Tailored Non-Pharmacotherapy Services for Chronic Pain: Testing Scalable and Pragmatic Approaches
Phase: NA
Conditions: Chronic Pain
Sponsor: Kaiser Permanente

 
 
Tailored Non-Pharmacotherapy Services for Chronic Pain:  
Testing Scalable and Pragmatic Approaches (RESOLVE Study) 
 
UH3 STUDY PROTOCOL 
 
 
Principal Investigator:  Lynn L. DeBar, PhD, MPH 
 
Grantee Institution:  
Kaiser Permanente Washington Health Research Institute (KPWHRI)  
 
Version Number: 5.0 
 
10 November 2022 
 
 
ClinicalTrials.gov Protocol Identifier: NCT04523714 

RESOLVE UH3 Protocol 
Version 5.0  
 
10 Nov 2022 
 
 
 
I 
STATEMENT OF COMPLIANCE 
 
The study will be conducted in accordance with the following: 
 
• 
The International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46) 
• 
Completion of Human Subjects Protection and ICH GCP training by the Principal 
Investigator and clinical trial site staff who are responsible for the conduct, management, 
or oversight of National Institute of Health (NIH)-funded clinical trials 
 

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II 
SUMMARY OF CHANGES 
 
Date 
Description of Change  
(Include specific sections affected) 
Rationale for Change 
07/15/20 
Corrected the description of clinical trial phase to 
phase III; it was incorrectly stated as phase IV. 
1.1 Synopsis 
4.1 Overall Design 
Inaccuracy in text 
 
07/15/20 
Added description of subgroup analyses based on 
age and race/ethnicity, as required for NIH phase III 
clinical trial. 
3.4 Exploratory (Tertiary) Objectives 
15.7 Additional Effectiveness Analyses for Primary 
Outcome (Moderators and Mediators)  
Required by NIH and requested 
by NIA 
 
08/06/20 
Corrected description of modified BPI-SF to be 11 
items (vs. 10 items) and pain intensity subscale to be 
4 items (vs. 3 items) 
3.1 Primary Objective 
3.2 Secondary Objectives 
Inaccuracy in text 
 
08/06/20 
Added final info on perceived support measure to 
mediator table  
3.4 Exploratory (Tertiary) Objectives 
Finalized based on pilot study 
completion 
08/06/20 
Changed randomization stratification based on sex to 
be based on EHR data and not self-reported sex in 
baseline survey 
4.3 Study Arm Assignment/Randomization 
Changed due to ability to ensure 
availability of EHR variable (i.e., 
not missing) 
08/06/20 
Added information on KP CHR (KPNW) as site of 
virtual health coaches 
10.1 Description of Interventions 
Update to team structure/ 
intervention staffing 
09/25/20 
Changed KPGA site PI from Dr. Bradlyn to Dr. 
McCracken since Dr. Bradlyn is retiring and revised 
page to just include contact info and not signatures 
Page iii. Investigator Contact Information 
Current KPGA site PI is retiring 
in Dec. 2020 
09/25/20 
Edited the follow-up data collection windows to reflect 
final data collection decisions: 3-month changed to 
80-140 days (from 75-110); 6-month changed to 170-
230 days (from 165-200); and 12-month changed to 
350-410 days (from 345-480). In addition, revised 
description of duration of active intervention to clearly 
specify max. duration is 12 weeks by moving to 
footnote in Table 1.  
1.2 Schedule of Activities and Table 1 
Changed to reflect final 
decisions related to follow-up 
data collection  
09/25/20 
Added assessment of MCID for two subscales of pain 
severity composite measure (MCID in pain intensity 
and MCID in pain-related interference)  
3.2 Secondary Outcomes  
15.6 Secondary Effectiveness Analyses 
In response to DSMB 
recommendation 
09/25/20 
Added rural/medically underserved residency as 
stratum for randomization and adjustment variable  
4.3 Study Arm Assignment/Randomization 
15.5 Primary Effectiveness Analyses 
In response to DSMB 
recommendation  

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III 
Date 
Description of Change  
(Include specific sections affected) 
Rationale for Change 
09/25/20 
Specified one additional EHR-based inclusion 
criterion to be applied at KPWA site only: no opioid 
use disorder (OUD) ICD-10 codes  
5.1 Participant Inclusion Criteria 
To ensure coordination with 
another HEAL study at KPWA 
site specifically treating those 
with pain and OUD 
09/28/20 
Added step to recruitment process where patients 
who are referred by their clinician can contact the 
study staff directly. For these individuals, consent to 
access their medical record to assess eligibility will be 
obtained. 
6.1 Recruitment of Patients 
8.1 Informed Consent of Patients 
Another method was identified 
by health care system 
stakeholders and 
accommodated by study for how 
patients might be referred  
09/28/20 
Added ClinicalTrials.gov registration info to the title 
page 
Study registration with 
ClinicalTrials.gov was posted 
08/24/20  
11/10/20 
Removed statement related to obtaining waiver of 
written consent and alteration of HIPAA from IRB as it 
was not accurate.   
8.1 Informed Consent of Patients 
Removed at request of VUMC 
IRB 
11/10/20 
Revised the section on informed consent to clearly 
delineate consent processes related to screening and 
study enrollment.  
Revised in response to VUMC 
IRB questions 
11/23/20 
Clarified that no consent is required for the population 
EHR-based eligibility screening 
8.1 Informed Consent of Patients 
Revised at request of VUMC 
IRB 
11/23/20 
Clarified that sample of patients who do not complete 
the active interventions and will participate in 
qualitative interviews are still enrolled in the study. 
This is already specified in section 9.1, which has not 
been edited, but text was added to other places in 
protocol where these interviews are described. 
3.5 Qualitative Evaluation Objectives 
6.1 Recruitment of Patients 
11.3 Qualitative Interviews 
Add text to clarify in response to 
VUMC IRB questions 
11/24/20 
Added text to indicate virtual intervention sessions 
completed by secure video encounter that are 
recorded will generate a video recording 
2.4.1 Potential Risks 
17 Source Documents 
Finalization of procedures 
related to recording virtual 
sessions 
11/24/20 
Added Ms. Firemark as staff person involved in 
intervention supervision and fidelity monitoring 
10.4 Study Intervention Fidelity Monitoring 
Procedures 
Finalization of staff/study team 
roles 
03/22/21 
Updated info on number of health coach interviews 
from “up to 10” to reflect that all coaches (currently 
projected at 12 so described as “approx.12”) will be 
offered to complete an interview  
1.1 Synopsis 
6.2 Recruitment of Stakeholders for Qualitative 
Evaluation 
11.3 Qualitative Interviews 
Finalization of hiring/staffing of 
health coaches 

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IV 
Date 
Description of Change  
(Include specific sections affected) 
Rationale for Change 
03/31/21 
Modified EHR-based inclusion criteria related to the 
minimum number of pain-related encounters (criterion 
#4 in section 5.1) for the 3 KP sites; changed to ≥ 2 
encounters that are at least 30 days apart. Essentia 
remains at least 1 encounter.  
5.1 Participant Inclusion Criteria  
High rate of refusal prior to 
screening due to no chronic pain 
and ineligibility among those 
screened at KP sites. By 
increasing threshold for required 
pain visits, more likely to 
efficiently identify people likely 
to have chronic pain.   
03/31/21 
Added an EHR-based exclusion criterion related to 
surgery in the past 60 days for all sites  
5.2 Participant Exclusion Criteria  
High rate of refusal and 
reporting recent surgery and 
therefore no current chronic 
pain. By adding criterion, more 
likely to efficiently identify 
people likely to have chronic 
pain.   
03/31/21 
Added exclusion criterion related to 
planned/scheduled surgery in next year.  
5.2 Participant Exclusion Criteria 
7 Eligibility Screening 
Multiple virtual health coach 
intervention participants have 
indicated upcoming surgery; 
common exclusion criterion for 
pain studies   
03/31/21 
Updated description of virtual intervention fidelity 
monitoring to include more details and specific info on 
final plan.  
10.4 Study Intervention Fidelity Monitoring 
Procedures 
Provide more details on final 
plan/procedure 
03/31/21 
Added information on third framework to be used in 
qualitative evaluation, Theoretical Framework of 
Acceptability   
16 Qualitative Evaluation Analyses 
Expanded constructs for 
qualitative interviews to include 
more related to acceptability  
02/24/22 
Revised description of active interventions throughout 
entire document to clarify painTRAINER as “CBT-
based.” This affected wording in many places 
throughout protocol. Most significantly, it changed 
Aim #1 wording from this:  
Aim #1: Determine the effectiveness of a web-based 
CBT-CP program and virtual coach-led 
(telephonic/video) CBT-CP on achieving clinically 
meaningful improvements in patients’ pain severity 
(pain intensity + pain-related interference) relative to 
those receiving usual care at 3 months. 
     
To revised: 
Aim #1: Determine the effectiveness of an online, 
CBT-based pain management program and virtual 
coach-led (telephonic/video) CBT-CP on achieving 
clinically meaningful improvements in patients’ pain 
severity (pain intensity + pain-related interference) 
relative to those receiving usual care at 3 months. 
NIH Project Scientist, Dr. 
Wandner, requested edit; using 
the consistent description of 
painTRAINER as CBT-based 
and not CBT was agreed upon 
for all HEAL studies that include 
painTRAINER.   

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Date 
Description of Change  
(Include specific sections affected) 
Rationale for Change 
02/24/22 
Removed references to painTRAINER as an 
“application” and replaced with “online program” as it 
is not an application (“App”) that can be downloaded 
to a mobile device but can only be used online via a 
web browser. Also removed “web-based” as 
descriptor and replaced with “online” as it is clearer to 
describe as “online CBT-based.” (vs. web-based, 
CBT-based) 
“Application” was inaccurate 
description.  
02/24/22 
Revised description of active interventions throughout 
entire document to be independent/standalone. 
Previously, painTRAINER had substantial detail but 
the virtual coach-led CBT-CP was only described as 
“having content analogous to painTRAINER.” The 
structure of Section 10 was changed to provide an 
overview of the core elements of both interventions 
and then give specifics on each one.  
Precis  
Section 10 Study Interventions 
Both active interventions 
needed equal description and 
previous text inaccurately 
presented the coach-led 
intervention as derived from 
painTRAINER.  
02/24/22 
Added descriptions of the onboarding and ongoing 
support/outreach for both active interventions. In 
addition, described the motivational interviewing 
language included in the painTRAINER onboarding 
script.   
Section 10 Study Interventions 
Requested by DSMB 
02/24/22 
Added this information in each location where 2,380 
enrollment target is stated: 
Note: The number enrolled might need to be greater 
than 2,380 to ensure reaching the randomized 
participant target of 2,331 (as not all who 
consent/enroll go on to be randomized). 
Clarify that the target number 
consented/enrolled is variable 
and may change in order to 
meet the 2,331 target for 
number randomized, which is 
invariable.  
02/24/22 
Clarified that intervention staff who support 
participant engagement with painTRAINER will also 
be invited to complete qualitative interviews. 
1.1 Synopsis 
6.2 Recruitment of Stakeholders for Qualitative 
Evaluation 
11.3 Qualitative Interviews 
Oversight in original description 
as just stated “health coaches” 
02/24/22 
Added information to Section 8.1 indicating that, as 
needed, sites may follow-up by phone with individuals 
who enrolled by web in order to briefly welcome them 
to the study and clarify next steps.   
Section 8.1 Informed Consent   
Added as a contact and strategy 
to support retention.  
11/10/22 
Updated Dr. DeBar’s KP site affiliation to KP CHR (as 
of 1/1/23). Removed Dr. Elder as KP CHR site PI. 
Added Dr. Cook as KPWHRI site PI.  
Section: Investigator Contact Information 
Dr. DeBar is transferring to KP 
CHR (as of Jan. 1, 2023) and it 
will become the prime site.  

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Date 
Description of Change  
(Include specific sections affected) 
Rationale for Change 
11/10/22 
Updated the number to be enrolled to approximately 
2,500 from 2,380. Clarified that the total number 
enrolled and randomized by each of the 4 sites may 
vary (range of 595-625) in order to reach the overall 
study target for number randomized within the study 
timeline with some sites enrolling more than others 
(i.e., Essentia and KPGA vs. KPWA). 
1.1 Synopsis 
6.1 Recruitment of Patients 
As the study nears the end of 
recruitment, we are aiming to 
enroll more at Essentia and 
KPGA where enrollment rates 
have remained steady in order 
to ensure we have the overall 
target N. KPWA rates have 
been lower than the other sites 
and seem to be decreasing 
slightly in recent months. This 
approach was approved by NIA 
and JHU via email on 10/31/22.  
11/10/22 
Clarified the target N to be randomized is at least 
2,331 or 777 per arm.  
1.1 Synopsis 
6.1 Recruitment of Patients 
15.1 Sample Size Determination 
Clarify that the N randomized 
will not be exactly 2,331 but 
might be slightly over.  
11/10/22 
Indicated that up to 2 interviews will be conducted 
with each healthcare system stakeholder and that 
interviews will be conducted in years 4-5 of the study 
(vs. years 2-3).  
1.2 Schedule of Activities 
3.5 Qualitative Evaluation Objectives 
Study team would like to be able 
to interview healthcare system 
stakeholders more than one 
time.  
 
 
 
 
 

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VIII 
TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................. I 
SUMMARY OF CHANGES ......................................................................................................... II 
INVESTIGATOR CONTACT INFORMATION........................................................................... VII 
TABLE OF CONTENTS .......................................................................................................... VIII 
LIST OF ABBREVIATIONS ....................................................................................................... XI 
1 
PROTOCOL SUMMARY .................................................................................................... 1 
1.1 
Synopsis ................................................................................................................. 1 
1.2 
Schedule of Activities (SoA) .................................................................................... 4 
2 
INTRODUCTION ................................................................................................................ 5 
2.1 
Background Information .......................................................................................... 5 
2.2 
Rationale ................................................................................................................ 6 
2.3 
Specific Aims .......................................................................................................... 7 
2.4 
Potential Risks and Benefits ................................................................................... 7 
2.4.1 
Potential Risks ............................................................................................ 7 
2.4.2 
Potential Benefits ........................................................................................ 9 
3 
OBJECTIVES AND OUTCOME MEASURES ................................................................... 10 
3.1 
Primary Objective ................................................................................................. 10 
3.2 
Secondary Objectives ........................................................................................... 10 
3.3 
Economic Evaluation Objectives ........................................................................... 12 
3.4 
Exploratory (Tertiary) Objectives ........................................................................... 13 
3.5 
Qualitative Evaluation Objectives .......................................................................... 15 
4 
STUDY DESIGN .............................................................................................................. 17 
4.1 
Overall Design ...................................................................................................... 17 
4.2 
Study Arms ........................................................................................................... 17 
4.3 
Study Arm Assignment/Randomization ................................................................. 17 
4.4 
Scientific Rationale for Study Design .................................................................... 18 
4.5 
Justification for Interventions ................................................................................. 18 
4.6 
End-of-Study Definition ......................................................................................... 19 
5 
STUDY POPULATION ..................................................................................................... 20 
5.1 
Participant Inclusion Criteria ................................................................................. 20 
5.2 
Participant Exclusion Criteria ................................................................................ 21 
6 
RECRUITMENT PROCEDURES AND RETENTION STRATEGIES ................................ 22 
6.1 
Recruitment of Patients ......................................................................................... 22 
6.2 
Recruitment of Stakeholders for Qualitative Evaluation ......................................... 23 
6.3 
Retention Strategies ............................................................................................. 24 
7 
ELIGIBILITY SCREENING ............................................................................................... 25 
8 
INFORMED CONSENT PROCESSES ............................................................................. 26 
8.1 
Informed Consent of Patients ................................................................................ 26 
8.2 
Informed Consent of Stakeholders and Staff ......................................................... 28 
9 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................... 29 

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9.1 
Discontinuation of Study Intervention .................................................................... 29 
9.2 
Participant Discontinuation/Withdrawal from Study ............................................... 29 
9.3 
Loss to Follow-Up ................................................................................................. 29 
10 
STUDY INTERVENTIONS ............................................................................................... 30 
10.1 
Description of Interventions................................................................................... 30 
10.1.1 painTRAINER ............................................................................................ 31 
10.1.2 Virtual Coach-led CBT-CP ......................................................................... 32 
10.2 
Intervention Administration and Dosing ................................................................. 33 
10.3 
Masking and Measures to Minimize Bias .............................................................. 33 
10.4 
Study Intervention Fidelity Monitoring Procedures ................................................ 33 
10.5 
Concomitant Therapy ............................................................................................ 34 
11 
STUDY ASSESSMENTS AND PROCEDURES ............................................................... 35 
11.1 
Baseline Assessment ............................................................................................ 35 
11.2 
Follow-Up Assessments ....................................................................................... 35 
11.3 
Qualitative Interviews ............................................................................................ 35 
12 
ADVERSE EVENTS AND UNANTICIPATED PROBLEMS INVOLVING RISKS TO 
SUBJECTS OR OTHERS ................................................................................................ 37 
12.1 
Definition, Classification and Reporting of Adverse Events ................................... 37 
12.1.1 Definition of Adverse Events (AEs) ............................................................ 37 
12.1.2 Definition of Serious Adverse Events (SAEs) ............................................ 37 
12.1.3 Definition of Adverse Events of Special Interest (AESI) ............................. 38 
12.1.4 Severity of Adverse Events ....................................................................... 38 
12.1.5 Relationship to Research Participation ...................................................... 38 
12.1.6 Expectedness of Adverse Events/Serious Adverse Events ....................... 39 
12.1.7 Reporting Procedures for Adverse Events/Serious Adverse Events .......... 39 
12.2 
Definition and Reporting of Unanticipated Problems ............................................. 39 
12.2.1 Definition of Unanticipated Problems ......................................................... 39 
12.2.2 Reporting of Unanticipated Problems ........................................................ 39 
13 
STUDY OVERSIGHT ....................................................................................................... 41 
13.1 
Halting Rules ........................................................................................................ 41 
14 
STUDY MONITORING ..................................................................................................... 42 
14.1 
Clinical Site Monitoring ......................................................................................... 42 
15 
STATISTICAL CONSIDERATIONS .................................................................................. 43 
15.1 
Sample Size Determination................................................................................... 43 
15.2 
Populations for Analyses ...................................................................................... 44 
15.3 
General Approach to Statistical Analyses ............................................................. 44 
15.4 
Baseline Descriptive Statistics .............................................................................. 44 
15.5 
Primary Effectiveness Analyses ............................................................................ 44 
15.6 
Secondary Effectiveness Analyses ....................................................................... 45 
15.7 
Additional Effectiveness Analyses for Primary Outcome (Moderators and 
Mediators) ............................................................................................................. 45 
15.8 
Economic Evaluation Analyses ............................................................................. 46 
15.9 
Exploratory Effectiveness Analyses ...................................................................... 47 

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15.10 Safety Analyses .................................................................................................... 47 
15.11 Planned Interim Analyses ..................................................................................... 48 
16 
QUALITATIVE EVALUATION ANALYSES ....................................................................... 49 
17 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 51 
18 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 53 
19 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 54 
19.1 
Ethical Standard ................................................................................................... 54 
19.2 
Institutional Review Board .................................................................................... 54 
19.3 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 54 
19.4 
Subject Confidentiality .......................................................................................... 54 
19.4.1 Certificate of Confidentiality ....................................................................... 55 
20 
DATA HANDLING AND RECORD KEEPING ................................................................... 56 
20.1 
Data Management Responsibilities ....................................................................... 56 
20.2 
Schedule and Content of Reports ......................................................................... 56 
20.3 
Study Records Retention ...................................................................................... 56 
20.4 
Protocol Deviations ............................................................................................... 56 
21 
PUBLICATION ................................................................................................................. 58 
22 
DATA SHARING .............................................................................................................. 59 
23 
REFERENCES ................................................................................................................. 60 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
BPI - SF 
Brief Pain Inventory – Short Form 
CBT-CP 
Cognitive Behavioral Therapy for Chronic Pain 
CCC 
Clinical Coordinating Center 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
CSI 
Clinical Site Investigator 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDA 
Exploratory Data Analysis 
EDC 
Electronic Data Capture 
EH 
Essentia Health 
EHR 
Electronic Health Records 
EQ-5D-5L 
EuroQoL 5 Dimensions – 5 Levels 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HCS 
Health care system 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
JHU 
Johns Hopkins University 
KP 
Kaiser Permanente  
KP CHR 
Kaiser Permanente Center for Health Research 
KPGA 
Kaiser Permanente Georgia 
KPNW 
Kaiser Permanente Northwest 
KPWA 
Kaiser Permanente Washington 
KPWHRI 
Kaiser Permanente Washington Health Research Institute  
MCID 
Minimal Clinically Important Difference 

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mHealth 
Mobile Health 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NIA 
National Institute on Aging 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OR 
Odds Ratio 
PEG 
Pain, Engagement of Life & General Activity 
PCP 
Primary Care Providers 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PO 
Program Official, NIH 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QA 
Quality Assurance 
QALY 
Quality-Adjusted Life Year 
QC 
Quality Control 
QoL 
Quality of Life 
RIC 
Recruitment Innovation Center 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIRB 
Single Institutional Review Board 
SOP 
Standard Operating Procedure 
TIC  
Trial Innovation Center 
UC 
Usual Care Study Arm / Group  
UP 
Unanticipated Problem 
 
 

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1 PROTOCOL SUMMARY  
 
1.1 
Synopsis 
 
Title: 
Tailored Non-Pharmacotherapy Services for Chronic Pain: Testing Scalable 
and Pragmatic Approaches (RESOLVE Study) 
 
Précis: 
The RESOLVE study is a multicenter comparative effectiveness trial 
evaluating two cognitive-behavioral therapy (CBT)-based chronic pain 
treatments delivered via different telehealth modalities: 1) online program 
and 2) live, coach-led, virtual sessions (telephone and/or video conference). 
The study uses a 3-arm, parallel intervention design; both intervention arms 
will be compared to usual care services.  
 
Participants randomized to the two intervention arms will complete 8 CBT-
based sessions for chronic pain (approximately 1 per week) via the online 
program (self-directed) or one-on-one with the live coach.  Those 
randomized to usual care will receive an education resource manual for 
chronic pain management. All study participants will be enrolled for 12 
months and complete self-reported assessments at baseline, notification of 
randomization, and 3-, 6- and 12-months. A subset of participants will 
participate in the qualitative evaluation and complete an hour-long interview 
at approximately 3-5 months follow-up and 12-14 months follow-up.  
 
In addition, qualitative interviews will be completed with approximately 20 
health care system stakeholders across the 4 study sites and the staff who 
support the painTRAINER intervention administration and those who deliver 
the virtual CBT-CP sessions (approximately 12). 
Specific Aims: 
Aim #1: Determine the effectiveness of an online, CBT-based pain 
management program and virtual coach-led (telephonic/video) CBT-CP on 
achieving clinically meaningful improvements in patients’ pain severity (pain 
intensity + pain-related interference) relative to those receiving usual care 
at 3 months. 
1a. Examine the impact of the active interventions on secondary 
pain outcomes and related quality of life outcomes (social role 
functioning, physical functioning, and patient global impression of 
change); as well as exploratory outcomes, which include long-term 
opioid use; comorbid symptomology (depression, anxiety, and 
sleep disturbance); and high impact chronic pain and graded 
chronic pain.  
1b. Conduct subgroup analyses to determine the impact of the 
active interventions on specific populations and explore for 
potential heterogeneity of treatment effects by sex; rural/medically 
underserved residency; multiple pain conditions; mental health 
mood disorders; and negative social determinants of health.  
1c. Examine the role of theory-based mediators, pain 
catastrophizing, pain-related self-efficacy, and perceived support, 
on pain-severity.  
Aim #2: Assess the cost and incremental cost-effectiveness of the online 
and virtual coach-led CBT-CP interventions compared to each other and 
usual care.  
Aim #3: Conduct a qualitative evaluation to understand: 1) patient 
experiences of the interventions, including how they relate to treatment 

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response, variability by site, and rural/medically underserved residency 
status; and 2) health system issues, including adaptations and contextual 
factors at the site and external levels, barriers and facilitators to intervention 
success and potential for adoption, sustainability, and dissemination. 
 
Population: 
Approximately 2,500 participants with high-impact chronic pain, as 
demonstrated by initial electronic health records (EHR)-based eligibility 
criteria and subsequent screening, will be enrolled in this study with the 
goal of randomizing approximately 2,331 participants (at least 777 per 
study arm). [Note: The number enrolled might need to be greater than 
2,500 to ensure reaching the randomized participant target of at least 2,331 
(as not all who consent/enroll go on to be randomized).]     
 
Participants will be recruited from four integrated health care 
systems/clinical sites: 1) Kaiser Permanente Georgia (KPGA), 2) Kaiser 
Permanente Northwest (KPNW), 3) Kaiser Permanente Washington 
(KPWA), and 4) Essentia Health.  
 
Of the randomized participants, 120 will participate in the interviews for the 
qualitative evaluation. The health care system stakeholders to be 
interviewed will be administrators in the areas of quality improvement, 
primary care, and/or pain management at each of the 4 study sites and 
referring clinicians. The intervention / health coaching staff to be 
interviewed will be the centralized staff who support painTRAINER 
engagement as well as those who deliver the virtual CBT-CP sessions.   
 
Phase: 
Phase III Clinical Trial 
 
Anticipated Number of 
Sites: 
Four clinical sites: 
1. Kaiser Permanente Georgia (KPGA) 
2. Kaiser Permanente Northwest (KPNW) 
3. Kaiser Permanente Washington (KPWA) 
4. Essentia Health 
 
Description of 
Interventions: 
Two interventions will be tested in this comparative effectiveness trial.  
1) An online, CBT-based pain coping skills training program 
(painTRAINER) 
2) A virtual, live coach-led CBT-CP intervention (telephone or 
video-administered)  
Both interventions are comprised of 8 sessions which participants are 
expected to complete weekly. The content of the 2 interventions is 
analogous and focuses on interactive training in evidence-based pain-
coping skills. 
 
Those randomized to the usual care arm of the study will be sent a bound 
copy of the 2020 edition of the American Chronic Pain Association 
Resource Guide to Chronic Pain Management.  
 
All enrollees can receive any pharmacologic and nonpharmacologic 
treatments available to them without restriction. 
 
Study Duration: 
48 months from start of enrollment to completion of data analyses 
 

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Subject Participation 
Duration: 
 
12-14 months 
(The majority of subjects will participate for 12 months. The subset of 
qualitative evaluation subjects will complete the last follow-up interviews at 
12-14 months.) 
 
Estimated Time to 
Complete Enrollment: 
25 months 
 
 
 

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1.2 
Schedule of Activities (SoA) 
 
The schedule of activities in Table 1 below pertains to the patients who will participate in the 
RESOLVE UH3 trial.  
 
For the health care system stakeholders who participate, study activities will include 
approximately two hour-long interviews conducted by phone. For the health coach / intervention 
staff who participate, study activities will include two approximately hour-long interviews 
conducted by phone early and later in the study implementation. 
 
Table 1. UH3 Schedule of Activities for Patients 
Procedures 
Eligibility Screening and Consent1 
Day -14 to -1 or Day 0 
Baseline and Randomization1 
Day 0 
Randomization Notification 
Approx. Day 1 to 7 
Intervention Session #1 
 Approx. Day 8 to 14 
Intervention Session #2 
 Approx. Day 15 to 21 
Intervention Session #3 
 Approx. Day 22 to 28 
Intervention Session #4 
Approx. Day 29 to 35 
Intervention Session #5 
 Approx. Day 36 to 42 
Intervention Session #6 
 Approx. Day 43 to 49 
Intervention Session #7 
Approx. Day 50 to 56 
Intervention Session #82 
 Approx. Day 57 to 63 
3-Month Follow-Up  
Day 80 to 140 
6-Month Follow-Up  
Day 170 to 230 
12-Month Follow-Up / Final Assessment  
Day 350 to 410 
Eligibility screening  
X (or) X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X (or) X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline assessment  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Notification of study arm 
assignment  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Administer study 
intervention (if 
applicable, based on 
study arm assignment) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse event review 
and evaluation 
 
 
X-----------------------------------------------------------------------------------------------------X 
Study assessments 
completion  
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Interviews with subset of 
participants 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
1. The eligibility screening, consent and baseline survey can all be completed in the same phone encounter or online 
survey session, if feasible for the participant. If these activities are not completed in the same encounter or 
session, efforts will be made to complete the consent and baseline survey with those eligible individuals who want 
to participate in the study within 14 days of them completing the eligibility screening. 
2. The active intervention sessions are intended to occur approximately weekly over the course of 8 weeks; 
however, completion may vary due to personal circumstances of the participants. The maximum duration for 
active intervention sessions is 12 weeks. (See Section 10.2 for further information). 

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2 INTRODUCTION  
 
2.1 
Background Information  
 
Chronic pain, defined as pain lasting for 3 months or longer, is one of the most common, 
disabling, and costly public health problems in the United States.1 It is one of the primary 
reasons patients seek medical care. It often involves high levels of disability and emotional 
suffering.1,2 High impact chronic pain, defined as pain that has lasted 3 months or longer and 
is accompanied by at least one major activity restriction, such as being unable to work outside 
the home, go to school, or do household chores affects about one in ten adults.1,3,4  
 
Rural residency is associated with higher prevalence of high impact chronic pain with 
complicating features such as depression and medical comorbidities.5,6 Rural residents with 
chronic pain report higher pain frequency and intensity and more pain-related disability and 
depression than urban residents with pain.7,8 Health care disparities between rural and urban 
areas are widely recognized with rural residents often affected by difficulties in availability, 
accessibility, and affordability of health services.9 These disparities put rural patients with 
chronic pain at higher risk for adverse outcomes and suboptimal pain management.  
 
Most patients with chronic pain are treated by primary care clinicians and medications are 
mainstays of pain management. While opioids were, until recently, viewed favorably for long-
term chronic pain management, supporting evidence was weak.10 Recent evidence shows 
opioid-related harms and widespread opioid use has left an aftermath of adverse effects for 
patients and communities.11,12 These consequences have been especially pronounced in rural 
communities where the abuse rates of prescription opioids and drug-related overdoses are 
disproportionally higher than in urban areas.13,14 Consequently, primary care clinicians and 
their patients, especially in medically underserved areas, urgently need increased access to 
viable nonopioid options and treatments for long-term chronic pain management.    
 
Cognitive-behavioral therapy for chronic pain (CBT-CP) is the most widely accepted and 
effective treatment1,15,16 and is shown to benefit low-literacy adults in rural areas.17 CBT-CP is 
based on the theory that patients' beliefs, attitudes, behavior, and coping styles play central 
roles in determining (mediating) the impact of persistent pain.18 CBT-CP effects can be 
maintained long after treatment ends, without the negative side effects of opioids and other pain 
medications. CBT-CP is an attractive adjunct or alternative to pharmacological treatments. It 
focuses on helping patients develop and master skills to manage pain and its associated 
disability and emotional distress to improve functioning and quality of life. The National Pain 
Strategy calls for wider implementation of CBT-CP self-management programs,19 noting that 
despite supporting evidence, 20-29 CBT-CP implementation lags due to significant barriers.  
 
Outside Veterans Affairs health care systems,20 few clinicians are trained to deliver CBT-CP. 
CBT-CP services in community practice often vary in quality despite the growing emphasis on 
standardized training methods.21 In community settings, fidelity to best treatment practices is 
rarely assessed.22 Frontline behavioral health providers offering CBT-CP generally have high 
caseloads and pressure to prioritize treatment for mental disorders, limiting CBT-CP availability. 
These problems are especially critical in rural areas and medically underserved 
communities7,9,23 where there are generally few behavioral health and psychotherapy providers 
and extreme scarcity in those trained to deliver CBT-CP.24 In addition, conventional CBT-CP 
programs can be difficult to use for patients with limited time, transportation or mobility barriers, 

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or competing demands. Most CBT-CP programs require weekly in-person sessions of 50 
minutes or more over 2-3 months, often in group formats with inflexible scheduling. Patients 
referred for CBT-CP may attend too few sessions to receive an adequate treatment dose.25 
Further, the stigma associated with what are perceived to be “psychological” interventions can 
limit patient uptake.26,27 Providing CBT-CP by telephone or in an online program may help 
destigmatize its use and encourage patients to view it as complementing conventional medical 
management of chronic pain, while helping them achieve functional and quality-of-life goals. 
 
Lastly, there are gaps in primary care providers’ (PCP) referral to CBT treatment. PCPs who 
lack familiarity with CBT-CP are often concerned about not having enough time to discuss CBT-
CP, lack ways to provide a compelling rationale for CBT-CP, or have difficulty explaining why a 
psychologically informed treatment may help manage a physical condition. Moreover, guidelines 
do not exist for determining which patients might benefit from CBT-CP.2  
 
Technologies to deliver and assist treatment such as online- and telephone-based treatment 
programs28-30 offer ways to increase access to evidence-based pain care, including CBT-CP 
and related self-management approaches.31,32 Because mobile health (mHealth) and 
telehealth services have lower marginal costs than in-person care, they can reach large 
numbers of patients and support health behavior change and self-management efforts while 
overcoming system, patient, and clinician barriers.33 mHealth interventions can improve self-
management33 and chronic illness care outcomes.34 Finally, following the Covid-19 outbreak, 
mHealth and telehealth services are rapidly becoming the norm with a particular push towards 
video visits both to best approximate in-person visits and increase likely payment.35 Further, as 
Eccleston and colleagues (2020) note, “preventing [and managing] chronic pain is complex at 
the best of times but in a global health pandemic, risk factors for pain morbidity and mortality 
will be magnified. (p.8904)”36 
 
2.2 
Rationale 
 
High impact chronic pain is persistent and limits life and work activities. It affects about one in 
ten adults.1,3 Treatment is inadequate, with overuse of long-term opioid therapy and underuse 
of evidence-based nonpharmacologic treatments.15 Cognitive-behavioral therapy for chronic 
pain (CBT-CP) is the most widely accepted and effective of these treatments.1,15,16 Enhanced 
availability of CBT-CP services for high impact chronic pain is of critical public health 
importance37, particularly for medically underserved and rural populations devastated by the 
opioid epidemic.13,14 However, professionals trained to deliver CBT-CP are typically in urban 
areas. Making CBT-CP widely available and low cost would reduce barriers to use of CBT-CP 
for the majority of the US population, particularly those in rural and medically underserved 
areas.  
 
This comparative effectiveness research trial will evaluate two potentially low-cost and 
scalable CBT-based treatments for chronic pain: 1) an established online, CBT-based 
pain coping skills training (PCST) program (painTRAINER), and 2) a virtual, coach-led 
(telephone/video-administered) CBT-CP intervention. Both modalities will be compared 
to usual care services.  
 
 
 
 

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2.3 
Specific Aims  
 
Aim #1: Determine the effectiveness of an online, CBT-based pain management program and 
virtual coach-led (telephonic/video) CBT-CP on achieving clinically meaningful improvements (≥ 
30%) in patients’ pain severity (pain intensity + pain-related interference) relative to those 
receiving usual care at 3 months. 
 
1a. Examine the impact of the active interventions on secondary pain outcomes and 
related quality of life outcomes (social role functioning, physical functioning, and patient 
global impression of change); as well as exploratory outcomes, which include long-term 
opioid use, comorbid symptomology (depression, anxiety, and sleep disturbance), and 
high impact and graded chronic pain.  
 
1b. Conduct subgroup analyses to determine the impact of the active interventions on 
specific populations and explore for potential heterogeneity of treatment effects by sex; 
rural/medically underserved residency; multiple pain conditions; mental health mood 
disorders; and negative social determinants of health.  
 
1c. Examine the role of theory-based mediators, pain catastrophizing, pain-related self-
efficacy, and perceived support, on pain-severity.  
 
Aim #2: Assess the cost and incremental cost-effectiveness of the online and virtual coach-led 
CBT-CP interventions compared to each other and usual care.  
 
Aim #3: Conduct a qualitative evaluation to understand: 1) patient experiences of the 
interventions, including how they relate to treatment response, variability by site, and 
rural/medically underserved residency status; and 2) health system issues, including 
adaptations and contextual factors at the site and external levels, barriers and facilitators to 
intervention success and potential for adoption, sustainability, and dissemination. 
 
2.4 
Potential Risks and Benefits 
 
2.4.1 
Potential Risks 
 
The RESOLVE study poses minimal risks. Those risks that might exist fall into four categories: 
(a) risks of the intervention; (b) risks associated with research assessments; (c) risks associated 
with potential loss of confidentiality; and (d) risks of worsening physical or emotional state. 
These minimal risks and the procedures to help mitigate the risks are described further below.  
 
Risks associated with the intervention. The intervention programs consist of either an 
online program or virtual coach-led (telephone and/or video) CBT-CP sessions. CBT-CP 
focuses on helping people change how they think and act in response to pain-related 
stressors38 and on increasing patients’ coping skills to help them better manage their 
pain and improve their emotional and physical functioning. Therefore, individuals who 
participate in the interventions might experience emotional or physical discomfort related 
to challenges in modifying their thoughts and behaviors related to pain. For example, 
someone might feel discouraged or frustrated during the intervention process or they 
might be physically challenged by behaviors they try to address in increasing physical 
activity. However, these risks are minimal, in that the probability and magnitude of 

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discomfort is no greater than what someone might encounter in daily life. CBT-CP 
interventions have been used by the current study team and other investigators without 
adverse effects in studies as well as in clinical practice with patients with chronic pain 
and other health conditions.  
Procedures to help mitigate these risks. All behavioral health staff who will be conducting 
the intervention sessions with participants will receive comprehensive training and 
supervision from one or more of the following individuals: Drs. DeBar (PI), Balderson 
(Co-Investigator at KPNW), and Keefe (Co-Investigator at Duke University), all with 
considerable experience supervising and training the delivery of such clinical research 
interventions. Finally, participants who experience emotional or physical discomfort 
during the intervention have the option of seeking services in the participating health 
care system in which they are insured/served as well as outside of the health care 
system, if they prefer; enrollees can receive any pharmacologic or non-pharmacologic 
treatments available to them without restriction.   
 
Risks associated with research assessments. Research assessments consist of 
accessing data from participants’ electronic health records (EHR) data, conducting 
surveys and interviews, and collecting data related to the delivery of the intervention 
programs, including audio- and video-recordings of virtual CBT-CP sessions and the 
collection of painTRAINER usage data. Any risks related to the collection of research 
data and the potential for accidental disclosure of protected health information (PHI), are 
described specifically below. Survey and interview questions focus on pain and 
associated impairment and functioning, comorbid conditions (including depression and 
anxiety), and use of treatments outside of traditional health care. Some of the questions 
might make participants feel uncomfortable. However, the study surveys and interviews 
involve no specific risk or discomfort beyond those associated with a standard clinical 
interview.  Proposed assessment tools, or ones assessing similar domains, have been 
used by the research team in previous research, with no known problems or distress on 
the part of participants.  Virtual intervention sessions will be audio- or video-recorded, for 
the purpose of review by senior research staff, who will make quality assurance ratings 
of staff performance. (Note: The audio recording of the session is the only data needed 
for quality assurance review, however if the participant completes a session via video, 
the recording will generate a video recording from which the audio recording will be 
extracted.) If participants are uncomfortable with having their session recorded, they can 
refuse having their session recorded and still participate in the study. 
Protection for risks associated with research assessments. Participants will be told that 
they are free not to respond to specific survey or interview questions or to terminate 
involvement in completing a survey or interview at any time, with no adverse 
consequences.  If a participant appears to be distressed during assessments, research 
staff will halt the survey or interview and offer to call back to complete the assessment. 
The assessment will only re-commence when and if the participant reports feeling 
capable of doing so.  Survey assessments will be conducted by research staff who are 
trained to address anticipated participant concerns; interviews will be conducted by 
experienced research staff who have previously conducted interviews with the target 
population and are sensitive to these issues.   
 
Risks associated with potential loss of confidentiality. The confidentiality of participants 
could be compromised by an accidental release of protected health information (PHI) 
that are accessed or collected as part of this study’s research assessments. The 
recruitment design used in this study carries the potential risk of loss of privacy and or 

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unwanted contacts because EHR data are queried, and pertinent information extracted 
for potentially eligible individuals. As in any research study, there is the slight risk that 
records might be accessed or obtained by persons who are not authorized to do so. 
Procedures to help mitigate these risks. All participant information is considered 
confidential and will be used only for research purposes.  This confidentiality will be 
ensured through several mechanisms. Each participant will be assigned a study ID and 
direct identifiers will only be linked to subjects’ study ID in circumstances where staff 
need to access information in order to contact participants to conduct study activities. 
Analytic datasets will be de-identified. All study forms, paper and electronic records, and 
all participant data (both hard copies and electronic) will be stored in secure areas, with 
access restricted to select study staff, or on secure servers, as relevant at the 
participating institutions. Third, access to participant data and information will be 
restricted to authorized personnel as necessitated by their professional role and tasks on 
the project. Data transfer between participating institutions will be done using Secure 
Socket Layer (SSL) encryption. In accordance with HIPPA regulations and local IRB 
requirements, all appropriate compliance requirements for data transfer and data use will 
be met after consultation with compliance officers. 
 
Risks of worsening mental or emotional state. Many of the study participants are 
expected to have comorbid depression, anxiety and/or other mental health conditions. It 
is expected that mental and emotional symptoms experienced by these individuals will 
fluctuate throughout the study period and some participants may have worsening pain 
and/or other mental health symptoms during the study period. However, these are risks 
inherent in the population and would occur regardless of study enrollment.  
Procedures to help mitigate these risks. All patient participants enrolled in the study will 
have access to treatment through their health care system and will be encouraged to 
seek care in the event that their symptoms significantly worsen during the intervention. 
This is consistent with the standard of care provided within the participating health care 
systems (KPGA, KPNW, KPWA, and Essentia). Participants in the study are free to 
withdraw from the study at any time with no consequence to their health care. If a patient 
reports imminent risk of a psychiatric crisis, study staff will take appropriate immediate 
action by connecting the patient with emergency services in his/her region.  
 
2.4.2 
Potential Benefits 
 
Potential benefits for those participating in the intervention arms of the study include access to 
evidence-based intervention programs that may help participants develop the skills to better 
manage their pain, improve their functioning, and potentially lower their reliance on opioid 
medication. While those in the usual care arm will not receive such care, the American Chronic 
Pain Association Resource Guide to Chronic Pain Management39 is detailed and 
comprehensive and may help them better navigate the treatment options available to them 
through their health care system and surrounding communities.  
 
Although patients, clinical staff, and administrators participating in the interview portions of the 
study may not directly benefit from participation in interviews, many individuals enjoy the 
opportunity to provide their opinions and tell their stories. Further, these individuals may derive 
personal satisfaction from being part of a study that may have public health implications and 
that will further scientific knowledge concerning various treatment and self-care options for pain 
management.  

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3 OBJECTIVES AND OUTCOME MEASURES  
 
3.1 
Primary Objective 
 
Primary Objective 
Brief Description of Measure 
Outcome Measured By  
Time Frame 
Determine whether the 
active interventions result 
in a higher proportion of 
patients achieving a 
reduction in pain severity 
that is a minimal clinically 
important difference 
(MCID) relative to those 
receiving usual care at 3 
months. 
 
Minimal clinically important 
difference (MCID) in pain 
severity (pain intensity + pain 
interference) is defined as a 
30% decrease in score on 
modified 11-item version of the 
Brief Pain Inventory – Short 
Form (BPI-SF)40-42 from 
baseline (consistent with 
IMMPACT consensus 
guidelines)43 (Binary; Yes/No) 
 
Patient self-reported pain 
at baseline and 3 months 
 
 
Baseline to 3 
months 
 
3.2 
Secondary Objectives 
 
Secondary Objectives 
Brief Description of Measure 
Outcome Measured By  
Time Frame 
Determine whether the 
active interventions 
result in a higher 
proportion of patients 
achieving a MCID in pain 
severity relative to those 
receiving usual care at 6 
and 12 months. 
 
See above (Binary; Yes/No) 
Patient self-reported pain 
at baseline, 6 and 12 
months 
 
Baseline to 6 
and 12 months 
Determine whether the 
active interventions 
result in a higher 
proportion of patients 
achieving a MCID in pain 
intensity 
Minimal clinically important 
difference (MCID) in pain 
intensity is defined as a 30% 
decrease in score on 4-item pain 
intensity subscale of the Brief 
Pain Inventory – Short Form 
(BPI-SF)40-42 from baseline 
(Binary; Yes/No) 
Patient self-reported pain 
at baseline, 6 and 12 
months 
 
Primary: 
Baseline to 3 
months 
 
Secondary: 
Baseline to 6 
and 12 months 
Determine whether the 
active interventions 
result in a higher 
proportion of patients 
achieving a MCID in 
pain-related interference  
Minimal clinically important 
difference (MCID) in pain 
intensity is defined as a 30% 
decrease in score on 7-item 
pain-related interference 
subscale of the Brief Pain 
Inventory – Short Form (BPI-
SF)40-42 from baseline (Binary; 
Yes/No) 
Patient self-reported pain 
at baseline, 6 and 12 
months 
 
Primary: 
Baseline to 3 
months 
 
Secondary: 
Baseline to 6 
and 12 months 

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Secondary Objectives 
Brief Description of Measure 
Outcome Measured By  
Time Frame 
Examine the impact of 
the active interventions 
on pain severity 
Brief Pain Inventory – Short 
Form (BPI-SF)40-42 (11 items; 
continuous) 
Patient self-reported pain 
at baseline, 3, 6 and 12 
months 
 
Primary 
Baseline to 3 
months 
 
Secondary 
Baseline to 6 
and 12 months 
 
Examine the impact of 
the active interventions 
on pain intensity 
Pain intensity subscale of the 
BPI-SF (4 items; continuous) 
Patient self-reported pain 
at baseline, 3, 6 and 12 
months 
 
Primary 
Baseline to 3 
months 
 
Secondary 
Baseline to 6 
and 12 months 
 
Examine the impact of 
the active interventions 
on pain-related 
interference  
Pain-related interference 
subscale of the BPI-SF (7 items; 
continuous) 
Patient self-reported pain 
at baseline, 3, 6 and 12 
months 
 
Primary 
Baseline to 3 
months 
 
Secondary 
Baseline to 6 
and 12 months 
Examine the impact of 
the active interventions 
on social role functioning  
 
PROMIS Ability to Participate in 
Social Roles 4A44 (4 items; 
continuous) 
 
 
Patient self-reported 
social role functioning at 
baseline, 3, 6 and 12 
months 
Primary 
Baseline to 3 
months 
 
Secondary 
Baseline to 6 
and 12 months 
 
Examine the impact of 
the active interventions 
on physical functioning 
 
PROMIS Physical Functioning 
Short Form 6b (6 items; 
continuous) 
 
Patient self-reported 
physical functioning at 
baseline, 3, 6 and 12 
months 
Primary 
Baseline to 3 
months 
 
Secondary 
Baseline to 6 
and 12 months 
 
Examine the impact of 
the active interventions 
on patient global 
impression of change 
(PGIC) 
Guy/Farrar Patient Global 
Impression of Change (1 item 
each for pain status and overall 
status) 
Patient self-reported 
impression of change at 3, 
6 and 12 months 
Primary 
Baseline to 3 
months 
 
Secondary 
Baseline to 6 
and 12 months 
 
 
 

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3.3 
Economic Evaluation Objectives 
 
Economic Evaluation 
Objectives 
Brief Description of Measure 
Outcome Measured By  
Time Frame 
Assess the costs and 
incremental cost-
effectiveness of the 
active interventions 
compared to each other 
and usual care 
Costs based on health care 
utilization and intervention costs 
will be assessed. 
 
Using the framework of cost-
effectiveness, the incremental 
cost per additional patient with a 
MCID in pain severity (30% 
reduction from baseline) will be 
estimated at 12 months, and the 
quality-adjusted life year (QALY) 
gained—utilities will be 
estimated using the EQ-5D-5L.45 
Health care utilization 
costs: EHR data costed 
using standard costing 
algorithms46,47 and 
Medicare fee schedules 
 
Intervention costs: 
Process data related to all 
relevant resources used in 
the intervention delivery  
 
EQ-5D-5L: Patient self-
report at baseline, 3-, 6- 
and 12-months 
 
Baseline to 12 
months  
 
 
 

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3.4 
Exploratory (Tertiary) Objectives 
 
Exploratory Objectives 
Brief Description of Measure 
Outcome Measured By  
Time Frame 
Examine the impact of 
the active interventions 
on long-term opioid use 
Opioid prescription orders or fills 
indicating a continuous ≥ 60-day 
supply during the prior 90-day 
period; account for prescriptions 
prior to 90-day look-back which 
carry into the assessment period 
(Binary) 
Electronic health record 
(EHR) opioid prescription 
data assessed quarterly 
 
90-day periods for 
quarterly variables  
(Baseline survey date = Day 0) 
Baseline = Day -89 to day -0  
3 months = Day 1 to day 90 
6 months = Day 91 to day 180 
9 months = Day 181 to day 270 
12 months = Day 271 to day 360 
 
Baseline to 3, 6 
and 12 months 
 
Examine the impact of 
the active interventions 
on depression 
symptomology 
Patient Health Questionnaire-8 
(PHQ-8)48 (8 items; continuous) 
Patient self-reported 
depression 
symptomatology at 
baseline, 3, 6 and 12 
months 
  
Baseline to 3, 6, 
and 12 months 
 
 
Examine the impact of 
the active interventions 
on anxiety 
symptomology 
Generalized Anxiety Disorder-7 
(GAD-7)49 (7 items; continuous) 
Patient self-reported 
anxiety symptomatology 
at baseline, 3, 6 and 12 
months 
 
Baseline to 3, 6, 
and 12 months 
 
 
Examine the impact of 
the active interventions 
on sleep disturbance 
PROMIS Sleep Disturbance – 
Short Form 6a50 (6 items; 
continuous) 
Patient self-reported sleep 
disturbance at baseline, 3, 
6 and 12 months 
  
Baseline to 3, 6, 
and 12 months 
 
 
Examine the impact of 
the active interventions 
on high impact chronic 
pain and graded chronic 
pain 
High Impact Chronic Pain4,51  
 
Graded Chronic Pain Scale-
Revised51 
Patient self-reported pain 
intensity, duration, and 
pain-related disability 
Baseline to 3, 6, 
and 12 months 
 
The following moderators will be assessed related to MCID in pain severity at 6 months.  
 
Moderator 
Definition 
Data Source 
Sex 
Male vs. Female/Other 
 
Sex at birth as reported by subject; assessed 
using HEAL CDE Demographic question 
 
Patient self-report at baseline 
Age 
<65 vs. ≥ 65 years old 
 
EHR data 
Race/Ethnicity 
White/Non-Hispanic 
Black or African American/Non-Hispanic, 
Hispanic 
Other 
 
Patient self-report at baseline 

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Moderator 
Definition 
Data Source 
Rural/medically 
underserved residency 
Urban vs. Rural/medically underserved 
 
Rural is defined as subject’s resident Census 
Tract corresponds to US Census 2010 Rural-
Urban Commuting Area (RUCA) Codes 4, 5, 
6, 7, 8, 9 or 10 
(https://www.ers.usda.gov/data-products/rural-
urban-commuting-area-codes/documentation/) 
 
Medically underserved is defined as subject’s 
resident Census Tract corresponds to HRSA-
designated primary care or mental health 
geographic or geographic high needs health 
professional shortage area 
(https://data.hrsa.gov/tools/shortage-
area/hpsa-find) 
 
EHR patients’ geocoded data 
extracted at baseline  
Multiple non-malignant 
musculoskeletal pain 
conditions 
1 pain cluster vs. >1 pain cluster 
 
> 1 pain-related ICD-10 diagnosis 
corresponding to more than one  (>1) of the 
non-malignant musculoskeletal chronic pain 
condition clusters developed for the National 
Pain Strategy chronic pain condition clusters52 
1. Back pain  
2. Neck pain  
3. Limb/extremity pain, joint pain, and 
arthritic disorders  
4. Fibromyalgia  
5. Headache 
6. Orofacial, ear, and temporomandibular 
disorder pain  
7. Musculoskeletal chest pain  
8. General pain subcategory of the Other 
painful conditions cluster  
EHR data; diagnoses in patient’s 
EHR extracted at baseline for prior 
360 days 
Mental health mood 
disorders 
ICD-10 diagnosis for depression and/or 
anxiety diagnosis 
EHR data; diagnoses in patient’s 
EHR extracted at baseline for prior 
360 days 
 
Negative social 
determinants of health 
(SDH) 
Negative SDH/existing need vs. No SDH need   
Patient endorses need in one or more of the 
following domains:   
1. Financial Resource Strain (1 item) 
2. Food Insecurity (2 items) 
3. Transportation/Access 
Needs (2 items) 
4. Housing Instability (3 items) 
Patient self-report at baseline 
 
 
 
 
 
 

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The following mediators will be assessed related to MCID in pain severity at 6 months. 
 
Mediator 
Brief Description of Measure 
Measured By  
Pain catastrophizing  
 
Pain Catastrophizing Scale (PCS)– Short 
Form 653 (6-item; continuous) 
 
 
 
Patient self-report at baseline and 
3 months 
 
 
Pain self-efficacy 
Self-Efficacy for Pain Management subscale 
of the Chronic Pain Self-Efficacy Scale54 (5-
item; continuous) 
Patient self-report at baseline and 
3 months 
 
Perceived support 
2 items developed in UG3 phase 
Patient self-report at notification of 
randomization and 3 months 
 
3.5 
Qualitative Evaluation Objectives 
 
Qualitative Evaluation Objectives 
Measured By  
Time Frame 
during the 4-year 
UH3 study period 
Understand health system issues, 
including adaptations and contextual 
factors at the site and external levels, 
barriers and facilitators to intervention 
success and potential for adoption, 
sustainability, and dissemination  
from perspective of health care 
systems 
Interviews with health care system 
stakeholders (including referring 
clinicians) using semi-structured interview 
guides designed to assess relevant domains.  
 
 
Conducted in 
years 4-5 of study  
Understand patient experiences of the 
interventions, including how they relate 
to treatment response, variability by 
site, and rurality/medically underserved 
residency status 
Interviews with a purposeful sample of 
patients who participate in the active 
interventions, stratified by site, active 
intervention (online program vs. virtual coach-
led), response to treatment, and 
rurality/medically underserved residency 
status. Interviews will use semi-structured 
interview guides designed to assess relevant 
domains.  
• 
Interviews at 3-5 months will focus on 
participants’ experience with the 
intervention and intentions to change 
or maintain changes learned from the 
intervention 
• 
Interviews at 12-14 months will focus 
on participants’ maintenance of 
behavioral skills practice since 
intervention, and changes in domains 
likely affected by treatment. 
 
Conducted in 
years 1-3 for 3- to 
5-month 
interviews 
 
Conducted in 
years 2-3 for 12- 
to 14-month 
interviews 

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Qualitative Evaluation Objectives 
Measured By  
Time Frame 
during the 4-year 
UH3 study period 
Understand patient experiences 
related to discontinuation of the 
intervention 
Interviews with a sample of patients who did 
not complete the active interventions to 
which they were randomized (but are still 
enrolled in the study) using a semi-structured 
interview guide designed to assess relevant 
domains  
 
Conducted in year 
1 
Process evaluation of trial 
implementation and delivery, including 
barriers and facilitators to 
accomplishing aims, lessons learned 
and changes to planned activities.  
 
Interviews with intervention staff/health 
coaches to chronicle the process of trial 
implementation and delivery 
Conducted years 
1 and 3 of study 
 
 
 

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4 STUDY DESIGN  
 
4.1 
Overall Design 
 
This phase III, randomized, comparative effectiveness research trial will evaluate two CBT-
based chronic pain treatments delivered via different remote modalities: 1) an established 
online, CBT-based program (painTRAINER), and 2) a centralized, virtual coach-led CBT-CP 
intervention. Both modalities will be compared to usual care services.  
 
The study uses a three-arm, parallel intervention design. Participants will be recruited from the 
populations of four integrated health care systems which serve as the clinical sites: 1) Kaiser 
Permanente Georgia (KPGA), 2) Kaiser Permanente Northwest (KPNW), 3) Kaiser Permanente 
Washington (KPWA) and 4) Essentia Health in Minnesota, North Dakota, and Wisconsin. 
 
 
4.2 
Study Arms  
 
The three study arms to which participants will be randomized for the UH3 randomized clinical 
comparative effectiveness trial will be: 1) The painTRAINER online, CBT-based, pain coping 
skills training (PCST) program, 2) Virtual CBT-CP delivered by health coaches, and 3) Usual 
care.  See section 10 for details on study arms 1 and 2 (the active interventions).  
 
Those randomized to the usual care arm of the study will be mailed a bound copy of the 2020 
edition of the American Chronic Pain Association Resource Guide to Chronic Pain 
Management.39  
 
Patients randomized to either of the active intervention arms or the usual care arm of the study 
can receive any pharmacologic and nonpharmacologic treatments available to them without 
restriction during the study period. 
 
4.3 
Study Arm Assignment/Randomization  
 
After completion of the baseline data collection, study participants will be individually 
randomized in equal ratio to one of the three study arms.  
 
Randomization will be stratified on: 
 
Variable 
Source 
Sex 
Sex from electronic health record (Male vs. 
Female or Other) 
Pain severity score 
Score on BPI-SF from baseline survey (< 7 
vs. ≥7) 
Clinical site 
KPWA, KPNW, KPGA, Essentia 
Rural/medically underserved residency 
Residency geocode for Census Tract from 
electronic health record  
 
Within each stratum, to contain concealment and balance randomization over time, a random 
permutated block design will be used with random variable block sizes of 3, 6, or 9 to ensure 
approximately equal accrual into the three study arms.  

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The TIN JHU/Tufts Lead biostatistician, in collaboration with the study Biostatistician, will 
develop the randomization scheme and the TIN Utah DCC will implement the scheme by 
developing the randomization tables, which will be provided to KP CHR for integration into the 
electronic data capture system.  
 
Randomization will occur within the KP CHR-hosted electronic data capture system after 
baseline assessment completion. 
 
4.4 
Scientific Rationale for Study Design 
 
An enhanced usual care study arm has been included to address the critical question: What is 
the incremental benefit of the study interventions over what treatments patients are already able 
to access to help manage their pain? This is important to understand from a research, cost-
analysis, health care-implementation and dissemination perspective. The study team recognizes 
that those motivated to join the study have effectively expressed an interest in obtaining 
additional resources for helping them manage their pain so those randomized to the usual care 
study arm will be sent a bound copy of the 2020 edition of the American Chronic Pain 
Association Resource Guide to Chronic Pain Management. This is a detailed informational 
guide to medical, interventional, behavioral, pharmacological and rehabilitation therapies, that 
can serve as a helpful, up-to-date resource to recipients for considering a broad range of 
treatment and self-management options that might help with their needs.   
 
4.5 
Justification for Interventions 
 
Online, CBT-based pain coping skills training (PCST) program. Multiple meta-analyses support 
the efficacy of web-based CBT-CP interventions for improving pain and pain-related 
impairment.32,55,56 Although overall effect sizes are modest, these reviews suggest the potential 
impact of these treatment approaches with respect to lower costs and greater safety than 
pharmacologic pain treatments. painTRAINER has been shown to be effective in a number of 
studies with high completion rates compared to other studies.57-59 painTRAINER uses a novel 
approach by incorporating the expertise of experienced CBT-CP clinicians into the program’s 
decision rules (tailoring algorithms) and knowledge database to retain critical therapeutic 
features of in-person CBT-CP.60 In a randomized control feasibility trial of painTRAINER, 
participants demonstrated increases in self-efficacy from baseline to post intervention compared 
with the control group (effect size d=0.43), and women who completed the program had 
reduced pain compared to those in the assessment-only control condition (effect size d=0.33). 
The study sample included those who might be considered to have significant barriers to using 
online programs, including older adults (mean age of 68, range 38-90 years), minorities (35% 
African American), and people largely from rural, low-income areas. Some had little computer 
experience, and many had lower education levels (29% with high school education or less). 
Importantly, 93% of participants agreed the program was easy to use, and 91% completed all 8 
sessions, a much higher rate than for most online interventions, and many in-person CBT-CP 
interventions. Overall, pain levels were mild to moderate in the feasibility trial sample, limiting 
benefits and indicating a need for more rigorous screening to target persons with high impact 
chronic pain. Screening procedures for the RESOLVE study are designed to ensure that 
patients in the trial have greater potential for clinical benefit (i.e., they report their pain as more 
disabling).  
 

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Virtual coach-led CBT-CP (telephone/video). Large trials have demonstrated clinically meaningful 
benefits of telephone-based CBT-CP for pain-related outcomes in the context of multicomponent 
interventions.30,61,62 In a trial with 442 patients, evaluating telephonic CBT-CP and graded exercise 
for treating chronic widespread pain (an often treatment-resistant pain variant), telephonic CBT-CP 
was associated with substantial, statistically significant improvements in patient global assessment 
at 6- (odds ratio [OR], 5.0; 95% confidence interval [CI] 2.0 to 12.5) and 9-month (OR, 5.4; 95% CI 
2.3-12.8) follow-ups.30 The PPACT trial used substantial telephone-based CBT-CP delivery for 
patients experiencing barriers to in-person treatment. This care was highly acceptable to patients 
and feasible for master's-level, trained clinicians to reliably deliver. Finally, KPWHRI has a long 
history of developing successful and highly deployable telephone interventions with national uptake 
to provide behavioral treatment for depression and smoking.28,29,63-67 Two small trials of telephonic 
CBT-CP had negative results: one was markedly underpowered and the other tested an intervention 
that did not emphasize behavioral activation,68,69 deficiencies which will be addressed in the 
RESOLVE virtual intervention. Although this arm of the trial was initially planned as a primarily 
telephone-based intervention, following the Covid-19 outbreak, the health care systems in which this 
study is being conducted, like many across the country, are pivoting towards remote delivery of 
health care.35 In this rapidly evolving treatment landscape in the participating, video-visits are 
preferred to telephone-visits because they are widely seen to be more satisfactory for patients given 
the better approximation of in-person visits as well as the additional utility of being able to share 
materials and see face and body language (Permanente Medicine staff communication, 4/16/20). 
Given that these video visits are quickly becoming the standard of care, together with findings from 
our pilot intervention that highlighted limitations of discussing key CBT-CP tools without being able 
to visually share, video visits when available and acceptable for patients will be provided.  
 
 
4.6 
End-of-Study Definition 
 
A clinical trial is considered completed when participants are no longer being examined or the last 
participant’s last study visit has occurred. Therefore, the study will be complete when the last 
participant has completed their 12-month follow-up assessment and any scheduled qualitative 
interviews which will occur up to 14 months follow-up from study randomization.  
 

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5 STUDY POPULATION  
 
5.1 
Participant Inclusion Criteria 
 
This study will primarily employ a population-based recruitment approach in which the 
individuals who are invited/recruited to potentially participate in the study will be identified based 
on the following electronic health records (EHR)-based criteria. In addition, health care 
providers can refer patients to the study; however, any patient referred must meet the same 
criteria described below. 
 
Individuals must first meet these EHR-based criteria in order to be invited to be screened for 
participation.  
1. Active/enrolled in one of the 4 participating integrated health care systems at the 
time of query and for the prior 360 days  
2. Age 18 years or older (based on date of birth documented in EHR) 
3. English speaking or do not need interpreter services  
4. Have at least one [at Essentia] or at least two which are >60 days apart [at KP 
sites] outpatient pain-related health care encounter with nonmalignant 
musculoskeletal pain diagnoses [as determined by ICD10 codes for any of the 
following: back- neck-, limb/extremity-, joint-pain, arthritic disorders, fibromyalgia, 
headache, orofacial/ temporomandibular pain, or musculoskeletal pain]52 within 
the past 360 days  
5. Do not have an encounter for surgery related to common musculoskeletal pain 
conditions (e.g., joint replacement, spinal fusion, carpal tunnel release surgery) 
[as determined by CPT and/or ICD-10 codes] within the past 60 days 
6. Do not have two or more separate encounters with a malignant cancer diagnosis 
other than non-melanoma skin cancer [as determined by ICD-10 codes] within 
past 60 days 
7. Do not have ICD-10 code(s), CPT code(s) or department/provider encounters 
indicating receipt of hospice or other palliative care within the past 360 days 
8. Do not have ICD-10 codes indicating severe cognitive impairment precluding 
participation in a behavioral/ lifestyle change program  
 
[Note: At the KPWA site only, one additional EHR-based exclusion criterion will be applied, 
which is: Do not have ICD-10 codes indicating opioid use disorder (OUD). This criterion is being 
applied because there is another HEAL study being conducted at KPWA that focuses on 
treating individuals with pain and OUD specifically.] 
     
Individuals who meet the above EHR criteria will be invited to respond to screening questions 
and must meet the following inclusion criteria: 
1. Have high-impact chronic pain (as indicated by self-report of having pain on most 
or every day in past 3 months and pain limiting life or work activities on most or 
every day in past 3 months)4  
2. Have persistent pain (as indicated by self-report PEG score of ≥ 12) 
3. Be able to participate in either of the active interventions (i.e., have internet and 
phone access required for accessing treatments) 
 
 

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5.2 
Participant Exclusion Criteria 
 
Individuals screened who meet the inclusion screening criteria (and the initial EHR criteria 
described above) cannot endorse any of the following exclusion criteria: 
1. Have received CBT for pain or pain-related psychoeducation or behavioral skills 
training within in the past 6 months (in-person, by phone or videoconference, or 
online) 
2. Currently receiving or will be starting CBT for pain or pain-related 
psychoeducation or behavioral skills training in the next month (in-person, by 
phone or videoconference, or online) 
3. Currently receiving or will be starting inpatient or intensive outpatient services for 
substance use disorder in the next month 
4. Have a planned/scheduled surgery in next 12 months related to pain condition   

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6 RECRUITMENT PROCEDURES AND RETENTION STRATEGIES 
6.1 
Recruitment of Patients 
 
Each of the 4 sites will be responsible for recruiting and enrolling approximately 595-625 
patients per site but the final number will vary slightly across sites. In order to reach the overall 
study target for number randomized within the study timeline, some sites may enroll more than 
others (i.e., Essentia and KPGA vs. KPWA). [Note: The study aims to randomize 2,331 
individuals (at least 777 per arm) and, as such, the number needed to enroll may be larger than 
the 2,500 target as not all who consent/enroll go on to be randomized.]  Study activities from 
recruitment through completion of baseline survey will be completed by each site for their 
population of patients.   
 
For recruitment, each site will query their EHR data warehouses to identify a sample of patients 
who meet the EHR-based inclusion criteria on a set frequency. The sample of patients will be 
stratified by urban vs. rural or medically underserved residence, based on the individuals’ 
resident Census Tract/geocoded data in the EHR. The table below provides definitions to be 
used for these categories.  
 
Urban 
Rural or Medically Underserved (MUA) 
Urban is defined as subject’s resident Census 
Tract corresponds to US Census 2010 Rural-
Urban Commuting Area (RUCA) Codes 1, 2 or 3 
(https://www.ers.usda.gov/data-products/rural-
urban-commuting-area-codes/documentation/) 
 
Rural is defined as subject’s resident Census 
Tract corresponds to US Census 2010 Rural-
Urban Commuting Area (RUCA) Codes 4, 5, 6, 7, 
8, 9 or 10 (https://www.ers.usda.gov/data-
products/rural-urban-commuting-area-
codes/documentation/) 
 
Medically underserved (MUA)is defined as 
subject’s resident Census Tract corresponds to 
HRSA-designated primary care or mental health 
geographic or geographic high needs health 
professional shortage area 
(https://data.hrsa.gov/tools/shortage-area/hpsa-
find) 
 
Then, a random sample of approximately 500-700 patients per month per site will be generated, 
with adjusted sampling for rural residency to ensure at least 20% in either the urban or 
rural/MUA subgroup at each site. Specifically, individuals who reside in rural or medically 
underserved areas will comprise 30-50% of the overall RESOLVE study population. Each site 
will have at least 20% enrollment in either subgroup (urban vs. rural/MUA) to enable sufficient 
sample size for subgroup analyses.  
 
Patients in the random sample will be mailed a recruitment letter and brochure which includes: a 
description of the study, instructions for how to call a research staff person to complete the 
screening survey by phone or complete it online, and select elements of informed consent, 
including a clear statement of the ability to opt out of further contact by calling the site-specific 
study telephone number. Finally, the letter states that patients might be contacted by phone in 
the following weeks to participate in the study if they have not called to opt-out of further contact 
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a recruitment email in follow-up to the mailing to patients in the sample who have an active 
email address. See section 7 for a complete description of the screening process. 
 
The population-based recruitment process described above will be the primary method for 
identifying potentially eligible patients for this trial. A secondary method will be by health care 
provider or self-referral. Health care providers, including primary care providers, physical 
therapists, health and wellness education staff, and others within the participating health care 
system, will be given information about the study via multiple methods such as staff messaging, 
staff intranet resources, and outreach/education at existing clinic and provider meetings. For 
patients who agree, health care providers will be able to electronically route a referral to a study 
staff member either within the EPIC EHR (that is linked to the patient’s record), by staff 
message, or by leaving pertinent information (patient name and health record number for 
retrieval of contact information) on a study-specific voicemail, accessible only by select study 
staff. Then, study staff would ensure that the patient meets the EHR-based inclusion criteria (by 
analyst executing a pre-developed program). Health care providers will also be able to provide 
patients with information about the study (brochure) and the number of the study-specific 
confidential voicemail so that patients can self-refer to the study or patients may obtain 
information about the study on their own. Study staff would contact patients who self-refer, 
obtain their permission to assess their EHR-based eligibility, and then the analyst would execute 
the pre-developed program.  If the person does not meet the EHR-based inclusion criteria, the 
study staff person will follow-up with the patient by phone or mailed letter to explain this and call 
or send a staff message back to the referring provider informing them. If the person does meet 
the EHR-based inclusion criteria, the study staff member will notify the referring clinician of this 
(if applicable), and the participant will then be mailed a recruitment letter and follow the same 
process as described above for those identified through the EHR query. 
 
In addition, a subset of approximately 100-120 patient participants will be invited to complete 
interviews as part of the qualitative evaluation. Approximately 20 of these interviews will be 
conducted once early in the launch of the UH3 trial with select participants randomized to the 
active intervention arms who drop-out of intervention participation early (i.e., only complete 2-5 
sessions) or are less consistent in their engagement with intervention activities; these 
individuals have not withdrawn from the study. The remaining approximately 100 interviews will 
be conducted with a subset of individuals randomized to the active intervention arms; sampling 
for these interviews will be based on 1) clinical site, 2) active intervention arm, 3) treatment 
response at 3 months (based on 3-month BPI-SF assessment), and 4) rural/medically 
underserved vs. urban residency. This larger subset of interviewees will be recruited to 
complete interviews at approximately 3-5 months and again at 12-14 months following 
randomization. Individuals who are recruited for interviews will have endorsed their willingness 
to potentially participate in the interviews on their baseline survey. The Utah Data Coordinating 
Center (DCC) will work with the study team to provide a report of individuals to enable 
stratification for interview sampling based on the criteria listed above. These individuals will first 
be mailed a letter describing the goals of the interview, the process, and who to contact on the 
study team if they are interested. Finally, the letter states that patients might be contacted by 
phone in the following weeks about participating in an interview if they have not called to opt-in 
or out of participating. Study staff will follow-up by phone and/or email to schedule interviews.   
 
6.2 
Recruitment of Stakeholders for Qualitative Evaluation 
 

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Recruitment of health care system stakeholders and referring clinicians. Up to 20 health care 
system stakeholders will be interviewed, including select clinicians, from KPGA, KPNW, KPWA, 
and Essentia in the areas of quality improvement, primary care, and/or pain management. 
Stakeholders and clinicians will be identified by the research investigators at each site in 
collaboration with health care system study partners based on their expertise and roles within 
the health care system as it pertains to pain management / service delivery. Approximately 8 
interviews will be with health care system leadership and up to 12 interviews with referring 
clinicians across the health care systems if this option is used routinely. Targeted stakeholders 
and clinicians will be sent a one-page fact sheet, which will include the consent elements that 
are pertinent to the interview process, and invitation email from the site PI or co-I, inviting them 
to do an interview. If the individual agrees, they will be connected to the KP CHR qualitative 
research team members who will schedule the interview.  
 
Recruitment of intervention / health coaching staff for qualitative evaluation.  
All (approximately 12) of the health coaching staff [centralized at KPWHRI (KPWA) and KP 
CHR (KPNW)] who deliver the virtual intervention and the intervention staff who support 
participant engagement with painTRAINER will be invited to complete study interviews with 
members of the qualitative research team at KP CHR describing their experiences delivering the 
study protocol and working with participants in the active intervention arms of the study. 
Intervention staff / health coaches will be free to decline these interviews and will be told that 
their names will not be attached to any data derived from this interview data. 
 
See section 8 for a description of the consent processes for these individuals.  
6.3 
Retention Strategies 
 
Retention of patients. The following strategies will be used to maximize follow-up rates: 1) allow 
participants to complete assessments using the mode they prefer (online, by telephone, or a mailed 
survey); 2) confirm and update contact details at each survey contact; 3) use standard tracking or 
EHR/administrative records to locate persons who move; and, 4) provide incentives that adequately 
compensate subjects for the time spent completing assessments (see table below) and increase as 
subjects continue in the study. Specifically, participants will receive $25 at baseline and $30, $35, 
and $40 at each follow-up time point respectively, if they complete by paper or phone, and $5 
more at each follow-up time point for completing by web (with the rationale that the additional 
funds compensate for the cost of broadband necessary to complete the assessments online).  
 
 
Time Point 
Completion Mode 
Baseline 
3-month 
6-month 
12-month 
Phone 
$25 
$30 
$35 
$40 
Paper 
N/A 
$30 
$35 
$40 
Web 
$25 
$35 
$40 
$45 
 
Patients who participate in the qualitative evaluation will receive $30 for each interview 
completed.   
 

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7 ELIGIBILITY SCREENING 
 
Patient screening process. Upon receiving the recruitment letter and brochure or recruitment 
email (if applicable at the site), patients can choose to complete the eligibility screening survey 
by web or call study staff at their specific clinical site to complete the questions by phone. In 
addition, as described in section 6.1 on recruitment, study staff will also conduct outreach calls 
to conduct eligibility screening with individuals who do not complete the screening by web or call 
in on their own. The specific procedures for each screening mode are described below.   
 
The eligibility screening survey will take approximately 10-15 minutes and assess the following 
eligibility criteria: 
• English speaking 
• Do not have a cognitive impairment severe enough to preclude participation in study 
• Be able to participate in either of the active interventions (i.e., have email, internet 
and phone access required for accessing CBT-CP treatments).  
• Meet the following definition of high impact chronic pain.  
o Experience pain on most or every day of the past 3 months  
AND  
Pain limits life or work activities most or every day of the past 3 months  
• Score ≥12 on the 3-item PEG assessment 
• Not currently receiving, about to start, or have received in the past 6 months CBT for 
pain or similar pain-related psychoeducation or behavioral skills training   
• Not currently receiving or about to start substance abuse treatment services 
(inpatient or intensive outpatient) 
• Not planning/scheduled for surgery related to pain condition in next 12 months  
 
Screening by web. Patients who choose to complete the eligibility screening by web will 
either go to the study website and access the screening survey by entering the unique 
survey code from their recruitment letter or click on the unique survey link provided in the 
recruitment email (if applicable for their site). As described above, the web-based 
screening survey should take approx. 10-15 minutes to complete. Upon completion of 
the screening survey, patients will be informed whether they are eligible to participate in 
the study or not.  
If ineligible, they will be presented with a closing webpage thanking them for their 
time and interest, briefly explaining the reasons for ineligibility, and giving them 
the site study contact phone number if they have further questions. 
If eligible, they will be able to complete the informed consent and baseline survey 
via web, as described in section 8.   
 
Screening by phone. Patients who opt for phone screening will complete the 10-15 
minute screening survey with the health care system research staff supporting telephone 
screening. If ineligible, they will be informed during the call and able to ask questions. If 
eligible, they will be given the options of 1) completing the informed consent immediately 
by phone as well as the baseline survey, or 2) being contacted at a later time to 
complete the informed consent and baseline survey by phone. 
 
 

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8 INFORMED CONSENT PROCESSES 
8.1 
Informed Consent of Patients  
 
Electronic Health Records (EHR)-Based Population Screening and Recruitment 
• 
No consent is required to conduct the population-based screening and recruitment 
process described in section 6.1, which involves each site querying existing 
administrative EHR records to extract PHI limited to the information necessary for 
determining potential eligibility and conducting further screening. 
• 
This also applies (no consent required) to the patients who are referred by their health 
care provider to be screened for study eligibility. The provider will discuss the study 
directly with the patient; if s/he agrees, a referral will be electronically routed to a study 
staff member who will assess whether the patient meets the EHR-based inclusion 
criteria, as also described in section 6.1.  
• 
A waiver of the documentation of informed consent will be obtained for patients who self-
refer to the study after receiving the brochure from their provider or obtaining the 
information on their own. Because these individuals will contact study staff directly, it is 
feasible to obtain verbal consent to verify their potential eligibility based on the EHR-
based inclusion criteria. The provider recruitment brochure and EHR eligibility consent 
phone script address the elements of consent that are applicable to this screening 
process. In addition, patients will agree to the use of their PHI to assess their eligibility.      
 
Eligibility Screening Survey  
A waiver of the documentation of informed consent will be obtained in order to conduct the 
eligibility screening survey. All potentially eligible patients (based on the EHR data) will have 
been mailed a recruitment letter and brochure, as described in section 6. Upon receiving the 
recruitment letter and brochure, patients can choose to go to the website to complete the 
eligibility screening survey or call their clinical site to complete the eligibility screening survey by 
phone. If a potentially eligible patient does not complete the screening survey by web or 
proactively call the study on their own, study staff will attempt to reach them by phone, as 
described in section 6.1 on recruitment.  
 
Screening Survey by Web: If a patient goes to the website to complete the screening, 
before they are presented with the opportunity to answer the eligibility questions, they will 
be presented with a written statement that contains the elements of informed consent that 
are applicable to the screening process. In addition, the statement will provide a phone 
number to call research staff if they have questions. After being presented with this 
statement to read, patients will be asked to electronically endorse their consent to complete 
the eligibility screening before they can answer the eligibility questions. 
 
Screening Survey by Phone: If a patient calls into the study phone line or is called by study 
staff after receiving the recruitment letter and brochure, a staff member will review the same 
information that is presented to patients who go to the website using a script that contains 
the elements of informed consent that are applicable to the screening process. In addition, 
the research staff will ask patients if they have any questions. After reviewing this 
information, patients will be asked to verbally confirm their consent to proceed with the 

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eligibility screening and their response will be documented by study staff in the electronic 
data capture system. Only after providing verbal consent will, they be asked the eligibility 
screening questions by the research staff. 
 
Study Enrollment 
A waiver of the documentation of informed consent will be obtained in order to conduct the 
informed consent process for the study by phone (consent obtained verbally) or by web 
(electronic endorsement of consent). All participants are provided with information 
containing all elements of informed consent, as they apply to all parts of the study, however 
participants will not document consent with a signature. 
 
If a patient is determined to be eligible based on the screening survey, s/he can proceed 
with the informed consent process by web or phone during the same encounter as the 
screening survey. Or, if a patient would prefer to conduct the informed consent process at a 
later time s/he can return to the website later to complete it electronically or schedule a time 
to complete it by phone with a study staff member.  
 
Website: If a patient is determined to be eligible based on the screening survey 
completed by web, s/he will be able to continue with the informed consent process. 
Patients will be directed to download and read (via PDF link) the combined master 
information sheet and site-specific information sheet, which includes all elements of 
consent and HIPAA authorization information and encouraged to keep it for their 
records. They will also be directed to call their site’s study-specific phone line if they 
have any questions before they decide to participate. Patients will be asked to 
electronically endorse their consent and HIPAA authorization. After completion of the 
consent process by web, participants will be mailed a copy of the information sheet for 
their records. In addition, sites may follow-up by phone with individuals who enrolled by 
web in order to briefly welcome them to the study and clarify next steps.     
 
Phone: If a patient is determined to be eligible based on the screening survey completed 
by phone, s/he will be able to continue with the informed consent process. The study 
staff person will review the elements of consent and HIPAA authorization information 
which are contained in the study information sheet, using the consent phone script. 
While on the phone, the staff person will direct the patient to the study website where the 
combined master information sheet and site-specific information sheet can be 
downloaded and reviewed by the patient as the staff person explains/reviews its content. 
Verbal consent will be obtained as well as verbal HIPAA authorization. After completion 
of the verbal consent process, participants will be mailed a copy of the information sheet 
for their records.  
 
For the subset of individuals who are recruited to complete interviews, they will have consented 
to the interview as part of the study’s informed consent process. When the KP CHR study team 
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received the information sheet and confirm that the interviewee agrees to have the interview 
recorded before any recording begins.  
8.2 
Informed Consent of Stakeholders and Staff 
 
As noted in section 6.2, which describes recruitment strategies, stakeholders will have received 
an email invitation with a one-page fact sheet attached, which includes the consent elements 
that are pertinent to the interview process prior to agreeing to schedule an interview. When the 
KP CHR study team member calls these individuals at the pre-scheduled time, s/he will ask if 
the stakeholder interviewee has received the fact sheet and if s/he has any questions before the 
interview commences. In addition, the KP CHR study team member will confirm that the 
stakeholder interviewee agrees to have the interview recorded before any recording begins.  
Consent will not be obtained from the individuals who choose to complete a stakeholder 
interview. They are given a fact sheet, containing elements of consent, as described above. The 
interview itself focuses on organizational processes, and although the stakeholder does share 
opinions and perspectives on organizational topics, they do not share personal or protected 
health information. This is an appropriate consent procedure given the minimal risk to the 
stakeholder posed by the interview and the fact that the interview involves discussing 
organizational topics commonly discussed in work-related meetings. In addition, due to the 
professional focus of the interviews (and often the organizational prohibitions restricting such 
individuals from accepting an incentive), stakeholders will not be paid an incentive for their 
participation. 
 
Informed consent process for intervention / health coaching staff. The intervention / health 
coaching staff will be given a one-page fact sheet, which includes the consent elements that are 
pertinent to the interview process prior to agreeing to schedule an interview. They will be 
informed that they can refuse participation with no impact on their work. When the KP CHR 
study team member calls these individuals at the pre-scheduled time, s/he will ask if the 
interviewee has received the fact sheet and if s/he has any questions before the interview 
commences. In addition, the KP CHR study team member will confirm that the interviewee 
agrees to have the interview recorded before any recording begins. Consent will not be obtained 
from the staff who choose to complete an interview based on the rationale outlined above for 
the stakeholders.  
 
 

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9 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
 
9.1 
Discontinuation of Study Intervention 
 
There are no criteria for the PI to discontinue the administration of the study intervention that are 
related to specific adverse events or serious adverse events.  
 
There may be rare instances in which an individual decompensated (or was threatening to study 
staff) and was consequentially unable to continue to actively participate in a behavioral 
intervention of the type administered in this trial. In this event, the reason for discontinuation will 
be documented and an attempt to connect the participant to relevant behavioral health 
resources/support in their region will be made. 
 
If a participant informs the study staff that they will discontinue participation in the intervention, 
staff will assess their reasons for discontinuation and determine whether the participant wants to 
continue with the other study activities or withdraw from the study entirely.  
 
9.2 
Participant Discontinuation/Withdrawal from Study  
 
There are only rare circumstances under which the PI would discontinue/withdraw a participant 
from the study. As noted above, in the rare instance in which an individual decompensated (or 
was threatening to study staff) and was consequentially unable to continue to complete study 
assessments, the reason for discontinuation would be documented and an attempt to connect 
the participant to relevant behavioral health resources/support in their region.  If a participant 
informs the study staff that they will discontinue participation in the study, staff will assess and 
document their reasons for discontinuation. As specified in the consent, any data collected up to 
the point of withdrawal will be retained. 
 
9.3 
Loss to Follow-Up 
 
Participants randomized to the online program or virtual CBT-CP will be considered lost to 
follow-up after 1) they have missed 2 or more of the weekly sessions or 2) a study staff member 
has been unable to reach them after making multiple contact attempts (up to 7 calls or emails 
and 2 mailed letters) over a 4 to 6-week period.  
 
If a participant is considered lost to follow-up for the active intervention, the individual will still be 
contacted per the follow-up assessment outreach process for each time point unless there is no 
active/working phone, email, or mailing address available for them.  
 

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10 STUDY INTERVENTIONS 
 
10.1 
Description of Interventions  
 
Both active intervention arms are based on the same core CBT-CP program (pain-coping skills 
training) developed and refined by Dr. Keefe and colleagues at Duke University over the past 
three decades. In addition, the virtual coach-led CBT-CP coach manual and participant workbook 
are based on the PPACT intervention, which was tested in a large pragmatic trial led by Dr. 
DeBar.70,71  
 
CBT is the most widely accepted, evidence-based, nonpharmacologic treatment for chronic pain 
and has been shown to benefit low-literacy adults in rural areas.1,16,17 CBT-CP is based on the 
theory that patients' beliefs, attitudes, behavior, and coping styles play central roles in 
determining (mediating) the impact of persistent pain.18  
 
CBT-CP effects can be maintained long after treatment ends, without the negative side effects of 
opioids and other pain medications and is an attractive adjunct or alternative to pharmacological 
treatments. CBT-CP It focuses on helps patients develop and master skills to manage pain and 
the disability and emotional distress associated with pain in order to improve their functioning 
and quality of life. CBT-CP enhances the use and perceived self-efficacy of pain coping skills 
that address cognitive processes (e.g., reducing catastrophizing) and behaviors (e.g., engaging 
in meaningful activities and goals).  
 
The table below provides an overview of the core content for both of the RESOLVE study 
interventions. Both interventions include elements to enhance learning and mastery of skills that 
are guided by social cognitive theory (e.g., social  modeling, vicarious learning),72,73 adult 
learning theory (e.g., tying skills to personal goals and experiences),74,75 principles of multimedia 
instruction (interactive exercises, graphics to reinforce explanations),76 and behavior change 
theory77 (e.g., behavior tracking). 
 
  
 
 
 

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10.1.1 painTRAINER  
 
Overview. painTRAINER is an online, 8-session, pain coping skills training program (PCST) 
based on cognitive behavioral therapy (CBT). Each session takes 45-60 minutes to complete 
and provides interactive training in one or more evidence-based pain-coping skills.59 
Participants complete sessions on their own, in a set order, and are encouraged to complete 
one session per week. Session completion is flexible – participants can close a session before 
completing it and later resume where they left off. They can also go back to review completed 
sessions or sections of completed sessions (e.g., an audio recording of a skill practice, or 
instructions on how to use a skill). The sessions are led by a recorded “virtual coach” who 
speaks directly to users. Thus, content is provided in audio to minimize reading and facilitate 
program completion for low-literacy patients. painTRAINER was designed to include features of 
therapist delivered PCST, while providing training in an easy-to-use format that includes 
animated demonstrations, interactive exercises, working through common barriers to behavior 
change/skills practice, and tailored feedback to reinforce learning.  
 
Onboarding and Registration. Following randomization, participants who are assigned to 
painTRAINER are mailed materials that include instructions for registering for the program, 
unique login information, a participant workbook, and study team contact information (in case of 
questions or technical difficulties). Approximately a week after the materials are mailed, study 
staff call participants to “onboard” them to the program. This entails providing a verbal overview 
of the program and making sure participants register and are able to access/log into 
painTRAINER. Study staff follow specified guidelines to complete the onboarding call which 
include suggested language/scripting. [Note: On 08/09/21 VUMC IRB approved revised 
onboarding guidelines which added motivational interviewing-based language. This language 
was to be used, as feasible.] The primary goal of the onboarding call is to ensure that 
participants register and have no technical difficulties. The inclusion of MI-based language 
allows the staff person doing the onboarding to ask participants to consider potential barriers to 
participation and how they might plan in advance to overcome such challenges as well as to 
reaffirm their rationale and commitment to utilize painTRAINER to learn skills to manage their 
pain.  
 
Ongoing Support and Engagement. After participants begin the painTRAINER program, 
automated email reminders are sent to practice skills and complete modules. Support is also 
provided by study staff if a participant is not adhering to the recommended completion schedule. 
Specifically, a study staff person will follow-up with a participant by phone in the following 
circumstances: 
 
• 
It has been more than 7 days since the participant registered and session 1 has not 
been initiated. 
• 
A session has been initiated but is still incomplete after more than 7 days. 
• 
It has been more than 10 days since the most recent session completion date and 
another session has not been initiated.  
• 
Sessions are being completed too quickly (3 or more sessions completed in 9 days).   
 
Study staff utilize specified guidelines to complete follow-up calls which include suggested 
language/scripting. The goal of the follow-up call is to identify and resolve the reason for non-
adherence. 

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10.1.2 Virtual Coach-led CBT-CP 
Overview. The coach-led program includes 8 sessions of CBT-CP provided one-on-one via 
telephone or video encounters. Each session takes 60 minutes and provides interactive training 
in one or more evidence-based pain-coping skills. Sessions are scheduled at the participant's 
convenience with approximately one session per week and participants have the option of 
meeting with the coach by telephone only, using video conferencing or a combination of the two. 
The live virtual-enabled coaching provided can enhance patient motivation and engagement. 
This approach is likely to be especially useful for depressed or anxious patients (common 
chronic pain comorbidities) for whom de-activation and/or avoidance may create barriers to 
implementing effective pain-coping skills. Coaches providing these virtual visits are required to 
have at least master's-level behavioral health training and conduct coaching sessions from the 
study sites at KPWHRI in Seattle and KP CHR in Portland. This telehealth model of centralized 
behavioral health services is being widely adopted across health care systems nationally, and 
thus represents a critically important approach for this active arm of the study.  
 
Onboarding. Following randomization, participants assigned to Virtual Coach-led CBT-CP are 
mailed materials that include a brief biographical description of their health coach and a 
participant workbook with handouts for the 8 sessions and materials for logging skills practice.  
The assigned coach calls the participant approximately one week after the materials are mailed.  
The primary goal of this outreach by the coach is to introduce themselves and to “onboard” the 
participant to the program. The onboarding call includes verifying receipt of the packet of 
materials and orienting the participant to the Virtual Coach-led program structure and format.  
Participants are informed that coaching calls are confidential, asked their preference for 
telephone or video coaching calls and for permission to record all coaching calls. The coach will 
use the onboarding call as an opportunity to respond to questions from the participant and to 
schedule the first coaching call. Coaches follow specified guidelines to complete the onboarding 
call which include suggested language/scripting.  
 
Ongoing Support and Engagement. Coaches work with participants to schedule sessions at the 
most convenient time for them, with an emphasis on completing one coaching call per week for 
8 weeks. Frequently, a standing weekly meeting time is identified for the 8 weeks, however 
there is flexibility in this schedule and coaches can accommodate scheduling challenges, as 
necessary. Coaches remind participants 1-2 days before a scheduled session via phone or 
email (based on participant preference). If a participant does not attend a scheduled call, the 
coach will first reach out by telephone to reconnect and reschedule the missed appointment. 
When reached, the coach may explore possible barriers to completing the program and work 
with the participant to problem-solve for any challenges, as appropriate. If the participant is not 
reached right away, as described in Section 9.3. multiple outreach attempts will be made over 
the course of several weeks, using different contact modes, including phone, email and mailed 
letters. (Note: In the rare circumstance that a participant cannot be reached by phone, email or 
letter, the coach will send a text as a last resort for outreach.)  
 
 
 
 

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10.2 
Intervention Administration and Dosing 
 
Both the painTRAINER program and the virtual coach-led CBT-CP sessions are intended to 
follow a weekly administration schedule (1 session per week over the course of 8 weeks). 
However, completion may vary due to the personal circumstances of the participants. The 
maximum intended duration for the active intervention period is 12 weeks, meaning study staff 
will proactively follow-up to ensure session completion during that time period. If someone has 
not completed all 8 sessions within 12 weeks, study staff will not do any further follow-up to 
encourage completion of online sessions or schedule telephonic/video sessions.  
• 
The exception to this is when a participant is actively engaged with coaching staff and 
requests and is able to complete any remaining intervention sessions beyond yet close 
to the 12-week target. These instances will be reviewed by clinical supervisors and 
decisions will be made on a case-by-case basis before virtual intervention activities 
continue. All intervention-related contacts are documented and any that occur after the 
active intervention period can be identified/flagged for analytic purposes.       
• 
Note: painTRAINER remains open to participants and access cannot be restricted after 
12 weeks. However, the program automatically collects data on any logins that occur 
after the 12-week period and information related to completion of sessions after the 
intervention period may be used analytically.  
 
Participants are considered to have received a full dose of the interventions if at least 75%, or 6 
of the 8, sessions have been completed.   
 
10.3 
Masking and Measures to Minimize Bias 
 
It is not feasible for participants to be masked to treatment arm assignment due to the 
behavioral nature of the intervention. The PI and select Co-Investigators and study staff who are 
involved in the oversight and delivery of the interventions will also be aware of treatment 
assignment. Outcome assessors will be masked to treatment assignment. Assessments 
completed on paper will be entered by research staff who are blinded to the randomization 
status of the study participants.  
 
10.4 
Study Intervention Fidelity Monitoring Procedures  
 
Training and monitoring intervention fidelity for virtual coach-led CBT-CP. Maximum 
generalizability and relevance to community providers will be addressed by applying the 
Treatment Fidelity Workgroup of the NIH Behavioral Change Consortium80 framework to ensure 
interventions are delivered as intended. Treatment fidelity is maximized by use of fidelity 
induction and monitored by fidelity assessment. In this study, fidelity induction will be achieved 
by the use of proactive strategies including: a formal structured orientation and training 
process for health coaches, use of standardized treatment manuals and training materials, 
repetition and practice of training skills, and adequate achievement of proficiency in core skills 
before health coaches start to work with study participants.  
 
All coaches will receive training prior to conducting treatment sessions with study participants. 
The initial training will consist of approximately 16 hours of didactic and experiential coursework 
conducted by Drs. Balderson, DeBar, Murphy and/or Keefe. Interventionists will be provided 
with the treatment manual and the treatment strategies will be taught through didactic 
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scenarios. Health coaches will complete two role plays of the eight intervention sessions, one as 
a coach and one as a participant (i.e., 16 mock sessions total). Upon completion these initial 
training activities, a health coach will be assigned active study patients.  
 
During the first 4 months post-completion of training, recordings from at least two completed 
encounters for each session number from the coaches’ first 5 patients will be reviewed and 
scored for proficiency by at least one of the following individuals: Drs. Balderson, DeBar, Keefe, 
Murphy and/or Ms. Firemark. For each encounter that is reviewed, two assessments will be 
completed: 1) Fidelity to Session Content 2) Fidelity to Cognitive-Behavioral Therapy Treatment 
(using a modified version of the VA Cognitive Behavioral Therapy for Chronic Pain Therapist 
Rating Scale).20 During this acute phase of session review, written and/or verbal feedback is 
provided to coaches on a weekly basis. 
 
After health coaches reach proficiency in the delivery of each session (based on scored 
recordings), ongoing ratings of recorded sessions will be conducted by one or more of the 
following individuals: Drs. Keefe, Balderson, DeBar, Murphy and /or Ms. Firemark monthly as 
coaches gain experience with the intervention. Ongoing telephonic treatment protocol 
adherence will be monitored via multiple methods that include: 1) therapists’ completion of a 
self-assessment of protocol fidelity adherence after every session using the session-specific 
Fidelity to Session Content checklists, 2) review and scoring of recorded sessions with patients 
using the Content checklists and the Cognitive Therapist Rating Scale, and 3) coach request for 
recording review for any challenging session or sessions viewed as potentially problematic in 
treatment fidelity.  Identified deviations from the treatment protocol will be addressed 
immediately by providing any coach identified as having poor adherence to the intervention 
manual with more intensive supervision and monitoring until adherence criteria is re-
established. This is consistent with how this would occur in everyday clinical care. This 
approach was used successfully in previous CBT-CP studies.25,71,81-83   
 
10.5 
Concomitant Therapy  
 
As noted in the exclusion criteria, study participants cannot at the time of study enrollment or in 
the 6 months prior receive Cognitive Behavioral Therapy (CBT) for pain or a similar 
psychoeducational skill-based training for pain (nor indicate that they have scheduled to begin 
such treatment). However once enrolled, participants can receive any pharmacologic or 
nonpharmacologic treatments available to them without restriction. At each study assessment 
(3-, 6- and 12-month follow-ups), participants’ use of CBT for pain or a similar 
psychoeducational skill-based training for pain (in-person, by phone or via online or App-based 
programs) will be assessed.  
 
 

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11 STUDY ASSESSMENTS AND PROCEDURES 
 
Section 8 describes the informed consent process in detail. The consent process will occur prior 
to initiation of the baseline survey but ideally during the same phone encounter or web survey 
session as the screening.  
 
11.1 
Baseline Assessment 
 
Patient baseline assessment. Patients who consent to participate in the study will be asked to 
complete the baseline assessment either by phone or online immediately following the informed 
consent process. The baseline assessment will include the measures described in section 3.1. 
In addition, the baseline assessment will confirm contact information, collect preferences for the 
administration mode of follow-up assessments, and assess subjects’ willingness to potentially 
participate in the interviews as part of the qualitative evaluation. It is expected that the informed 
consent and baseline assessment will take approximately 45-60 minutes.  
 
11.2 
Follow-Up Assessments 
 
Patient assessment at the time of notification of randomization. At the time that participants are 
mailed the materials notifying them of their study arm assignment, they will also be mailed a 
brief paper survey and a pre-posted return envelope. The paper survey will assess the 
participants’ perceived support of the intervention to which they have been assigned and will 
serve as the baseline assessment of this potential mediator variable. The paper survey will take 
no more than 5 minutes to complete. (Note: This assessment is offered only by paper due to the 
fact that it is mailed with the other materials related to randomization notification and logistically 
it is most feasible to administer this way at this particular time point.) 
   
Patient follow-up assessments at 3-, 6- and 12-months. Based on the preference for survey 
administration mode (online, phone or paper) indicated at the time of the baseline assessment, 
participants will initially be sent the follow-up survey via their preferred mode. (Note: At any point 
during the study, a participant can change their preferred survey mode.) The protocol for follow-
up with non-responders within the assessment window will employ the other modes of contact in 
order to maximize the opportunity to reach participants. For example, subjects who prefer email 
contact for the assessments will also be contacted by phone if they do not complete the 
assessment using the web link in the emails within a set period of time. Each follow-up 
assessment will take approximately 30 minutes to complete. The specific protocol for contacts 
related to follow-up assessments is described in the study’s operating procedures.  
 
11.3 
Qualitative Interviews 
 
Patient interviews. A subset of approximately 100 patients will be invited to complete two 
approximately one-hour long interviews by phone at approximately 3-5 months and 12-14 
months post-randomization. A different subset of 20 individuals who do not complete the 
interventions but are still enrolled in the study (see details related to selection criteria for these 
interviews in section 6.1) will complete one interview approximately one-hour in length by 
phone. Interviewers will use semi-structured interview guides for all patient interviews. These 
interviews will be audio-recorded. 
 

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Stakeholder and referring clinician interviews. The stakeholder interviews will be approximately 
an hour in length and conducted primarily by phone using a semi-structured interview guide; in 
the instance that a stakeholder is unable to complete the interview in one encounter due to 
scheduling issues that may arise which allow less an hour for the phone call, follow-up to 
complete questions may be conducted by phone or email. These interviews will be audio-
recorded. 
 
Intervention staff / health coach interviews: Qualitative research team members will attempt to 
conduct interviews with all (approximately 12) of the intervention/health coaching staff. These 
interviews will be approximately one-hour in length and conducted twice (early in study 
implementation and later); they will be audio-recorded. 

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12 ADVERSE EVENTS AND UNANTICIPATED PROBLEMS INVOLVING RISKS TO 
SUBJECTS OR OTHERS  
 
12.1 
Definition, Classification and Reporting of Adverse Events 
 
12.1.1 Definition of Adverse Events (AEs)  
 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including abnormal signs, symptoms, or diseases, temporally associated with the subject’s 
participation in the research, whether or not considered related to the subject’s participation in 
the research.  
 
Because the RESOLVE study involves minimal risk and the study population includes patients 
with high impact chronic pain, who have fluctuating physical and emotional symptoms as part of 
the natural course of their condition, such symptoms will not be systematically solicited as part 
of the trial. 
 
AEs will be identified if:  
• 
Participants proactively contacts study staff at any time to self-report an AE;  
• 
Participants happen to self-report an AE during a regular study contact with intervention 
or study staff; or  
• 
Participants attribute study withdrawal or dropout to unfavorable medical / health-related 
issues.84 
 
AEs will not be solicited uniformly from all study participants, as capture of these events will be 
biased by study arm (i.e., telephone CBT-CP participants will have greater interaction with study 
staff by phone and more opportunity to self-report these symptoms and events).   
 
AEs will be entered by study staff into the Utah/DCC REDCap AE database at the time of 
reporting by the participant.  
 
12.1.2  Definition of Serious Adverse Events (SAEs) 
 
For this comparative effectiveness trial, a serious adverse event (SAE) is defined as an event 
that:  
• 
Results in death during a patient’s active participation in the trial. 
• 
Results in inpatient hospitalization during a patient’s active participation in the trial. 
(Planned hospitalization scheduled before the enrollment of a study participant is not an 
SAE.)  
 
Because the patients who participate in the RESOLVE study will be older and have co-morbid 
health conditions, it is expected that subjects will experience inpatient hospitalizations, which 
are unrelated to study participation, during the course of the study. In addition, it is expected 
that deaths, which are also unrelated to study participation, might occur among study enrollees 
based on prior studies. Specifically, in the study PI’s recently completed pragmatic trial, PPACT, 
which provided an intensive in-person behavioral intervention and enrolled 850 patients with 
chronic pain, there were 12 deaths during the study, all unrelated to study participation, and 287 
hospitalizations (116 for intervention participants and 171 for usual care). 
 

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SAEs will be systematically assessed every 6 months for active study participants based on 
electronic health records (EHR) data.  
 
• 
Each clinical site will query active participants’ electronic health records data every 6 
months (in alignment with the DSMB meeting schedule) to identify any deaths or 
hospitalizations throughout the interval of active participant enrollment in the trial.  
• 
An independent physician within each health care system/clinical site will conduct a 
chart review for each death and hospitalization to assess its potential relatedness to 
study procedures and interventions.  
• 
The summary of SAEs and findings of these reviews will be submitted to the DCC. 
 
In addition to the semi-annual EHR queries, SAEs may be identified by participant self-report. If 
this occurs, the event will be documented and reviewed by the independent physician as part of 
the semi-annual review described above.   
 
12.1.3 Definition of Adverse Events of Special Interest (AESI) 
 
This protocol will not collect solicited adverse events of special interest (AESI). There is no 
clinical or empirical basis for hypothesizing that either of the active interventions would increase 
risk of AESIs. In addition, the unequal contact with study staff among participants in the three 
study arms inherently results in differential opportunities for ascertainment of “events.” 
Therefore, between-group comparison of adverse events reported to or discovered by study 
staff would be biased and hence not meaningfully interpretable or actionable.  
 
12.1.4 Severity of Adverse Events 
 
For an AE, the following guidelines will be used to describe severity:  
• 
Mild – event does not generally interfere with usual daily activities and/or does not require 
medical care.  
• 
Moderate – event interferes with usual daily activities and/or requires self-medical care or 
outpatient medical care. 
• 
Severe – event interrupts usual daily activities and/or requires inpatient medical care or 
medical care with overnight stay in hospital observation services. 
 
12.1.5 Relationship to Research Participation  
 
For an SAE, the following guidelines will be used to describe relatedness to study procedures and 
study interventions: 
• 
Related – There is clear evidence to suggest a causal relationship between the study 
procedures or study interventions and the SAE, and other possible contributing factors can 
be ruled out. 
• 
Possibly Related –There is a reasonable possibility that the study procedures or study 
interventions caused the SAE. Reasonable possibility means that there is evidence to suggest 
a causal relationship between the study procedures or study interventions and the SAE. 
• 
Not Related – There is not a reasonable possibility that the study procedures or study 
interventions caused the SAE, there is no temporal relationship between the study procedures 
or study interventions and event onset, or an alternate etiology has been established. 
 

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12.1.6 Expectedness of Adverse Events/Serious Adverse Events 
 
An AE/SAE will be considered unexpected if it occurs in one or more subjects, the nature, 
severity, or frequency of which is not consistent with either: 
• 
The known or foreseeable risk of adverse events associated with the procedures involved in 
the research that are described in Section 2; or 
• 
The expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile 
for the adverse event.  
 
12.1.7 Reporting Procedures for Adverse Events/Serious Adverse Events 
 
Any AEs self-reported by participants to study staff will be entered into the Utah/DCC REDCap 
AE database. 
 
As described above, every 6 months in alignment with the DSMB meeting schedule, the study 
sites will provide a summary of SAEs to the DCC.  
 
12.2 
Definition and Reporting of Unanticipated Problems 
 
12.2.1 Definition of Unanticipated Problems 
 
This study protocol uses the following definition of Unanticipated Problems (UPs) to include, in 
general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected;  
• 
Related or possibly related to participation in the research; and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
“Unexpected” means the nature, severity, or frequency is not consistent with either (a) the study 
procedures or study interventions that are described in section 2; and (b) the characteristics of 
the participant population being studied. 
 
“Related” means there is clear evidence that the unanticipated problems were caused by the 
study procedures or study interventions involved in the research and “possibly related” means a 
reasonable possibility that the unanticipated problem(s) may have been caused by the study 
procedures or study interventions involved in the research. 
 
12.2.2 Reporting of Unanticipated Problems 
 
The study site investigator will report UPs to the lead principal investigator (PI). The lead PI will 
report UPs to the IRB of record. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• 
A detailed description of the event, incident, experience, and/or outcome  

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• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP 
• 
A description of any changes to the protocol or other corrective actions that have been taken 
or are proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the timeline specified 
in the written reliance agreement between the IRB of record and the relying IRB at each study 
site.  
 

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13 STUDY OVERSIGHT  
 
Study oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
comprised of members with expertise in appropriate clinical, statistical, scientific, ethical 
disciplines.  
 
The DSMB will meet before study enrollment begins and every six months thereafter, until the 
end of the study; to approve the study protocol prior to implementation; assess safety and 
effectiveness data; to monitor accrual of study participants; to study progress, and data integrity 
for the study.  If safety concerns arise, ad-hoc meetings and more frequent standing meetings 
may be held.  
 
The DSMB will operate under the rules of a charter that will be approved at the initial DSMB  
organizational meeting. At that time, data elements that the DSMB needs to assess will be 
clearly defined. The DSMB will provide recommendations to the funding agency, the National 
Institute on Aging, regarding proceeding with the study as planned, proceeding with 
modifications, or terminating the study, as noted in the DSMB Charter. 
 
This study may be suspended or prematurely terminated if, in the opinion of the investigators or 
the NIA, there is reasonable cause. Written notification, documenting the reason for study 
suspension or termination, will be provided by the suspending, or terminating party. The 
investigators will promptly inform the IRB, providing the reason(s) for suspension or termination.  
 
Circumstances that may warrant termination include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants. 
• 
Insufficient adherence to protocol requirements. 
• 
Data that are not sufficiently complete and/or evaluable. 
 
   
13.1 
Halting Rules 
 
The DCC will monitor the safety data submitted by the study site investigator. The DCC will 
notify the DSMB chair when any SAEs deemed to be unexpected and related to study 
procedures or study interventions occur during the study. 
 
In such an instance, the DSMB chair will provide recommendations regarding the temporary 
suspension of enrollment and/or administration of study procedures or study interventions. If 
warranted, an ad-hoc DSMB meeting will be convened.  
 

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14 STUDY MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, 
that the study is implemented in accordance with the protocol and/or other operating 
procedures, and that the quality and integrity of study data and data collection methods are 
maintained. Clinical site monitoring and remote monitoring for this study will be performed by 
the Duke/Vanderbilt (Clinical Coordinating Center or CCC) and Utah (Data Coordinating Center 
or DCC) Trial Innovation Centers, respectively. 
 
14.1 
Clinical Site Monitoring  
 
The CCC utilizes risk-based methodology to identify and correct problems that may arise at 
sites. Details of clinical site monitoring will be documented in a supplemental study-specific risk-
based Clinical Monitoring Plan (CMP), separate from this protocol. The CMP will specify the 
frequency of monitoring, monitoring procedures, the level of clinical site monitoring activities 
(e.g., the percentage of participant data to be reviewed), and the distribution of monitoring 
reports.  
 
Site monitoring will be performed by a trained site monitor during the study period to ensure 
regulatory compliance, patient safety, and to monitor the quality of data collected. Essential 
document binders, regulatory documents and data collection forms may be reviewed. Interim 
monitoring will take place depending on grant budget, site enrollment, and compliance issues 
identified. The site monitor will provide each site with a written report, and sites will be required 
to follow up on any deficiencies. It is anticipated that the study monitoring for this protocol will 
consist of site initiation (prior to patient enrollment), interim monitoring, and close out. The site 
initiation may take place as group training made up of site investigators and research assistants. 
 
Study monitors will evaluate study processes and documentation based on the International 
Council for Harmonisation (ICH), E6: Good Clinical Practice guidelines (GCP). Documentation 
of monitoring activities and findings will be provided to the site study team, the study PIs, NIH, 
and NIH Program staff. The NIH reserves the right to conduct independent clinical site 
monitoring as necessary. 
 
The CCC may conduct clinical site monitoring remotely. Remote monitoring involves detailed 
review of the data entered by the clinical sites (KPGA, KPNW, KPGA and Essentia) and 
consultations with the clinical site investigators and/or research coordinator/manager to review 
safety and data quality. This may require uploading patient study files, regulatory 
documentation, or other source documents for the monitor to review. Alternatively, other 
methods, such as remotely viewing source documentation, may be utilized. This helps assure 
protocol compliance and accurate data collection. The CCC may conduct more remote 
monitoring activities early in the trial to assure protocol compliance and identify any training 
issues that may exist. Remote monitoring documents will be retained in accordance with federal 
requirements. Safety of subjects will be monitored and ensured in accordance with the Data and 
Safety Monitoring Plan (DSMP). 
 

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15 STATISTICAL CONSIDERATIONS 
 
This section provides an overview of the planned statistical analyses for the RESOLVE study. 
See the RESOLVE Statistical Analysis Plan (SAP) for specific details related to the study 
hypotheses and analytic approaches.   
  
15.1 
Sample Size Determination 
 
For the primary study outcome, clinically meaningful improvement (MCID; 30% reduction in 
overall BPI-SF score) in pain severity at 3 months, sample size requirements were calculated 
for a two-sided comparison of independent proportions with 90% power using Fisher’s Least 
Significant difference method to account for three-way comparisons (specifically conduct 
Omnibus Wald Test for any difference between three groups and then conduct pairwise 
comparisons given an overall difference is statistically significant at the 0.05 alpha level). 
Sample size calculations assumed a usual care outcome rate of 15% who achieve the MCID of 
30% reduction in pain severity from baseline to 3 months. The 15% usual care rate was chosen 
because this rate was observed among participants in the usual care arm of the study PI’s 
recently completed PPACT trial71 and it is similar to rates observed by others in the usual care 
arm of similar trials.85 The necessary sample size of 1,863 (621 per arm) was calculated to 
detect a difference of 7.5% between a given intervention group relative to usual care in the 
proportion of individuals who attain a clinically meaningful change (30% reduction from 
baseline) in pain severity. A retention rate of 80% is estimated. Thus, to achieve this final 
sample size, at least 2,331 individuals will be randomized, 777 per intervention arm. A 7.5% 
detectable difference corresponds to 22.5% (relative change of 150%) of individuals in an 
intervention arm attaining a clinically meaningful change in pain severity.  
 
Power for secondary analyses related to aim 1b (subgroup analyses) was also estimated. 
Sample size requirements for these secondary analyses were calculated using the same 
assumptions described above (i.e., a two-sided comparison of independent proportions using 
Fisher’s Least Significant difference approach to account for three-way comparisons, with 
sample size calculations assuming an improvement rate of 15% in the usual care arm). The 
subgroup sample size was projected to range between 20% and 40% of the original 1,863 
sample size since this should cover the range of the subgroup sample sizes of interest.  
 
Power for Subgroup Analyses Ranging the Size of the Subgroup 
Assumptions 
80% Power to Detect: 
Subgroup         
Sample Size 
Usual Care 
(UC) 
Intervention 
(Int) 
Detectable 
Difference 
Relative Change 
N (% of 1,863) 
% UC 
  
% Int 
%Int - %UC 
% Int / %UC 
372 (20%) 
15.0% 
31.0% 
16.0% 
206.7% 
558 (30%) 
15.0% 
27.7% 
12.7% 
184.7% 
744 (40%) 
15.0% 
  
25.8% 
10.8% 
172.0% 
 
There is 80% power to detect a 10.8% difference (relative change of 172%) between each 
intervention group and UC if subgroup sample size is 40% of the overall study population and 
16.0% difference (relative change of 206.7%) if the subgroup sample size is 20% of the overall 
study population.   
 

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Note that in previous studies of this study team, sex, and comorbid mental health conditions 
(depression, anxiety) were not less than 40% of the population suggesting there is high power 
for the primary subgroups of interest. Further, the study is aiming to have at least 20% of 
rural/medically underserved residency and therefore there is good power for this subgroup. 
Individuals with negative social determinants of health comprise an exploratory subgroup since 
it is not clear how many people in this population a priori will have this indication. 
 
15.2 
Populations for Analyses 
 
All analyses will be conducted following an intent-to-treat approach, including all individuals 
randomized regardless of their engagement with or exposure to the intervention.  
 
15.3 
General Approach to Statistical Analyses 
 
All confidence intervals and p-values will be two-sided and statistical significance at the 0.05 level.   
 
15.4 
Baseline Descriptive Statistics 
 
Descriptive statistics of the baseline study population by intervention arm will be provided, 
presenting percentages for categorical variables and means and standard deviations for 
continuous variables. The RESOLVE Statistical Analysis Plan (SAP) provides specifics on the 
planned analyses related to demographics and baseline characteristics.  
 
15.5 
Primary Effectiveness Analyses 
 
Primary Outcome (Aim 1) Statistical Hypothesis: Both active interventions are 
expected to result in a higher proportion of patients achieving MCID (30% reduction in 
overall BPI-SF score) in pain severity relative to those receiving usual care at 3-month 
follow-up (primary time point). 
 
Secondary Time Point Statistical Hypotheses: Both active interventions are expected 
to result in a higher proportion of patients achieving MCID (30% reduction in overall BPI-
SF score) in pain severity relative to those receiving usual care at the 6 and 12-month 
follow-ups (secondary time points).  
 
 
Modified Poisson regression86,87 fit using generalized estimating equations (GEE) will be used to 
model the binary primary outcome, MCID in pain severity (30% reduction from baseline), 3 
months (primary time point) and 6 and 12 months (secondary time points).   
 
Interactions between each intervention and indicators of time (3, 6, 12 months) will be included 
to estimate time-specific intervention effects; the primary comparisons will be between the 
interventions and usual care at 3 months (i.e., primary effectiveness will test the size of the 
intervention coefficient at the 3-months timepoint). Adjustment will be made for baseline levels 
of pain severity, other stratification variables (sex, clinical site, and rural/medically underserved 
residency), and a priori variables predictive of outcome (multisite pain and co-occurring mental 
health condition). 
 

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The RESOLVE Statistical Analysis Plan (SAP) provides further information on the rationale for 
this approach as well as the specific details on the planned analyses. 
 
15.6 
Secondary Effectiveness Analyses  
 
Secondary Outcomes (Aim1a) Primary Statistical Hypotheses: Those in both 
active intervention conditions will show greater improvements in overall pain severity, 
pain intensity (MCID and overall), pain-related interference (MCID and overall) and 
related quality of life outcomes (social role functioning, physical functioning, and patient 
global impression of change) relative to those receiving usual care at the 3-month 
follow-up.  
 
Secondary Outcomes (Aim1a) Secondary Statistical Hypotheses: Those in both 
active intervention conditions will show greater improvements in overall pain severity, 
pain intensity (MCID and overall), pain-related interference (MCID and overall) and 
related quality of life outcomes (social role functioning, physical functioning, and patient 
global impression of change) relative to those receiving usual care at the 6- and 12-
months follow-ups (secondary time points). 
 
Analyses of secondary outcomes (Aim 1a) will follow the same proposed approach as Aim 1. 
Linear regression will be used to assess continuous outcomes and Poisson regression for 
binary and count outcomes. An interaction between intervention arms and time indicators will be 
included, and the primary time point for all secondary analyses will be 3 months following 
randomization; baseline levels of pain severity and all stratification variables will be included as 
covariates.  
 
The RESOLVE Statistical Analysis Plan (SAP) provides details on these planned secondary 
outcome analyses. 
 
15.7 
Additional Effectiveness Analyses for Primary Outcome (Moderators and 
Mediators)  
 
Moderator (Aim 1b) Statistical Hypotheses: For patients with more complex conditions 
(concomitant mood or anxiety disorders; multisite pain) or challenging social / environmental 
factors (rural/medically underserved or unmet social needs) the contact with a telephonic 
coach will result in better pain-severity outcomes when compared to those receiving online 
CBT-CP.   
 
Moderator Analyses: Subgroup analyses will be conducted to determine the impact of the active 
interventions on specific populations and explore for potential heterogeneity of treatment effects 
by sex, age, race/ethnicity, rural/medically underserved residency, multiple pain conditions, 
mental health mood disorders, and negative social determinants of health. Analyses for Aim 1b 
will follow the same general approach as for Aim 1 but will be focused on assessing 
heterogeneity of treatment effects (sub-groups). Heterogeneous treatment effects by each 
potential moderator will be assessed separately. For each moderator, included in the regression 
models described in the analytic plan for Aim 1 will be a main effect for the moderator and an 
interaction between the moderator, intervention, and follow-up time, to estimate time-specific 
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comparison for Aim 1b will be of the interaction terms associated with each intervention arm at 
the 3-months follow-up time.  
 
Mediator (Aim1c) Statistical Hypotheses: Changes in pain catastrophizing, pain-
related self-efficacy, and perceived support from baseline to 3 months will be mediators 
of treatment outcomes at 6 months for those in both active interventions. 
 
Mediator Analyses: Mediation analyses will be used to assess and quantify the effect of theory-
based mediators (pain-catastrophizing, pain self-efficacy, perceived support). Primary mediation 
analyses will assess the effect of the potential mediators on the primary outcome at 6 months, 
MCID in pain severity, while explanatory secondary analyses will investigate mediator impacts 
on secondary outcomes at 6 months.  
 
The RESOLVE SAP provides further detail on the planned moderator and mediator analyses.  
 
15.8 
Economic Evaluation Analyses 
 
For aim #2, a full economic evaluation of the CBT-CP interventions, compared to usual care, will 
be conducted, using the framework of cost-effectiveness, including the costs of implementation 
and maintenance, following best practice in economic evaluation.88,89 This analysis will be 
conducted for the Kaiser Permanente clinical sites where the capture of all health care utilization 
is available through administrative data. Information on resources used to implement the 
intervention will come from the trial data collection instruments and from medical office staff, 
provider interviews, and study staff. All relevant resources used in the intervention delivery (e.g., 
training, counseling, fidelity assurance) will be included. EHR data will be used to identify and 
classify health care encounters and prescription medications. Using the framework of cost-
effectiveness, the incremental cost per additional patient with a MCID in pain severity (30% 
reduction from baseline) will be estimated at 12 months, and the Quality-Adjusted Life Year 
(QALY) gained—utilities will be estimated using the EQ-5D-5L.45 
 
Costs to be collected. Medical care utilization and intervention costs will be considered. Medical 
care utilization includes pharmacy, outpatient visits (including specialty care), inpatient stays, 
and referrals, and will be costed using standard costing algorithms46,47 and Medicare fee 
schedules. In addition to total medical care costs, we will also undertake an analysis of pain-
related care focused on utilization linked to pain conditions, identified by diagnostic and 
procedure codes, and pain-related medications. Intervention costs include program 
implementation (e.g., training, meetings, and supervision; patient identification, invitation, and 
screening) and delivery (e.g., online hosting, clinician calls). The analysis will take the 
perspective of the health plan (a principal decision maker for future implementation), so it will 
include all health system costs of intervention implementation and delivery in clinical settings.  
 
Cost-effectiveness calculations. As done in prior economic evaluations of trials,90 the cost-
effectiveness of the intervention will be estimated using net benefit regression methods.91,92 This 
technique uses a "net benefits" framework, comparing the incremental cost-effectiveness ratio 
to a range of potential values for a decision maker’s willingness-to-pay (WTP)  for a unit of 
health gain. A cost-effectiveness acceptability curve (CEAC) is constructed that illustrates the 
intervention’s probability of being cost-effective at various levels of WTP for a unit of outcome 
(e.g., cost per QALY of $30,000 to $100,000). The regression framework allows ready 
evaluation of cost-effectiveness in subgroups (following the intervention’s findings). Net benefit 
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effect and cost data; λ = WTP level and is varied to construct the CEAC). Sensitivity analyses 
will be performed to assess the applicability of costs to other settings, the estimation of 
replication costs, and economies of scale.93 
 
Health care cost comparisons: A comparison of the health care costs between the randomized 
groups will be conducted. These comparisons will include overall, and pain-specific costs.  The 
table below describes the proposed categories of health care costs. Health care costs will be 
analyzed using generalized estimating equations with appropriate link functions. 
  
Categories of Health Care Costs to be Assessed 
 
Pain-related1 
Total 
Prescription medications 
  
 
Ambulatory encounters 
  
 
Primary Care 
  
 
Physical Therapy, Occupational 
Therapy and / or Physiatry2 
  
 
Pain Medicine/Pain Clinic 
 
 
Mental/Behavioral Health or 
Addiction Medicine 
  
 
ER or Urgent Care 
  
 
Other specialty medical care3 
 
 
In-patient hospital4 
  
 
1. Pain-related medications are identified by medication class (i.e., opioids, etc.). Pain-related 
in-person health care encounters are identified based on ICD-10-CM diagnostic codes. 
2. Physical Therapy includes Physical Therapy, Occupational Therapy and Physiatry visits. 
3. Specialty medical care includes in-person encounters with any non-primary care department 
that is not already included in the table. 
4. Pain-related hospitalizations have a primary (or principal) pain-related ICD-10-CM 
diagnostic code. 
 
15.9 
Exploratory Effectiveness Analyses 
 
The impact of the active interventions on exploratory outcomes will be assessed. These 
exploratory outcomes are described in detail in section 3.4 and include long-term opioid use, 
depression symptomology, anxiety symptomology, sleep disturbance, high impact chronic pain, 
and graded chronic pain. The same approach that is proposed for secondary outcomes and 
outlined above will be used.   
 
15.10 
Safety Analyses 
 
Safety monitoring analyses will be prepared for the external Data Safety and Monitoring Board 
(DSMB) twice per year to align with the DSMB meeting schedule. See the Data and Safety 
Monitoring Plan for specific details on the data and safety monitoring procedures and reporting 
guidelines.      
 

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15.11 
Planned Interim Analyses 
 
There are no planned interim analyses of primary or secondary outcome data before the study 
is completed. However, if in context of evaluating the safety outcomes the DSMB requests 
interim effectiveness estimates they will be provided.  No formal futility or effectiveness interim 
analyses will be conducted.  

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16 QUALITATIVE EVALUATION ANALYSES 
 
The qualitative evaluation (Aim #3) will be guided by three frameworks. First is the EPIS 
implementation framework.94  The EPIS framework emphasizes both the inner (organizational) 
and outer context (environmental context), which are both important to monitor.  The outer 
context may pose unique issues in each implementation site and impact the intervention even 
when the inner context is stable and being implemented with a high level of fidelity and 
consistency.   
 
The RE-AIM model95,96 will be used to document and help triangulate and explain the research 
outcomes. This model has four components: Reach, Effectiveness, Adoption, Implementation, 
and Maintenance. Reach reflecting the percentage and characteristics of persons who receive 
or are affected by a program. The project will use EHR data to examine: 1) the percentage of 
patients excluded from the trial and the rationale for exclusion, and 2) the percentage of patients 
who participate in the program based on the denominator of all patients who were approached 
for participation in each health care system, as well as all potentially eligible patients in the 
health plan regardless of whether or not they were approached for participation. Effectiveness 
measures the impact of the intervention on primary and secondary outcomes. Further, the 
qualitative evaluation is critical for understanding the reach, recruitment, and effectiveness 
findings. Adoption is less relevant to the current study as the telehealth programs can and will 
be made available to patients completely outside the ambulatory care setting, thereby reducing 
or eliminating routine barriers for adoption of health care treatments. Implementation will be 
assessed by examining participant adherence to the two CBT-CP-based programs (data 
collected in an automated fashion from the painTRAINER platform and by the virtual CBT-CP 
coaches in that arm of the study). Finally, Maintenance, or the opportunity thereof, will be 
assessed through stakeholder interviews with clinical and operational leaders in each of the 
participating health care systems.  
 
In addition to EPIS and RE-AIM, we will utilize the Theoretical Framework of Acceptability 
(TFA)97 to explore in-depth issues of satisfaction. The TFA is a multifaceted construct that 
reflects the extent to which people delivering or receiving a health care intervention consider it 
to be appropriate. The TFA is complimentary to constructs in the other two frameworks, while 
further examining issues of acceptability, particularly for patients, less explored in either RE-AIM 
or EPIS. The TFA consists of eight primary domains that have temporal aspects (e.g., before, 
during, and after an intervention) and consider both anticipated reactions to an intervention as 
well as cognitive and emotional responses experienced with an intervention. The domains 
include affective attitude, burden, ethicality, intervention coherence, opportunity costs, perceived 
effectiveness, and self-efficacy.  As with EPIS and RE-AIM, we will use the TFA to guide 
interview question development for all our stakeholders and will code for TFA related constructs 
(e.g., sense of burden to participate) in our analysis process.   
All audio-recorded interviews will be professionally transcribed, and coding will be completed by 
trained coders using qualitative analysis software that aids management and interpretation of 
text-based and other non-quantitative data. Reliability will be addressed by creating coding 
definitions and modifying them as needed, clarifying coding instructions, and using an iterative 
process of coding the same text and comparing codes and discussing discrepancies. Analytic 
techniques best suited to answer the study aims, maximize validity, and develop an evolving 
understanding of study findings will be utilized. These techniques can include using queries to 

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produce reports of text associated with primary codes and synthesizing themes from this text. 
Retrieving coded information in multiple ways, including by participant features (e.g., gender, 
pain diagnoses) by a code alone, or by combinations of co-occurring codes. Searches for text 
strings that occur in the qualitative dataset will also be conducted. Analysis will involve 
comparing themes and responses across participants and within categories of participants to 
examine common patterns and differences in beliefs, attitudes, behaviors, and experiences. 
Additionally, to ensure validity, searches for areas of contradiction across participants98-100 and 
across groups will be conducted. This approach to coding and data reduction will enable the 
examination of issues from a number of perspectives and ensures a thorough review of the data 
increase the breadth and depth of insights generate from the qualitative data gathered.   
 
 

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17 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS  
 
Study staff will maintain appropriate medical and research records for this study, in compliance 
with ICH E6, regulatory and institutional requirements for the protection of confidentiality of 
participants. Study staff will permit authorized representatives of the Data and Clinical 
Coordinating Centers (DCC & CCC), upon request, for source verification of study 
documentation, quality assurance reviews, audits, and evaluation of the study safety, progress, 
and data validity.  In addition, health information and data generated by this study must be 
available for inspection upon request by representatives of the NIH and the Institutional Review 
Board (IRB) for each study site. 
 
Sources of Materials 
Data will be obtained from multiple sources: electronic health records and administrative health 
plan records; participant self-report (via online, mailed survey, or telephone administered 
surveys); audio recordings of participant interviews; audio/video-recordings of virtual 
intervention sessions; and utilization data from the painTRAINER website. Only approved 
research staff with a need to review or analyze data will have access to study assessment data, 
intervention program use data, aggregate EHR data or study transcripts. Only study staff 
involved with administering study-related assessments (survey or interviews for the qualitative 
evaluation activities), or study interventions will have access to individually identifiable private 
information about participants.  
 
Electronic Health Record (EHR) and Administrative Data. Patient health care utilization and 
administrative data will be used for the identification of patients who are potentially eligible for 
the study and to examine pertinent health care utilization patterns among study participants 
(including health care encounters and pharmacy-related outcomes). All data will be extracted 
from EHR and administrative databases in each of the health care systems participating in the 
study. Prior to consent in order to identify potentially eligible patients, select variables will be 
extracted and uploaded into the study’s electronic data capture system (EDC), which will be 
password-protected and accessible only to authorized study staff. Only the minimum variables 
needed to identify and recruit patients will be uploaded into the EDC. As part of the consenting 
process, participants will be informed that their EHR data will be linked to their assessment data 
and shared with the investigative team at KPWHRI to be included in analyses. No individual 
identifying data will be published or released, and data will be summarized and presented only 
in summary or statistical form. 
 
Participant self-report data. Self-report data will be collected via online, mailed survey, or 
telephone-administered survey and entered into either the KP CHR REDCap or the University of 
Utah REDCap system, which will be password-protected and accessible only to authorized 
study staff. 
 
Audio- and video-recordings. Audio-recordings related to subject interviews will be kept in 
password-protected electronic files on the servers maintained by KP.  Audio- or video-
recordings related to the delivery of the virtual CBT-CP intervention will be kept in password-
protected electronic files maintained by KPWHRI and KP CHR on its servers. When relevant 
(for interviews), transcription will occur with participant identifiers removed. No individual-
identifying data will be published or released, and data will be summarized and presented only 
in summary or statistical form.  
 

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Utilization data from the painTRAINER website. All data collected during participant interaction 
with the painTRAINER intervention will be done through a secure, password-protected, mobile-
optimized website.   
 

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18 QUALITY CONTROL AND QUALITY ASSURANCE 
 
The Clinical Monitoring Plan, maintained by the CCC, and Data Management Plan, maintained 
by the DCC, describe the processes related to quality management for the study.  
 
Quality control (QC) procedures will be implemented beginning with the data collection and data 
QC checks that will be run on the database. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the study monitors will verify that the 
clinical trial is conducted, and data are generated, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonisation Good Clinical Practice 
(ICH GCP), and applicable regulatory requirements.  
 
The study sites will provide access to all trial-related locations, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 

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19 ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
19.1 
Ethical Standard 
 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, as drafted by the US National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 
46 and/or the ICH E6.  
 
19.2 
Institutional Review Board 
 
The Vanderbilt University Medical Center (VUMC) IRB will serve as the single IRB (SIRB) for 
this study. The local IRBs for KPGA, KPNW, KPWA and Essentia will cede oversight to the 
VUMC IRB. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is enrolled.  Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented in the study.   
   
19.3 
Exclusion of Women, Minorities, and Children (Special Populations) 
 
Children under the age of 18 will be excluded. mHealth versions of CBT-CP have been 
developed for children and adolescents,101,102 but they all include a family component that differs 
substantially from the telehealth CBT-CP programs under evaluation in this study, both of which 
were developed and tested among adult samples. Further, our standardized assessment 
measures were validated in adult samples and as such, are not always applicable to children 
and adolescents. 
 
Adults who do not speak English will be excluded from study participation. The interventions to 
be studied in this comparative effectiveness trial have not been developed for or tested for 
effectiveness in non-English speaking populations and are therefore not available for inclusion 
in this trial.    
 
19.4 
Subject Confidentiality 
 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the study 
sponsor(s) and their agents. This confidentiality is extended to any study information relating to 
participants. 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the study sponsor. 
 
The study monitor(s) or other authorized representatives of the Data and Clinical Coordinating 
Centers (DCC & CCC), NIH and the Institutional Review Board (IRB), may inspect all study 
documents and records required to be maintained by the site investigators. 

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19.4.1 Certificate of Confidentiality 
 
To further protect the privacy of study participants, the Secretary, Health and Human Services 
(HHS), has issued a Certificate of Confidentiality (CoC) to all researchers engaged in 
biomedical, behavioral, clinical, or other human subjects research funded wholly or in part by 
the federal government. Recipients of NIH funding for human subjects research are required to 
protect identifiable research information from forced disclosure per the terms of the NIH Policy 
(https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 75.303(a) and NIHGPS 
Chapter 8.3, recipients conducting NIH-supported research covered by this Policy are required 
to establish and maintain effective internal controls (e.g., policies and procedures) that provide 
reasonable assurance that the award is managed in compliance with Federal statutes, 
regulations, and the terms and conditions of the award. It is the NIH policy that investigators and 
others who have access to research records will not disclose identifying information except 
when the participant consents or in certain instances when federal, state, or local law or 
regulation requires disclosure. NIH expects investigators to inform research participants of the 
protections and the limits to protections provided by a Certificate issued by this Policy. 
 
 
 
 

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20 DATA HANDLING AND RECORD KEEPING 
 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data and kept in a secure file container throughout 
the duration of the study. The investigators will maintain adequate case histories of study 
participants, including accurate case report forms (CRFs), and source documentation. 
 
20.1 
Data Management Responsibilities 
 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the investigator. All source documents must be reviewed by the study team and 
data entry staff, who will ensure that they are accurate and complete. Study staff are 
responsible for training interviewers and providing participants’ clear and adequate instructions 
for survey completion so that valid data capture is accomplished.   
 
Unanticipated problems and AEs identified must be reviewed by the investigator or designee.   
 
Data will be stored at the University of Utah and KP CHR, which are responsible for security of 
their information systems.   
 
20.2 
Schedule and Content of Reports 
 
The Data Coordinating Center will be responsible for creating the following reports or making 
the data available to the appropriate TIC/RIC: recruitment and data collection reports, ongoing 
QA monitoring and DSMB reports, and intervention monitoring reports. For safety analyses and 
DSMB report production, the JHU-Tufts Statistical Core, physically located at the Johns Hopkins 
University will examine or oversee data quality, create secondary variables, and perform 
exploratory data analyses (EDA). 
 
20.3 
Study Records Retention  
 
Study records will be maintained for at least three years from the date that the last grant federal 
financial report (FFR) is submitted to the NIH. 
 
Completion of the research for this protocol should be anticipated to include planned primary 
and secondary analyses, as well as subsequent derivative analyses.  
 
Completion of the research also entails completion of all publications relating to the research. All 
records shall be accessible for inspection and copying by authorized representatives of the 
regulatory authorities at reasonable times and in a reasonable manner [45 CFR §46.115(b)]. 
 
20.4 
Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical study protocol or Good Clinical 
Practice requirements. The noncompliance may be on the part of the participant, the 
investigator, or study staff. As a result of deviations, corrective actions are to be developed by 
the study staff and implemented promptly as determined by the IRB. 
These practices are consistent with ICH E6: 

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• 
Compliance with Protocol, section 4.5 
• 
Quality Assurance and Quality Control, section 5.1 
• 
Noncompliance, section 5.20 
 
It is the responsibility of the Principal Investigator(s) to use continuous vigilance to identify and 
report any deviations within 7 calendar days of identification of the protocol deviation to the 
HEAL ERN within the DCC REDCap system.  Protocol deviations that result in increased risk or 
affect the participant’s rights, safety, or welfare will also be reported to the IRB and the NIA 
Program Official within 7 calendar days of identification of the problem. 

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21 PUBLICATION 
 
The study PI in collaboration with select study team members will develop a publication policy 
which will specify publication procedures and authorship requirements. The study will comply 
with NIH’s Public Access Policy and Policy on the Dissemination of NIH-Funded Clinical Trial 
Information, as described below.   
 
NIH Public Access Policy 
The NIH Public Access Policy requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to PubMed Central immediately upon acceptance for 
publication. This ensures that the public has access to the published results of NIH funded 
research.  
 
NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information 
The study is a clinical trial and will comply with the NIH policy that establishes the expectation 
that all investigators conducting clinical trials funded in whole or in part by the NIH will ensure 
that these trials are registered at ClinicalTrials.gov, and that results of these trials are submitted 
to ClinicalTrials.gov.   
 

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22 DATA SHARING 
 
This study will comply with all applicable NIH Data Sharing Policies. (See 
https://grants.nih.gov/policy/sharing.htm for policies and resources) 
The DCC will produce a public/releasable database from the RESOLVE study. The releasable 
database will be completely de-identified in accordance with the definitions provided in the 
Health Insurance Portability and Accountability Act (HIPAA). Namely, all identifiers specified in 
HIPAA will be recoded in a manner that will make it impossible to deduce or impute the specific 
identity of any patient. The database will not contain any institutional identifiers.  
The DCC will also prepare a data dictionary that provides a concise definition of every data 
element included in the database. If specific data elements have idiosyncrasies that might affect 
interpretation or analysis, this will be discussed in the dictionary document. Data elements that 
are considered unreliable will be deleted, and this will be noted in the documentation. 
The policies for release of this database will be determined by the NIH.  These policies are 
expected to focus primarily on the timing of data release. The preliminary plan is to release the 
database (defined below) at the time of publication of the primary manuscript, or within 12 
months of last patient procedure, whichever comes first.  Implementation of the plan will follow 
the HEAL Public Access and Data Sharing Policy as outlined at 
https://heal.nih.gov/about/public-access-data. 
In accordance with policies of the NIH, the DCC will send the releasable database and its 
relevant documentation to the entity determined by the NIH or specific institute to be the 
repository for data created under the HEAL initiative.   
Access to the releasable database housed in the NIH-assigned repository will be in accordance 
with procedures and regulations of the NIH or specific institute.  
 

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