating that opioid risks are not limited to individuals receiving opioid prescriptions. 
Additionally, individuals on higher doses of COT are at greater risk for overdose death24 and for the 
development of misuse or abuse. The annual societal cost of opioid abuse was estimated at $55.7 billion 
in 2007.25 In younger persons, new marijuana use and new misuse of prescription opioids are roughly 
equivalent.26,27 Other substantial unintended consequences include opioid-induced decreases in quality 
of life. The Centers for Disease Control and Prevention (CDC), the Federation of State Medical Boards, 
and individual state medical boards have issued guidelines to promote the safe and effective prescribing 

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Background and Rationale 
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of opioid analgesics. These guidelines advise that opioids only be used when other pharmacological and 
nonpharmacological treatment modalities are not effective. Clinical guidelines for opioid prescribing 
emphasize patient selection for opioid initiation, monitoring, and reducing opioid misuse and abuse. 
However, the guidelines and scientific literature generally provide only limited discussion of opioid 
reduction or discontinuation if an opioid-based approach is not working for the patient. That is, 
guidelines address only the technical aspects of reducing medication dosages for COT (i.e., how quickly 
to decrease the dosage).28-32 Importantly, the existing literature does not discuss how to motivate 
individuals to discontinue or decrease their opioid dosage or to reduce the risk of opioid misuse;33 nor 
how to manage pain symptoms in a patient-centered fashion during and after opioid reduction or 
discontinuation. This evidence gap leads to a predictable clinical practice gap. In the absence of an 
evidence base to guide providers and patients on how to decrease opioids, reduction in opioid dosage or 
discontinuation of COT is infrequent. 
This study focuses on the Mid-South area of the United States, where the opioid epidemic has had a 
disproportionate impact. The study will include opioid users from North Carolina and Tennessee. 
Individuals living in the Southeastern United States (especially in rural Appalachia), younger persons, 
and individuals with mental health disorders are at particularly high risk of serious opioid adverse 
effects. Appalachian areas have very high rates of opioid use. For example, using data from IMS Health, 
which collects a variety of healthcare information and is the largest vendor of U.S. physician prescribing 
data, McDonald and colleagues reported that Tennessee was 55% over and North Carolina was 18% 
over the national per-capita mean milligrams of opioids.34 Also using IMS Health data,35 the CDC 
reported that both Tennessee and North Carolina are among the 13 states with the highest rates of 
opioid prescribing, ranging from 96 to 143 opioid prescriptions per 100 residents. In 2014, the age-
adjusted rates of drug overdose deaths were 19.5 in Tennessee and 13.8 in North Carolina.35  
1.2 Name and Description of Investigational Product or Intervention 
Clinical practice for CNCP patients using COT is changing. Physicians are being asked to maintain patients 
on the lowest dose of opioids needed to control their pain or to use non-opioid therapies. Often, 
physicians are not referring patients to cognitive behavioral therapy (CBT) as a non-opioid therapy—
partly because this is a challenge to do within a primary care setting and partly because patients are 
unaware that this is a useful modality for pain management. Shared decision-making may also be a 
useful modality for managing opioid therapy in those with CNCP.  
This study will provide evidence on a key decisional dilemma facing prescribing opioids to CNCP patients: 
What is the best way to facilitate opioid reduction or discontinuation of opioids in patients who are not 
receiving benefits from the opioids and/or who are interested in dose reduction? The study takes a 
biopsychosocial approach to addressing pain, as outlined in the National Pain Strategy (NPS).36 
Combining evidence-based behavioral interventions with pharmacological pain management is 
consistent with the NPS developed by the Interagency Pain Research Coordinating Committee,36 and 
recommendations from a recent National Institutes of Health (NIH) panel.37 The NPS endorsed a 
“biopsychosocial model that is grounded in scientific evidence, integrated, multimodal, and 
interdisciplinary while at the patient level is tailored to individual needs.”36 

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The study will examine the comparative effectiveness of two interventions for treating chronic pain 
patients in a multisite, pragmatic trial. In Arm 1, patients and providers will engage in Shared Decision 
Making (SDM) along with guideline concordant opioid pharmacotherapy. In Arm 2, patients will 
participate in Motivational Interviewing Plus Cognitive Behavioral Therapy for Chronic Pain (MI+CBT-CP), 
along with receiving guideline concordant pharmacotherapy. 
1.2.1 Shared Decision Making 
SDM is a process in which providers and patients work together to make decisions about tests and 
treatments by discussing the clinical evidence, balancing the risks and expected outcomes, and 
respecting patient preferences and values.38 SDM is an essential component of patient-centered health 
care39 and is critical for improving the quality of health care.  
Providers and patients often need to make decisions about tests to be done or treatments to initiate, 
but the optimal decision for a patient can only be made if the patient is appropriately informed about 
the expected benefits, risks, and potential harms of all available options. This is particularly relevant 
when patients are at risk of negative outcomes from continued opioid use, such as hyperalgesia and 
addiction, but are unaware that alternative options such as CBT, exercise, or mindfulness (e.g., 
meditation) may be beneficial. Studies have demonstrated the benefit of SDM in improving patient-
centered outcomes for chronic illnesses such as diabetes, depression, and cardiovascular disease.40 
Unlike the traditional patient-provider interaction, the SDM intervention uses decision aids or 
conversational aids to educate the patient and encourage thoughtful consideration of alternative pain 
management strategies, with the goal of promoting more meaningful conversations between patients 
and providers. Decision aids have been found to improve knowledge of treatment options, help patients 
feel better informed, promote more accurate expectations of benefits and harms, and increase 
participation in decision making.41 SDM promotes a reciprocal rather than directive approach to care. 
RTI International, in collaboration with the University of North Carolina at Chapel Hill (UNC), recently 
completed an assessment and analysis of the “state of the science” on SDM and practice improvement 
in clinical encounters for AHRQ.42 For this project, SDM was defined as “a health care provider and a 
patient working together to make a health care decision that is best for the patient. The optimal 
decision takes into account evidence-based information about available health care options, the 
provider's knowledge and experience, and the patient's values and preferences.”43 This work built on 
prior research led by Dr. McCormack that RTI conducted for AHRQ to develop decision support tools for 
patients and conversational aids for providers to promote shared decision making in clinical settings.44 
1.2.2 Motivational Interviewing Plus Cognitive Behavioral Therapy for Chronic Pain 
The MI+CBT-CP behavioral approach has a broad evidence base.45 MI is an evidence-based, focused, 
goal-oriented counseling technique used to enhance an individual’s own intrinsic motivation for 
behavioral change.46 MI has been studied most extensively in substance abuse treatment, but is 
effective for a wide range of clinical issues where patient motivation is important, such as obesity47 and 
type 2 diabetes.48 The North Carolina State Medical Board guidelines refer explicitly to both MI and SDM 
as promising modalities for effective patient engagement:29 

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Motivational interviewing and shared decision making provide practical and well-
described methods to accomplish patient-centered care in the context of situations 
where medical evidence supports specific behavior changes and the most appropriate 
action depends on the patient’s preferences. Many clinical consultations may require 
elements of both approaches, however. Both motivational interviewing and shared 
decision making are patient-centered methods that promote the ethical imperative of 
respecting autonomy, and both have been associated with improved patient 
outcomes.”49, p. 270 
Recently, MI also has been used to help patients engage in CBT-CP. MI involves four processes: 
engaging, focusing, evoking, and planning. However, MI is not a protocol, but rather a way of talking and 
conversing with patients. Importantly, MI can be combined with psychotherapy, such as CBT-CP. We will 
use MI to enhance motivation both for (1) the CBT-CP intervention in general, to work toward goals of 
improved functioning, and (2) for opioid reduction or cessation. We believe this approach offers the 
greatest likelihood of decreasing reliance on opioids. 
CBT is an evidence-based psychotherapy used for an array of behavioral health and physical health 
conditions—including depression, for which it was initially developed, and for anxiety, insomnia, and 
chronic pain, such as lower back pain.50-55 CBT-CP is a well-established intervention for chronic pain and 
is recommended by pain guidelines and reviews.30,50,56-59 Group CBT-CP therapy has been shown to be as 
effective as individual CBT-CP therapy.60-62 
We anticipate our behavioral approach will be useful for a broad range of CNCP patients. CBT-CP aims to 
identify, challenge, and change maladaptive thoughts, emotions and behaviors, and replace them with 
more adaptive thoughts, emotions, and behaviors.50 By doing so, it helps patients improve their 
affective state, engage in more positive behaviors, and manage their pain condition to foster improved 
functioning. CBT-CP posits that thoughts, emotions, and behaviors are linked, and that each acts 
bidirectionally with the others and can influence the interpretation of pain, pain coping skills, and 
overall functioning. For example, a patient may have the negative thought, “nothing can be done to help 
my pain,” a type of thought that is known as “catastrophizing” that can lead to negative emotions such 
as depression and anger. Depression can worsen pain perception and make pain more difficult to treat. 
Further, depression can affect behaviors. For example, a depressed person may be less likely to engage 
in activities that might decrease the pain, such as moderate exercise, or pleasurable activities that might 
improve mood. This, in turn, can reinforce the pain cycle. 
1.3 Nonclinical and Clinical Study Findings 
Cross-reference: UNC IRBIS Application section A.5.1. 
While multimodal approaches for treating pain are recommended, the evidence base for such 
interventions is relatively small, because in general pharmacotherapy and psychotherapy approaches 
have been tested in isolation. Further, little is known about the effects of multimodal approaches on 
opioid dose, and whether individuals receiving multimodal approaches might require lower opioid 
doses. Perhaps for this reason, the NPS stated that “research and demonstration efforts are needed that 
build on current knowledge, develop new knowledge, and support further testing and diffusion of model 
delivery systems.”36 

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Background and Rationale 
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To date, no evidence-based interventions have been successful in a large-scale study at reducing opioid 
dose long-term while adequately managing pain symptoms. Although little has been published on opioid 
reduction, in a small study, Veterans (n=50) selected for opioid reduction were able to decrease their 
opioid dose by a mean of 46% over 12 months, with 67% of these patients experiencing either no 
change in pain or reduced pain.63 In a more recent study,64 patients (N = 35) receiving COT for CNCP and 
interested in tapering their opioid dose were randomly assigned to a 22-week taper support 
intervention (psychiatric consultation, opioid dose tapering, and 18 weekly meetings with a physician 
assistant to explore motivation for tapering and learn pain self-management skills) or usual care. At 22 
weeks, adjusted mean daily MED in the past week (primary outcome) was lower in the taper support 
group; however, this difference was not statistically significant (adjusted mean difference = -42.9 mg; 
95% confidence interval [CI], -92.42 to 6.62; p = .09). Pain severity ratings (0 to 10 numeric rating scale) 
decreased in both groups at 22 weeks, with no significant difference between groups (adjusted mean 
difference = -0.68; 95% CI, -2.01 to .64; p = .30). The taper support group improved significantly more 
than the usual care group in self-reported pain interference, pain self-efficacy, and prescription opioid 
problems (all p-values < .05). This demonstrates that a supported opioid reduction intervention, such as 
we are proposing for this study, is feasible and shows promise in reducing opioid dose while not 
increasing pain severity or interference with activities of daily living. 
This research has the potential for high public health impact because the public health burden of high-
dose COT is significant, and the societal harm associated with the epidemic of opioid misuse and abuse 
and overdose is unlikely to diminish without opioid dose reduction and discontinuation among CNCP 
patients. The significance of the study lies in the interventions, which are patient-centered, designed to 
be easily implemented and adopted in clinical practice, and have the potential for high public health 
impact. The MI+CBT-CP and SDM interventions do not require extensive training and are relatively 
straightforward to implement within existing care models. Both interventions are economically feasible 
because providers will be able to bill private insurers, Medicaid, and Medicare for the treatment. The 
CBT-CP portion, and some of MI, of the MI+CBT-CP intervention is delivered in a group setting, making 
the treatment more affordable. Perhaps more important is the fact that the group design allows more 
CNCP patients to receive the intervention, especially in underserved areas. Additionally, the MI+CBT-CP 
intervention can be delivered by licensed clinicians, such as Masters- or PhD-level psychologists, licensed 
clinical social workers, or licensed professional counselors, and can be delivered in-person, or via 
telehealth. 
This real world, translational study will provide important evidence for health policymakers. While the 
interventions are evidence-based for pain management, the evidence for using these interventions for 
reducing opioid dose is based on smaller and shorter-term studies and thus, adoption of the 
interventions is not widespread. If this study shows the interventions are effective in a large-scale study 
and patients are willing to incur modest costs, this provides important data for influencing future 
coverage decisions and policy-level change.  
Opioid dose reduction is the primary outcome; however, participants will be free to choose whether 
they want to maintain their current opioid dose, decrease their opioid dose, or discontinue opioids 
completely. Moreover, we anticipate that our intervention will simultaneously improve outcomes across 
several domains: somatic pain, functioning, psychological well-being, and quality of life. The study will 

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Background and Rationale 
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help address decisional uncertainty facing patients and help ensure patients have a better 
understanding of the limitations of the science regarding opioids. Finally, this study will also provide 
information on each intervention’s feasibility, effectiveness, and potential scalability in reducing opioid 
use in patients who are using high dose opioids (at least 20 morphine equivalent doses [MED]). Beyond 
evaluating which intervention is best for reducing opioid dosage, the study will assess patient 
acceptability of the interventions including involvement in their implementation and willingness to incur 
out-of-pocket costs associated with the visits. 
 

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Study Objectives and Design 
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2 STUDY OBJECTIVES AND DESIGN 
Cross-reference: UNC IRBIS Application section A.1.2 (objectives), A.4.2 (study design), B.3.4 (setting) 
This study will compare the effectiveness of two interventions on potential opioid dose reduction, 
functioning and pain interference. The study will be conducted in primary care and specialty pain clinics 
at 3 university hospitals, 2 in North Carolina—The University of North Carolina at Chapel Hill (UNC) and 
Duke University, and 1 in Tennessee—Vanderbilt University Medical Center (VUMC). RTI was awarded 
funding from PCORI and is the data coordinating center for this study. 
2.1 Primary Objective 
To test whether CNCP patients who receive guideline-concordant pharmacotherapy with a MI+CBT-CP 
intervention (Arm 2) have greater opioid dose reduction relative to their counterparts who receive 
guideline-concordant pharmacotherapy integrated with SDM (Arm 1). 
2.2 Secondary Objectives 
To test whether CNCP patients who receive guideline-concordant pharmacotherapy with an MI+CBT-CP 
intervention (Arm 2) have improved physical functioning relative to their counterparts who receive 
guideline-concordant pharmacotherapy integrated with SDM (Arm 1). 
To test whether CNCP patients who receive guideline-concordant pharmacotherapy with an MI+CBT-CP 
intervention (Arm 2) have lower pain interference relative to their counterparts who receive guideline-
concordant pharmacotherapy integrated with SDM (Arm 1). 
2.3 Study Design 
Cross-reference: UNC IRBIS Application Section A.4.2. 
We will conduct a multisite, randomized pragmatic trial to examine the comparative effectiveness of 2 
interventions: a guideline-concordant opioid pharmacotherapy approach with SDM (Arm 1) compared 
with a guideline-concordant opioid pharmacotherapy approach with MI and CBT-CP (Arm 2). The study 
design is shown in Figure 1 and a CONSORT flow diagram shell is presented in Figure 2. 
Figure 1. Study Design 
 
 
2.4 Random Allocation to Treatment Groups and Blinding 
Cross-reference: UNC IRBIS Application Section A.4.3.  
This study will use real-time 1:1 ratio randomization to limit participant loss prior to treatment. Eligible 
participants will be randomized using a stratified, permuted-block design because this constrained 
randomization approach ensures balance between treatment groups within each of the 3 institutions 
Randomization
Time 1 
Baseline 
measures
SDM 
Intervention
MI+CBT 
Intervention 
Study Sample
Time 2 
6-month 
outcomes
T2
6-month 
outcomes
Time 3
12-month 
outcomes
T3
12-month 
outcomes
T4
18-month 
outcomes
T4
18-month 
outcomes
Compare 
Outcomes

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(our only stratification factor) at the completion of each block. Consequently, throughout the trial, the 
intervention arms are expected to have approximately equal sample sizes both within an institution and 
across the study. We will not be able to blind participants or providers to intervention arm assignment 
because this is the nature of a real-world pragmatic trial. 
Figure 2. CONSORT 2010 Flow Diagram Shell
Assessed for eligibility after pre-screening review (n=...)
Excluded (n=…): 
• 
Did not meet inclusion criteria (n=…)
• 
Opioid use is for pain directly related to 
an active cancer diagnosis (n=...)
• 
Opioid use is for maintenance treatment 
for an opioid use disorder (n=...) 
• 
Suicide attempt within the past 3 years 
(n=...)
• 
Active suicidal ideation (n=...)
• 
Currently receiving CBT (n=...)
• 
Non-English speaking (n=...)
• 
Other reason at the discretion of the 
investigator (n=...)
• 
Other reasons (n=...)
• 
Declined to participate (n=...)
• 
Could not contact (n=...)
Randomized (target n=608)
Allocated to SDM intervention (target n=304):
• 
Received allocated intervention 
(n=...)
• 
Did not receive allocated intervention 
(give reasons) (n=...) 
Allocated to MI-CBT intervention (target 
n=304):
• 
Received allocated intervention 
(n=...)
• 
Did not receive allocated intervention 
(give reasons) (n=...)
Lost to follow-up (give reasons) (n=...)
Discontinued intervention (give reasons) 
(n=...)
Analyzed (n=...):
• 
Excluded from analysis (give reasons) 
(n=...)
Lost to follow-up (give reasons) (n=...)
Discontinued intervention (give reasons) 
(n=...)
Analyzed (n=...):
• 
Excluded from analysis (give reasons) 
(n=...)
Enrollment
Allocation
Follow-Up
Analysis
 

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2.5 Study Duration 
Cross-reference: UNC IRBIS Application sections A.4.2, A.4.5, B.3.3 
We anticipate that in its entirety the study will last 72 months, from February 2018 to January 2024. 
Enrollment is expected to begin in April 2019 and will continue until enrollment has been completed, 
but no later than March 2022, as shown in Figure 3. 
Figure 3. Study Timeline 
 
2.6 Study Enrollment and Number of Subjects 
Cross-reference: UNC IRBIS Application section A.4.2, A.2.1, A.2.3.  
Total anticipated enrollment is 608, with about 304 participants in each arm. We expect to enroll about 
203 participants per institution. However, there may be site-specific variation in recruitment to allow 
one or more institutions to recruit over 203 participants to achieve the overall study target of 608 
participants. We will not limit each institution to a prescribed maximum number of enrolled patients 
because some sites may be able to enroll more patients more efficiently than other sites but will adhere 
to any IRB guidance on maximum number of enrollees per institution. However, we will not enroll more 
than 608 participants across all 3 institutions.  
2.7 Study Population  
Cross-reference: UNC IRBIS Application section A.4.2, B.3.5.  
Participants will be from the Southeastern United States, a population disproportionately impacted by 
the opioid epidemic. The trial will be conducted in primary care and specialty pain clinics at 3 university 
health systems: UNC, Duke, and VUMC. These clinics have experience in opioid management with CNCP 
patients and have large populations of patients on COT. The 3 universities are part of the PCORNet 
Stakeholders, Technology and Research Clinical Research Network (STAR CRN), formerly known as the 
Mid-South CDRN.  
RTI was awarded funding from the Patient-Centered Outcomes Research Institute (PCORI) and is the 
data coordinating center. To the extent permitted under applicable law, RTI has full responsibility and 
liability for the conduct of the study and for the results reported. Prescreening, recruitment, screening, 
consent, and enrollment for the study will occur at primary care and/or pain specialty clinics at the 3 
participating clinical institutions. 

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2.8 Inclusion and Exclusion Criteria 
Cross-reference: UNC IRBIS Application: A.2.7 (age range), A.3.1 (inclusion and exclusion criteria), A.4.2  
To be eligible to participate in this study, an individual must meet all the following criteria:  
• 
Aged 18 to 85 years 
• 
History of CNCP 
• 
Receiving high-dose COT for chronic non-cancer pain (CNCP) as evidenced by current or most 
recent prescription of an average daily morphine-equivalent dose (MED) of 20 mg or greater for 
CNCP. Specific opioid analgesics are noted in Section 3. 
• 
Receiving care at a participating clinic from a participating provider, as evidenced by at least 1 
in-person visit within the past 12 months 
Participants must be using at least 20 mg daily MED to be eligible for the study. If MED data are not 
available via the institution’s data warehouse, a proxy of 3 or more opioid prescriptions to treat chronic 
pain within the past 12 months may be used to identify these patients in the prescreening phase. 
However, we will confirm in the EHR that the actual dosage prescribed is at least 20 mg daily MED. 
Because patients will be taking various opioid medications, daily opioid dose will be standardized to 
daily MED using standard opioid conversion tables. 
An individual who meets any of the following criteria will be excluded from participation in this study: 
• 
Not meeting the above inclusion criteria 
• 
Opioid use is for pain directly related to an active cancer diagnosis 
• 
Opioid use is for maintenance treatment of an opioid use disorder (OUD) 
• 
Suicide attempt within the past 3 years  
• 
Active suicidal ideation 
• 
Currently receiving CBT 
• 
Non-English speaking 
• 
Other reason at the discretion of the investigator 
 
Self-report screening items that are not ascertained via medical record data are provided in the 
Participant Screening and Consent Script (see attached).  
Two exclusion criteria pertain to past medical history: a) If the patient does not have a history of chronic 
non-cancer pain, they will be excluded; b) if the patient has a history of suicide attempt within the past 3 
years, they will be excluded. There is no exclusion based on accidents or injury.  
Patients may be excluded for a limited set of other reasons based on the investigator’s discretion. It is 
difficult to anticipate the rare, often unique types of situations in which a patient may not be fit for the 
intervention and to develop specific exclusion criteria for each hypothetical instance.  
We include this discretionary category to allow institutions to handle rare cases in which patients would 
clearly be inappropriate for the study such as: a) unstable behavior or b) cognitive impairment. If the 
patient is exhibiting clearly unstable behavior or if the patient is clearly not cognitively intact the 
research coordinator will note this behavior during the screening process in this category. In addition, 

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the research coordinator will confirm this determination with the institution PI and will document the 
reason a patient is excluded via a Case Report Form (CRF). While we recognize the limitations of 
subjective determinations, we do not want to burden respondents by having them complete a 
quantitative screening measure to assess the rare occurrence of unstable behavior or cognitive 
impairment.  
If institution policy requires blanket permission from each individual provider to recruit their patients, 
investigators at the site will contact providers at the clinic to request permission. Clinicians at clinics 
participating in the INSPIRE study at each institution are told about study and that their patients may be 
recruited. None of these processes involve sharing any individual patient information. Patients whose 
providers opt-out of blanket permission to recruit patients will not be eligible and will not be contacted. 
2.8.1 Clarification about Cancer-Related Pain Exclusion Criterion 
 If the patient has active cancer, then the patient is not eligible if any of the following 3 are true:  
a) Opioids are being used to treat pain that is directly related to the cancer.  
b) The opioids are not being used to treat cancer pain, but it is expected that opioids might be 
required soon to treat cancer pain. 
c) The opioids are not being used to treat cancer pain, but the patient’s clinician feels that bringing 
up the issue of tapering would be emotionally upsetting. A tapering discussion might not be 
good for the patient at a time when the patient is already under a lot of stress. 
Otherwise, in a patient with active cancer receiving chronic opioids, if the opioids are not being used to 
treat cancer-related pain, then the patient is potentially eligible.  
If the patient does not have active cancer (i.e., it is in remission or “cured”), then they are potentially 
eligible for the study.  
If necessary, a final decision regarding eligibility will be determined by the site PI in consultation with the 
patient’s clinician.  
2.8.2 Factors that Are Not Exclusion Criteria 
Current or Past Substance Use Disorders 
Based on participating providers’ input, we expect that substance use disorder (SUD), including the use 
of “street narcotics,” will be uncommon in this population. Clinics are already responsible for screening 
patients on COT for SUD via urine drug testing (UDT), as per standard of care. As this is a pragmatic trial, 
clinics will continue to test patients as they would normally. We will collect data about SUD diagnoses 
from the PCORnet CDM to use as a covariate in the analyses. Generally, SUDs will not be an exclusion 
criterion; as noted above, the only exception will be when the opioid (either buprenorphine or 
methadone) is being used for medication assisted treatment (MAT) for an OUD. 
Urine Drug Testing in Past Year 
If a patient has not had a UDT in the past year, they may receive testing during the study period as part 
of the standard of care. That is, they will not be excluded for not having had a UDT in the past year.  

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Opioid Treatment Agreement 
Opioid treatment agreements, sometimes known as “pain contracts” are required for patients on COT in 
some clinics. If a participant does not already have a treatment agreement in place, they may be asked 
to sign one during the intervention period. That is, they will not be excluded for not having a treatment 
agreement in place.  
Insurance Status 
Patients are not required to have insurance to be eligible for the study. However, we recognize that lack 
of insurance may be a barrier to participation for some patients. For this reason, we have provided 
additional information on the costs of participating in the study and that the uninsured may have to pay 
for the costs of additional visits or CBT treatment, potentially on a sliding scale. If patients cite lack of 
insurance as a reason for refusing to participate or withdrawing from the study, we will record this as we 
would any other reason for refusal or withdrawal. 

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3 STUDY PROCEDURES 
A flow diagram of the study phases is presented in Figure 4 with an explanation of each phase below. 
Figure 4. Study Phases Flow Diagram 
 
 
A summary of the study phases and procedures prior to enrollment is provided in Table 1 and Table 2. 
Table 1. Pre-enrollment Study Phases, Procedures, and Materials 
Study Phase 
Procedures 
Patient-facing materials 
Prescreening 
(Identification of 
Potential 
Participants) 
Extract recruitment phenotype data from 
local Research Data Warehouses  
None 
Verify patient eligibility via EHR  
None 
Recruitment 
Recruit participants by mail or e-mail 
Recruitment Letter 
Recruitment Email Announcement 
Recruit participants by telephone or 
in-person  
Screening and Consent script 
Message Script 
Respond to questions using FAQ Guide 
Advertise study  
Study Advertisement 
Study Brochure 
Study Posters 
Screening  
Screen patients  
Screening and Consent script 
Screening Consent  
Respond to questions using FAQ Guide 
Informed consent 
Ask for informed consent  
Study Informed Consent Form 
HIPAA Authorization 
Remote Enrollment Forms Emails 
 

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Table 2. Study Phases, Procedures, and Materials for Enrolled Participants 
Study Phase 
Procedures 
Participant-facing materials 
Enrollment 
Collect participant contact information 
Participant Contact Form 
Remote Enrollment Forms Emails 
Collect baseline data via self-report survey  
T1 Survey 
T1 Emails 
Baseline Incentive Receipt Form 
Thank you letter with incentive 
Randomization 
Allocate participants to intervention Arm 1 or 
Arm 2 
None 
Intervention 
Deliver guideline concordant care to 
participants in Arm 1 and Arm 2 
None 
Deliver SDM intervention to participants in 
Arm 1  
SDM Patient Materials 
Deliver MI+CBT-CP intervention to 
participants in Arm 2  
CBT Session Sign-In Form 
MI+CBT-CP Patient Materials 
Intervention delivery based on MI-CBT 
Therapist Manual 
Post-CBT Session Form 
Thank you letter with incentive  
Follow-up 
Collect baseline and follow-up data via clinical 
data extraction 
None 
Collect 6-month follow-up data via self-report 
survey 
T2 Recruitment Materials 
T2 Survey (web based and CATI) 
Thank you letter with incentive 
Collect 12-month follow-up data via self-
report survey 
T3 Recruitment Materials 
T3 Survey (web based and CATI) 
Thank you letter with incentive 
Qualitative data 
collection (see 
section 3.9.3 
below) 
Recruit participants 
INSPIRE Qualitative Research Recruitment 
Materials  
Collect qualitative data via focus groups and 
interviews 
Informed Consent for CBT Participant Focus 
Group 
Informed Consent for SDM Participant 
Interview 
CBT Focus Group Guide 
SDM Interview Guide 
Thank You Letter 
 
3.1  Identification of Potential Participants 
Cross-reference: UNC IRBIS Application A.9.1 (identifiers), A.9.2, B.1.2, B.1.3, B.2.1 (PHI and confidentiality), C.1.1 
(data sources) 
Potential participants will be identified via each institution’s research data warehouse and electronic 
health records (EHR). Health Insurance Portability and Accountability Act (HIPAA) rules, other relevant 
federal or state laws, and local institutional requirements will be followed, as applicable. Study staff will 
upload this file into a local database for use in pre-enrollment study phases such as screening and 
recruitment (hereafter referred to as the Pre-enrollment database). Personally Identifiable Information 

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(PII) and Protected Health Information (PHI) data in the Pre-enrollment database will stay at each 
institution. 
The study will collect a minimal set of information on patients who are identified, including those who 
are determined to be ineligible, refused, or unable to be reached. This will help to ensure transparent 
reporting, to meet CONSORT publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes demographics, eligibility criteria, and reasons for 
nonparticipation. This information will be stored in the Pre-enrollment database.  
Information to be obtained via query of existing clinical data includes the following: 
• 
Date of EHR query 
- The date on which the query was conducted 
• 
Patient contact information 
- First name 
- Last name 
- Street address 
- City 
- State 
- ZIP code 
- Telephone number (cell, home, and work, if available) 
- E-mail address 
• 
Other participant information 
- EHR unique identifier (medical record number) 
• 
Recruitment phenotype information 
- Date of birth 
- Name of clinic patient is being seen at 
- Name of primary care or pain clinic provider 
- Date of last clinic visit 
- Date of next upcoming clinic visit 
- Daily MED for the most recent prescription 
- Number of opioid prescriptions within the past 12 months. Includes these generic drugs 
and their brand name equivalents: 
o buprenorphine 
o codeine and acetaminophen (not codeine alone) 
o transdermal fentanyl only 
o hydrocodone 
o hydromorphone 
o levorphanol 
o meperidine 

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o methadone 
o morphine 
o oxycodone 
o tapentadol 
o tramadol 
Note that we will not include pentazocine alone (Talwin) or 
pentazocine/naloxone (Talwin Nx). 
• 
Opioid prescription information for each prescription in the past 12 months 
- Order ID 
- Patient EHR unique identifier 
- Provider name (prescription provider) 
- Prescription ordering date 
- Prescription name (generic name) 
- Form of drug (e.g., tablet) 
- Drug strength (dispensing units) (e.g., 100 mg) 
- Drug route of administration (e.g., oral, transdermal – IV will not count) 
- Dosing instructions 
- Drug dose (e.g., 1 capsule, 2 tablets) 
- Dose frequency (e.g., daily, twice daily) 
- Total number of units prescribed (quantity) 
- Number of refills 
• 
Patient demographic information 
- Gender 
- Race 
- Ethnicity 
3.2 Eligibility Screening 
Cross-reference: UNC IRBIS Application sections B.1.4, B.1.5 
First, research coordinators at each institution will review EHR information for the list of potential 
participants and will identify potential participants meeting basic eligibility criteria (e.g. age, active 
patient status, opioid dose, and absence of exclusionary medical or psychiatric comorbidities). Research 
coordinators will verify whether they may be eligible for the study.  
Then, potential participants will be contacted by research coordinators, who will introduce the study 
and invite them to complete a brief screening in-person or remotely. This is described in section 3.4 
below.  
3.3 Recruitment 
Cross-reference: UNC IRBIS Application sections B.1.1, B.1.5, B.1.9 (contact methods), B.1.10 (roles), B.3.2 (number 
of contacts) 

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Research coordinators (RCs) at each institution will recruit potential participants. Physicians are not 
contacting patients to recruit or enroll them. The RC will follow a separate, detailed recruitment plan, 
the Recruitment Manual (see Appendix). This plan is briefly summarized below and shown in Figure 5. 
More specific details are in the Manual.  
Any of the following methods that are IRB-approved may be used to approach patients about the study: 
mail, e-mail, telephone, study advertisements, brochures, or in-person in the clinic. During recruitment, 
if the potential participant indicates interest, the RC will offer to conduct screening in person or 
remotely. If the patient refuses, the RC will make no further contact with them about the study.  
The number of contact attempts will vary by availability of participant. Because this is a challenging 
study for recruiting patients (i.e., eligibility criteria and potential financial burden), we will minimize 
intrusion by contacting the participants up to 6 times to elicit their interest in participating in the study, 
by any of the above methods. RCs will be instructed on how to leave a voicemail on the initial attempt if 
a patient is not home (see Messages Script in the Appendix). 
A patient may refuse to participate in the INSPIRE study. If at any time, a patient indicates they do not 
want to be in the study (gives a hard refusal), the RC will stop contacting them. Refusals will be 
documented on the Recruitment Log Case Report Form maintained at the institution; this does not go to 
RTI. Each institution will be responsible for developing a procedure to ensure that participants are not 
recruited more than once, and refusals are documented so that patients who refuse are not contacted 
again for participation.  
On a monthly basis, each institution will report aggregate consent status outcomes data using the 
Recruitment Summary CRF to the RTI Data Coordinating Center (DCC) via the web-based REDCap data 
management system. No identifiable data will be reported to the DCC.  Aggregate consent status 
outcomes will be reported to PCORI on a monthly basis. 

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Figure 5. Recruitment Diagram 
Extract recruitment phenotype data
Sites identify patients through EHR research data warehouses using recruitment phenotype 
EHR Review
Research Coordinator (RC) checks the patient’s EHR to verify potential eligibility (e.g. opioid dose)
Recruitment (approach to assess eligibility)
• RC may approach the patient up to 6 times via mail, email,, phone, or in-person 
• At minimum, the RC will call all patients to discuss the study in more detail
• If the patient is interested in learning more, the RC will schedule an in-person or remote screening 
and enrollment visit
Clinician On-boarding
• Clinicians receive study overview and training 
• Clinicians give permission for researchers to contact their patients about the INSPIRE study (if 
required by institution) 
Screening
• RC meets with patient in the clinic (Screening and Enrollment Visit) or remotely (via phone) 
• RC asks patient to sign Informed Consent for Screening
• RC conducts screening to verify eligibility
Pre-Screening
Enrollment
Consent
• RC asks eligible patient to read the Study Informed Consent Form 
• RC reviews the key points with the patient and conducts an Understanding Check 
• Eligible patient signs consent form if he/she agrees to participate
Baseline Survey
RC asks the participant to take the T1 Baseline Survey
Randomization
RC randomizes participant to Arm 1 or Arm 2
Intervention
• Patient receives more information about his or her assigned intervention
• RC coordinates visit scheduling
Allocation
 
 

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We will implement the following strategies to increase participant recruitment: 
• 
Each clinic will have a “clinic champion” (a practicing clinician who has completed the necessary 
trainings and serves on the Study Advisory Committee [SAC]) onsite to provide clinic-specific 
advice on the consent and enrollment processes. 
• 
The RC will try to establish a connection with each potential participant and communicate 
proactively and respectfully to ensure that participants are comfortable in their understanding 
of the study intervention and processes, and that participation presents no undue burdens. 
• 
All potential participants will be given IRB-approved materials that contain a toll-free number to 
call to ask additional questions or to opt-out of further study recruitment efforts if they choose. 
• 
Patient representatives from our SAC have reviewed and provided input on patient-facing 
materials. 
• 
The materials are written in plain language and at an appropriate reading level for a lay 
audience. 
• 
RCs will use a Frequently Asked Questions (FAQ) Script (see Appendix) to help answer questions 
that may arise in a consistent way 
• 
This population faces significant transportation barriers to accessing health care. To make the 
study more accessible, we will now offer remote enrollment and remote participation in the 
intervention.  
• 
RCs may recontact potential participants who previously declined in order to tell them about the 
remote option for taking part in the study. They will see if they are interested in participating 
remotely.  
They will only recontact participants who were not previously offered the remote option. They will 
not re-contact patients who requested to not be contacted again, and they will provide 
potential participants with the option to no longer be contacted by the research team going 
forward. 
Strategies such as these will increase enthusiasm for the study among patients, providers, and clinic 
staff, which can help promote successful recruitment. 
3.3.1 Mail and E-mail Recruitment  
RCs may contact potential study participants by mail, e-mail, or both to invite them to participate in the 
study. An IRB-approved Recruitment Letter (see Appendix), which is the same content whether 
delivered by mail or email, will tell the patient about the study, and it will ask them to contact the 
Research Coordinator if they are interested in participating. If the letter is returned as undeliverable, the 
Research Coordinator will attempt to confirm the patient’s address and resend the letter. If there is no 
response, a follow-up letter may be sent.  
3.3.2 Telephone Recruitment 
The RC may use an IRB-approved Recruitment Script (see Appendix) to call potential participants to 
recruit them for the study. The RC will follow a standard script to ensure consistency. The RC will 
confirm they are speaking with the patient, tell them briefly about the study, assess interest, and set up 
an enrollment appointment. They will also offer the patient the option to enroll remotely. The remote 

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enrollment approach means that the RC will talk the patient through the enrollment process over the 
phone and email them links to electronic consent forms to complete screening and consent. 
As detailed in the Recruitment Manual (see Appendix), if the patient does not answer the telephone, 
the RC will leave a brief message to request a callback; this message will not contain any information 
about the study or the patient’s health (see Appendix for the Messages Script).  
3.3.3 Study Advertisements 
The RC may post an IRB-approved Study Recruitment Ad or Study Recruitment Poster (see Appendix) 
within clinics, locally, or online (including social media) to tell potential participants about the study. 
These materials will follow any institutional policies regarding the posting of study ads.  
3.3.4 Study Brochure  
The brochure will be used during recruitment. It will be given to patients by study staff. The intent of the 
brochure is to provide information to patients about the study. Text for the brochure was adapted from 
the consent form and other IRB-approved participant-facing materials. All pictures are stock images (no 
actual patients are pictured).  
3.3.5 In-person Recruitment 
The RC may approach potential participants in-person at the clinic to tell them about the study. The RC 
may use an IRB-approved Recruitment Script (see Appendix) to approach potential participants to 
recruit them for the study. RCs will follow a standard script to ensure consistency. The Recruitment 
Script contains instructions for both in-person and phone recruitment.  
3.3.6 Provider Warm Hand-off 
The patient’s provider may briefly introduce the study to the patient during a clinic visit. This provides a 
chance for the patient to learn about the study and ask questions. Providers will use a standard set of 
Provider Talking Points (see Appendix) to ensure consistency and to minimize undue influence or 
coercion. These talking points indicate that it is up to the patient to decide that they will support the 
patient for their pain management no matter what they decide. If the patient is interested in the study, 
the provider may make a “warm hand-off” to (i.e., introduce the patient to) an RC.  
A “warm hand-off” may occur during a telehealth appointment. The recruitment coordinator may 
approach patients about the study during telehealth appointments, with the permission of the health 
care provider. Research staff will adhere to any institution or clinic policies regarding virtual patient 
appointments.  
3.4 Screening 
Cross-reference: UNC IRBIS Application section A.6.2 (steps to minimize psychol. risks) 
Participant screening will occur in-person at the clinic or remotely. The RC will follow the Participant 
Screening and Consent Script (see Appendix). If the screening is conducted remotely, the RC will do 
remote screening and enrollment over the phone with the patient, guiding them through electronic 
forms that are hosted securely at the clinical institution.  
Written or verbal consent for screening will occur before eligibility screening is conducted.  

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If recruitment occurs in-person, prior to study screening, the RC will ask the patient to sign the Informed 
Consent for Screening (see Appendix).  
If recruitment occurs remotely, we will make an adaptation to this process. The RC will obtain consent to 
screen verbally by reading the screening consent form aloud and asking if the patient agrees. All of the 
same information will be provided to the patient, and screening will only proceed if the patient tells us 
they understand and agree. The study is collecting sensitive and personally identifiable information 
during the screening process. Depending on the responses to suicidal ideation questions, individuals 
need to be consented before screening activities occur. The informed consent for screening clearly 
outlines what information will be shared, retained, and how it will be used.  
The study screening, provided in the Participant Screening and Consent Script (see Appendix), asks 
about sensitive information, including: (1) whether the patient is receiving CBT currently, (2) is using 
opioids for pain due to cancer, and (3) suicide risk (2 questions, with one follow-up question if the 
subject indicates having thought about suicide recently). Suicide ideation includes both thoughts of 
being better off dead and thoughts of intentionally harming oneself.  
The research coordinator (RC) will invoke the INSPIRE Study’s Safety Protocol (see Appendix) if the 
patient expresses active self-harm, if the patient has a positive screen on the suicide risk assessment, or 
if imminent self-harm or harm to others is suspected.  
The safety protocol requires that the RC contact the clinic and work with on-site or on-call personnel 
(such as the prescribing physician, lead clinical investigator, or other designated crisis responder, 
hereafter referred to as “designated responder”) to arrange for further assessment. If the designated 
responder cannot be reached, the RC will call 911 and ask for a crisis intervention team specialist. If the 
research coordinator feels that 911 is the most appropriate due to suspicion of very imminent self-harm 
or harm to others, the RC will notify 911. The RC will report the event to the institution PI, institution 
project manager, RTI study PI, and RTI project manager within 48 hours for further consideration of 
action and follow-up. IRB, DSMB, and/or PCORI will be notified as needed.  
3.5 Informed Consent 
Cross-reference: UNC IRBIS Application section D.1, A.3.2 (language) 
Once screened, eligible participants will be asked to provide written or electronic consent to participate 
in the study. For remote consent, the RC will email the patient a link to the form and walk them through 
it verbally on the phone (see Remote Enrollment Forms Email Templates in the Appendix).  
A consent form describing in detail the study intervention, study procedures, and risks will be given to 
the participant, and written or electronic documentation of informed consent is required prior to 
starting the intervention. The Study Informed Consent Form is submitted with this protocol as an 
appendix. Each institution will have an approved form that is tailored to their policies and contact 
information. The RC will also ask the individual to read and sign (in writing or electronically) a HIPAA 
Authorization Form (see Appendix). Both of these electronic forms will be hosted securely at the clinical 
institution. 
It is outside the scope of the study to conduct the interventions in languages other than English. For that 
reason, we will not obtain consent in languages other than English.  

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3.5.1 Steps to Minimize Undue Influence during the Consent Process 
Cross-reference: UNC IRBIS Application section D.1.6 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the patient will be asked to read and review the document. Study 
staff will explain the research study to the patient and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the patient’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. Patients will 
have the opportunity to carefully review the written or electronic consent form and ask questions prior 
to signing. To minimize coercion or undue influence, the researchers will encourage the potential 
subjects to review the consent forms in private. Patients will be encouraged to discuss the study with 
their family, provider, or others, or think about it prior to agreeing to participate. The patient will sign 
the informed consent document prior to any procedures being done specifically for the study. Patients 
will be informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. All consent documentation will be written at a lay-friendly reading level. A copy of 
the informed consent document will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the form 
signed, either in writing or electronically, before the participant undergoes any study-specific 
procedures. The rights and welfare of the patients will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study.  
Because of the nature of the interventions, we will not obtain surrogate consent for those unable to 
consent on their own behalf.  
3.6 Enrollment and Baseline Data Collection 
Cross-reference: A.4.6 (data collection methods) 
Once a patient has signed the consent form, they will be considered enrolled in the study. Consented 
participants will be asked to provide the following contact information:  
• 
Salutation 
• 
First name 
• 
Middle name 
• 
Last name 
• 
Preferred name 
• 
Suffix 
• 
Mailing address, City, State, ZIP code 
• 
E-mail address(es) 
• 
Phone number(s) – home, mobile, work, other 
• 
Reminder preference (e.g., telephone, text message, e-mail, mail) 
• 
Information preference (e.g., paper, electronic) 
• 
Contact preferences (e.g. days and times) 

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Participants who enroll remotely can be asked to provide this information in an electronic form that will 
be hosted securely at the clinical institution (see Remote Enrollment Forms Email Templates in the 
Appendix).  
Patients who have consented to participate in the study will be entered into the study’s Enrolled 
Participant REDCap database hosted at RTI. Only information for consented participants will be stored in 
this database. The Enrolled Participant Database will include study status and participant data collected 
at and after enrollment.  
This study is not FDA regulated, so 21 CFR Part 11 compliance is not applicable.  
Participants will be asked to complete the baseline survey (T1) for assessment of patient-reported 
outcomes. The baseline survey may be self-administered electronically or verbally administered by study 
staff (or on paper if necessary). Participants can complete the survey in-person at the clinic or remotely. 
The T1 Baseline Survey is provided as an appendix. Participants must complete the baseline survey 
before being randomly assigned to the study intervention.  
For remote administration, RCs will send participants an email with a private, secure survey link, asking 
them to complete the survey using the T1 Emails template for email invitations and reminders (see 
Appendix). 
3.7 Screen Failures 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomly assigned to the study intervention or entered in the study. For example, this 
could occur if a participant signs the consent form but does not complete the T1 baseline survey.  
A minimal set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
3.8 Randomization and Intervention Delivery 
After enrollment, participants will be randomly assigned to one of the two intervention arms as 
described in Section 2.4. Interventions will be delivered as described in Section 6.  
3.9 Follow-up Assessment Procedures 
Cross-reference: UNC IRBIS Application section A.4.4, A.4.6, B.3.2 (number of contacts), C.1.1 (data sources) 
We will use a comprehensive, multimode data collection method that includes the collection of patient-
reported outcomes through web-based and telephone approaches and leverage existing harmonized 
EHR data maintained by the PCORnet STAR CRN. 
We will collect follow-up data in two ways:  
1. EHR data extraction from the PCORI Patient-Centered Clinical Research Network (PCORNet) 
STAR CRN.  
2. Patient surveys to collect patient-reported outcomes data.  

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3.9.1 Clinical Data Extraction 
We will extract existing clinical data to measure the primary outcome of opioid dosage at baseline, 6, 12, 
and 18 months. Clinical data will be extracted from the PCORnet STAR CRN data warehouse, which will 
add efficiency and consistency to the project while reducing delays related to data access and 
management. Data extraction and transfer procedures are described in section 10.2.1 below.  
3.9.2 Self-report Survey 
Follow-up assessments will include the collection of patient-reported outcomes data via self-report 
surveys at two follow-up timepoints: 6 and 12 months after enrollment. The T2 and T3 Follow-Up 
Survey is included in the Appendix. The measures included in the surveys are described in Section 4. 
Each clinical site will provide participant contact information for randomized study participants to RTI so 
that research staff at RTI can conduct follow-up recruitment at T2 and T3. Clinical site staff may assist in 
contacting hard-to-reach participants.  
Access to technology and individual preferences for completing the surveys will differ across 
participants. To increase retention and data quality, the survey can be self-administered via the Web or 
on paper or administered verbally by study staff.65  
Staff will collect survey data according to a Follow-Up Protocol in the study Manual of Procedures. Our 
data collection approach is based on standard best practices in the field of survey research.66 Our phone 
follow-up protocol is consistent with best practices including that used by the CDC Behavioral Risk 
Factor Surveillance System (BRFSS).67 
Introduction/Lead letter or email 
One week prior to follow-up survey data collection at T2 and T3, RTI study staff will send a lead 
letter/email to enrolled participants. The purpose of the lead letter/email is to remind the participants 
about the follow-up surveys. The lead letter/email can be found in the Appendix (T2 and T3 Recruitment 
Materials document) 
Web-based Administration 
RTI study staff will send participants up to 4 emails over 4 weeks with a private, secure survey link, 
asking them to complete the survey. Email reminders can be found in the Appendix (T2 and T3 
Recruitment Materials document.) 
We will ask enrolled participants to complete the survey by phone or by mail if they a) do not complete 
the follow-up Web-based survey within 4 weeks or b) do not have a valid email address.  
If a participant does not complete the web survey after 4 weeks, we will close the web survey option.  
Computer-Assisted Telephone Interviewing Administration 
RTI study staff will contact participants who a) do not complete the follow-up Web-based survey 
approximately 4 weeks after the initial invitation or b) do not have a valid email address.  
For participants who do not have a valid email address, we will make up to 9 contacts over a 6-week 
period. For participants who have a valid email address but did not complete the web survey, we will 
make up to 5 phone contacts over a 2-week period. A contact is defined as when the caller reaches 

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someone live, by voicemail, or by text message. The calls will be made at varying days and times to 
increase the chance of reaching the participant. 
We will ask the participant to complete the survey via telephone using standard telephone interviewing 
techniques for Computer-Assisted Telephone Interviewing (CATI). Phone scripts can be found in the 
Appendix (T2 and T3 Recruitment Materials document). 
Mail Administration 
Study staff may mail participants a paper copy of the T2/T3 survey for the participant to fill out and mail 
back at no cost to the participant.  
Hard-To-Reach Protocol 
Before a participant is deemed lost to follow-up, study staff will make every effort to regain contact with 
the participant. 
RTI staff will use web-based location resources—such as search engines, Superpages.com, etc.—and will 
check with local site study staff to update contact information.  
RTI will notify the local site study staff of participants who cannot be reached. The research coordinator 
may follow-up with the participant to remind them about the survey and to set up an appointment time 
for RTI to call the patient to conduct the survey. 
Strategies for Retention 
Because the study involves enrollment over several months, we will use procedures to enhance 
participant retention, including the following:  
• 
Using multiple methods for contacting participants. 
• 
Using study reminders. 
• 
Providing incentives for survey completion and clinic visit attendance (described below). 
• 
Confirming current personal contact information with the participant.  
• 
Giving patients an INSPIRE Appointment and Survey Reminders Handout (see Appendix) that 
summarizes their steps for taking part in their assigned intervention in one clear, easy-to-read 
page.  
• 
Sending a periodic newsletter to enrolled participants. The newsletters will include information 
such as survey and intervention reminders, background on what the study hopes to achieve, and 
stories from SAC members. Any pictures used will be stock images (no patients or study 
participants will be pictured). Newsletter content will be submitted to IRB for approval.  
Additionally, institution leadership will meet regularly and obtain input from the SAC, which includes 
patient members, to review and assess retention.  
3.9.3 Qualitative Data Collection 
We will also qualitatively assess the patient-reported experience as part of this pragmatic trial by 
conducting virtual individual interviews with participants in Arm 1 and virtual focus groups with those in 
Arm 2.  

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Number of participants 
Total anticipated recruitment in the qualitative research is up to 78 participants. For Arm 1, we will 
recruit up to 24 participants for individual interviews. For Arm 2, we will conduct up to six focus group 
sessions. We will recruit up to 9 participants for each focus group, for a total of 54 participants.  
Recruitment 
We will ask participants during the consent process for the main study for permission to contact them 
for additional research activities related to this study. RCs will contact the participants who gave 
permission to be re-contacted using a standard script (See Attachments, Qualitative Recruitment 
Materials). During recruitment, the RC will confirm that the participant is willing and able to take part in 
a web conference call and will ask the participant upfront if they agree to be audio-recorded if they 
decide to participate.  
Informed Consent 
The RC will send the participant a confirmation email with a copy of the informed consent form (see 
attachments, Informed Consent for CBT Participant Focus Group and Informed Consent for SDM 
Participant Interview). 
At the beginning of the qualitative session, the interviewer will review key points of the informed 
consent with the participant(s) and ask if they have any questions. The moderator will ask each 
participant to provide verbal consent to participate and the notetaker will document the consent.  
Interview and Focus Group Administration 
An interviewer and note-taker, both from RTI, will facilitate the interviews and focus groups. The 
moderator will use a semi-structured moderator guide (see attachments, CBT Focus Group Guide and 
SDM Interview Guide) to gather data on participant experiences with the interventions, communication 
with their health care providers, pain management, and opioid use. We will conduct the interviews and 
focus groups via a web conferencing platform. Each session will last up to 60 minutes. To facilitate 
engagement, we will ask participants to turn on their video/webcam if able. For privacy and security 
reasons, we will not video record the session. We will only record audio from the session. We will use 
the audio recordings to create transcripts, both of which will be stored on a password protected portion 
of the project share drive The RC will mail participants a $75 gift card at the conclusion of the focus 
group or interview as a thank you for their participation.  
3.10 Incentives for Study Participation 
Cross-reference: UNC IRBIS Application section A.9.3 (SSNs), B.4.1 (incentives), B.4.2 (incentives) 
The following incentive will be provided for study participation: 
• 
Participants will receive a $30 incentive payment for completing the baseline survey.  
• 
Participants will receive a $25 incentive payment for each follow-up survey completed.  
• 
Participants will receive a $10 incentive payment for each group CBT-CP session completed.  
 
If the participant completes the T1 survey remotely or completes a group CBT-CP session remotely, the 
RC will mail them the incentive and Thank You Letter with Incentive (see Appendix). The incentive 

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payments for the follow-up surveys will include the T2/T3 Thank You Letter, which is included in the 
Appendix.  
The total compensation a subject could receive for either arm is under $200, therefore we are not 
collecting SSNs for payment. Participants receiving an incentive payment in person will be asked to sign 
a receipt form acknowledging receipt. 
If they choose to take part in the additional qualitative research activities, participants will receive a $75 
incentive payment for completing a qualitative interview or focus group.  
3.11 Study Completion 
The patient’s participation in the intervention is complete about 12 months after the completion of the 
T1 baseline survey; participation in the study is complete after completion of the T3 survey. 
Key tracking data pertaining to visit completion and follow-up completion will be captured. These 
tracking data will be used to coordinate the distribution of incentive payments to participants and to 
identify trends in data collection; for example, to identify patterns of loss to follow-up that can inform 
outreach methods. 
3.12 Withdrawal from the Study 
Cross-reference: UNC IRBIS Application section A.7.3.  
Participants are free to withdraw from participation in the study at any time upon request. An 
investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
If any adverse event (AE) or other medical condition or situation occurs such that continued 
participation in the study would not be in the best interest of the participant. 
• 
Disease progression that requires discontinuation of the study intervention. 
• 
If 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 in the Enrolled 
Participant Database. The study will retain participant data collected prior to withdrawal. We will not 
contact the participant to obtain any more self-report data, and the participant will not receive any 
further intervention. However, if the participant has completed any part of the intervention, we would 
like to continue to extract the participant’s EHR data, and we will use the Withdrawal Consent 
Addendum (see Appendix) to seek permission to do so. If the participant withdraws prior to 
participating in the intervention, we will not collect any more of their data.  
3.13 Loss to Follow-up 
A participant will be considered lost to follow-up if they discontinue the intervention or are unable to be 
contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
As this is a pragmatic trial, the clinic will follow standard clinical operating procedures for missed 
appointments. 

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4 STUDY EVALUATIONS AND MEASUREMENTS 
4.1 Efficacy Evaluation 
4.1.1 Primary Outcome 
Opioid dose, as measured by prescribed milligrams of daily MED, is the primary study outcome.68 The 
primary outcome will be examined at baseline and months 6, 12, and 18 using opioid prescription data 
(Table 3). Prescribing data (including drug name, start and stop dates, dose, and frequency) will be 
derived from the EHR and provided by the PCORnet STAR CRN warehouse common data model (CDM). 
The field generally accepts prescribing data as documenting ingestion; other current and previously 
published studies also use prescribed dose as the primary endpoint.17,20,21,68-72 However, we recognize 
that ingestion may not be the same as the prescribed regimen. We will analyze the absolute (primary) 
decrease (or increase) in opioid MED from the baseline period (average of 90 days prior to 
randomization) until 18 months after randomization. We also will examine percentage decrease. Total 
morphine equivalents for each prescription will be calculated by multiplying the quantity of each 
prescription by the strength of the prescription (milligrams of opioid per unit dispensed). The quantity-
strength product is then multiplied by conversion factors derived from published sources to estimate 
the milligrams of morphine equivalent to the opioids dispensed in the prescription. The total average 
dose in morphine equivalents per day supplied is calculated by summing the morphine equivalents for 
each prescription filled during a given period and dividing by the number of days supplied. 
4.1.2 Secondary Outcomes 
The 2 secondary study outcomes, physical function and pain interference, are based on patient self-
report (Table 3). These outcomes will be examined at baseline and months 6 and 12. They will be 
measured using validated scales that are widely recognized in the pain literature as core outcomes.73 
Both of the secondary outcomes were selected with input from patients and in consultation with pain 
experts,74 and they are part of the Patient-Reported Outcomes Measurement Information System 
(PROMIS). PROMIS is a set of patient-centered measures that evaluates and monitors physical, mental, 
and social health in adults and children. The PROMIS pain interference (PROMIS-PI) is an 8-item 
assessment of the extent to which pain interferes with daily functioning. It is a standard outcome in pain 
clinical trials73 and has excellent reliability and construct validity. The PROMIS physical functioning 
(PROMIS-PF) is an 8-item assessment of self-reported capability of general physical functioning over the 
past week rather than actual performance of physical activities.75 It is considered by experts to be a 
standard for comparative effectiveness research in chronic pain. 
 
 

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Table 3. Primary and Secondary Outcomes 
Domain 
Outcome 
Data Source 
Title 
# 
Items 
Timepoints 
Description  
 
Primary 
outcome: 
Clinical 
measure 
Opioid dose  
PCORnet STAR 
CRN warehouse 
data derived 
from electronic 
health records 
n/a 
n/a 
Baseline 
and 
months 6, 
12, and 18 
Average daily opioid 
dose in milligrams of 
morphine 
equivalent (MED).  
Key 
secondary 
outcomes: 
Patient 
Reported 
Outcomes 
(PROs) 
Pain 
interference 
Patient survey  
PROMIS Short Form 
v1.0 – Pain 
Interference 8a 
8  
Baseline 
and 
months 6 
and 12 
Assesses self-
reported 
consequences of 
pain on relevant 
aspects of one’s life. 
5-point Likert 
scale.74 
Physical 
function 
Patient survey 
PROMIS Short Form 
v1.0-- Physical 
Function 8a  
8  
Baseline 
and 
months 6 
and 12 
Assesses self-
reported capability 
rather than actual 
performance of 
physical activities. 5-
point Likert scale.75 
Note: MED = morphine equivalent dose; PROMIS = Patient-Reported Outcomes Measurement Information System 
4.1.3 Other Self-Reported Outcomes 
We will obtain additional self-reported outcome measures regarding pain intensity (both verbal  5-point 
Likert scale and numeric 10-point scale ratings) and numeric rating of physical function using the 
PROMIS pain intensity scale and may also use the 11 validated items of the Brief Pain Inventory (BPI) 
(Table 4).76 Using both verbal and numeric ratings is recommended in the literature as an outcome 
measure for trials of chronic pain treatments. Doing so makes it possible to compare results across 
studies and limits the amount of missing data that results if some patients have difficulty completing 
one of the ratings.73  
Chronic pain is often accompanied by emotional distress, anxiety, and depression,73 and for this reason, 
we will measure anxiety and depressive symptoms at baseline, 6, and 12 months using PROMIS 
measures.  
Intent to taper will be measured via self-report at baseline and months 6 and 12. The follow-up 
assessments at months 6 and 12 will also include a self-report measure of relative opioid use (no longer 
taking opioids, higher dose than baseline, or lower dose than baseline).  
Covariates will include demographic characteristics, health insurance status, health literacy level, and 
patient-centered communication. Age, gender, race, and ethnicity will be included on the baseline 
survey. These self-report variables will be cross-referenced to EHR-derived data to confirm alignment of 
the two data sources. 
 
 

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Table 4. Additional Self-Reported Outcome Measures 
Measure 
Title 
# Items 
Timepoints 
Description 
Pain Intensity  
(verbal rating) 
PROMIS Scale v1.0 
Pain Intensity 3a 
short form 
3 
Baseline, 
months 6 
and 12 
Assesses how much a person hurts using a 5-
point Likert scale. The first two items assess 
pain intensity over the past seven days. The 
last item for asks patients to rate their pain 
intensity “right now.” 77 
Pain Intensity 
(numeric rating) 
Brief Pain Inventory 
(BPI) – pain 
intensity sub-scale 
4 
Baseline, 
months 6 
and 12 
These items ask about level of pain and over 
the past week, with responses on a numeric 
scale of 0 to 10.76 
Pain Interference 
(numeric rating) 
Brief Pain Inventory 
(BPI) pain 
interference sub-
scale 
7 
Baseline, 
months 6 
and 12 
These items ask about pain interference 
over the past week, with responses on a 
numeric scale of 0 to 10.76 
Emotional 
distress 
(Anxiety) 
PROMIS—Anxiety, 
4-item Short Form 
4 
Baseline, 
months 6 
and 12 
Assesses generalized anxiety/distress over 
the past 7 days. 5-point Likert scale. 78 
Depressive 
symptoms 
PROMIS Short Form 
v1.0 – Depression 
4a 
4 
Baseline, 
months 6 
and 12 
Assesses depressive symptoms over the past 
7 days. 5-point Likert scale.78 
Demographic 
characteristics 
n/a 
8 
Baseline 
Age, race, ethnicity, assigned sex at birth, 
gender identity, education, marital status, 
and employment status 
Health insurance 
status 
n/a 
1 
Baseline, 
months 6 
and 12 
This item assesses if a patient has health 
coverage and what type 
Health literacy 
Health Literacy 
Skills Instrument 
(HLSI) 
4 
Baseline 
Assesses the patient’s understanding of 
health information.  
Patient-centered 
communication  
Patient-centered 
communication  
6 
Baseline, 
months 6 
and 12 
Assess the patient’s experience with care 
and communication  
 
4.1.4 Other EHR-Derived Outcomes 
Cross-reference: UNC IRBIS Application section A.9.1 (identifiers). 
Other measures collected through the PCORnet CDM include: 
• 
Demographic information (birth date, sex, race, and ethnicity) 
• 
Patient height and weight 
• 
Health care provider information 
• 
Death information (death date and source) 
• 
Health care visit information (visit dates, primary payer, facility type, and provider ID) 
• 
Diagnosis and condition information (condition data and type, diagnosis dates, and associated 
ICD/CPT codes) for:  
▪ 
Mental health disorders, defined by ICD-10 codes (e.g., depression, anxiety, 
schizophrenia, bipolar disorder, suicide attempt/intent) 

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▪ 
Number and type of CNCP conditions per ICD-10 codes (e.g., back pain, neck pain, 
headache, arthritis, HIV) 
▪ 
Alcohol/substance misuse or abuse as measured by ICD-10 codes.  
• 
Overall comorbidity using the Charlson Comorbidity Index per ICD-10 codes79 
• 
Opioid prescription information including RxNorm CUI (drug prescribed), prescription dates, 
dose, units, frequency, route, quantity, refills, and supply days. 
 
We will calculate time to discontinuation of opioids, where discontinuation will be measured based on 
our previous work,20,21 except that the discontinuation will be defined as the first day of a minimum 90-
day period with no opioid prescriptions (see Section 5.2 for additional information about the definitions 
and analyses). 
A Schedule of Assessments indicating the timing and source of efficacy, safety, and fidelity measures is 
presented in Table 6.  
4.2 Safety Evaluations 
See Section 8 for information about the study’s safety evaluations and procedures. 
4.3 Process Evaluation 
Cross-reference: UNC IRBIS Application section A.9.1 (identifiers). 
The research team will develop a set of intervention fidelity measures to assess the extent to which the 
intervention was implemented as planned. The research team will evaluate fidelity via: EHR 
documentation review with a random sample of notes, clinical data extraction, and patient self-report. 
The measures are described in Table 5.  
Table 5. Process Evaluation 
Evaluation 
Measure 
Data Source 
SDM intervention 
fidelity 
Extent to which patients read or viewed 
SDM materials 
Patient self-report (T2 and T3 surveys) 
Number of visits to an SDM-trained 
provider during the intervention period 
Extracted from EHR using intervention-
specific templates  
Visit status data entered into REDCap by 
the Research Coordinator 
Content covered during SDM 
intervention visits  
Provider report via EHR encounter notes 
using intervention-specific templates  
MI+CBT-CP 
intervention fidelity 
Number of intervention sessions 
attended 
CBT session attendance logs which will be 
entered as visit status data in REDCap by 
the Research Coordinator 
Content covered during sessions 
Provider report via EHR encounter notes 
using intervention-specific templates 
Opioid care 
guidelines (GCC) 
fidelity 
Elements of GCC covered, e.g. the 
patient has had a UDT within the past 12 
months, Prescription Drug Monitoring 
Program [PDMP] was checked 
Provider report via EHR encounter notes  

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Table 6. Schedule of Assessments 
Measurement 
Screening  
(Month -12 to 
0) 
Enrollment/ 
Baseline 
Survey  
(Month 0) 
Baseline 
Clinical Data 
Extraction 
(Month -3 to 
0) 
Intervention 
visits 
(Months 1-12) 
Clinical Data 
Extraction 
(Months 6, 12, 
18) 
T2 follow-
up survey 
(Month 6) 
T3 follow-up 
survey  
(Month 12) 
Qualitative 
research 
activities 
Informed consent 
● 
 
 
 
 
 
 
● 
Demographics 
 
● 
● 
 
 
 
 
 
Randomization 
 
● 
 
 
 
 
 
 
Average daily opioid dose 
 
 
● 
 
● 
 
 
 
Charlson Comorbidity Index (ICD-9/10) 
 
 
● 
 
 
 
 
 
Chronic noncancer pain conditions (ICD-9/10) 
 
 
● 
 
 
 
 
 
Mental health disorders (ICD-9/10) 
 
 
● 
 
 
 
 
 
Alcohol/substance use disorders (ICD-9/10) 
 
 
● 
 
 
 
 
 
Body mass index (based on height and weight) 
 
 
● 
 
 
 
 
 
Health insurance payer 
 
● 
● 
 
● 
 
 
 
Opioid withdrawal or overdose medication 
prescriptions 
 
 
● 
 
● 
 
 
 
Study intervention intensity (based on number of 
intervention visits) 
 
 
 
 
● 
 
 
 
PROMIS self-report scales: (Pain Interference, 
Physical functioning, Pain Intensity, Anxiety, 
Depression) 
 
● 
 
 
 
● 
● 
 
Brief Pain Inventory (11 key items) 
 
● 
 
 
 
● 
● 
 
Health literacy level 
 
● 
 
 
 
 
 
 
Patient centered communication  
 
● 
 
 
 
● 
● 
● 
Self-reported relative opioid use  
 
 
 
 
 
● 
● 
 
Intent to taper 
 
● 
 
 
 
● 
● 
● 
Use of intervention content 
 
 
 
 
 
● 
● 
● 
Satisfaction with care 
 
● 
 
 
 
● 
● 
● 
Adverse Events and death review and evaluation 
 
 
● 
● 
● 
● 
● 
 
Fidelity review and evaluation  
 
 
 
● 
 
● 
● 
 
Cross-reference: UNC IRBIS Application section A.9.1 (identifiers). 

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Statistical Considerations 
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5 STATISTICAL CONSIDERATIONS 
5.1 Summary of Statistical Analysis 
Cross-reference: UNC IRBIS Application section A.8.1. 
Statistical analyses for this study have been designed to compare (1) the effectiveness of the 2 
interventions (MI+CBT-CP and SDM) in reducing opioid dosage among patients with CNCP, and (2) the 
effects of the 2 interventions on pain interference and physical function. The analyses will use data 
collected at baseline, 6, 12, and 18 months to evaluate these effects, and will formally test the primary 
hypothesis that the reduction in opioid dose (absolute change in MED) differs between the 2 
intervention arms at 12 months and will describe differences in absolute change in opioid dose at 6 and 
18 months and percent change in dose at each timepoint. The analysis also will formally test 
intervention arm differences for 2 key secondary outcomes: change in pain interference and physical 
function at 12 months. Change in outcomes at 6 months will be described. Primary and secondary 
analyses will use model-based approaches that take advantage of the longitudinal structure of the 
outcome data to address missing data caused by patient loss to follow-up or nonresponse. 
The primary analyses will be based on the intention-to-treat (ITT) principle, with data from all 
participants analyzed according to the arm to which they were randomized irrespective of intervention 
received, as will key secondary analyses of pain interference and function. As in most clinical trials, some 
participants in this trial may not adhere to the intervention they were allocated to receive or comply 
with the intervention as prescribed, reducing fidelity to the intervention as designed and potentially 
changing the effectiveness of the intervention. The most likely form of noncompliance will be absence 
from group therapy sessions in the MI+CBT-CP arm or with patients on the SDM arm ceasing interaction 
with the assigned provider. The potential impact of this noncompliance is the dilution of the true 
treatment effect. In addition to the ITT analyses described above, we will conduct secondary analyses 
using a per protocol population that received a substantial portion of the randomized intervention, 
defined as at least 4 SDM sessions and at least 4 MI or CBT sessions. Details of the definition of this per 
protocol population will be provided in the Statistical Analysis Plan. The analysis plan will be drafted 
prior to the receipt of the initial PCORnet data extraction (Section 2.6) and finalized prior to REDCap 
study database lock and the final PCORnet data extraction.  
Secondary analyses also will explore differences in the intervention effect according to participant 
characteristics, such as age, health literacy level, patient-centered communication, baseline pain level, 
baseline opioid dose, body mass index, and the presence of physical comorbidities, mental health 
comorbidities, or a history of substance abuse. 
One single primary formal hypothesis test is planned for this study at the 0.05 level of significance, 
which is the comparison of the intervention arms for the primary outcome at the primary timepoint. 
Additionally, regardless of significance of the primary outcome, statistical significance of the 2 key 
secondary outcomes will be assessed, with adjustment for multiple comparisons using the Hochberg 
modification to the Bonferroni adjustment.80 Primary and secondary hypothesis tests resulting in 
nonsignificant p-values will be interpreted as inconclusive. All other treatment group comparisons will 
be considered descriptive in nature with no adjustment for multiple comparisons, and all confidence 
intervals will be generated using 95% bounds. 

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5.2 Study Endpoints  
5.2.1 Primary Endpoint 
The primary outcome for this study is the absolute change in opioid dose (in MED) from baseline at 12 
months post-randomization. Secondary timepoints for the primary outcome are at 6 and 18 months. 
Consistent with the pragmatic approach taken by this study, change in opioid dose will be based on data 
on opioid dose extracted from the medical record, as available in the PCORnet CDM. Opioid dose will be 
calculated as the prescribed milligrams of daily MED averaged over the 90-day period prior to 
randomization and 3, 6, 9, 12, 15, and 18 months post randomization. For each of the post-
randomization periods, change in daily opioid dose will be computed as the difference between the 
dose calculated during that period and the dose from the baseline period. Although the primary 
outcome is the change at 12 months (with secondary timepoints at 6 and 18 months), analyses will be 
based on a linear mixed model using data from all 4- through 18-month time periods to account for 
missing data and thereby maximize information used for the primary analysis. Percentage change in 
MED from the baseline period also will be evaluated in a secondary analysis focusing on key clinical 
dosing thresholds. The distribution of opioid doses will be evaluated prior to finalizing the analysis plan, 
and if opioid dose change from baseline is determined to be highly skewed and substantially non-
normal, then opioid doses will be transformed to the natural log scale, and the primary analysis will 
compare the intervention arms based on the relative dose reduction. Details of the algorithm used to 
calculate milligrams daily MED and for modelling the primary outcome measure will be provided in the 
Statistical Analysis Plan. 
5.2.2  Key Secondary Endpoints 
We will examine 2 key secondary effectiveness endpoints: (1) change from baseline in self-report of pain 
interference at 12 months, and (2) change in self-report of physical functioning at 12 months. Each 
outcome will also be assessed at 6 months. 
Pain interference is a measure of the extent to which pain interferes with patient physical, mental, and 
social activities. It is an outcome that has been identified by patients in the target population as a critical 
patient-centered outcome for evaluating the potential effects on an opioid-reduction strategy. For this 
study, pain interference will be measured through patient-reported assessments at baseline, 6 and 12 
months using a standardized instrument, the 8-item PROMIS-PI scale. The outcome measure is defined 
as the change in the total pain interference scale score from baseline to 6 and 12 months. The PROMIS-
PI scale is a T-score based on PROMIS normative data such that a score of 50 represents the average 
score for the normative population and 10 is the standard deviation (SD) of that population. 
A concern frequently expressed by patients with CNCP is a reduction in physical function that can be 
associated with both the chronic pain and opioid use. For this study, we will measure physical 
functioning using the 8-item PROMIS-PF instrument. The outcome measure is defined as the change in 
the total physical functioning scale score from baseline to 6 and 12 months. The PROMIS-PF scale is a T-
score based on PROMIS normative data such that a score of 50 represents the average score for the 
normative population and 10 is the standard deviation (SD) of that population. 
5.2.3 Other Endpoints 
Other effectiveness endpoints include self-report of pain intensity, anxiety, depressive symptoms, and 
PROMIS pain intensity. Outcomes are defined as the change in T-score based on the PROMIS normative 

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population from baseline to 6 and 12 months. The 4 items within the Brief Pain Inventory (BPI) pain 
intensity subscale are analyzed individually, and a summary measure is calculated as the average of the 
items. The 7 items of the pain interference subscale are averaged to make a summary score for the 
subscale, provided that at least 4 of the 7 items are non-missing. 
Time to opioid discontinuation is an exploratory effectiveness endpoint. We will examine opioid 
discontinuation using time-to-event models. For this study, a participant is considered to have 
discontinued opioids after a span of at least 90 days in duration after the run-out of the last prescription 
(generally 30 days) and continuing until study completion at 18 months. To distinguish clearly between 
opioid discontinuation and switching to an alternate health care system, participants must also have at 
least 1 clinic visit within 180 days after the run-out of the last prescription to be considered an opioid 
discontinuation event. The day of opioid discontinuation is defined as the run-out date (generally 30 
days) after the last opioid prescription. Participants who have a prescription within 120 days (or 
prescription run-out within 90 days) prior to study completion at 18 months (or the last data extraction), 
or have not been seen in clinic for 180 days, have withdrawn, or otherwise been lost to follow-up 
without first meeting opioid discontinuation status will be right censored at the end of the dosing period 
for their last recorded opioid prescription (generally 30 days) and included in the time to opioid 
discontinuation analyses as a censored outcome using standard statistical procedures. Additional details 
of the computation of this outcome measure will be included in the Statistical Analysis Plan. 
Safety outcomes for this pragmatic open-label intervention trial are limited to SAEs and are noted in 
Section 8. 
5.2.4 Intervention Adherence and Fidelity Assessments 
Assessments of fidelity to the planned intervention are described in Section 4.3. 
5.3 Statistical Analysis Methods 
The following sections briefly describe the methods that will be used for the analyses related to the 
primary and secondary outcome measures describe above. Additional details for these methods will be 
provided in the Statistical Analysis Plan. 
5.3.1 Primary Analysis Methods for Opioid Usage Outcome 
For reduction in opioid use, we will use a constrained linear mixed model81-83 to generate point and 
interval estimates of the reduction in opioid dose MED from baseline to 4, 6, 8, 10, 12, 14, 16, and 18 
months and to test the hypothesis that this reduction differs between the 2 intervention arms. While 
the primary and secondary time assessments are at 6, 12 and 18 months, all available opioid 
prescription data from baseline through 18 months will be included in the model. This approach will 
provide consistent estimates and valid inferences under missing at random (MAR) data assumptions 
while accounting for correlation among multiple measures on the same participant. This mixed model 
will improve the power of the study and the precision of all estimates by allowing all available measures 
for an individual to be incorporated in the analysis, even if other timepoints are missing. The model will 
include fixed effects for the treatment group, time interval (as a categorical variable), treatment-by-time 
interaction, baseline opioid dose, the stratification effect of institution, and random effects for 
participant. An intervention-arm‒specific Toeplitz correlation structure will be assumed for the within-
participant measures, to reflect the changing correlation of these measures over time and permit the 

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correlation structure to differ between study arms. The model will be used to generate point and 
interval estimates and to test differences in mean changes in opioid dose between the 2 intervention 
groups at 12 months (primary timepoint) and to generate point and interval estimates at 6 and 18 
months (secondary timepoints). 
This model treats missing data as ignorably missing, assuming any missing data are missing at random, 
after accounting for baseline opioid dose. Sensitivity analyses based on multiple imputation procedures 
will be performed to evaluate departures from critical distributional and missing data assumptions. 
Plans to address missing data are further presented below (see Missing Data Section) and will be 
described in detail in the Statistical Analysis Plan. Assessments of model assumptions and goodness-of-
fit will also be specified in the Statistical Analysis Plan. 
5.3.2 Secondary Analysis Methods 
Opioid Usage 
Secondary analyses of reduction in opioid use for the per protocol population will use models analogous 
to those described above for the primary analysis. Comparable models also will be used to explore the 
effect of potentially important covariates for both the ITT and the per protocol populations. 
PROMIS Pain Interference and Physical Functioning 
Secondary analyses will generate point and interval estimates of mean change in physical function as 
measured by the 8-item PROMIS-PF scale and mean change in pain interference as measured by the 8-
item PROMIS-PI score from baseline to 6 and 12 months and point and interval estimates of the mean 
difference between the 2 intervention arms. These secondary analyses will use appropriate linear mixed 
model-based approaches analogous to those described for the primary outcome analysis.  
Other secondary outcomes (PROMIS anxiety, PROMIS depression, and BPI pain intensity and pain 
interference will be analyzed similarly. 
We will explore the percentage of participants per group who experienced an increase in pain and a 
decrease is in dose. Additional analyses will compare the treatment groups for the incremental impact 
of opioid dose -reduction per unit change in pain interference and physical functioning score.  
Incidence of self-reported intent to taper opioid medication, collected at baseline, 6 and 12 months, will 
be compared between treatment groups using chi-square test and logistic regression with adjustment 
for baseline dose and intent. 
Opioid Discontinuation 
To evaluate the time to opioid discontinuation, a Cox proportional hazards model with adjustment for 
baseline opioid dose and clinical institution will be used for both the ITT and the per protocol 
population. The model will be used to generate point and interval estimates of the hazard ratio 
comparing likelihood of opioid discontinuation for the two intervention arms. 
Safety Analysis for Adverse Events 
Each of the safety outcomes described above can be characterized as a binary outcome. For each 
measure, contingency tables will be generated that summarize the risk of occurrence by intervention 
arm. Because AEs are expected to be relatively rare, contingency table methods will be used to generate 

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point and interval estimates of the risk of each AE by intervention arm, with the interval estimates based 
on exact binomial confidence limits. Cochran-Mantel-Haenszel tests stratified by the 3 clinical 
institutions will be used to generate p-values that assess potential differences in odds ratios by 
intervention arm. 
Assessments of Intervention Adherence and Fidelity 
Adherence and fidelity of the intervention arms in terms of both the average amount of planned 
intervention received by the participants and the quality of the intervention administered relative to the 
required components (as assessed by the random sample of EHR note logs) will be described overall and 
will be compared across the time-course of the study and between institutions with descriptive 
statistics. Fidelity of GCC, to be provided in each of the intervention arms, also will be compared 
between intervention arms. Details for these analyses will be provided in the Statistical Analysis Plan. 
5.3.3 Other Analysis Considerations 
Subgroup Analyses (Heterogeneity of Treatment Effect) 
While multiple subgroup analyses have an inherent risk of inflating Type I error, this trial offers a unique 
opportunity to generate hypotheses about the profile of patients most likely to benefit from the 
intervention. Consequently, planned secondary analyses will assess potential differential treatment 
effects for two subgroups: 1) defined by participants with comorbid mental health conditions and 2) sex. 
Descriptive testing of the heterogeneity of treatment effect, which is meant to be hypothesis 
generating, will be established based on the interaction test from a mixed effects model in which the 
subgroup variable and an intervention arm by subgroup interaction term are added to the model used 
for the primary and secondary outcome analyses to test the interaction between intervention arm and 
the subgroup at the primary 12-month timepoint. To account for the inherent decrease in power 
associated with interaction tests, these tests will be conducted at a level of significance of 0.1. Because 
the subgroup is of interest, model-based estimates of treatment effects will be generated within the 
subgroups even if formal heterogeneity tests are not statistically significant. Any reporting of subgroup 
analyses will document the number of subgroup analyses conducted to facilitate valid interpretation of 
subgroup results. 
The study also will include descriptive analyses to explore heterogeneity of effect according to age, 
baseline pain score, comorbidities (including physical comorbidities and mental health disorders, and 
past or current alcohol or other substance abuse and related disorders), those taking other medications, 
patient health literacy level, BMI, and opioid dose used at baseline in 3 categories consistent with CDC 
guidelines: low (20-49 MED), moderate (50-89 MED), high (90 or more MED). Testing for heterogeneity 
of treatment effects for these subgroups will be considered exploratory as opposed to confirmatory, and 
the results will be interpreted with appropriate caution. Heterogeneity of effect based on receipt of 
intervention by telehealth versus in-person, and based on categorized number of intervention sessions 
received will be similarly explored. 
Missing Data 
The study will implement multiple procedures to prevent and reduce the amount of missing data and 
use appropriate statistical procedures to evaluate whether the results are robust to missing data. The 
risk of missing patient-reported outcome measures has been reduced by limiting the number of visits 
and assessments to those essential to achieve study goals and using “short” versions of instruments to 

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reduce burden. It is possible, however, that there may be some nonresponse to the 6- and 12-month 
patient reported outcome surveys. The sample size calculation assumed as high as 25% non-response at 
12 months. EHR-derived data on opioid dosage is expected to be virtually complete based on standard 
PCORnet data extraction procedures, yet sample size calculations allow for up to 12% missing data at 12 
months from lost to follow-up within the EHR or withdrawal of consent for use of EHR data. To reduce 
the risk of being unable to calculate the primary outcome because of missing or uninterpretable dosing 
instructions, MED will be derived using only the standardized and highly accurate fields: drug name, 
strength, and number of pills. In the event of missing medication information for a prescription (such as 
strength or number of pills), we will impute medication information from the 2 closest prescriptions by 
date, using an algorithm developed by our clinical content experts, and conduct sensitivity analyses with 
and without the imputed data. 
Logistic regression models will be used to compare the demographic characteristics of participants who 
provided 18 months of EHR data as compared with participants who were lost to follow-up within the 
EHR or withdrew consent for study participation to identify possible differential attrition. For primary 
and secondary outcomes analysis, the planned likelihood-based analysis will produce unbiased results if 
the data are MAR; that is, not related to the unobserved value of the outcome, but can be related to 
observed values of the outcome or model covariates. 
Although the MAR assumption is often reasonable, in this study it will be possible that even after 
controlling for other correlates of missingness and outcome data observed before participants are lost, 
likelihood of attrition may be associated with key outcomes of interest, including opioid use, physical 
function, and pain interference. Consequently, sensitivity analyses to the MAR assumption based on 
multiple imputation strategies to include control-based imputation as well as tipping-point analysis will 
be described in the Statistical Analysis Plan. 
5.4 Sample Size and Power 
Cross-reference: UNC IRBIS Application Section A.8.3.  
Sample size estimates were generated to provide robust power to detect minimal clinically important 
differences (MCID) in reduction of opioid use between the 2 study arms. 
Based on anecdotal information from the clinics participating in the study and data available from the 
Liebschutz84 and Sullivan et al.64 studies, a reasonable estimate of mean baseline opioid use across the 
planned study is 55 mg/day. Based on doses of this magnitude, providers involved with the study 
indicated that differences in dose reduction of 10 MED or greater were likely to be viewed as clinically 
meaningful. Consequently, sample size estimates were generated based on an effect size of a difference 
of 10 MED between the 2 intervention arms. The data available from the Liebschutz84  and Sullivan et al. 
64  studies indicate that a reasonable estimate of the coefficient of variation (ratio of standard deviation 
to the mean) for opioid dose levels is 1.45 (range of 1.19 to 1.54), suggesting that a reasonable estimate 
for the standard deviation of the dose level for this study is 80 MED. Finally, data from Liebschutz84 and 
Sullivan et al. 64  suggest that correlation between the baseline and follow-up opioid use levels will result 
in a standard deviation of the change in opioid use of the same magnitude of the baseline standard 
deviation, and that controlling for baseline opioid use in an Analysis of Covariance model will reduce the 
residual mean square error for the test of treatment differences in the change in opioid use to no more 

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than 50% of the baseline level, or 40 mg/day. Based on these assumptions and an assumed minimally 
important difference of 10 mg/day, the number of evaluable independent participants required to 
achieve 80% power to detect a difference of this size is approximately 253 per study arm (total of 506), 
assuming no attrition. 
The data available from Liebschutz84 and Sullivan et al. 64  indicate opioid doses are approximately 
normally distributed on the natural log (ln) scale. If the change from baseline in opioid dose is also 
lognormally distributed, then based on the assumptions above the standard deviation of the change 
from baseline ln-dose, after adjusting for baseline dose would be approximately 0.650. Correspondingly, 
253 participants per study arm provides 80% power to identify a 15% relative dose reduction. 
To account for potential variance inflation associated with CBT group delivery (based on a group size of 
8 and an interclass correlation coefficient of 0.01) and a potential loss of follow-up information on as 
many as 10% to 12% of participants because of attrition, the sample size was inflated by 20% to yield a 
total randomized size of 304 per study arm needed for the primary outcome at 12 months. Therefore, 
the total study sample size will be 608 randomized participants (Table 7). 
Additional estimates of sample size requirements were generated based on the known psychometric 
properties of the secondary outcomes, PROMIS physical functioning and pain interference, under the 
assumption that at least 80% power is desired for the PROMIS Pain Interference scales. The scoring 
algorithm for the PROMIS scales is designed to construct a 100-point scale with a mean of 50 and 
standard deviation of 10. Furthermore, studies of the properties of the instruments indicate that the 
minimally important difference (MID) for the physical function scale is 2 units, whereas the MID for the 
pain interference scale is 3.5 units. Under an assumption of independent observations, a sample size of 
786 evaluable participants would be required to achieve 80% power to detect the MID of 2.0 units for 
the physical function scale, and a sample size of 260 evaluable participants would be required to achieve 
80% power to detect the MID of 3.5 units for the pain interference scale. With the planned total of 608 
randomized participants, the power for the PROMIS Pain Interference score is 96%, while the power for 
the PROMIS Physical Functioning scale is 57%, with a 25% increase to account for attrition or missing 
PROMIS scale responses. No power calculations have been specified for subgroup assessments (Table 
8). 
A review of the opioid MED change from baseline will evaluate if the data is normally distributed or 
skewed and thus requires log transformation prior to analysis. If the change in MED is highly skewed, 
analyses will compare intervention arms for relative rather than absolute dose reduction. The study has 
comparable power to identify a 15% relative dose reduction between intervention arms. 
 
 

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Table 7. Sample Size Required to Obtain 80% Power for Primary and Key Secondary Outcomes 
Parameter 
Mean 
difference 
between 
groups for 
change from 
baseline 
SD 
Power 
N  
(total) 
Percentage 
increase to 
account for 
1-year 
attrition and 
within-cohort 
correlation 
N with 
increase for 
attrition* 
Average Daily 
MED 
10 
40 
80% 
506 
20% 
608 
PROMIS Pain 
Interference 
Scale 
3.5 
10 
80% 
260 
25% 
350 
PROMIS 
Physical 
Functioning 
Scale 
2 
10 
80% 
786 
25% 
1060 
*The n is increased by 20% in the calculation to account for expected within-cohort correlation and attrition from 
the study before the primary 12-month timepoint. A further 5% attrition was assumed for the PROMIS scales 
collected via web or phone.  
 
Table 8. Power for Primary and Key Secondary Outcomes with N=608 Randomized Participants 
Total sample 
size 
Primary aim: 
Power for opioid 
MED* 
Secondary aim: power for 
PROMIS Pain Interference* 
Secondary aim: 
Power for PROMIS Physical 
Functioning* 
608 
80% 
96% 
57% 
*MID, SD, and loss to follow-up rates are the same as noted in  
Table 7. 
 
5.5 Interim Analysis 
The Data and Safety Monitoring Board (DSMB) will routinely monitor the study for safety, conduct, and 
fidelity assessments of GCC, SDM, and CBP-MI with details of the monitoring approach specified in the 
DSMB Charter (see Appendix), the Data and Safety Monitoring Plan (DSMP), and the Statistical Analysis 
Plan. The DSMB will not formally monitor efficacy or effectiveness outcomes for purposes of stopping 
the study early (either due to demonstrated efficacy or futility). 
 
 

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6 STUDY INTERVENTION 
Cross-reference: UNC IRBIS Application Section B.3.5.  
This section describes the 2 interventions we will compare for managing CNCP patients on COT: a 
guideline-concordant pharmacotherapy approach with SDM (Arm 1) compared with a guideline-
concordant pharmacotherapy approach with MI and CBT for chronic pain (Arm 2). Both arms of the 
intervention will be integrated into the usual workflow of the clinics. The first three months of the SDM 
intervention are the most intensive, similar to how the first three months of the CBT arm are the most 
intensive.  
Participants in each of the study arms will receive guideline-concordant care (GCC), based on CDC 
clinical guidelines for COT for CNCP at their opioid management visits for the 12-month intervention 
period. 
In light of the COVID-19 outbreak, the study will take measures to protect research participants, 
researchers, and the larger community from risk of infection.  
Participant research visits will be performed remotely when appropriate and possible, via phone or 
telehealth/telemedicine. Telehealth services used will meet the study’s security level clearance. The 
content of the interventions in the study will remain unchanged. Each institution will work with their IT 
departments to ensure they are using the telehealth services according to the institution’s policy.  
Participants who are currently enrolled in the trial will be given information about the change, the 
reasons for the change, and how the changes may impact their research activities. We will notify 
participants of the changes via phone call, letter, email, etc. and we will document how we notified 
them (see attached, Information for Participants on the INSPIRE study and COVID-19).  
6.1 Guideline Concordant Care Intervention 
CDC guidelines for treating adult patients for chronic pain in outpatient settings were developed to 
“improve communication between clinicians and patients about the benefits and risks of using 
prescription opioids to treat chronic pain; provider safer, more effective care for patients with chronic 
pain; and help reduce opioid use disorder and overdose.” As a guideline for providers, the intervention 
content is primarily directed toward the providers participating in the study. The guidelines give 
guidance about medication selection, dose and duration, when and how to assess progress, and 
discontinue medication if needed. They support the patient-provider team to jointly assess the benefits 
and risks of prescription opioid use. Participants in each study arm will receive guideline-concordant 
pharmacotherapy treatment, based on clinical guidelines for opioid therapy for CNCP.  
GCC specifies current best practices for primary care providers who are treating COT. The best practices 
include the following: 
• 
Determining when to initiate or continue opioids for chronic pain 
- Not using opioids as first-line therapy (not applicable in this study, as participants will 
already be taking opioids) 
- Establishing goals with the patient for pain and function 
- Discussing risks and benefits with the patients 

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• 
Determining opioid selection, dosage, duration, follow-up, and discontinuation 
- Using immediate-release opioids when starting (not applicable if participants are 
already taking opioids) 
- Using the lowest effective dose 
- Prescribing short durations for acute pain 
- Evaluating benefits and harms frequently 
• 
Assessing risk and addressing harms 
- Using strategies to mitigate risk—including patient risk assessment for prior SUDs and 
offering naloxone if increased risk or concurrent benzodiazepine use are present 
- Periodically reviewing state PDMPs to determine if patient is filling prescriptions or 
receiving opioid dosages elsewhere 
- Using UDT at least annually: UDTs are part of the opioid prescribing guidelines, which 
are now the standard of care for providers who prescribe opioids. They are not part of 
the intervention. Some clinics may use point of care UDTs, others may choose clinical 
laboratory tests in which the results will not be available during the clinic visit in which 
the urine was obtained. This will be up to each clinic on how they choose to handle the 
UDTs. 
- Avoiding concurrent opioid and benzodiazepine prescribing 
- Offering treatment for opioid use disorder 
6.2 SDM Intervention 
SDM seeks to explore and compare treatment options, assess a patient’s values and preferences, and 
reach a shared decision between a patient and provider regarding current pain management options. 
SDM occurs when an SDM-trained provider and patient work together to make a health care decision 
that is best for the patient, which for this study is how to best manage pain with or without opioids. The 
optimal decision considers evidence-based information about available health care options, the 
provider's knowledge and experience, and the patient's values and preferences. The best way to ensure 
that patients can make an informed decision about their care is for them to have sufficient information 
about the benefits and risks of their current opioid treatment, other available treatment options, and 
appropriate use of opioids. With SDM, patients are typically given information in the form of decision 
aids that have been found to improve knowledge of treatment options, help patients feel better 
informed, are likely to promote more accurate expectations of benefits and harms, and most 
importantly to increase participation in decision making. 
The SDM intervention will have both provider and patient educational components. The content of the 
provider component will be based on the AHRQ SHARE Approach, which is a 5-step SDM process that 
includes exploring and comparing the benefits, harms, and risks of each option through meaningful 
dialogue about what matters most to the patient. The patient materials are based on materials from 
AHRQ SHARE and the American Chronic Pain Association. The SDM Combined Patient Packet used 
across the course of the 12-month intervention period is provided in the Appendix. Patient-specific 
benefits and harms of continued opioid use are pertinent. Remote (e.g. phone and telehealth) visits are 
also documented in the EHR. 

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6.2.1 Enrollment Procedures for Arm 1 
Cross-reference: UNC IRBIS Application Section B.3.2. 
Arm 1 participants will receive GCC plus the SDM intervention during their opioid management visits. A 
provider trained in both GCC and SDM at their practice will conduct these visits. Patient visits may occur 
either in-person at the clinic or remotely using the clinic’s telehealth platform. 
The participant and provider will meet as often as needed for pain management. If the patient and 
physician decide that an opioid dose change is warranted, the patient may have more frequent visits 
with the SDM provider. A change in the frequency of visits due to medication changes is part of standard 
practice for opioid management and will be covered by health insurance. The patient may have a total 
of 4 to 12 visits over an approximately 12-month period. (We expect about one or more visits every 3 
months to assess benefits and harms of opioid therapy. This would be for a patient on a stable dose of 
opioid medication who will not be adjusting the opioid dose during study follow-up. Patients who 
undergo opioid tapering may have more frequent follow-up visits to reinforce the provider-patient 
partnership, discuss potential withdrawal symptoms, such as temporary increase in pain, and assess 
pain and opioid management based on clinical judgement.) 
If participants are assigned to Arm 1 and their provider is trained in SDM, the participant will continue 
seeing this provider for the 12-month intervention period. If the provider is not trained in SDM, 
participants will be asked to switch providers for opioid management care, and an SDM-trained provider 
will be assigned to the participant based on availability. In the study’s consent form, participants are told 
about the potential need to change providers in order to receive opioid treatment from a trained 
provider. Participants will continue with their current PCP or another provider not trained in SDM for 
their non-opioid care—such as for acute or chronic conditions—with an understanding that only a 
provider trained in SDM can manage participants’ opioid care.  
Distribution of Patient Materials for Arm 1 
SDM patient materials will only be provided to participants who have been randomized to Arm 1 of the 
study. The Research Coordinator will provide the SDM Combined Patient Packet (see Appendix) to the 
participant at the enrollment visit, electronically, or by mail. The SDM Patient Packet will include all the 
educational handouts (e.g., decision aids) so that participants who do not have Web access will have 
these documents. The packet will also contain links to Web-based versions of the materials for those 
who prefer to view the materials electronically. Participants will be strongly encouraged to review the 
suggested materials before each visit with the SDM provider. 
To provide some structure to the SDM intervention, we have asked clinicians to review one or more 
study aids at each SDM visit as appropriate. The structure is intended to have some flexibility based on 
needs of the individual patient while providing guidance about content and order. 
6.2.2 Coordination of Care 
The SDM providers will document their opioid SDM discussion and management in an EHR note 
template, which will facilitate communication between the participant’s SDM-trained and non-SDM–
trained providers.  

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6.3 MI+CBT-CP Intervention 
Participants in Arm 2 will receive guideline-concordant pharmacotherapy, plus an empirically-based 
behavioral pain management behavioral therapy intervention, including MI to enhance motivation for 
active participation in CBT-CP and for opioid dose reduction or cessation, and CBT-CP for pain--coping 
skills enhancement. The MI+CBT-CP intervention is an empirically based behavioral pain management 
therapy intervention. MI and CBT-CP have both been used effectively with chronic pain.  
6.3.1 Enrollment Procedures for Arm 2 
For Arm 2 participants, the GCC portion of the intervention will be delivered by the participant’s primary 
care provider or pain specialist who is participating in the study and has been trained. The participant 
will continue to see the same provider for opioid management regardless of whether their provider is 
trained in SDM or not. Because Arm 2 participants will not receive SDM decision aids, the providers will 
be trained not to use SDM with these patients (even if they have been trained in SDM). 
Licensed clinicians, including masters- or PhD-level psychologists, licensed clinical social workers, or 
licensed professional counselors, will deliver the MI+CBT-CP intervention. To verify the training of 
MI+CBT-CP providers, RTI will request proof/documentation of fulfilling the study’s MI+CBT-CP training 
from each MI+CBT-CP provider. However, the MI/CBT-CP providers are clinical staff at their respective 
institutions and have experience with MI and CBT-CP. Thus, training will focus on the study MI/CBT-CP 
protocol, and not MI or CBT per se. 
The intervention will include 1 individual MI session as soon as this session can be scheduled after 
enrollment and up to 8 CBT-CP group therapy sessions. We anticipate the MI+CBT-CP component of the 
intervention may occur within 3 months of enrollment but could extend longer. The process for 
scheduling the participant may vary slightly based on the institution or clinic. Study or clinic staff will 
continue to follow up with the participant until the individual MI visit and the group CBT sessions are 
scheduled. The goal will be to arrange for CBT to begin as soon as possible after the baseline interview.  
The participant will be asked to attend one individual MI session that will last about 30 to 60 minutes, 
either in-person or via the clinic’s telehealth platform.  
MI is a style of interviewing, or a process, and because of this it is difficult to formally “manualize.” 
(Indeed, it has generally been found to be less effective when manualized [personal communication, 
Stephen Rollnick, PhD].) Nevertheless, MI does have 4 processes: engagement, focusing, evoking, and 
planning, as described in Table 9 and in the MI-CBT-CP Therapist Manual (see Appendix). The MI 
session can be conducted anytime between the baseline interview and Session 6 of CBT. Further, 
additional MI will be woven into the CBT-CP sessions, as described in the CBT-CP session outline below.  
If the participant is a no-show for the visit, standard clinic procedures will be used for any follow-up. This 
is consistent with a pragmatic trial and an ITT analysis.  

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Table 9. Motivational Interviewing Processes 
1. Engaging 
a. Make patient feel comfortable, listen to their concerns 
b. Establish trust and mutually respectful working relationship 
c. 
Traps to avoid in the engagement phase: 
1. Assessment trap 
2. Expert trap 
3. Premature focus trap—i.e., don’t focus before engagement 
4. Labeling 
5. Blaming trap 
6. Labeling trap 
2. Focusing 
The focus is largely dictated by the setting and scope of the service provided (REF: M and R). 
Participants will enter the current study knowing that the purpose is to improve their functioning with 
chronic pain. A part of the effort to improve functioning is a discussion on how opioids fit with their 
pain management, their functioning, and other life goals—and the possibility of decreasing opioids. 
Consequently, the initial focus will be on the patient’s chronic pain, well-being, their goals, barriers, and 
obstacles to their goals. One aspect of this will be a discussion on the role of opioids and possibly 
decreasing the dose. 
3. Evoking 
The purpose is to strengthen motivation for change. Self-talk helps the patient express and resolve 
ambivalence. The patient expresses the pros and cons of available alternative strategies. In the case of 
opioids, the client would express what he or she sees as the advantages and disadvantages of decreasing 
opioids. 
4. Planning 
MI addresses people according to their "level of change" (whether "precontemplative," 
"contemplative," or further along, such as in the "action" stage). While some patients may enter the 
study with a desire to reduce opioid dose, we anticipate that many will enter the study ambivalent 
about this. Regarding opioid dose, we anticipate that the patient could express a desire to (1) maintain 
the current opioid dose, (2) decrease opioid dose by taper, but continue to take opioids at a lower dose, 
(3) taper off opioids completely, or (4) increase opioids. While some plans may be developed at the 
initial MI session, planning will generally evolve during the CBT-CP sessions, which will also involve 
elements of MI. 
 
Eight sessions of CBT-CP will be delivered in a group setting, in the clinic or over the clinic’s telehealth 
platform. These sessions will focus on 
• 
education about chronic pain, 
• 
pacing and exercise, 
• 
relaxation techniques, including deep breathing and progressive muscle relaxation, 
• 
behavioral activation, including identification and scheduling of pleasurable activities, 
• 
cognitive restructuring, including the identification and challenging of maladaptive thoughts, 
and 
• 
behavioral sleep management training. 

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The topic of each CBT-CP session, aim, agenda, and patient handouts is outlined in the MI-CBT-CP 
Therapist Manual, which is included in the Appendix. The MI-CBT-CP Session Guide and Handouts for 
patients are also in the Appendix. These will be provided in-person, electronically, or by mail.  
While the primary focus of CBT-CP will be to improve physical functioning, education on opioids also will 
be introduced. For example, we will include education on opioid effectiveness for CNCP (e.g., that 
opioids are not effective for many people) and opioid side effects. In the cognitive restructuring 
component, we will discuss common catastrophizing thoughts about medication (e.g., “I don’t know 
what else to do for this pain other than take opioids”). 
The provider will document the intervention delivery in the EHR. 
6.3.2 Coordination of Care  
If during the MI or CBT-CP sessions, the participant expresses a desire to reduce their opioid dose or 
discontinue opioids, the therapist will inform the primary provider, with the participant’s permission. 
The communication linkage between the therapist and the primary physician is crucial for the success of 
the trial. 
To facilitate this linkage, following MI+CBT-CP group sessions, we will ask Arm 2 participants to self-
report their perceptions of: the helpfulness of the CBT group sessions; the quality of their current 
approach to pain management; their ability to manage pain; and their goal with their opioid dose. The 
purpose of the form is to facilitate coordination of care. The information will only be used for clinical 
purposes and will not be used for data analysis. 
This will be done via a form, the Post-CBT Group Session Form (see Appendix). The form is voluntary, 
and patients may skip any question they do not wish to answer. This form was developed with the input 
of patient representatives, primary care physicians, therapists, and the research team.  
The form will ask the participant if their responses can be shared with their health care provider. If the 
patient says yes, the therapist will communicate the responses to the provider.  
The form will be administered on paper if the CBT session is conducted in-person, and by mail or 
electronically if the CBT session is conducted remotely.  
The inter-provider messaging system within the Epic EHR system will be the primary means of 
communicating the participant’s motivation to decrease opioids.  
We have worked with our clinical sites to solicit provider input to determine what is customary and 
feasible for this pragmatic trial. Means of communication may include copying the primary provider on 
the therapy note, sending information via secure email, requesting read receipts, requiring a response 
from the provider acknowledging they have read the note, and/or including the provider’s nurse on the 
messages.

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7 STUDY INTERVENTION TRAINING AND DOCUMENTATION 
Cross-reference: UNC IRBIS Application section A.4.7.  
7.1 CDC Guidelines Training Material Content for Providers 
All primary care and pain care providers who provide opioid management to study participants will 
provide CDC GCC. Only providers who have the requisite GCC training will be able to see enrolled study 
participants. 
7.1.1 CME Training for Opioid Therapy in Chronic Pain Patients 
Many providers have already taken commensurate training as a requirement for maintaining their 
licenses or board certification, and they would be exempt from the study training. Training should have 
been completed within the past 12 months and administered by the state of North Carolina or 
Tennessee or an authoritative medical board. To document providers’ qualifications to provide GCC, the 
study team will ask each study provider to (1) affirm documentation of state-level Continuing Medical 
Education (CME) training for opioid therapy in chronic pain patients or (2) complete study-specific 
training with the CDC guideline training modules. 
7.2 SDM Provider Training 
All primary care and pain care providers at clinical institutions will be asked to complete the SDM 
training. Only providers who have completed the study specific SDM training will be able to deliver the 
SDM intervention. 
The content of the provider training will be based on the AHRQ SHARE Approach, which is a 5-step 
process for SDM that includes exploring and comparing the benefits, harms, and risks of each option 
through meaningful dialogue about what matters most to the patient, as shown in Table 10. 
Table 10. SHARE Approach to Shared Decision Making 
Review essential steps of shared decision making: 
Step 1: Seek your patient’s participation. 
Step 2: Help your patient explore and compare treatment options. 
Step 3: Assess your patient’s values and preferences. 
Step 4: Reach a decision with your patient. 
Step 5: Evaluate your patient’s decision. 
7.3 MI+CBT-CP Provider Training 
The study team will identify one to four providers to provide the MI+CBT-CP intervention. Only 
providers who have completed the study-specific MI+CBT-CP training will be able to deliver the MI+CBT-
CP intervention. The training process will be based on Motivational Interviewing by Miller and Rollnick 
and Managing Chronic Pain: A Cognitive Behavioral Therapy Approach Therapist Guide.,85 
7.4 Research Coordinator Training 
All Research Coordinators will complete a study training prior to beginning of recruitment to review all 
elements of the protocol and their specific responsibilities.  
 

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8 SAFETY MANAGEMENT 
8.1 Potential for Risk 
8.1.1 Potential Psychological Risks 
Cross-reference: UNC IRBIS Application section A.6.1, A.6.2. 
There is a risk that some of the survey questions or intervention content could result in a participant 
feeling some emotional distress or embarrassment. The participant may refuse to answer the questions 
and may stop participation in this study at any time. A safety protocol (suicide prevention plan) will be 
activated in very rare instances in which a participant is feeling severe or life-threatening distress. 
Protocol Section 3.3, Screening, describes the procedures we will use to minimize these risks.  
The chance of a breach of confidentiality is rare. There is a very small risk that someone could get access 
to study information we have stored about participants and may misuse it. Confidentiality is very 
important to us. We will take several steps to protect it, such as training staff, using secure databases, 
de-identifying data, collecting only the minimum amount of information necessary, and limiting access 
to the information. RTI will apply for a Certificate of Confidentiality from NIH. Research staff who have 
direct contact with participants are under the purview of HIPAA at their respective agencies. Other 
measures we are taking to mitigate risks to subjects’ privacy and confidentiality are described in section 
9.3, Protecting Confidentiality.  
8.1.2 Potential Social Risks 
Cross-reference: UNC IRBIS Application section A.6.3, A.6.4. 
No potential social risks have been identified. 
8.1.3 Potential Economic Risks 
Cross-reference: UNC IRBIS Application sections A.6.5, A.6.6 (risks), B.5.1 (costs). 
If the participant is randomized to the CBT arm, a co-pay may be required for each CBT session 
attended.  
If the participant is randomized to the SDM arm, and if the participant changes opioid dose, there may 
be additional visits. These visits are part of the standard of care for opioid management. Clinical sites 
(Duke, UNC, VUMC) will work with clinic management to tailor delivery of the SDM intervention based 
on needs of their clinic. For example, one site may choose to enroll only the patients seen by SDM-
trained providers whereas another site may have the patient switch all care to an SDM-trained clinician.  
Thus, clinics can do one or more of the following if they deliver the intervention as outlined in the 
protocol: 
• 
Enroll patients from only SDM-trained providers 
• 
Adhere to clinic guidelines that use dual management of pain patients (which is currently in place in 
some of the clinics)  
• 
Have SDM providers provide primary care as well  

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We will be fully transparent with the potential respondents when we explain the study to them, that 
they will be responsible for additional co-pays that may be incurred as part of the research. 
8.1.4 Potential Legal Risks 
Cross-reference: UNC IRBIS Application section A.6.7, A.6.8. 
The study will collect information about alcohol/substance abuse and misuse via the subject’s electronic 
medical record data, as measured by ICD-9/10 codes. The subject will not be asked about these topics 
via self-report surveys. 
The major legal risk to subjects would come from a breach of privacy & confidentiality. To mitigate this 
risk, the EHR data will be de-identified and will use a study identifier instead of patient identifiers. We 
will have data use agreements in place to share the data across institutions. Other measures we are 
taking to mitigate risks to subjects’ privacy and confidentiality are described in section 9.3, Protecting 
Confidentiality.  
8.1.5 
Potential Physical Risks 
Cross-reference: UNC IRBIS Application section A.6.9, A.6.10. 
There is some potential risk that participants may experience increased pain if they reduce or 
discontinue their opioid medication.  
We expect any side effects to be rare or infrequent and mild-to-moderate. 
This study is comparing two different behavioral interventions for patients with chronic pain who are 
already on chronic opioid therapy. Some of the intervention content is about tapering or discontinuing 
opioids. The participant may choose to request to taper or discontinue opioids. Lowering the dose of 
opioids has the potential for side effects from withdrawal. But, there are no extra risks from this study 
compared to discontinuation as part of usual care. 
The approach of this trial is to promote a controlled opioid reduction, which in some cases might lead to 
complete discontinuation, with a patient’s consent. The protocol does not specify or foresee abrupt 
tapering. 
If patients do choose to taper, the physicians will be doing a very gradual taper of their opioids (as per 
CDC guidelines, 10% per week), which has rare to infrequent risk of withdrawal. If withdrawal is 
experienced, mild to moderate symptoms are expected. These symptoms may include low energy; 
irritability; anxiety; agitation; insomnia; sweats; muscle aches and pain; as well as abdominal cramping, 
nausea, and vomiting. Patients will be advised to call their provider if they experience symptoms of 
withdrawal.  
To reduce physiological risk, certain safeguards will be implemented at RTI and at all clinical institutions. 
Procedures to reduce clinical risk include intensive medical monitoring of AEs and medical management 
common for this study population. 
 

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8.2 Risk Monitoring 
8.2.1 Human Subjects Protection 
We have developed a plan for protecting human subjects, beginning with obtaining IRB approval. The 3 
clinical institutions that are part of the PCORnet STAR CRN—UNC, Duke, and VUMC—have taken steps 
to enter into a reliance agreement to utilize a single IRB at UNC to review this project. 
Assurances that the benefits of study participation outweigh the risk are made through informed 
consent procedures, maintenance of participant confidentiality, adherence to HIPAA regulations, and 
close monitoring and reporting of AEs. All research staff who will assist with this pragmatic trial (i.e., 
those who contribute to the scientific development or execution of the study in a substantive, 
measurable way) will complete the appropriate Collaborative Institutional Training Initiative (CITI) 
modules, so that they are aware of requirements for protection of human subjects. Each of the 
participating institutions and RTI holds a Federal-Wide Assurance (FWA) for the Protection of Human 
Subjects, which ensures that the institution’s human research activities comply with the requirements 
set forth in 45 CFR 46. In addition to the federal regulations, RTI will take into consideration any state or 
local laws regarding human subjects that may be more protective than the federal statutes. 
All the institutional IRBs will monitor the research process at their respective practice under the SMART 
/single IRB arrangement noted above to ensure that the procedures for protecting human subject rights 
are followed by their staff. RTI and the participating institutions will maintain all records of initial and 
annual approvals.  
8.2.2 Data and Safety Monitoring Board 
Cross-reference: UNC IRBIS Application A.7.2.  
The study has a DSMB that consists of individuals who are not participating investigators in this trial. The 
primary responsibility of the DSMB is to review cumulative study data to evaluate safety, study conduct, 
scientific validity, and data integrity to ensure that the study is operating in a safe and ethical manner. 
The DSMB will meet 2 times per year to review the accumulating data and recommend necessary 
changes to the conduct of the trial. The RTI Coordinating Center will prepare and submit reports to the 
DSMB. The report will include all AE data reported in REDCap (available from the PCORnet CDM data 
extraction or provided by self-report during participant surveys) and will be summarized by the RTI Data 
Coordinating Center and sent to the DSMB biannually for review. 
8.2.3 Data and Safety Monitoring Plan 
Cross-reference: UNC IRBIS Application A.7.2, C.1.1.  
The study team has developed and finalized a DSMP. This plan will adhere to the PCORI guidelines on 
DSMPs. 
8.3 Adverse Event/Serious Adverse Event monitoring and reporting procedures 
An AE is any untoward or unfavorable medical occurrence in a human subject, including any abnormal 
sign (for example, abnormal physical exam or laboratory finding), symptom, or disease temporally 
associated with the subject’s participation in the research, whether or not considered related to the 

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subject’s participation in the research (modified from the definition of AEs in the 1996 International 
Conference on Harmonization E-6 Guidelines for Good Clinical Practice). 
An SAE is an AE that meets any one of the following criteria: results in death, is life threatening, or 
requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent 
or significant disability/incapacity, birth defects or based on medical judgement may jeopardize the 
participants health or may require medical or surgical intervention. This study does not involve an 
investigational product, device intervention, or highly invasive data collection procedure. However, 
recognizing that unanticipated events (see below) can occur during any study, the following reporting 
protocols will apply. 
Study participation and exposure to the interventions are expected to have a moderately low risk of AEs 
for participants, in the form of adverse effects associated with reduction of opioid dosage. At the same 
time, the underlying chronic conditions of the participants may naturally lead to deleterious health 
outcomes. To efficiently collect safety information that is relevant to study participation and the 
interventions, detailed information concerning a prespecified set of AEs and SAEs will be collected and 
evaluated throughout the conduct of the trial.  
8.3.1 Reportable Adverse Events and Serious Adverse Events 
For the purposes of this study, an event will be considered reportable (collected for data entry) if it 
meets at least one of the criteria below. The AEs and SAEs shown in Table 11 will be recorded and 
reported. SAEs not on this list will not be recorded or reported. 
Table 11. Reportable Events and Assessment Methods 
Reportable Event 
Assessment Method 
Suicide risk (active suicidal ideation or attempted suicide) 
(see section 8.3.5 below) 
Adverse Event Case Report Form  
All Deaths (including opioid-related, suicide, and all other 
deaths) 
Adverse Event Case Report Form, PCORnet EHR-
based data, National Death Index (available after 
study completion), publicly available data  
Hospitalizations or Emergency Department (ED) visits 
related to opioid use (overdose or withdrawal) or related 
to suicide attempt 
Adverse Event Case Report Form, PCORnet EHR-
based data, patient self-report via 6- and 12-month 
follow-up surveys 
 
 
When one of these AEs is identified, the institution PI or designee will assess the event to evaluate 
whether it is one of the following: 
• 
Unanticipated (i.e., unexpected). These events are AEs that are new or greater than previously 
known, in terms of nature, severity, frequency or occurrence, as documented in the protocol, 
consent, or other study documents approved by the IRB (OHRP- 
https://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-unanticipated-
problems/index.html). 
• 
Related (possibly related, probably related, or definitely related) to study participation. 

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Institutions will record all reportable events in REDCap in the Adverse Event Case Report Form.  
Reporting will either follow an expedited or periodic timeline.  
8.3.2 Expedited Reporting 
Expedited reporting procedures must be followed when an SAE meets both of these conditions:  
• 
SAE is considered unanticipated/unexpected, AND  
• 
at a minimum, possibly related to study participation. 
Institutions must report expedited SAEs within 2 business days of the Institution’s awareness to the 
single UNC IRB and to RTI. RTI must notify DSMB of the event within 24 hours. RTI must provide a 
summary report of the event to DSMB within 7 days.  
8.3.3 Periodic (Non-Expedited) Reporting 
Periodic (Non-Expedited) reporting procedures must be followed when the SAE meets both of these 
conditions: 
• 
SAE is considered unanticipated/unexpected OR expected AND 
• 
SAE is NOT related to study participation. 
RTI must provide a summary report of the event to DSMB at the next DSMB meeting as part of the 
regular DSMB meeting report.  
8.3.4 Unanticipated Problems 
The study will collect and report unanticipated (i.e., unexpected) problems that may involve risk to the 
participant or study staff, but do not necessarily result in an AE (i.e., harm). An example of an 
unanticipated problem that may not result in an AE is misplacement of a participant’s research record 
containing PII such that the risk of loss of confidentiality is introduced. This event is reportable 
regardless of whether the confidentiality is breached or not breached.  
Institutions must report other unanticipated problems that are not SAEs but involve substantial harm (or 
genuine risk of substantive harm) to the safety, rights, or welfare of the institution’s research 
participants, research staff, or others to the single UNC IRB and RTI within 5 business days. 
Otherwise, the institution will report unanticipated problems to the single IRB and RTI on an annual 
basis at the time of continuing review. 
8.3.5 Suicidality  
We will capture suicide risk (active suicidal ideation or attempted suicide) during the intervention period 
during clinical encounters. As this is a pragmatic unmasked behavioral intervention trial, suicide risk will 
only be captured if the participant indicates intent to self-harm during the clinical intervention visit; the 
provider will not conduct a study-specific suicide risk assessment. If the clinic becomes aware of suicide 
ideation, the provider will follow the institution’s or clinic’s protocols, as described in our Safety 
Protocol (see Appendix). Similarly, if active suicide ideation is self-reported to the research coordinator 
during the screening visit review of exclusion criteria, the provider will be notified and will follow the 
institution’s or clinic’s protocols. 

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The therapists delivering the MI +CBT-CP intervention will all be masters- or PhD-level mental health 
providers with training and experience handling suicidal patients. If a participant does express suicidal 
ideation, the therapist will handle it in the manner that they would in their clinical practice. Similarly, if a 
participant being seen in the SDM intervention (Arm 1) expresses suicidal ideation, the clinic will handle 
it in the manner that they would in their clinical practice.  
The provider will report the event to the institution’s Research Coordinator, and the Research 
Coordinator will complete an Adverse Event Case Report Form. 
We will capture whether the participant has been to the ED or had an inpatient hospitalization because 
of self-harm via self-report and PCORNet CDM data extraction. We will capture information on when 
and where this occurred. 
8.3.6 Deaths 
If site study staff become aware of the death of a participant, the site will report the event via the 
adverse event case report form. We will include the cause of death in the report. If the cause of death is 
unknown and not available in the EHR, the study’s DSMB has requested that the study try to obtain 
cause of death information from the participant’s death certificate. The DSMB will use the information 
to make an objective decision about whether the death was possibly related to the study.   
Study staff at the enrolling site will request a copy of the death certificate from the appropriate state 
agency, if such information is publicly available. Whether death certificates are available publicly 
depends on the state. The NC Department of Health and Human Services makes available uncertified 
copies of death certificates for informational purposes to anyone who requests them, unless legal 
restrictions apply. Study staff will abide by the applicable state and local laws in making any such 
request. When requesting death certificates, study staff will not disclose any information linking the 
decedent to their participation in the INSPIRE study.  
 
Once the death certificate is obtained, the site will provide the cause of death information to RTI via the 
adverse event case report form. RTI will then use this information to update Serious Adverse Event (SAE) 
reports that are provided to the DSMB.  

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9 DATA MANAGEMENT 
Cross-reference: UNC IRBIS Application Section A.8.4.  
9.1 Pre-Enrollment Data Management 
Most eligibility inclusion and exclusion criteria will be determined from data recorded in the institution’s 
EHR. Institution informatics staff will use specified criteria to develop an EHR recruitment phenotype 
report, in the form of a file that lists patients names, demographics, provider names, and key selected 
criteria for patients who meet this initial screening criteria. This file will be produced by each institution 
at regular intervals and be stored in a secure study folder on a HIPAA-compliant server, with access 
restricted to study staff. Prior to study startup, the study team will validate the phenotype and make any 
adjustments as needed. 
All details of participant screening and recruitment will be tracked by the clinical institutions in a Pre-
Screening Database stored in a secured electronic environment within each clinical institution.  
To facilitate remote enrollment, we will use electronic versions of the enrollment forms (Consent to 
Screen, the Study Consent, the HIPAA Authorization, and the Participant Contact Information) in a 
REDCap database stored securely at each clinical institution. These REDCap databases will be separate 
from the central REDCap study database stored at RTI because they will contain PII. Electronic signatures 
will be captured using REDCap’s Consent module. REDCap will generate and store a signed version of the 
consent form as a PDF. The participant will have the option to download a copy of their signed consent 
form.  
Summary/aggregate screening data (such as counts) will be reported by the institutions to the RTI Data 
Coordinating Center via a central REDCap study database accessible by RTI to facilitate accurate 
reporting according to CONSORT standards. 
9.2 Enrolled Participant Data Management 
We will use REDCap86 as our core data capture system and repository for the aggregation of participant 
screening, recruitment, enrollment, tracking, and baseline self-reported outcome data.  
REDCap is a secure (Health Insurance Portability and Accountability Act of 1996 [HIPAA], 21 Code of 
Federal Regulations [CFR] Part 11), and Federal Information Security Management Act (FISMA)-
compliant web application designed to facilitate participant enrollment, randomization, tracking, and 
multiple modes of data entry. 
For consented participants, baseline monitoring and screening information will be entered into the 
central REDCap study database stored at RTI, and eligible participants will be randomized directly in 
REDCap. Collection of patient-reported outcomes at baseline will be performed using REDCap’s web-
based survey tools. Should some participants find the tablet challenging, paper forms will be available. 
Subject status and adverse events will also be recorded in the REDCap Study database. 
 

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9.3 Follow-Up Survey Data Management 
RTI staff will collect the 6- (T2) and 12-month (T3) follow-up surveys using a combination of Voxco for 
survey data collection (via web and CATI) and the RTI’s in-house survey management system (Nirvana) 
system for case management. Follow-up data collection will be scheduled automatically at the 
appropriate assessment time from the participant’s randomization date.  
Voxco is an integrated interviewing and case management system that provides state-of-the-art tools 
for conducting telephone survey research. The Voxco system runs in RTI’s Federal Information 
Processing Standards (FIPS) moderate network, providing a secure data collection environment for data 
collection projects.  
RTI’s in-house survey management system, Nirvana, is a control and case management system for 
multimodal survey projects and runs in RTI’s FIPS moderate network.  
9.4 Qualitative Data Management 
RTI staff will collect qualitative data using a web conferencing platform (for example, Zoom or 
BlueJeans). We will take security measures including: 
• 
Using a unique, automatically generated meeting ID 
• 
Requiring a password for the meeting 
• 
Using the “virtual waiting room” to approve meeting participants before entering  
• 
Locking the meeting after it has started 
• 
Preventing participants from screen sharing 
 
RTI staff will consult with the RTI Privacy Officer to make sure that the platform used adheres to 
institution requirements.  
9.5 Quality Assurance 
All staff involved with data collection will be required to have training on use of the study data 
management systems. Staff may contact the RTI Data Coordinating Center by telephone or e-mail with 
questions about recording study data or conducting randomizations in REDCap. The REDCap, Nirvana, 
and Voxco data collection screens will have embedded quality control measures such as reports on 
missing data fields and range-checks on data fields where applicable. Additional reports may be 
developed to check cross-form and cross-data source consistencies. These reports facilitate timely 
identification and resolution of problems in data collection and processing. 

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10 CONFIDENTIALITY OF THE DATA 
10.1 Procedures for Maintaining Confidentiality 
Cross-reference: UNC IRBIS Application A.10.1, A.11.2, B.1.8, B.3.6 (privacy procedures) 
As with any research, the potential exists for a breach in confidentiality; however, this is very unlikely. 
Study sites will establish and maintain the appropriate administrative, technical, and physical safeguards 
to protect the confidentiality of the data and to prevent unauthorized use or access to the data. The 
study will not disclose data nor permit others to use the data except as described in this protocol.  
Access to hard copy or electronic data is restricted to authorized staff members. 
 
To maintain confidentiality during enrollment: 
• 
During in-person enrollment, survey data will be collected in a private location, which reduces 
the risk that answers to interview questions will be overheard by others not directly involved in 
the research and which promotes comfort in discussing sensitive issues.  
• 
Similarly, during remote enrollment, the RC will ask the patient to complete screening and 
enrollment in a private location.  
• 
Information obtained through these processes will not be disclosed to anyone who is not 
directly involved in the study, except in cases where potentially life-threatening conditions are 
revealed. 
To maintain confidentiality during group intervention sessions: 
• 
Participants will be told that all information shared during the session is private and should not 
be shared with anyone outside the group session.  
• 
The therapist will record information about these sessions in the form of a Patient Encounter 
note within the EHR to be used as an indicator of adherence with the study intervention.  
• 
Because the post-CBT group session form is only used for clinical purposes, it is not linked to the 
participant ID. Participants will be asked to complete the form in a private location and return it 
at their next session in an envelope, in order to reduce the risk that their responses will be seen 
by others. After the therapist confidentially reviews the form, he/she will destroy the hard copy 
form as per institution policy.  
To maintain confidentiality of the data:  
• 
To ensure consistent data linking across all clinical institutions, the PCORnet data warehouse 
uses a global unique identifier (GUID) to uniquely identify a patient’s EHR data. A GUID is a long, 
unique, alphanumeric identifier generated by key identifiable information that is typically 
collected as part of the patient’s medical record. Use of a GUID facilitates the unique 
identification of each patient, without the need to transmit PHI or PII. 

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• 
Identifiers will be stored separately from the research data. Research data will be coded with a 
study-specific participant identifier. The linkage file between the participant ID and PII will be 
stored in a different file location maintained by study recruitment staff.  
• 
The participant ID will be used to link research data across data collection sources and the 
study’s REDCap, Voxco, and Nirvana data capture systems.  
• 
All transfers of EHR data from each clinical institution’s PCORnet data warehouse to the RTI Data 
Coordinating Center will be limited to protocol-specified data elements for randomized study 
subjects and will be identified only by the participant ID and not the GUID.  
To maintain confidentiality during qualitative research activities:  
• 
Participants will be told that all information shared during the session is private and should not 
be shared with anyone outside the group session.  
• 
We will use a secure web conferencing platform and adhere to RTI requirements for use of web 
conferencing with research studies.  
• 
We will only record audio and not video. We will also tell participants not to record the session 
or take screenshots.  
• 
Audio recordings will be stored on secure, encrypted computers. They will only be used to 
create transcripts.  
• 
Qualitative data will not be connected with the participant’s main study participant ID.  
• 
Participant responses will be coded with a separate identifier for the qualitative research 
component. The linkage file between the qualitative ID and PII will be stored in a different, 
secure file location maintained by RTI staff.  
• 
Transcripts will not contain PII.  
• 
Qualitative data will not be shared with site research staff or health care providers.  
10.1.1 Certificate of Confidentiality  
Cross-reference: UNC IRBIS Application A.10.4, B.3.6 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH). This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
10.2 Procedures for Data Transmission 
Cross-reference: UNC IRBIS Application section A.10.2, A.11.1, A.11.2, C.1.2, C.1.3, C.2.1 (DUAs) 
Data Use Agreements (DUAs) will be completed between RTI and each study site prior to the transfer of 
any data if required by the institution. 

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Confidentiality of the Data 
Page 73 of 81 
10.2.1 PCORnet DataMart Extractions and Data Transfer 
RTI and clinical and data warehousing staff will collaborate to identify a specification of data elements 
within the PCORnet common data model required for the study. The STAR CRN uses the PCORnet CDM 
to map EHR data to the same format across all participating institutions. PCORnet data warehousing 
staff will develop and implement software to extract the specified data elements into a study-specific 
DataMart extraction, which after validation at the institutions, will be transferred to the RTI Data 
Coordinating Center at prespecified times during the study. 
The EHR data extracted from each study site’s CDM will be uploaded to the RTI Data Coordinating 
Center via a HTTP Secure File Transfer Protocol (SFTP) setup by RTI. SFTP provides a high level of security 
(SSL Encryption) and allows sites to transfer files via a web browser. Each site will only have connection 
to their own sites’ SFTP folder, which is accessed via a username and password. These credentials will 
only be provided to each site’s Project Manager and CDM programmer. The EHR data will be housed on 
the FIPS Low server at RTI because they will not contain PHI/PII.  
10.2.2 Transfer of Participant Contact Information for Follow-Up Surveys 
Each clinical site will provide participant contact information (as described on page 37) to RTI 
International so that RTI can conduct the T2 and T3 follow-up surveys. Only contact information for 
randomized study participants will be shared.  
A separate SFTP will be setup to transfer the participant contact information to the Data Coordinating 
Center in order to conduct the follow-up surveys. Because these data contain PHI/PII, they will be 
housed on a FIPS Moderate server at RTI that meets FIPS-199 requirements for PII, including Risk/Impact 
Levels of confidentiality (moderate), integrity (moderate), and availability (low).  
10.3 Collection of Sensitive Information 
Cross-reference: UNC IRBIS application A.10.3.  
The research data collected from the EHR will include the following information that some individuals 
may consider sensitive:  
• 
Mental health disorders, defined by ICD-10 codes (e.g., depression, anxiety, schizophrenia, 
bipolar disorder, suicide attempt/intent) 
• 
Alcohol/substance misuse or abuse as measured by ICD-10 codes 
These data will not contain any identifiers and will be labeled only with the study-specific participant ID.  
10.4 Post-study disposition of identifiable data 
Cross-reference: UNC IRBIS application A.12.1 
At the end of the study, a de-identified public-use study database will be delivered to PCORI. The 
de-identified database will be limited to the items specified in Section 4 (Study Evaluations and 
Measurements) and will not include any participant identifying information, such as dates, text fields, 
extremely rare and potentially identifying events, or other potentially identifying data. 

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Plans for Publication 
Page 74 of 81 
11 PLANS FOR PUBLICATION 
We plan to disseminate the study findings via conference presentations and peer-reviewed publications 
in professional journals. Any study findings that are reported in professional journals or at meetings will 
not contain any PII or PHI. The study leadership team will develop a publication policy for the study. No 
patient identifying information will be included in any disseminated products.  
 

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