Clinical trial NCT03026790
Conditions: Chronic Pain
Keywords: Opioid analgesics Opioid partial agonists Health care delivery Back pain Osteoarthritis Veterans health
Sponsor: University of Minnesota
Start date: 2017-10-19; Completion date: 2022-10-30
Enrollment: 820 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
Background and significance: Treatment with opioid pain medications (like hydrocodone and morphine) is common for severe pain, but studies show these medications may not always help and can cause serious problems. High daily doses of opioids can be especially unsafe. To help patients with chronic pain have better quality of life and avoid medication toxicity, health care teams need to manage pain while helping patients reduce opioid medication doses to safer levels.

Detailed description:
Study aims: This study will test which of two pain treatment strategies is better for managing pain and helping patients improve safety of opioid medication. For patients on high opioid doses who want to reduce, this study will also test whether offering an extra option for tapering (buprenorphine-naloxone) helps them succeed. Finally, the study will examine patients' and clinicians' experiences with the interventions.

Study description: The study will compare two treatment strategies among patients with pain who are taking long-term opioid pain medications prescribed by VA healthcare facilities across the country. Patients who wish to enter the study will be assigned by chance to telecare collaborative management (TCM) or integrated pain team (IPT). TCM involves a pharmacist and supervising physician working together to find the best medication options for each individual patient. In IPT, a team of clinicians focuses on non-medication pain management options, in addition to pain medication.

All participants will be asked to stay in the study for 12 months. Patients for whom it would be unsafe to participate will not be invited to join. With either treatment strategy, TCM or IPT, participants will have individualized pain care tailored to their needs and preferences. Participants on high opioid medication doses who want to reduce their opioid medication dose will be assigned by chance to get either a regular step-wise taper or a choice between a regular taper or switching to a different medication (buprenorphine-naloxone).

At the end of the study, the two treatment strategies will be compared to see which worked better to (1) decrease pain severity and (2) reduce opioid medication dose. Other outcomes important to patients will also be tracked. These include quality of life, sleep, fatigue, depression, anxiety, and side effects.

Arms: arm 1: Uses medication management approach delivered by a clinical pharmacist care manager with a collaborating physician to address common barriers to effective pain medication management in primary care. arm 2: Uses a biopsychosocial management approach delivered by a multidisciplinary team that emphasizes non-pharmacological pain management options. arm 3: The standard taper options arm uses patient education and shared decision-making to guide opioid medication management. arm 4: The expanded taper options arm uses patient education and shared decision-making to guide opioid medication management and includes the additional option of rotation to buprenorphine-naloxone.
Interventions: intervention 1: Medication management intervention 2: Non-pharmacological pain management intervention 3: Buprenorphine-Naloxone
Intervention descriptions: intervention 1: Individualized management of medications for pain intervention 2: Individualized management of non-medication pain treatment approaches intervention 3: Option of using buprenorphine-naloxone to assist with opioid dose reduction or discontinuation

Protocol documents:
Prot_SAP_000.pdf: 
CIRB Protocol #17-11 date   02/01/2022   1 
 
 
 
Veterans’ Pain Care Organizational Improvement 
Comparative Effectiveness (VOICE) Study  
 
Funded by the Patient-Centered Outcomes Research Institute (PCORI) with 
project title “Comparative effectiveness of patient-centered strategies to 
improve pain management and opioid safety for Veterans” (OPD-1511-33052) 
 
Principal Investigator  
Erin E. Krebs, MD, MPH 
Minneapolis VA Health Care System 
University of Minnesota 
 
Co-Principal Investigators 
Karen H. Seal, MD, MPH 
San Francisco VA Medical Center 
University of California, San Francisco 
 
William C. Becker, MD 
VA Connecticut Health Care System 
Yale University 
 
 
 
Protocol v   16.0 
 
 


CIRB Protocol #17-11 date   02/01/2022   2 
 
Table of Contents 
STUDY ABSTRACT ..................................................................................................................... 7 
Study Title ................................................................................................................................... 7 
Background and significance ...................................................................................................... 7 
Study aims ................................................................................................................................... 7 
Study design ................................................................................................................................ 7 
Intervention and comparators ..................................................................................................... 7 
Study population ......................................................................................................................... 8 
Outcomes .................................................................................................................................... 8 
Analytic methods ........................................................................................................................ 8 
1. STUDY OBJECTIVES ............................................................................................................... 9 
1.1 Primary Objectives ............................................................................................................ 9 
1.1.1 Aim 1 ............................................................................................................................. 9 
1.1.2 Aim 2 ............................................................................................................................. 9 
1.2 Secondary Objectives............................................................................................................ 9 
1.2.1 Subgroup analyses ......................................................................................................... 9 
1.2.2 Secondary outcomes .................................................................................................... 10 
1.2.3 Predictors of variation .................................................................................................. 10 
1.2.4 Implementation Process Evaluation ............................................................................. 10 
2. BACKGROUND AND RATIONALE ..................................................................................... 11 
2.1 Chronic Pain and Opioid Therapy ...................................................................................... 11 
2.2. Study Rationale .................................................................................................................. 11 
2.2.1 Rationale for TCM intervention ................................................................................... 12 
2.2.2 Rationale for IPT intervention ..................................................................................... 12 
2.2.3 Rationale for expanded taper options intervention ...................................................... 13 
3. STUDY DESIGN...................................................................................................................... 13 
3.1 Overview of Study Design .................................................................................................. 13 
3.2 Pragmatic Features .............................................................................................................. 14 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .................................................... 14 
4.1 Inclusion Criteria ................................................................................................................ 14 
4.2 Exclusion Criteria ............................................................................................................... 14 
4.3 Recruitment, Enrollment, and Study Arm Assignment ...................................................... 15 
4.3.1 Recruitment overview .................................................................................................. 15 
4.3.2 Study population and sampling considerations ............................................................ 16 


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4.3.3 Eligibility pre-screening ............................................................................................... 16 
4.3.4 Centralized recruitment procedures ............................................................................. 17 
4.3.5 Local site-based recruitment procedures ..................................................................... 17 
4.3.6 Eligibility interview ..................................................................................................... 17 
4.3.7 Eligibility chart review ................................................................................................ 18 
4.3.8 Enrollment.................................................................................................................... 18 
4.3.9 Randomization ............................................................................................................. 19 
4.3.10 Masking...................................................................................................................... 19 
5. STUDY INTERVENTIONS .................................................................................................... 19 
5.1 Intervention overview ......................................................................................................... 19 
5.2 Common intervention elements .......................................................................................... 21 
5.3 Telecare Collaborative Management (TCM) Intervention ................................................. 22 
5.3.1 TCM defining elements ............................................................................................... 22 
5.3.2 TCM visit schedule ...................................................................................................... 22 
5.3.3 TCM medication management ..................................................................................... 24 
5.3.4 TCM team processes .................................................................................................... 24 
5.4 Integrated Pain Team (IPT) Intervention ............................................................................ 24 
5.4.1 IPT defining elements .................................................................................................. 24 
5.4.2 IPT visit schedule ......................................................................................................... 25 
5.4.3 IPT pain management .................................................................................................. 27 
5.4.4 IPT team processes ...................................................................................................... 28 
5.5 Standard Taper Intervention ............................................................................................... 28 
5.6 Expanded Taper Intervention .............................................................................................. 28 
5.6.1 Buprenorphine rotation protocol overview .................................................................. 29 
5.6.2 Buprenorphine regulatory issues .................................................................................. 29 
5.6.3 Buprenorphine rotation management ........................................................................... 30 
5.6.4 Buprenorphine protocol consent process ..................................................................... 31 
5.6.5 Buprenorphine visit schedule ....................................................................................... 32 
5.7 Intervention Management of Adherence and Adverse Effects ........................................... 32 
5.7.1 Clinical monitoring of opioid adherence ..................................................................... 32 
5.7.2 Clinical management of opioid-related risk and opioid adherence problems .............. 32 
5.7.3 Clinical management of opioid use disorder (OUD) ................................................... 33 
5.7.4 Clinical management of adverse effects ...................................................................... 33 
5.8 Intervention Fidelity............................................................................................................ 33 


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5.8.1 IPT motivational interviewing (MI) fidelity ................................................................ 34 
5.9 Intervention Discontinuation and Transitions of Care ........................................................ 34 
6.STUDY DATA COLLECTION ................................................................................................ 35 
6.1 Data Collection Overview ................................................................................................... 35 
6.2 Patient-reported measures ................................................................................................... 35 
6.2.1 Timing and duration of assessment interviews ............................................................ 35 
6.2.2 Alternative patient-reported assessment procedures .................................................... 36 
6.2.3 Description of patient-reported measures .................................................................... 36 
6.3 Administrative Data ............................................................................................................ 36 
6.3.1 Data sources ................................................................................................................. 36 
6.3.2 Opioid dispensing data ................................................................................................. 37 
6.3.3 Pain treatment data ....................................................................................................... 37 
6.3.4 Intervention treatment data .......................................................................................... 37 
6.4 Qualitative Data .................................................................................................................. 38 
6.4.1 In depth interviews with patient participants, clinician participants, and other VA 
employees ............................................................................................................................. 38 
6.4.2 Informal interviews and observation ........................................................................... 39 
7. STATISTICAL ANALYSIS .................................................................................................... 39 
7.1 Sample Size Considerations ................................................................................................ 39 
7.1.1 Power estimates for primary analyses .......................................................................... 39 
7.1.2 Subgroup power estimates ........................................................................................... 39 
7.2 General Analytic Approach ................................................................................................ 40 
7.3 Statistical Analysis of Primary Aim ................................................................................... 40 
7.4 Pre-Specified Subgroup Analyses ....................................................................................... 41 
7.5 Secondary Analyses and Analysis of Secondary Outcomes ............................................... 41 
7.6 Analysis of Tapering Strategies .......................................................................................... 41 
7.7 Analysis of Adverse Events ................................................................................................ 42 
8. PROJECT MANAGEMENT .................................................................................................... 42 
8.1 Project Management Overview ........................................................................................... 42 
8.2 Study Application ............................................................................................................... 42 
8.3 Local Site Facilitation ......................................................................................................... 42 
8.4 Local Site Rollout ............................................................................................................... 43 
8.5 Cross-Site Communication ................................................................................................. 43 
8.6 Local Site Contingency Plans ............................................................................................. 44 
9. IMPLEMENTATION PROCESS EVALUATION ................................................................. 44 


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9. 1 Process Evaluation Overview ............................................................................................ 44 
9.2 Process Evaluation Questions ............................................................................................. 44 
9.3 Process Evaluation Methods ............................................................................................... 44 
9.4 Qualitative Analysis ............................................................................................................ 45 
10. DATA & SAFETY MONITORING PLAN ........................................................................... 45 
10.1 Overview of Data and Safety Monitoring Procedures ...................................................... 45 
10.2 Data and Safety Monitoring Board (DSMB) .................................................................... 46 
10.3 Frequency of Data and Safety Monitoring ........................................................................ 46 
10.4 Known Risks and Potential Harms ................................................................................... 46 
10.4.1 Known risks of study interventions ........................................................................... 47 
10.4.2. Known risks and potential harms associated with the underlying condition or study 
population ............................................................................................................................. 47 
10.4.3 Known risks in pregnancy and lactation .................................................................... 47 
10.5 Definitions of Potentially Reportable Events and Problems ............................................. 48 
10.5.1 Assessment of adverse events .................................................................................... 49 
10.5.2 AE/SAE tracking ....................................................................................................... 49 
10.6 Reporting of AEs and Research-Related Problems .......................................................... 50 
10.6.1 Unanticipated and related deaths ............................................................................... 50 
10.6.2 Unanticipated and related SAE .................................................................................. 50 
10.6.3 Serious and related unanticipated problems involving risks to participants or others50 
10.6.4 Noncompliance and protocol deviations .................................................................... 50 
10.6.5 Improper use or disclosure of research data .............................................................. 51 
10.6.6 Communication of prompt reports to local sites ........................................................ 51 
10.6.7 Study termination or suspension ................................................................................ 51 
10.7 Data Management ............................................................................................................. 51 
10.7.1 Data Quality ............................................................................................................... 51 
10.7.2 Privacy and Confidentiality ....................................................................................... 52 
10.7.3 Information security ................................................................................................... 52 
10.8 Regulatory and Administrative Compliance ..................................................................... 52 
10.8.1 Institutional Review Board (IRB) approvals ............................................................. 52 
10.8.2 ClinicalTrials.gov registration ................................................................................... 53 
10.8.3 Reporting to PCORI ................................................................................................... 53 
10.8.4 Research records retention ......................................................................................... 54 
10.8.5 Completion of local site engagement ......................................................................... 54 
11. DISSEMINATION AND DATA SHARING ..................................................................... 54 


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11.1 Submission of Primary Study Results .......................................................................... 54 
11.2 Peer-Reviewed Publications ......................................................................................... 54 
11.3 Results Reporting to Study Participants ....................................................................... 55 
11.4 Dissemination of Additional Research Products .......................................................... 55 
11.5 Data Sharing Plan ......................................................................................................... 55 
12. STUDY GOVERNANCE ....................................................................................................... 55 
12.1 Leadership Committee ...................................................................................................... 55 
12.2 Other Committees ............................................................................................................. 56 
12.2.1 Engagement................................................................................................................ 56 
12.2.2 Implementation evaluation ......................................................................................... 56 
12.2.3 Data ............................................................................................................................ 56 
12.3.4 Publications ................................................................................................................ 56 
PROTOCOL REVISION HISTORY ........................................................................................... 57 
Version Number: 1.0 ................................................................................................................. 57 
Version Number: 2.0 ................................................................................................................. 57 
Version Number: 3.0 ................................................................................................................. 57 
Version Number: 4.0 ................................................................................................................. 57 
Version Number: 5.0 ................................................................................................................. 57 
Version Number 6.0 .................................................................................................................. 57 
Version Number 7.0 .................................................................................................................. 58 
Version Number 8.0 .................................................................................................................. 58 
Version Number 9.0 .................................................................................................................. 58 
Version Number 10.0 ................................................................................................................ 58 
Version Number 11.0 ................................................................................................................ 58 
Version Number 12.0 ................................................................................................................ 59 
Version Number 13.0 ................................................................................................................ 59 
Version Number 14.0 ................................................................................................................ 59 
Version Number 15.0 ................................................................................................................ 59 
Version Number 16.0 ................................................................................................................ 59 
 
  
 
 


CIRB Protocol #17-11 date   02/01/2022   7 
 
STUDY ABSTRACT 
Study Title 
Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) Study 
Background and significance 
Long-term opioid therapy became a mainstay of chronic pain management over the past two 
decades, despite a lack of evidence for effectiveness. Now, in response to evidence that opioid 
therapy is associated with serious dose-related harms, clinicians and health systems are 
challenged to achieve a patient-centered shift in pain management from over-reliance on long-
term opioid therapy to more effective use of evidence-based pain treatment approaches. 
Clinicians and health care decision-makers face gaps in evidence however for how to achieve 
these goals. Our approach is informed by patient partners who emphasized the primary need for 
individualized pain care and support to achieve improved pain outcomes. Accordingly, our 
central focus is on optimizing pain care, which we see as the first and most important step toward 
patient-centered opioid dose reduction.  
Study aims 
The overall objective of this research is to improve effectiveness and safety of pain management 
among patients with chronic pain. This 12-month pragmatic randomized trial will compare two 
pain care delivery strategies, which differ substantially in comprehensiveness and resource 
intensity, to improve pain and reduce opioid use among Veterans. We will also conduct an 
opioid tapering strategy substudy that will examine comparative effectiveness of tapering with or 
without the option for buprenorphine rotation in the high-dose subgroup of study participants.  
Aim 1: To compare telecare collaborative pain management versus integrated pain team 
management for improving pain and reducing opioid use in VA patients on long-term moderate 
to high-dose opioids for chronic pain. 
Aim 2: To compare standard taper options versus expanded taper options for improving pain and 
reducing opioid use among VA patients on long-term high-dose opioids for chronic pain. 
Secondary Aim: To understand patients’ and clinicians’ experiences with the study interventions 
and identify strategies to enhance future implementation and dissemination of effective pain care 
interventions. 
Study design 
This is a pragmatic comparative effectiveness trial at ten VA sites to compare two distinct 
interventions augmenting primary care management of chronic pain for patients on long-term 
opioid therapy. Randomization at the individual patient level will assign patient participants to 
either 1) telecare collaborative management (TCM) or 2) integrated pain team (IPT) management 
arms for 12 months. In both arms, patients receive pain care and opioid taper planning tailored to 
preferences and adjusted as needed to achieve individualized treatment goals. Among 
participants in a high-dose subgroup, the opioid taper strategy substudy will examine 
comparative effectiveness of tapering with or without the option for buprenorphine rotation.  
Intervention and comparators 
 
The TCM arm uses a medication management approach delivered by a clinical pharmacist care 
manager in collaboration with a consulting physician to address common barriers to effective 


CIRB Protocol #17-11 date   02/01/2022   8 
 
pain medication management in primary care. The IPT arm uses a biopsychosocial management 
approach delivered by an interdisciplinary team and emphasizes multimodal pain management 
and behavioral activation. For participants who agree to opioid dose reduction or discontinuation, 
opioid tapering will be conducted in both arms. Participants receiving moderate-doses (20-69 
ME mg/day) will receive standard taper options, which incorporate shared decision-making to 
guide medication selection and rate of dose changes. Patients on high-dose opioids (≥70 ME 
mg/day) will be randomized to standard options or expanded options. The expanded options arm 
differs from standard options only in that it includes the additional option of buprenorphine 
rotation. 
 
Study population 
VA primary care patients receiving long-term moderate to high-dose opioid therapy for chronic 
pain of at least moderate severity will be eligible. Long-term is ≥ 90 consecutive days. Moderate 
to high dose is ≥ 20 morphine-equivalent (ME) mg/day. For subgroup definition, high-dose is ≥ 
70 ME mg/day. Exclusion criteria are cognitive impairment; unstable or severe untreated 
psychiatric disorder; severe unstable or end-stage medical disease; suspected controlled 
substance diversion; and inability to communicate by telephone.  
Outcomes 
The primary study outcome is pain response at 12 months, defined as a 30% improvement in the 
Brief Pain Inventory (BPI). The main opioid dose outcome is 50% reduction in opioid daily 
dose. The main composite outcome is the proportion with 30% improvement in pain and 50% 
decrease in opioid daily dose, representing dual improvements in pain and opioid safety. We will 
assess secondary patient-relevant outcomes including function, quality of life, symptoms (e.g., 
depression, anxiety, sleep, fatigue), and adverse effects. 
Analytic methods 
All participants will be assessed in the arms to which they are assigned. An estimated sample 
size of 970 patients from 10 sites provides 80% power for a 2-sided chi-squared test comparing 
pain response rates for TCM and IPT if IPT adds 10% to the response rate, and > 85% power if 
IPT adds 11% to the response rate. We will use all follow-up data in repeated-measures logistic 
regression modeling 30% reduction from baseline in BPI scores.  For the second aim, we 
estimate 80% power power to detect small to moderate effects (Cohen d or standardized 
difference) in mean BPI scores of 0.35 or more.  
 
We will evaluate heterogeneity of treatment effects in 5 pre-specified subgroups that may be 
differentially responsive to treatment, at greater risk for opioid harms, or more likely to have 
difficulty reducing opioids (patients treated with high-dose opioids and those with depression 
symptoms, post-traumatic stress symptoms, potential substance use disorder (SUD), and 
fibromyalgia symptoms). We will use repeated-measures linear regression to examine 
interactions of subgroup with treatment assignment.  
 
 


CIRB Protocol #17-11 date   02/01/2022   9 
 
1. STUDY OBJECTIVES 
1.1 Primary Objectives 
1.1.1 Aim 1 
Aim 1 is to compare telecare collaborative pain management (TCM) versus integrated 
pain team (IPT) management for improving pain and reducing opioid use in VA patients 
on long-term moderate to high-dose opioids for chronic pain.  
All participants will be randomized to one of two care management approaches: 1) TCM 
or 2) IPT. To assess improvement in pain and reduction in opioid use, we will compare 
TCM versus IPT groups on three main outcomes. First, the primary outcome is pain 
response, defined as a 30% improvement in Brief Pain Inventory (BPI) total score from 
baseline to the final study outcome assessment at 12 months. Our second main outcome 
is opioid daily dose reduction of 50% from baseline to 12 months, based on VA 
pharmacy dispensing data. The main composite outcome is the proportion with both a 
pain response and opioid dose reduction, representing dual improvements in pain and 
regimen safety.  
1.1.2 Aim 2 
Aim 2 is to compare standard versus expanded taper options for improving pain and 
reducing opioid use among patients on high-dose opioid therapy at baseline.  
Participants in the high-dose therapy subgroup will be randomized to receive one of two 
opioid taper arms: a) standard options or b) expanded options, which includes the 
additional option of buprenorphine rotation. To assess the primary outcome of pain 
severity, we will compare standard versus expanded options groups on mean BPI total 
scores. Between-group differences in opioid daily dose and the composite pain response 
and opioid dose reduction outcome will also be examined. We hypothesize that offering 
the option of buprenorphine rotation will improve BPI scores and reduce opioid daily 
dose. 
1.2 Secondary Objectives 
1.2.1 Subgroup analyses 
We will examine differential response to TCM and IPT among subgroups of study 
participants. Subgroups are not mutually exclusive and are defined as presence (yes/no) 
of the following characteristics at baseline:   
• High-dose opioid therapy (≥ 70 ME mg/day) 
• Depression symptoms 
• Post-traumatic stress symptoms  
• Potential SUD 
• Fibromyalgia symptoms 
We hypothesize that IPT will be superior to TCM in the following subgroups: high-dose 
opioid therapy, depression, post-traumatic stress, and SUD.   


CIRB Protocol #17-11 date   02/01/2022   10 
 
1.2.2 Secondary outcomes 
We will examine intervention effects on the following additional patient-reported 
outcomes: 
• Pain intensity 
• Pain interference with function 
• Quality of life  
• Adverse symptoms 
• Fatigue 
• Sleep 
• Mental health  
• Substance use 
• Use of nonpharmacological therapies 
We will examine intervention effects on the following additional opioid dose outcomes: 
• Proportion with 25% dose reduction from baseline to 12 months 
• Proportion with any dose reduction from baseline to 12 months 
• Mean dose change from baseline to 12 months 
• Proportion with dose escalation (increase in opioid daily dose of ≥ 25% from 
baseline to 12 months) 
1.2.3 Predictors of variation  
We will examine variation in intervention effects by sex, study site and time over the 
course of enrollment, as well as moderation of effects by relevant covariates.  
1.2.4 Implementation Process Evaluation 
Aim 3 is to understand patients’ and clinicians’ experiences with the study interventions 
and identify strategies to enhance future implementation and dissemination of effective 
pain care interventions. 
Data will be gathered to examine patients’ and clinicians’ perceptions of the 
interventions; to describe the context and processes of intervention delivery; and to assess 
potential for long-term sustainability and widespread dissemination of the interventions. 
Data collection methods will include in-depth semi-structured interviews with patient and 
clinician participants and other VA employees; unstructured conversational interviews 
with researchers, clinicians, and stakeholders; and observation of research and 
intervention implementation processes.  
Goals of this approach are threefold: 1) to increase the relevance of the primary research 
findings to patients, clinicians, and health care decision-makers; 2) to increase the 
likelihood of timely translation of research findings into diverse practice settings; and 3) 
to generate information to guide interpretation of primary trial findings. In addition to 
scientific reports and manuscripts, products of this process evaluation will include an 


CIRB Protocol #17-11 date   02/01/2022   11 
 
implementation toolkit (developed in collaboration with study partners) to support 
implementation of successful study interventions in diverse practice settings. 
2. BACKGROUND AND RATIONALE 
2.1 Chronic Pain and Opioid Therapy  
Chronic pain affects approximately 100 million Americans, with an estimated $560-635 
billion in annual health care and lost productivity costs. Furthermore, three of the top five 
causes of years lived with disability are painful conditions—back pain, neck pain, and other 
musculoskeletal disorders. Starting in the early 1990s, improved awareness of the burden of 
pain and concern about pain under-treatment drove a generalized expansion in opioid 
analgesic prescribing. Tragically, this expansive prescribing has triggered a new epidemic of 
opioid-related deaths and addictive disorders, while meaningful progress toward the original 
goal—reducing the burden of pain—has not been demonstrated.  
For many patients receiving long-term opioids for chronic pain, potential harms of 
continuing opioid therapy outweigh benefits. Indeed, benefits of long-term opioid therapy are 
often elusive. Most patients receiving long-term opioid therapy continue to experience severe 
pain and functional limitations. Counter to prior assumptions, studies have found that higher 
opioid doses are not associated with corresponding improvements in analgesic response. 
Patients prescribed higher-dose opioids may have worse quality of life than those receiving 
low-dose or no opioids. 
The frequency and severity of opioid-related harms among patients receiving long-term 
opioid therapy for pain are increasingly evident. Harms stemming from pharmacological 
properties include tolerance and physical dependence in most persons with long-term 
exposure and addiction in a substantial minority. Further, opioid involvement in respiratory 
control mechanisms can cause unpredictable fatal respiratory suppression when dosages are 
miscalculated or increased rapidly, too many pills are taken, or other drugs or conditions 
interact to potentiate opioid effects or cause buildup of toxic levels. Prescribed opioid dosage 
seems to be a major driver of risk for these and other harms.  
For patients with chronic pain on long-term opioid therapy, pain management should involve 
attention to both improving pain and reducing risk for opioid-related harms. Evidence 
supports the effectiveness of a wide variety of non-opioid therapies for improving chronic 
pain outcomes, but response to treatments is variable and individual therapies typically 
generate only partial improvement. Thus, multi-modal integrated care is favored as the 
optimal pain management approach.  
Unfortunately, little evidence is available for strategies to reduce or discontinue opioid 
therapy while managing pain. Although comprehensive pain rehabilitation programs have 
demonstrated success, expansion of these programs to accommodate vast numbers of patients 
on long-term opioid therapy is not likely. As most patients on opioid therapy for chronic pain 
are treated in primary care settings, evidence is needed for strategies to support deliver 
improved pain and opioid management in primary care. 
2.2. Study Rationale 
Our work has identified numerous barriers to improving pain and opioid management in 
primary care, including ineffective communication, patient and provider knowledge deficits, 
limited time and appointment availability, and insufficient resources in terms of clinical staff, 


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assessment tools, and treatment pathways. The 2014 NIH Pathways to Prevention opioids for 
chronic pain panel concluded that individual clinicians “are often overburdened and have 
insufficient resources,” so “systems of care must facilitate implementation” of pain and 
opioid management guidelines.  
In VA, national pain management and opioid safety initiatives direct local facilities to 
increase use of nonpharmacological pain care and improve opioid management, but clinical 
leaders at each facility must decide how to achieve these objectives. As in non-VA health 
care settings, clinical leaders need direct and high-quality evidence to guide decisions about 
how to allocate finite resources to achieve dual goals of improving pain while reducing 
opioid use. This study compares two systems of care strategies that each use patient-centered 
approaches to address barriers to improved pain and opioid management in primary care. 
Our overall approach is informed by our engagement with patient partners, who strongly 
emphasize the primary need for individualized pain care and longitudinal support to achieve 
pain management goals. A second point of partner emphasis was the need to address 
potential mistrust toward a health care system that initiated many Veterans on long-term 
opioids and now could be seen as pulling “the rug out from under [them].” Accordingly, the 
central focus of our interventions is on optimizing pain care. Likewise, our primary outcome 
is improvement in pain.  
2.2.1 Rationale for TCM intervention 
TCM is the low-intensity pain management intervention. It is based on the three 
component model, initially developed as a structured approach to addressing primary care 
barriers to depression care and subsequently extended to pain care. In the TCM arm, the 
central care provider is a pharmacist care manager who has regular follow-up visits with 
the patient and delivers care in collaboration with a consulting physician and the primary 
care team.   
TCM effectiveness for chronic pain has been demonstrated in multiple trials. In the 
SCOPE trial of TCM vs. usual care for chronic pain, participants in the TCM arm were 
nearly twice as likely to have a clinically important improvement in pain at 12 months. A 
pre-specified subgroup analysis found a positive response to the intervention among the 
third of study participants who were on opioids at baseline. TCM has not been 
specifically tested as an approach to achieve opioid dose reduction, but it was easily 
extended to include opioid tapering in the VA-funded SPACE trial.  
In patient-facing and public-facing materials (e.g., study brochure, recruitment letter), 
TCM will be referred to as “pharmacist pain care.” 
2.2.2 Rationale for IPT intervention  
IPT is the higher-intensity pain management intervention. It is based on the 
biopsychosocial model, which is the dominant heuristic to explain chronic pain as a 
complex phenomenon determined by biological inputs, as well as factors such as mood, 
cognitions, relationships, and health care systems issues. In the IPT arm, an 
interdisciplinary team delivers biopsychosocial care emphasizing multimodal pain 
management and behavioral activation.  
IPT effectiveness is supported by indirect evidence from trials of other interdisciplinary 
pain programs and observational evidence from similar programs implemented in VA. 


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RCTs have demonstrated the effectiveness of a variety of interdisciplinary pain programs 
that combine medical, psychological, and exercise approaches, as in the IPT arm. Further, 
several observational reports suggest that IPT clinics can improve care. For example, the 
Integrated Pain Clinic at the West Haven VA—staffed by a physician, psychologist and 
physical therapist—demonstrated improvement in patient and provider pain treatment 
satisfaction.  
In patient-facing and public-facing materials (e.g., study brochure, recruitment letter), 
IPT will be referred to as “integrated pain care.” 
2.2.3 Rationale for expanded taper options intervention 
All patients in the study will receive standard information about opioid tapering, which 
typically involves gradually decreasing daily doses of opioids over time. Patients 
randomized to the expanded options arm will receive information about buprenorphine 
rotation as an optional component of their personal treatment plan. Patients who opt in to 
buprenorphine rotation will complete a separate informed consent process for the 
buprenorphine rotation research protocol. 
Rotation to buprenorphine, a partial opioid agonist with analgesic properties similar to 
those of other opioids, may help patients reduce opioid use by effectively treating the 
opioid withdrawal syndrome while allowing more rapid dose reduction. Opioids cause 
physical dependence in most persons with long-term exposure. In physical dependence, 
interrupting or stopping opioids causes unpleasant withdrawal symptoms, which include 
increased pain and dysphoria and sometimes opioid craving. These problems are major 
barriers to opioid discontinuation, both for persons who use opioids illicitly and for those 
who take prescribed opioids. Slowly reducing opioid doses over time (usually over 
months) can prevent development of withdrawal symptoms, but some patients on high 
opioid doses may prefer a more rapid approach facilitated by buprenorphine rotation. 
In patients with opioid use disorders, strong evidence from multiple RCTs supports 
buprenorphine effectiveness for achieving sustained abstinence from illicit opioids. 
Observational evidence suggests buprenorphine is similarly effective for successful 
discontinuation of full-agonist opioids in patients on long-term opioids for pain and that 
patients transitioned from high-dose opioids to buprenorphine often have improved 
pain/function and decreased opioid AE.  
3. STUDY DESIGN 
3.1 Overview of Study Design 
This is a pragmatic comparative effectiveness trial that will enroll VA primary care patients 
receiving moderate or high-dose opioid therapy for chronic pain of at least moderate severity. 
The study will be conducted at ten VA sites. A central coordinating center will identify 
potentially eligible patients based on dose and duration of opioid therapy and conduct 
screening interviews by telephone. Eligible and interested patients will be scheduled for an 
enrollment visit with their local site coordinator. After providing written informed consent, 
patient participants will be randomly assigned at the individual level to either TCM or IPT, 
stratified according to their baseline opioid daily dose (moderate or high). In TCM, a 
pharmacist care manager optimizes medication management in collaboration with a 
consulting physician; in IPT, an interdisciplinary team delivers biopsychosocial care 


CIRB Protocol #17-11 date   02/01/2022   14 
 
emphasizing multimodal therapy and behavioral activation. In both arms, participants receive 
patient-centered care over 12 months, with specific pain treatments and opioid taper 
decisions based on individual clinical assessment and shared decision-making. All patients in 
the moderate-dose subgroup will be assigned to receive standard opioid taper options. 
Patients in the high-dose subgroup will be randomized to either standard or expanded 
(including buprenorphine rotation) taper options. Patients, clinicians, and local site research 
personnel will be unmasked to treatment arm assignment. Masked outcome assessors at the 
coordinating center will conduct telephone interviews at 3, 6, 9, and 12 months to collect 
patient-reported outcomes. If participants are unable to complete 6 or 12-month telephone 
interviews, they will be offered an alternative mode for completion of outcomes—an 
abbreviated questionnaire sent by mail.  Opioid dose and adverse event outcomes will be 
extracted from the electronic medical record. 
3.2 Pragmatic Features  
Pragmatic trials combine the strength of randomized treatment assignment with design 
elements intended to maximize applicability of findings to diverse patient populations and 
clinical practice settings. With the goal of maximizing pragmatism, we applied the PRECIS-2 
tool for trial design to assess the consistency of our design choices with our overall goals. We 
take a highly pragmatic approach to eligibility, setting, organization of care delivery, 
flexibility of intervention delivery, flexibility of intervention adherence, and analysis.  
The approach to intervention delivery is particularly pragmatic. TCM and IPT elements are 
defined in terms of “core” and “optional” components. During the first year of the study, 
each site will partner with key patient, clinician and administration stakeholders to establish 
their core and optional components based on site resources, preferences, and feasibility. 
Volunteer VA clinicians will be trained in the TCM and IPT care delivery models and will 
deliver the study interventions.  
The least pragmatic elements of the design are follow-up intensity and recruitment. Given the 
importance of patient-reported outcomes in pain research, we plan frequent follow-up 
contacts and telephone assessments by masked coordinating center staff to reduce 
ascertainment bias, minimize missing outcome data, and reduce participant attrition. For 
recruitment, we will use a proven centralized approach to achieve the target sample size 
while oversampling women.  
4. SELECTION AND ENROLLMENT OF PARTICIPANTS 
4.1 Inclusion Criteria 
Participants must meet all of the following inclusion criteria to be enrolled:  
• Moderate or high-dose long-term opioid therapy (≥ 20 ME mg daily) for chronic pain  
• Chronic pain of at least moderate severity (defined as pain that is present for ≥ 6 
months and with a score on the PEG 3-item pain measure of ≥ 5) 
• Willingness and anticipated availability to participate for 12 months 
4.2 Exclusion Criteria 
All candidates meeting any of the exclusion criteria at baseline will be excluded from study 
participation: 


CIRB Protocol #17-11 date   02/01/2022   15 
 
• Dementia diagnosis or moderate-severe cognitive impairment. 
• Unstable or severe untreated psychiatric disorder, including severe untreated 
substance use disorder and active suicidal ideation 
• Unstable or end-stage medical disease that would interfere with participation, 
including cancer requiring active treatment and life expectancy < 12 months 
• Documentation of suspected controlled substance diversion 
• Inability to communicate by telephone 
4.3 Recruitment, Enrollment, and Study Arm Assignment   
4.3.1 Recruitment overview 
This study will employ both centralized and local site-based recruitment approaches. As 
for our prior studies, a customized study tracking program will support coordinated 
completion of research tasks, including preparing recruitment mailings, scheduling 
participant contacts, and randomizing participants. This program will be located on a 
secure network drive behind the VA firewall and will be accessible only to approved 
study personnel. 
The centralized approach will use monthly data extractions to identify potentially eligible 
patients, followed by mailed invitations and telephone follow-up for eligibility screening. 
Prior to the start of recruitment at each site, local site investigators will inform local 
primary care providers (PCPs) about the study and request blanket permission for 
coordinating center personnel to approach eligible patients in their panels. Each month, a 
subset of the preliminarily eligible patients will be selected for contact using the 
centralized mail-then-call approach. Active monitoring of monthly eligibility and 
enrollment rates will allow adjustment of the number of patients contacted each month to 
maintain target enrollment rates. The initial approach will be based on our estimate that 
75% of telephone-contacted patients will be eligible and 33% of eligible patients will 
agree to enroll. If estimated rates prove accurate and 33% of eligible patients enroll, we 
will need to contact approximately half (i.e., 7550) of the preliminarily eligible patients 
over the course of enrollment.   
The local site-based recruitment approach will be based on clinician referrals. Local site 
study personnel will inform local site clinicians of the study using generalized outreach 
(e.g., presentations at clinical team meetings) and/or targeted outreach (e.g., providing 
clinicians with lists of their potentially eligible patients). Any clinician may refer their 
own patients to the study, including those who decline to provide blanket permission for 
patients to be recruited from their panels.  
The study will not engage in nontargeted direct-to-patient advertising because patients 
are unlikely to know whether they meet the opioid dose criteria (and the vast majority of 
patients with chronic pain do not). Patients may directly approach study personnel 
seeking to enroll if they find out about the study, for example through word-of-mouth 
from other patients or a brochure provided by a local clinician; this is expected to be 
uncommon. Patients who self-refer to the study will be screened in the same manner as 
those who are referred by their clinicians. 


CIRB Protocol #17-11 date   02/01/2022   16 
 
4.3.2 Study population and sampling considerations 
Women are underrepresented in US Veteran populations. To achieve better 
representation, we will oversample women by inviting all preliminarily eligible women 
and only a sample of men with the centralized recruitment approach. If estimated 
enrollment rates are accurate, we will enroll female participants at approximately twice 
the rate of their prevalence in the population. Local site study personnel will also reach 
out to women’s health clinicians to encourage referrals of female patients. 
We plan pre-specified analyses to assess heterogeneity of treatment effect in the 
following patient subgroups: high-dose opioid therapy, depression symptoms, post-
traumatic stress symptoms, potential substance use disorder (SUD), and fibromyalgia 
symptoms.   
To ensure we enroll enough patients on high-dose therapy to have adequate power for 
Aim 2, we will oversample this group. We will not oversample other patient subgroups, 
but anticipate that oversampling women will increase the prevalence fibromyalgia as it is 
a female-predominant condition. 
To take maximum advantage of the study’s geographic diversity, we will attempt to 
enroll similar numbers of participants at each site. Monthly monitoring of eligibility, 
contact, and enrollment rates will be done for the study overall and by site. The number 
of patients contacted each month will be adjusted to maintain overall target enrollment 
rates. If enrollment rates are lower than expected at an individual site, site-specific factors 
will be addressed as indicated. If needed, site-specific enrollment targets will be adjusted 
to achieve overall enrollment targets; for example, this could include increasing 
recruitment contacts at a successful high-volume site to make up for lower-than-expected 
enrollment at another site. 
4.3.3 Eligibility pre-screening 
Potentially eligible patients will be identified through pre-screening searches of VA 
datasets. This pre-screening will be done centrally by data team members at the 
coordinating center, creating monthly lists of potentially eligible patients by site.   
Pharmacy dispensing data will be used to identify patients on long-term moderate-to-high 
dose opioid therapy, defined for prescreening purposes as meeting the following criteria:  
• ≥ 84 days’ supply of qualifying opioid analgesic dispensed within the 90 days 
prior to the date of eligibility assessment; and 
• Opioid daily dose ≥ 20 ME mg in the prior 90 days 
To avoid recruiting patients with dementia, unstable psychiatric disorder, or those being 
treated for pain due to active cancer or terminal disease or for opioid use disorder, 
patients will not be selected if they have any of the following:  
• Any chemotherapy, radiation oncology, hospice care, dementia clinic, adult day 
clinic, current nursing home residence, or opioid treatment program visit in the 
year prior to the study period 
• Any diagnosis of dementia  
• Active CPRS flag indicating high risk for suicide  


CIRB Protocol #17-11 date   02/01/2022   17 
 
• Limited life expectancy health factor at any visit in the past 12 months 
 
To maintain a steady enrollment rate, only a selection of potentially eligible patients from 
permitting PCPs at active study sites will be contacted each month by the coordinating 
center for centralized recruitment. Selected preliminarily eligible patients will be given a 
study ID number and their names, addresses, and telephone numbers will be loaded into 
the study tracking application. 
4.3.4 Centralized recruitment procedures 
Coordinating center personnel will mail recruitment letters in batches to each new group 
of preliminarily eligible patients identified through the centralized pre-screening process. 
These letters will describe the study and include signatures of the PI and local site PI, as 
well as instructions for how to opt out of further contacts. Twelve days after each mailing 
(i.e., one week after letters are expected to arrive), study personnel will call patients to 
determine interest in participating and further assess eligibility. 
4.3.5 Local site-based recruitment procedures 
The lists of potentially eligible patients for each site will also be used to support local 
site-based recruitment. Local study personnel will use these lists for targeted outreach to 
local site clinicians, providing them with information about which of their patients are 
potentially eligible and reminding them about the study prior to upcoming appointments 
with potentially eligible patients. Clinicians will be encouraged to discuss the study with 
their patients and inform the local site study personnel if the patient is interested in 
discussing study participation. Study personnel will follow-up with referred patients in-
person or by telephone, depending on availability and patient preference.  
When patients are individually referred or self-referred, study personnel will check the 
pre-screening list of potentially eligible patients. If the patient is on the list, he or she will 
be considered preliminarily eligible. If the patient is not on the list, study personnel will 
conduct a brief chart review for eligibility criteria. When patients are determined to be 
preliminarily eligible, they will be given a study ID number and their names, addresses, 
and telephone will be loaded into the study tracking application.  
4.3.6 Eligibility interview 
When potentially eligible patients agree, a structured computer-assisted eligibility 
interview will be conducted to assess patient-reported inclusion and exclusion criteria. 
This will include the following:  
• Pain chronicity  
• Pain severity (PEG 3-item scale)  
• Current SUD treatment or untreated SUD 
• Availability for telephone interviews and clinical visits over 12 months 
• Participation in current research or clinical programs that might conflict/overlap 
When patients complete the eligibility interview and are determined to be eligible and 
interested in participating, study personnel will schedule the patient for an appointment 
with the local site coordinator/research assistant. Eligible patients who are unsure about 


CIRB Protocol #17-11 date   02/01/2022   18 
 
participation will be encouraged to discuss the study with their clinical care providers and 
given the option of a future follow-up recruitment call.  
4.3.7 Eligibility chart review  
As a final eligibility assessment step, local study site personnel will use a structured chart 
review form to conduct a brief review of recent clinic notes. This final step will look for 
evidence of exclusion criteria that may not be captured in prior steps. In case of 
uncertainty about eligibility (for example, in a patient with cancer and unclear prognosis), 
the patient’s clinical providers will be consulted prior to enrollment. The chart review 
will examine evidence of the following eligibility criteria:  
• Currently prescribed opioids (inclusion) 
• Dementia (exclusion) 
• Current life-threatening medical disease (e.g., active cancer treatment, end-stage 
organ failure) (exclusion) 
• Documented suspicion of controlled substance diversion (exclusion) 
• Severe untreated mental health or substance use disorder, active suicidal ideation 
(exclusion) 
Local study personnel will also use the chart review to look for current or impending 
enrollment in conflicting or overlapping local clinical programs (e.g., intensive pain 
management program) or research studies.  
4.3.8 Enrollment  
Eligible patients will have an enrollment appointment with local site study personnel. 
This enrollment appointment may be conducted in-person, via VA video-telehealth 
technology, or by telephone, per patient preference and local availability. At this initial 
appointment, the local site study coordinator or research assistant will provide additional 
study information, answer any questions, and complete the  informed consent process 
with the patient.   
For in-person appointments, patients will be given a folder, pen, pillbox with the study 
logo, and a $5 VA canteen service voucher (regardless of whether they join the study). 
The voucher will allow the patient to purchase water, coffee or a refreshment while they 
review materials. Local sites will also provide a travel payment to offset transportation 
costs; these will be paid via pre-paid debit card to patients who attend an in-person 
enrollment appointment, regardless of whether they enroll in the study. Local sites may 
opt to give all patients the same flat travel payment (between $20-50) or use a tiered 
system based on distance from patients’ home. 
For appointments conducted by video or telephone, study personnel will mail the patient 
a packet containing folder, pen, pillbox with the study logo, pre-paid debit card 
(containing no value, to be used for incentive payments after each completed study 
interview) and two copies of the informed consent document and HIPAA authorization 
forms. Study personnel will ask patients to sign one copy of the consent form and HIPAA 
authorization and mail it back, using a study provided postage-paid envelope. Patients 
will be instructed to keep the second copy. Upon receipt of the signed informed consent 
and HIPAA authorization forms from the participant, the local study coordinator/research 


CIRB Protocol #17-11 date   02/01/2022   19 
 
assistant will keep them on file, per local policy.  She/he will make a copy of the signed 
consent and HIPAA authorization forms and mail them back to the patient for his/her 
records.  
Participants are not considered enrolled until the signed written informed consent and 
HIPPA authorization forms are received. If the signed consent and HIPAA authorization 
forms are not received within 14 days, study personnel will follow-up with the patient by 
telephone to determine interest in participation and troubleshoot problems with the forms 
or mail. Replacement copies will be provided, if needed. If the signed consent/HIPAA 
forms are received after 45 days, baseline outcome measures must be repeated prior to 
randomization. If study personnel do not succeed in contacting the patient by 45 days 
after the enrollment visit, no additional attempts will be made. 
4.3.9 Randomization 
After obtaining the written informed consent document (either in person or upon receipt 
of the original mailed copy) and completing the baseline interview, the local site 
coordinator/research assistant will initiate randomization using the study application 
randomization form. The randomization code will not be visible to personnel conducting 
randomization and can be completed only once per study ID, preventing study personnel 
from influencing treatment allocation. This process will simultaneously inform the 
coordinator and participant of the primary study arm assignment.To prevent patients from 
feeling pressured to taper opioids, the taper option assignment will be revealed only when 
participants agree to discuss options for opioid dose reduction. Regardless of whether the 
taper intervention is delivered, participants will be evaluated in their assigned arm.  
Patients will be randomized within site and opioid dose (i.e., moderate or high) 
categories, in permuted blocks of size 4 or 8, to balance the proportions of participants 
with moderate-dose and high-dose opioid therapy in the intervention arms. Those in the 
moderate-dose group will be randomly assigned, with equal likelihood, to intervention 
arms. Those in the high-dose group will be randomly assigned, with equal likelihood, to 
intervention and tapering strategy combinations.    
4.3.10 Masking 
Participants will not be masked to treatment arm assignment due to the complexity of the 
intervention strategies. Local site treatment teams and local site study personnel will also 
be unmasked. To reduce risk of biased outcome ascertainment, all personnel conducting 
outcome assessments will be masked to treatment arm assignment. 
5. STUDY INTERVENTIONS 
5.1 Intervention overview 
Patient participants will be randomly assigned to either telecare collaborative management 
(TCM) or integrated pain team (IPT) arms for 12 months. In both arms, patients receive pain 
care and opioid taper planning tailored to preferences and adjusted as needed to achieve 
individualized treatment goals. Core and optional components of each arm are listed in Table 
1. In both arms, pain management approaches and medications are provided by volunteer 
clinicians as in usual VA care. No experimental therapies will be used, other than the 
buprenorphine rotation protocol, which is described in Section 5.6. 


CIRB Protocol #17-11 date   02/01/2022   20 
 
All patients will receive individualized information and recommendations related to their 
pre-existing opioid therapy, with timing determined by individual needs and preferences. 
When interested in reducing or discontinuing opioids, all patients will receive information 
about standard opioid tapering options, which involve gradual opioid dose reduction. Patients 
on high-dose opioids (≥ 70 ME mg/day) who are randomized to the expanded taper options 
arm will additionally receive information about the option of rotating to buprenorphine. 
 
Table 1: Core and optional components of IPT and TCM interventions 
 
IPT arm 
TCM arm 
Core 
Optional 
Core 
Optional 
Defining 
elements 
Interdisciplinary 
team care planning, 
multimodal pain 
therapy, behavioral 
activation sessions  
N/a 
Clinical pharmacist 
care management; 
structured symptom 
monitoring; pain 
medication 
optimization 
N/a 
Team 
members 
At least 3 clinical 
disciplines, 
including a medical 
provider; a mental 
health therapist; and 
a clinical pharmacist 
and/or rehabilitation 
clinician  
Other specialist or 
generalist clinicians. 
If team does not 
include a rehab 
clinician as a core 
member, a rehab 
point-of-contact 
should be identified  
Clinical pharmacist; 
consulting physician 
N/a 
Team 
processes 
Weekly case review 
meetings of all core 
team members 
Scheduled or as-
needed interval 
communication 
within team and 
with primary care 
Weekly case review 
meetings of core 
team members 
Scheduled or as-
needed interval 
communication 
within team and 
with primary care 
Pain care 
modalities  
Individual 
behavioral activation 
(goal setting, 
MI/CBT) sessions; 
multimodal pain 
care planning; 
opioid taper support 
Specific therapies 
per individual needs 
and local resources 
(e.g., group 
behavioral therapy, 
exercise therapy, 
complementary 
therapies) 
Pain medication 
management; opioid 
taper support 
Nonpharmacological 
therapies through 
usual care per local 
availability 
Initial visit 
Initial visit with 
medical provider 
and mental health 
therapist* 
Medical provider 
and mental health 
therapist may see 
patient together or 
sequentially; initial 
visit may include 
other team members  
Initial visit with 
pharmacist care 
manager* 
Initial visit may 
include consulting 
physician 


CIRB Protocol #17-11 date   02/01/2022   21 
 
Follow-up 
visits 
At least 2 visits* 
with medical 
provider (at least 
one within initial 3 
months); 8 
behavioral activation 
visits** with mental 
health therapist 
Additional visits 
with any IPT 
clinician 
At least 5 follow-up 
visits** with 
pharmacist (monthly 
x 2, then at least 
every 3 months) 
Additional follow-
up visits  
Core 
common 
elements 
Collaboration with primary care teams; patient-centered communication and study 
informational materials; shared decision-making about opioid dose reduction and pain 
therapies; individualized opioid taper assessment, preparation, and implementation. 
Any visit may be conducted in-person, by video, or by telephone if appropriate per local 
resources/policies and patient preferences.  *Face-to-face (i.e., in-person or video) visits are 
the preferred mode. **Telephone visits are the preferred mode. 
5.2 Common intervention elements 
The TCM and IPT interventions share several common approaches and processes, including 
the following:   
• Collaboration with primary care teams. During the study, TCM/IPT intervention 
clinicians will assume primary management of chronic pain care for patients enrolled in 
the study; however, both interventions are intended to supplement, rather than replace, 
primary care pain management. Intervention clinicians in both arms use structured CPRS 
templates to guide visits. Care management notes entered into CPRS are the primary 
method of communicating with the primary care team, consistent with usual practice in 
VA. If indicated by clinical or safety issues, clinical intervention teams will communicate 
directly with the patient’s primary care or mental health team. 
• Patient-centered informational materials. Patient-centered communication will be 
supported by development of informational materials. These materials will be used by 
clinicians in both intervention arms.  
• Shared decision-making. Both arms will use a shared decision-making approach to guide 
pain treatment and opioid dose reduction. Shared decision-making is an approach to 
clinical decisions that involves bidirectional information exchange, interactional 
deliberation about options, and agreement on a course of action. 
• Individualized opioid taper preparation. Clinicians in both intervention arms will manage 
pain with non-opioid therapies while assessing interest in and readiness for opioid dose 
reduction/discontinuation at each follow-up visit. When patients indicate interest in 
opioid dose reduction or in learning more about the process, detailed information about 
opioid tapering options will be provided. We anticipate participants will require a 
variable number of visits to develop readiness for opioid dose reduction/discontinuation, 
so timing of the process will be highly individualized. This approach allows patients time 
to establish trusting relationships and become more informed and activated. 


CIRB Protocol #17-11 date   02/01/2022   22 
 
5.3 Telecare Collaborative Management (TCM) Intervention 
5.3.1 TCM defining elements 
The TCM intervention arm has two defining elements: pharmacist care management, 
structured symptom monitoring and pain medication optimization. 
• Pharmacist care management: A clinical pharmacist care manager delivers 
medication therapy and facilitates communication among the patient, primary care 
team, and collaborating physician. 
• Structured symptom monitoring: At each TCM visit, the care manager will 
conduct a structured assessment using brief tools and a checklist of common 
adverse symptoms. Patients will be queried about progress toward their individual 
functional goals.  
• Pain medication optimization: Medication management in the TCM arm will be 
operationalized as a series of medication trials undertaken using a shared 
decision-making approach. After each change in medication, the presence or 
absence of a clinical response will be assessed. This information will be used to 
support deliberation about whether to continue or change pain medications, 
including opioids. 
5.3.2 TCM visit schedule 
An overview of TCM visit timing, along with research assessment interview timing, is 
presented in Figure 1. All visits may be completed using any mode (in-person, video, or 
telephone); when applicable, the preferred mode for each visit type is indicated in the 
figure and text below. 
 
 


CIRB Protocol #17-11 date   02/01/2022   23 
 
The first TCM visit with the care manager will scheduled as soon as possible after study 
enrollment and randomization. Face-to-face (i.e., in-person or video) is preferred for the 
initial visit. First visit tasks include the following:  
• Obtain history of current and past pain medication use, including opioid use, 
adherence, adverse effects, and response. 
• Administer initial structured assessment battery including PEG pain scale; PHQ-4 
depression and anxiety screener; and 3-item modified Prescribed Opioids 
Difficulties Scale (PODS)  
• Establish initial pain management goals 
• Provide pain management information; discuss initial options 
• Discuss readiness for opioid dose reduction and any opioid-related goals; explore 
ambivalence about opioids; complete signs of opioid risk elevation (SORE) 
checklist; provide specific advice related to any safety or adherence concerns; 
discuss taper options if appropriate. 
• Document visit on TCM initial visit template 
Follow-up visits with the care manager will be scheduled monthly for the following two 
visits; subsequent visits will be scheduled according to individual needs during the 
remainder of the 12-month intervention, with a maximum of three months between visits. 
Most follow-up visits will occur by telephone, although participants will have the option 
of face-to-face visits. Subsequent visit tasks include the following: 
• Administer structured follow-up assessment battery including PEG pain scale; 
global impression of change rating; PHQ-4 depression and anxiety screener 
• Assess progress toward pain management goals; revise goals when appropriate 
• Assess adherence, adverse effects, and response to medication therapy 
• Determine whether a medication change should occur, based on structured shared 
decision-making approach.  
• Provide pain management information; discuss options 
• Discuss readiness for opioid dose reduction and any opioid-related goals; explore 
ambivalence about opioids; complete SORE checklist; provide specific advice 
related to any safety or adherence concerns; discuss taper options when 
appropriate. 
• Documentation of visits on TCM follow-up visit template 
The final intervention visit will be scheduled as soon as possible after the 12-month 
outcome assessment interview. Prior to this visit, an individual study summary will be 
prepared for each exiting participant and an initial plan for medication transition will be 
developed. The final intervention visit will include the following:  
• Review of study summary, including treatment history and progress toward 
individual goals during the study 


CIRB Protocol #17-11 date   02/01/2022   24 
 
• Education about the transition plan and initial steps to implement the plan 
• After the visit, the individual study summary and transition plan will be 
documented in a final templated note with the PCP as cosigner. 
5.3.3 TCM medication management 
The general approach for medication management includes three steps: 1) individualized 
assessment, 2) patient education, and 3) shared decision-making. Main considerations for 
medication change decisions are the presence of pain response, defined as improvement 
in PEG score, patient global impression of change, and progress toward individual goals; 
adverse effects; and patient desire for change in medications. Medications may be 
discontinued, adjusted, or continued with the addition of adjunctive drugs, depending on 
the patient’s individual history of medication use (including dosing, scheduling, and 
adherence), therapeutic response, and adverse effects. Principles for medication initiation 
and adjustment include the following: 
• First-line choice will depend on prior medication trials, comorbidities, and adverse 
effect profiles. 
• Adjuvant drugs will be used alone or concurrently with first and second-line drugs 
when appropriate. 
• One medication will be adjusted at a time.   
If medication changes are made, the care manager will mail a letter outlining those 
changes, along with an updated medication list.  
5.3.4 TCM team processes 
The pharmacist care manager is the central care provider and will communicate directly 
with the patient via face-to-face and telephone visits, as well as mailed communication. 
Case review meetings of the care manager and consulting physician will be held at least 
weekly to review progress with pain management, adverse effects, and any clinical 
problems. During the final year of intervention, as the number of active study participants 
decrease at each site, the site PI, in consultation with the team clinicians and coordinating 
center fidelity monitoring team, may change the frequency of case review meetings to 
less than weekly (but at least once/month).   
The local site study coordinator/research assistant (or in their absence, coordinating 
center staff or local site PI/co-investigator) will attend these meetings. Medications will 
be prescribed or recommended by intervention clinicians according to individual patient 
needs. Medications will be dispensed through the local VA outpatient or VA centralized 
mail order pharmacy according to usual medication dispensing processes. 
5.4 Integrated Pain Team (IPT) Intervention 
5.4.1 IPT defining elements 
The IPT intervention arm has three defining elements: an interdisciplinary team, multi-
modal pain management, and behavioral activation sessions.   
• Interdisciplinary team: Three or four types of clinicians are core to 
interdisciplinary clinic models described in the literature or implemented within 
VA—medical providers (physician or NP/PA); psychologists or other mental 


CIRB Protocol #17-11 date   02/01/2022   25 
 
health therapists; clinical pharmacists; and rehabilitation clinicians (e.g., physical 
therapist, occupational therapist). IPT must have at least three types of clinicians 
in this study, including a medical provider and a mental health therapist. The third 
required position may be held by a clinical pharmacist and/or a rehabilitation 
clinician. Additional clinicians with pain expertise may also be included. If a 
rehabilitation clinician is not included in the core team, a rehabilitation clinician 
should be identified as a point-of-contact or “friend” of the team to facilitate 
clinical referrals and communication with rehabilitation services. 
• Multi-modal pain management: The IPT arm will use a multi-modal approach that 
targets biopsychosocial contributors to pain and disability.  
• Behavioral activation sessions: IPT clinicians will use MI communication 
techniques to engage patients, starting with eliciting core values and functional 
goals and developing individual pain care plans at the initial visit. Brief individual 
follow-up sessions conducted by the IPT mental health therapist will use MI and 
cognitive behavioral therapy (CBT) techniques to support patients’ progress 
toward individual self-management goals. Delivery of specific CBT modules will 
be at the discretion of the clinician, based on individual patient needs.  
5.4.2 IPT visit schedule 
An overview of IPT visit timing, along with research assessment interview timing, is 
presented in Figure 2. All visits may be completed using any mode (in-person, video, or 
telephone); when applicable, the preferred mode for each visit type is indicated in the 
figure and text below.  
 


CIRB Protocol #17-11 date   02/01/2022   26 
 
 
The first IPT visit (face-to-face preferred) will be scheduled as soon as possible after 
study enrollment and randomization. At this visit, the participant will meet with the IPT 
medical provider and mental health therapist, together or sequentially. First visit tasks 
include the following:  
• Obtain history of current and past opioid and non-opioid pain medication use, 
non-pharmacological therapies, and self-management techniques and adherence, 
adverse effects, and response to each 
• Administer initial structured assessment battery including PEG pain scale; PHQ-4 
depression and anxiety screener; and 3-item modified PODS. 
• Provide information on the biopsychosocial model of chronic pain, non-
pharmacological pain management options, and opioid harms 
• Develop pain care plan based on individual values and functional goals 
• Discuss readiness for opioid dose reduction and any opioid-related goals; explore 
ambivalence about opioids; complete SORE checklist; provide specific advice 
related to any safety or adherence concerns. 
• Complete initial MI session focused on pain care plan 
• Document visit and pain care plan on IPT initial visit template 
Follow-up IPT visits will be scheduled with individual IPT clinicians based on individual 
patient needs, including at least two follow-up visits with the medical provider (face-to-
◊ 
* Initial IPT visit: face-to-face (i.e., in-person or video) is preferred; required clinicians are medical provider and 
mental health provider; may be interdisciplinary visit or sequential visits. 
ⱡ Follow-up IPT visit: face-to-face is preferred; required clinician is medical provider; one must occur in first 3 
months, second required follow-up visit may occur anytime (shown in figure at month 5 as example). 
◊ Final IPT visit: may be telephone or face-to-face; any IPT clinician; after 12-month research assessment. 
* 
ⱡ 
ⱡ 


CIRB Protocol #17-11 date   02/01/2022   27 
 
face preferred; at least one in the first three months). The content of visits will be 
determined based on individual circumstances, but will include the following tasks:  
• Administer structured follow-up assessment battery including PEG pain scale; 
PHQ-4 depression and anxiety screener 
• Assess progress toward pain care plan goals (i.e., functional pain goals and opioid 
goals) 
• If appropriate to visit, discuss readiness for opioid dose reduction and any opioid-
related goals; explore ambivalence about opioids; complete signs of opioid risk 
elevation (SORE) checklist; provide specific advice related to any safety or 
adherence concerns; discuss taper options if appropriate. 
• Document visits on IPT follow-up template 
Follow-up behavioral activation sessions will be scheduled every month for the first six 
months and every 1-2 months for the remainder of the intervention period (i.e., ≥ 8 
sessions). These will be brief (15-20 minute) telephone sessions unless the patient prefers 
face-to-face follow-up. Visit tasks include the following: 
 
• Assess progress toward pain care plan goals and behavioral targets; build 
motivation for change; address ambivalence  
• Share decision-making on action items that may result in further commitment to 
or modification of pain care plan 
• Deliver CBT modules per individual needs 
• Document visit on pain coaching follow-up template 
A final intervention visit will be scheduled as soon as possible after the 12-month 
outcome assessment visit. The final visit may be conducted by telephone or face-to-face 
by any IPT clinician. Prior to this visit, an individual study summary will be prepared for 
each exiting participant. Final intervention visit tasks include the following:  
• Review of study summary, including treatment history and progress toward pain 
care plan goals during the study 
• Education about the transition back to primary care 
• After the visit, the individual study summary and transition plan will be 
documented in a final templated note with the PCP as cosigner. 
5.4.3 IPT pain management 
The pain care plan is the guiding document for IPT pain management. Starting with the 
initial visit, IPT clinicians will elicit patients’ core values and functional goals and 
collaborate with the patient to develop a pain care plan aligned with these values and 
goals. Specifically, the pain care plan will include up to three pain management 
approaches, including specific evidence-based therapies and self-management 
techniques, and up to three opioid harm reduction approaches, such as reducing the 
opioid dosage. Principles for pain care planning include the following: 
• Patients will generate goals in collaboration with the clinical team 


CIRB Protocol #17-11 date   02/01/2022   28 
 
• Goals will be specific, measurable, action-oriented, realistic and time-bound 
• Goals will be linked to multiple pain management approaches 
• Goals will be focused on patient activation and self-management and not dependent 
on actions of health care providers 
5.4.4 IPT team processes 
Case review meetings including all core IPT members will be held at least weekly to 
review progress with pain management, adverse effects, and any clinical problems. 
Additional intra-team communication strategies suitable for each individual site will be 
determined prior to enrollment at each site. The local site study coordinator or research 
assistant (or in their absence, coordinating center staff or local site PI/co-investigator) 
will attend these meetings. During the final year of intervention, as the number of active 
study participants decrease at each site, the site PI, in consultation with the team 
clinicians and coordinating center fidelity monitoring team, may change the frequency of 
case review meetings to less than weekly (but at least once/month).   
5.5 Standard Taper Intervention 
All participants who are interested in learning about opioid dose reduction or discontinuation 
will receive information about standard opioid tapering options. In the TCM arm, the 
pharmacist care manager will provide initial information; in the IPT arm, the medical 
provider will usually be the one to provide initial information. Because evidence is lacking 
for any particular approach to opioid tapering, the standard taper intervention is based on 
guideline recommendations and our own clinical experience. The standard taper intervention 
incorporates shared decision-making about the following decisions:  
• Taper target: Participants may choose to identify a target opioid dose and a tapering plan 
to achieve that target; alternatively, they may choose an open-ended approach, in which 
dose reduction is undertaken and re-evaluated one step at a time.  
• Dose reduction rate: Both the size and the frequency of dose reductions may be 
individually determined. Guidelines suggest tapering 10-50% of the original dose per 
week, but more gradual tapers are preferred by many patients.  
• Medication selection: In many cases, gradually reducing doses of original opioid 
medication is the most straightforward approach; in some cases, switching to a different 
opioid with greater dosing flexibility or availability of lower dosages is preferred. When 
patients take more than one opioid medication (in most cases, a short-acting formulation 
plus a long-acting formulation), either may be tapered first. 
Patients will be provided with written informational materials and a written taper calendar 
with instructions. The taper plan will be documented in CPRS.  
5.6 Expanded Taper Intervention 
Participants who are randomized to the expanded options arm and interested in learning 
about opioid dose reduction or discontinuation will receive information about buprenorphine 
rotation as an optional component of their taper plan.  


CIRB Protocol #17-11 date   02/01/2022   29 
 
5.6.1 Buprenorphine rotation protocol overview 
Patients who opt in to buprenorphine rotation will complete a separate additional written    
informed consent process specific to the buprenorphine rotation protocol. A 
buprenorphine-certified prescribing clinician will provide detailed buprenorphine 
education and manage the actual buprenorphine rotation for patients who choose this 
approach. If the buprenorphine prescriber is not a member of the assigned intervention 
team, an intervention clinician (i.e., TCM clinical pharmacist, IPT medical provider, or 
IPT clinical pharmacist) will provide initial information about standard taper and 
buprenorphine rotation approaches before referring to the buprenorphine prescriber. The 
local site coordinator (or other study staff approved to obtain informed consent) will 
conduct the informed consent process and work with the assigned intervention team and 
buprenorphine prescriber to ensure the protocol is followed throughout this process. 
5.6.2 Buprenorphine regulatory issues 
Although multiple buprenorphine formulations are FDA-approved, we plan to use the 
sublingual buprenorphine-naloxone formulation (i.e., Suboxone) that is most available in 
VA. The purpose of including naloxone, an opioid antagonist, in the formulation is to 
deter abuse of the medication by injection. If the combination medication is injected by a 
person with an opioid agonist in their system, the naloxone causes a precipitated 
withdrawal. When the combination medication is taken sublingually as prescribed, 
naloxone does not interfere with buprenorphine effects.  
Sublingual buprenorphine-naloxone is currently FDA-approved for medication assisted 
therapy in opioid use disorder by physicians and mid-level providers who have completed 
a training program and received DEA certification. Use of sublingual buprenorphine-
naloxone for physical opioid dependence due to prescribed long-term high-dose opioid 
therapy for chronic pain in patients who may not have addiction is an “off-label” 
unapproved use. FDA has determined that study use meets all of the following criteria for 
exemption from IND in 21 CFR part 312.2(b):  
• The drug product is lawfully marketed in the United States.  
• The investigation is not intended to be reported to FDA as a well-controlled study 
in support of a new indication and there is no intent to use it to support any other 
significant change in the labeling of the drug.  
• The investigation is not intended to support a significant change in the advertising 
for the drug. 
• The investigation does not involve a route of administration, dose, patient 
population, or other factor that significantly increases the risk (or decreases the 
acceptability of the risk) associated with the use of the drug product. 
• The investigation is conducted in compliance with the requirements for review by 
an IRB and with the requirements for informed consent.  
• The investigation is conducted in compliance with the requirements of § 312.7 
(i.e., the investigation is not intended to promote or commercialize the drug 
product). 


CIRB Protocol #17-11 date   02/01/2022   30 
 
Although the DEA clarified in 2004 that prescribers may use buprenorphine-naloxone 
off-label for pain without DEA certification, we will have at least two buprenorphine-
certified prescribers at each study site; one will be the primary prescriber in charge of the 
protocol and at least one will serve as a back-up prescriber. These buprenorphine-
certified prescribers may or may not be members of the IPT or TCM team. If a prescriber 
is not a member of a patient’s clinical intervention team, his or her role in the patient’s 
care will be limited to managing buprenorphine rotation as a consultant in collaboration 
with the team.  
At sites lacking two willing and already DEA-certified buprenorphine-naloxone 
prescribers, we will facilitate training to certify additional prescribers. Dr. Becker will 
run the 4-hour SAMHSA sponsored training webinar using video-linked interactive 
technology at no cost to participants. (The additional required training is available on-line 
at a time of the participant’s choosing).  An abbreviated interactive training will be 
provided to intervention pharmacists to ensure they are familiar with the buprenorphine 
rotation protocol and able to describe it in understandable terms to patients. Prescribers 
and intervention pharmacists will be trained in the specifics of the study protocol. 
5.6.3 Buprenorphine rotation management 
Decisions about how to initiate buprenorphine should be individualized, considering 
patient needs and preferences, as well as prescriber experience and local resources. 
Patients may initiate buprenorphine at home or in clinic. There are two methods for 
rotating from full-agonist opioids to buprenorphine: a traditional method and a newer 
method of microdose up-titration. In the traditional method, full-agonist opioids are 
stopped entirely prior to starting buprenorphine. Case series suggest that patients usually 
prefer tapering rapidly over 2-5 days, rather than discontinuing abruptly. The interval 
between last dose of the full-agonist opioid and the first dose of buprenorphine-naloxone 
depends on the duration of action of the full-agonist opioid. In most cases, 12-18 hours is 
appropriate for short-acting opioids. For long-acting opioids, a longer interval is typically 
needed, from approximately 18-24 hours for morphine SA to approximately 48-72 hours 
for methadone. Patients on methadone should first taper down to 30 mg daily dose of 
methadone, per standard protocol. Patients using the traditional rotation method are 
advised they will experience opioid withdrawal symptoms during the interval after 
stopping full-agonist opioids and before starting buprenorphine. 
 
In the microdose up-titration method,  buprenorphine is started at very low doses several 
days before the full-agonist opioid is stopped. Buprenorphine is up-titrated over several 
days (typically 3-5 days) and then the full-agonist opioid is discontinued once 
buprenorphine is at a therapeutic dose. Case series demonstrate that the microdose up-
titration method is well-tolerated; in our clinical experience, some patients on long-term 
opioid therapy for pain prefer this approach because they do not have to experience 
opioid withdrawal symptoms before initiating buprenorphine.  
 
Precipitated opioid withdrawal is the main potential adverse effect of buprenorphine-
naloxone rotation; it is avoided if participants follow the initiation protocol. When using 
the traditional rotation method, the most critical point patients need to understand is that 
the “old” opioids must be out of their system before buprenorphine-naloxone initiation. 
This means they need to wait for the onset of at least moderate withdrawal symptoms. 


CIRB Protocol #17-11 date   02/01/2022   31 
 
When using the microdose up-titration method, the critical point is to start at a very low 
dose and increase according to instructions over several days. All patients will be 
provided detailed written and verbal information about opioid withdrawal symptoms and 
about precipitated withdrawal. Understanding will be confirmed by teach-back.  
For patients who complete a rotation to buprenorphine-naloxone, decisions about 
subsequent buprenorphine management during and after the study will be made on an 
individual basis. Factors that will be considered include outcomes of therapy, patient 
preferences, and presence of a buprenorphine prescriber willing to continue prescribing 
beyond the study period. Options include the following:  
• Continue on buprenorphine-naloxone; 
• Taper off and completely discontinue opioids; or 
• Rotate back to a full-agonist opioid. In this case, the full-agonist opioid will be 
started at a lower dose due to incomplete cross-tolerance.  
5.6.4 Buprenorphine protocol consent process  
Patients who are randomized to expanded taper options will receive initial information 
about buprenorphine rotation from their intervention clinician (i.e., TCM clinical 
pharmacist, IPT medical provider, or IPT clinical pharmacist). Those who are interested 
in learning more will be scheduled for a visit with a buprenorphine prescriber. This visit 
may be conducted in-person, by video, or by telephone per patient preference and local 
site visit availability. Face-to-face (in person or video) visits are preferred, but telephone 
visits are acceptable if allowed by current regulations and policies. This visit will include 
assessment of buprenorphine appropriateness, discussion of risks and benefits of 
buprenorphine rotation, and provision of buprenorphine educational materials and 
resources. The local site coordinator (or other study staff approved to obtain informed 
consent) will attend this visit if acceptable to the patient or meet with the patient and 
prescriber as soon as possible (in person, via video or telephone) afterwards to ensure the 
study protocol is followed (e.g., informed consent process is completed before 
buprenorphine is prescribed). If the prescriber determines buprenorphine is clinically 
appropriate and the patient would like to proceed with buprenorphine rotation, the local 
site coordinator (or other study staff approved to obtain informed consent) will complete 
the buprenorphine informed consent process. 
To ensure patients make a fully informed decision about the buprenorphine protocol, 
written informed consent for the buprenorphine protocol will occur after the initial visit 
with the buprenorphine prescriber. Timing of the informed consent process may be 
immediately after this visit or at a later date if the patient would like additional time to 
consider.  
For buprenorphine protocol appointments conducted by video or telephone, study 
personnel will mail the patient buprenorphine informational materials and two copies of 
the informed consent document prior to the appointment. Study personnel will ask 
patients to sign one copy of the consent form and mail it back, using a study provided 
postage-paid envelope. Patients will be instructed to keep the second copy. Upon receipt 
of the signed informed consent form, the local study coordinator/research assistant (or 
other study staff approved to obtain informed consent) keep it on file.  Study staff will 


CIRB Protocol #17-11 date   02/01/2022   32 
 
make a copy and provide it to the local research pharmacy. A signed copy will also be 
mailed back to the patient.  
5.6.5 Buprenorphine visit schedule 
The initial buprenorphine visit with the buprenorphine prescriber may occur by any mode 
allowable by current regulations, as described above, but face-to-face (i.e., in-person or 
video) is preferred. First visit tasks include the following:  
• Obtain history of current opioid use; assess buprenorphine risk factors (including 
risk for pregnancy if applicable) 
• Provide standardized buprenorphine educational materials and resources 
• Use shared-decision making to determine whether to proceed with buprenorphine 
rotation 
• Document visit on buprenorphine initial visit template 
Following buprenorphine initiation, structured follow-up will occur at three time points: 2 
days, 1 week, and 3 weeks after initiation. These visits may occur by telephone or face-
to-face, as appropriate. Patients will be instructed on whom to contact for problems or 
concerns occurring between visits. After the three structured visits, follow up will occur 
according to the assigned TCM or IPT intervention. Most follow-up visits will occur by 
telephone, although participants will have the option of face-to-face visits. Follow-up 
visit tasks include the following: 
• Assess medication response and adverse effects, including withdrawal symptoms 
as appropriate 
• Administer standard satisfaction questions  
• Provide additional education and counseling as needed 
• Document visit on buprenorphine follow-up visit template 
5.7 Intervention Management of Adherence and Adverse Effects 
5.7.1 Clinical monitoring of opioid adherence 
The approach to opioid monitoring will augment, rather than replace, primary care 
management. Prior to the initial visit, intervention teams will review prior drug testing 
results and opioid fill patterns and determine whether local and national VA monitoring 
requirements have been met. If a patient is past due for any monitoring tasks, intervention 
clinicians will work with the primary care team to complete them. In addition, the PDMP 
will be checked and checklist of opioid non-adherence behaviors will be completed at 
each medication management visit.  
5.7.2 Clinical management of opioid-related risk and opioid adherence problems 
Intervention clinicians will facilitate use of opioid risk reduction strategies, including use 
of naloxone rescue kits, which are recommended by CDC guidelines for patients on 
moderate-to-high dose opioid therapy.   
If opioid adherence problems are identified, they will be evaluated and addressed by 
intervention clinicians with the goals of improving both pain management and safety. 
Nonadherence behavior will be discussed at intervention case review meetings and an 


CIRB Protocol #17-11 date   02/01/2022   33 
 
individualized monitoring plan will be developed to aid in diagnosing and addressing the 
underlying cause of the behavior. This plan may include: a) education; b) medication 
adjustment; c) additional study or primary care visits; d) review of state PDMP database; 
e) urine drug testing; f) shorter prescription intervals; or g) referral to a mental health or 
addiction clinician.  
5.7.3 Clinical management of opioid use disorder (OUD) 
Intervention clinicians will be instructed to evaluate patients with symptoms or signs of 
OUD or other SUD to establish a diagnosis.  OUD diagnostic criteria will be included in 
study templates for easy reference. The opioid dose reduction strategies proposed in this 
study are not sufficient treatment for opioid use disorder, so intervention clinicians will 
facilitate evidence-based addiction treatment for participants who receive an OUD 
diagnosis during the study. Depending on local site resources and usual care processes, 
addiction treatment may be integrated with primary care or may be delivered in an 
addiction specialty clinic. Regardless of the setting and degree of addiction care 
integration, intervention clinicians will collaborate with addiction treatment providers to 
maximize coordination of care for study participants. Participants who are diagnosed with 
OUD will continue to receive non-opioid analgesic and non-pharmacological therapies 
for their pain in their assigned TCM or IPT pain management arm. OUD will not be 
cause for withdrawal from the trial. 
5.7.4 Clinical management of adverse effects 
Medications will be prescribed and monitored by intervention clinicians according to 
usual standards of care and relevant clinical guideline recommendations. Prior to the start 
of trial enrollment, intervention clinicians involved in medication management will be 
provided with additional training on medication indications, contraindications, and 
interactions. Specific training will be provided to intervention clinicians on care of 
reproductive-aged women, including women who are pregnant, lactating, or could 
possibly be pregnant. Study medication management reference documents and 
educational tools will be available to all intervention clinicians on the study SharePoint 
site. The study pharmacist coordinator will ensure study medication management 
guidance is up-to-date and available throughout the study and will serve as a resource for 
intervention clinicians at all sites.  
Study note templates will include prompts to perform medication reviews, query about 
contraceptives and potential of pregnancy, and consider potential drug interactions. Study 
educational materials will address common/important benefits and risks of medications. 
Educational materials for reproductive-age women will address common/important issues 
related to pain medications and pregnancy. 
Study templates will also include prompts to inquire about treatment-related side effects 
and adverse symptoms. Intervention clinicians will manage these symptoms according to 
usual standards of clinical care, offering treatment for minor injuries and adjusting or 
discontinuing therapies as appropriate.  
5.8 Intervention Fidelity 
Delivery of intervention components will be tracked to ensure that patient participants at 
each site receive the core elements of each intervention and also to describe heterogeneity in 
intervention implementation and use of optional elements across sites. Intervention-specific 


CIRB Protocol #17-11 date   02/01/2022   34 
 
CPRS note templates will generate centrally retrievable electronic data elements (i.e., health 
factors), allowing us to measure the number and types of study visits attended by participants 
and examine aspects of intervention intensity and fidelity. 
The research team will monitor fidelity to core intervention elements throughout the active 
intervention phase of the trial. Data generated from use of note templates and other sources 
will be used to populate internal study fidelity reports. Fidelity reports will include summary 
data across and within sites. Reports will be reviewed and discussed at least every 6 months 
on all-site meetings and DSMB meetings. If site or intervention arm-specific problems are 
identified, these will be addressed with involved research personnel or intervention 
clinicians.  
5.8.1 IPT motivational interviewing (MI) fidelity 
Because behavioral activation sessions are a defining element of the IPT intervention, 
fidelity to MI principles in these sessions will be assessed using the Motivational 
Interviewing Treatment Integrity (MITI, v 4.2) coding instrument. The MITI will be used 
to rate audio-recordings of a sub-sample of audio-recorded behavioral activation 
telephone sessions. For this pragmatic trial, fidelity monitoring will focus on training in 
initial sessions; later assessments will allow better understanding of intervention 
processes. Interventionists will be instructed to record all sessions to avoid selection bias 
(e.g., only providing “good” sessions to the research team). For the initial several months 
after the start of study enrollment, we will randomly select 10% of the recorded 
behavioral activation sessions. Two co-investigators will use the audio-recordings to code 
sessions for MI fidelity. After IPT clinicians demonstrate MI competency based on MITI 
ratings, we will continue to monitor MI fidelity in 5% of randomly selected visits. 
Finally, 1% of sessions coded with the MITI will be double-coded to establish inter-coder 
reliability. 
5.9 Intervention Discontinuation and Transitions of Care  
TCM/IPT intervention clinicians will assume primary management of chronic pain care for 
patients while they are participants in the study. Chronic pain management by the 
intervention clinicians will last 12 months unless the patient does not want to continue for the 
full 12 months. Patient participants may elect to discontinue active intervention participation 
for any reason at any time. 
Patients will be encouraged to receive their chronic pain care from the TCM/IPT throughout 
their participation in the study; however, patients will not be restricted from seeking pain 
care from their PCP or other providers.  Patient participants may continue in the study 
regardless of adherence to intervention protocols.  
Chronic pain care will be transitioned from intervention clinicians back to the PCP when the 
patient completes participation in their assigned intervention. For most patients, this 
transition will occur at the scheduled end of their 12-month study participation after the final 
intervention visit. For patients who stop active participation in the intervention of their own 
accord, this transition will occur when they indicate their desire to discontinue participation. 
Regardless of when and why the transition back to the PCP occurs, intervention clinicians 
will retain responsibility for chronic pain care (e.g., active medications, referrals) until the 
PCP accepts responsibility for the patient’s pain care (i.e., the handoff is complete). The 
processes outlined below will be used to ensure continuity of care:  


CIRB Protocol #17-11 date   02/01/2022   35 
 
• Intervention clinicians will place a templated summary clinical care note in the 
patient’s medical record with the patient’s PCP added as a cosigner.  
• Intervention clinicians will check the state prescription monitoring program and 
include information about outside prescriptions in the transition note.  
• Intervention clinicians will contact PCPs directly to discuss anticipated transition 
needs or challenges. PCPs will be encouraged to contact intervention clinicians with 
any concerns. 
• Patients will be encouraged to contact their intervention clinicians if they have any 
questions or concerns about the transition in their pain care. 
• If intervention clinicians are prescribing medications at the end of the patient’s study 
participation period, an updated prescription order will be entered in the medical 
record by the intervention prescriber and flagged for the PCP to sign. If needed to 
prevent gaps in medication availability, a limited medication supply will be 
prescribed by the intervention prescriber to cover patient needs until the PCP resumes 
prescribing.   
6.STUDY DATA COLLECTION 
6.1 Data Collection Overview 
Three types of data will be collected for research purposes: 1) patient-reported measures; 2) 
administrative data; 3) qualitative data. 
6.2 Patient-reported measures 
Patient-reported measures, including outcomes and covariates, will be collected by 
interview at baseline and at 3, 6, 9, and 12 months. The baseline interview will be 
conducted by the local site study coordinator or research assistant after the patient 
provides verbal informed consent and before randomization. Follow-up outcome 
assessments will be conducted as telephone interviews by coordinating center research 
personnel who are masked to treatment arm assignment. Visual aids will be mailed to 
participants in advance so they can follow along with the interviews. If participants are 
unable to complete 6 or 12-month telephone interviews, they will be offered the 
alternative of completing mailed paper questionnaires. Participant responses will be 
recorded on machine-readable paper questionnaire forms, which will be subsequently 
double-scanned into an electronic database. Interviews are completed with the most 
critical measures first, to prevent missing core outcome data in case of interruption.  
6.2.1 Timing and duration of assessment interviews 
Full-length assessment interviews will be conducted at baseline, 6 months, and 12 
months. The duration of assessment interviews will be approximately 60 minutes at 
baseline and 45 minutes at 6 and 12 months. A small participant payment ($50 each) will 
be provided after each of these interviews. A nominal token of appreciation (e.g., jar 
opener with study logo) will be sent to participants before the 12-month interview.  
Abbreviated assessment interviews addressing core outcome measures will be conducted 
at 3 and 9 months. The duration of these abbreviated interviews will be approximately 
15-20 minutes. A small participant payment ($25 each) will be provided after each 
abbreviated interview. 


CIRB Protocol #17-11 date   02/01/2022   36 
 
Timing of follow-up assessment interviews will be based on the date of the baseline 
interview. Follow-up assessments may be completed up to 30 days early when 
extenuating circumstances (e.g., planned travel or move) suggest that data may be 
otherwise lost. 3 and 9 month assessments may be completed up to 30 days late. 6 and 12 
month assessments may be completed up to 60 days late. Data from assessments 
completed outside of these time windows will not be included in primary analyses.  
If the first intervention visit is delayed >30 days after baseline assessment date, 
participants will be asked to repeat core baseline measures (administered by masked 
assessors), prior to the first intervention visit. A small participant payment ($25 each) 
will be provided after the abbreviated, repeat baseline interview. 
At the end of the 12-month interview, the assessor will ask for permission to re-contact 
the Veteran, either for a qualitative interview (described below in 6.4.1) or other future 
interviews; participants will be reminded these future interview(s) are voluntary. 
6.2.2 Alternative patient-reported assessment procedures 
If assessment burden becomes a problem for participants at any point during the study, 
the option of completing a minimum assessment composed of core outcome measures 
will be offered. If participants are unable to complete interviews by telephone, a self-
complete machine-readable paper questionnaire will be mailed. Participant payments will 
be provided as described above. 
6.2.3 Description of patient-reported measures  
Consistent with guidelines for outcome assessment in pain clinical trials, we will assess 
multiple domains, including pain intensity, function, and symptoms and adverse events, 
using validated patient-reported measures.  Patient-reported outcome domains and data 
collection schedule are presented in Table 2. 
Table 2: Patient-reported outcome assessment schedule 
 
Schedule (month) 
Measure 
0 
3 
6 
9 
12 
Pain, pain characteristics 
X 
X 
X 
X 
X 
Health related quality of life 
X 
X 
X 
X 
X 
Functioning 
X 
X 
X 
X 
X 
Adverse effects 
X 
X 
X 
X 
X 
Fatigue/sleep 
X 
 
X 
 
X 
Mood (e.g., anxiety, depression, PTSD) 
X 
 
X 
 
X 
Substance use 
X 
 
 
 
X 
Predictors/explanatory variables 
X 
 
X 
 
X 
Use of health care services/self-care practices 
X 
 
X 
 
X 
COVID-19 questions 
X 
X 
X 
X 
X 
 
6.3 Administrative Data 
6.3.1 Data sources 
National VA datasets and the environment for analyzing them are provided by VA 
Informatics and Computing Infrastructure (VINCI). A VINCI project workspace will be 
used to access data, construct covariates, and perform primary and secondary analyses. 


CIRB Protocol #17-11 date   02/01/2022   37 
 
We will use administrative data to determine eligibility, covariates and outcomes, 
including the following: 
• Patient eligibility criteria from outpatient pharmacy and inpatient and outpatient data 
domains  
• Relationships of patients and primary care providers from PCMM domain  
• Patient demographics from patient data domain  
• Patients distance and drive time from VA facilities from geographic access data sets 
created by the planning services and support group  
• Physical and mental health diagnoses from inpatient and outpatient data domains 
• Prescriptions and drug dispensing from outpatient pharmacy domain 
• Pain treatment variables from outpatient and lab chemistry data; outpatient pharmacy 
data; and outpatient, procedure code, and fee basis data domains 
• Hospitalizations, ED visits, and SUD treatment admissions from inpatient, outpatient, 
procedure code, and fee basis data domains 
• COVID-19 test results 
6.3.2 Opioid dispensing data 
Opioid dose outcomes and medication covariates will be assessed using VA outpatient 
pharmacy dispensing data. Opioid daily dose at any given time will calculated as the 
mean dose over the prior 90 days, so the main opioid dose outcome will therefore be an 
average dose over the final 90 days of the study intervention period. To provide 
information about dose after the intervention is complete, our final dose assessment time-
point will be three months after the end of the study. Established conversion tables will 
be used to calculate morphine-equivalent (ME) mg. 
6.3.3 Pain treatment data 
Receipt of pain-related services outside of intervention visits will be estimated by 
capturing specialty, rehabilitation, and mental health visits. Complementary therapies are 
not all well captured in VA databases, but therapies with specific codes (e.g., 
acupuncture) will be assessed. Other complementary services may be variably recorded 
under general codes; for example, yoga could be coded as a recreational therapy visit. To 
maximize our capture of VA complementary therapy service delivery and validity of 
these data across sites, local study personnel at each site will be asked to inventory local 
complementary therapy availability and clinical coding practices on an annual basis; 
these inventories will be reviewed by the coordinating center data and statistical team and 
considered in administrative data extraction and cleaning protocols. 
6.3.4 Intervention treatment data 
Data will be collected on intervention visits to describe the care provided, as well as 
fidelity to the intervention arms (see 5.8). Intervention clinic visit notes will be used to 
count the number of intervention visits (face-to-face, video and telephone) in both arms 
over the study period. Structured notes will be designed to generate data objects that can 
later be captured from administrative data to describe intervention processes. 


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6.4 Qualitative Data 
Qualitative process evaluation data will be gathered to examine patients’ and clinicians’ 
perceptions of the TCM and IPT interventions; to describe the context and processes of 
intervention delivery; and to assess potential for long-term sustainability and widespread 
dissemination of the interventions. 
6.4.1 In depth interviews with patient participants, clinician participants, and other VA 
employees 
A purposeful sample of patient participants in both the TCM and IPT intervention arms 
will be interviewed by telephone after their study participation is complete. We will 
purposefully select participants who are diverse in terms of age, sex, race/ethnicity, study 
site, and level of participation in the intervention (defined by the number of intervention 
visits completed during 12 months). The data team will provide names of potential 
participants based on demographic characteristics, assigned arm, and level of 
participation; interviews will take place within approximately three months after 
completing the study intervention. A semi-structured interview guide will be used. 
Questions will address experiences with the interventions, perceptions of the value and 
convenience of the interventions, what (if any) aspects of the intervention were most or 
least influential in terms of their personal treatment outcomes, and any recommendations 
for improvements. Interviews will be audio-recorded and transcribed. Data collection will 
continue until theoretical saturation is reached. Based on recommendations for qualitative 
sampling, we expect to conduct 15 interviews for each study arm, for a total of 
approximately 30 patient interviews. 
In addition, a separate sample of VOICE participants across both intervention arms will 
be interviewed by telephone about COVID-19 pandemic-related experiences that could 
be relevant to their pain and pain care.  Interviews will be conducted using an original 
semi-structured interview guide following the same approach described above for other 
patient interviews.  We anticipate conducting approximately 30 additional interviews.  
A purposeful sample of clinician participants will be interviewed. Intervention clinicians 
at different sites, in both arms, and with differing roles will be asked to participate. 
Interviews will be one-time events and will be timed to obtain information about 
intervention implementation; therefore, they may be done before, during, or after 
intervention participation. Interview questions will address reactions to the intervention, 
perceptions of effects of the intervention on patient outcomes, key facilitators and 
barriers to maintaining the interventions as standard clinical practice, and 
recommendations for changes to the intervention to increase the “fit” of the intervention 
into the clinic. Clinicians will also be asked about effects of increased use of telehealth. 
To inform possible future implementation efforts, the interviews will also focus on 
perceptions of the facilitation method for implementation of the interventions in order to 
determine whether the level of facilitation was sufficient for high fidelity implementation, 
whether it created an undue burden on clinical personnel and any changes that could be 
made to improve facilitation. 
In addition, up to 46 VOICE clinicians involved in discussing buprenorphine as part of 
the expanded taper options intervention will be interviewed about their perspectives on 
buprenorphine and experiences with discussing buprenorphine. Buprenorphine-related 
clinician interviews are expected to take 30-60 minutes. If clinicians are also completing 


CIRB Protocol #17-11 date   02/01/2022   39 
 
the main interview described above, buprenorphine-related interview questions may be 
asked at the same session or at a second separate interview session, depending on 
logistics and the preferences of the clinician being interviewed.   
Finally, selected additional local site clinicians, administrative staff, and other VA 
employees will be interviewed during the study as part of the process evaluation. These 
additional VA employees will be selected based on their positions and experience with 
the study, with the goal of obtaining a diverse array of perspectives on intervention 
implementation processes. Unlike the patient participants and clinical participants 
described above, these employees will not have prior participation in the study. Study 
investigators will identify potential participants and Minneapolis coordinating center 
personnel will send invitations by email. Employees who agree to schedule an interview 
will be informed of the study purpose using an information sheet, provided the 
opportunity to have questions answered, and asked to provide verbal consent. Interview 
questions will address facilitators and barriers to maintaining the interventions as 
standard clinical practice, recommendations for changes to the intervention to increase 
the “fit” of the intervention into clinical practice, burden on clinical personnel, and any 
changes that could be made to improve implementation. 
6.4.2 Informal interviews and observation 
The study process evaluation team will collect data on study implementation processes 
using participant observer and unstructured conversational interview techniques. They 
will attend and observe meetings, including investigator meetings, local site rollout 
meetings, and intervention clinician team meetings. In the context of these meetings and 
other interactions, they will gather data from investigators, intervention clinicians, and 
stakeholders using unstructured conversational interview questions. Data will be recorded 
in the form of field notes. 
7. STATISTICAL ANALYSIS 
7.1 Sample Size Considerations 
For our power calculations, we used an effective sample of at least 776 patient participants 
(at least 80% of initial sample size of 970) for the comparison of 12-month outcomes. 
7.1.1 Power estimates for primary analyses 
Prior research observed 50% of patients achieving a 30% or greater reduction in BPI at 
one year with a TCM intervention. Assuming a similar response rate for TCM at a 
significance level of 0.05, a sample size of 970 enrolled participants provides 80% power 
for a 2-sided chi-squared test comparing pain response rates for TCM and IPT if IPT adds 
10% to the response rate, and > 85% power if IPT adds 11% to the response rate. For the 
second aim examining adding buprenorphine to the tapering protocol, with an unadjusted 
0.05 significance level, the estimated proportion of the sample on high-dose therapy 
(35%) will result in approximately 135 participants per treatment group and provide > 
80% power to detect small to moderate effects (Cohen d or standardized difference) in 
mean BPI scores of 0.35 or more. 
7.1.2 Subgroup power estimates 
A difference of 1 unit in BPI is considered clinically significant and the SD of the BPI 
scores is typically about 2 units. A sample size of 776 participants at the 12-month 


CIRB Protocol #17-11 date   02/01/2022   40 
 
assessment will provide > 80% power for detecting a clinically meaningful difference in 
intervention effects across subgroups with prevalence of at least 40%, assuming a 
Bonferroni corrected significance level of 0.01. For a 1.2-unit difference in intervention 
effects, the study will have > 85% power for subgroup prevalence of 25% or more. 
Within a subgroup, the study will have > 80% power to detect an intervention effect of 1 
unit or more for subgroup prevalence of > 25% and a 0.01 significance level. These 
power calculations for comparisons of 12-month outcomes consider just the data for this 
assessment point as a worst-case scenario. The repeated measures analyses discussed 
below should have power greater than discussed here for comparing the 12-month 
outcomes. Based on preliminary data, we anticipate the proposed sample size will 
provide adequate power for planned assessments of the HTE for all planned subgroups; if 
prevalence of any subgroup is <25%, assessment of HTE across subgroups will be 
exploratory.       
7.2 General Analytic Approach 
We will use an intent-to-treat approach, including all patient participants in the arm to which 
they were originally assigned. Preliminary descriptive analyses will summarize the 
distributions of the relevant baseline measures for each arm together with outcome 
distributions across the assessment points. We will summarize completeness of the outcome 
assessments and examine associations between completeness and the baseline measures as 
well as pain measurements, receipt of pain medicines outside the VA, and VA service 
utilization over the follow-up period. In previous and ongoing studies using similar eligibility 
criteria and follow-up structure, we have observed outcome completion rates in excess of 
95% at each assessment time-point and > 98% of participants have provided outcomes at one 
or more follow-up time-points. Initial analysis will use all available follow-up data and 
subsequent sensitivity analyses will examine the potential effect of response bias. 
7.3 Statistical Analysis of Primary Aim 
We will use all follow-up data in a repeated-measures logistic regression modeling 30% 
reduction from baseline in BPI scores at the quarterly follow-up assessments. The regression 
model will use assigned intervention, assessment point, and their interaction as explanatory 
measures. Assessment points will be incorporated as random effects, with non-zero means 
and an unstructured covariance, to model potential correlation among outcomes for 
individuals. Our primary assessment of intervention effects will examine differences in the 
log odds of attaining a 30% reduction in BPI at the 12-month assessment using a two-sided 
Wald test (0.05 significance level), together with the corresponding model-based odds ratio 
point and confidence interval estimates.  
To assess the sensitivity of these initial analyses to response bias, we will fit a series of 
weighted selection model analyses. Each analysis will use an EM algorithm to estimate 
weights to assign to potential values of the missing outcomes for use in logistic regression. 
The regression will model the log odds of a reduction in BPI at 12 months using the assigned 
intervention and relevant baseline measures as predictors. The EM algorithm will jointly use 
a logistic model for observation of the 12-month outcome to iteratively update the weight 
estimates. These latter logistic models will be varied to use different combinations of the 
following variables—12-month outcome, intervention, observation and value of the outcome 
at prior assessments, and baseline covariates together with pain measurements and services 
utilization over the follow-up period—as predictors to consider different potential missing at 


CIRB Protocol #17-11 date   02/01/2022   41 
 
random and missing not at random mechanisms generating the missing data. The approach 
outlined above will also be used to examine differences in reduction in opioid use at 12 
months, the combination of pain reduction and opioid use reduction, and the BPI severity and 
interference subscales. 
7.4 Pre-Specified Subgroup Analyses 
We will examine variation in the intervention effects on the change in BPI within clinical 
subgroups defined by presence or absence at baseline of the subgroup status/conditions 
described above. For each subgroup measure, we will fit a repeated-measures linear 
regression modelling change from baseline in BPI at the quarterly follow-up assessments 
using assigned intervention, assessment point, subgroup indicator and all interactions 
between these three measures together with baseline BPI score and its interaction with 
assessment point as explanatory measures. Assessment points will be incorporated as random 
effects, with an unstructured covariance, to model potential correlation among outcomes for 
individuals. Our primary assessment of an interaction between intervention and the subgroup 
measure will use the model-based two-sided Wald test for an interaction at the 12-month 
assessment, using a 0.005 significance level. Weighted selection model analyses similar to 
those described above will examine sensitivity of 12-month results to response biases. 
7.5 Secondary Analyses and Analysis of Secondary Outcomes 
If the proportion of patients in the standard options arm achieving the 50% dose reduction 
outcome falls in the range 20%-70%, the anticipated sample size will provide 80% power to 
detect between-group differences in the range of 14 and 17%. The study will have this same 
level of power for comparable differences in the proportions achieving a 25% dose reduction 
and proportions with any dose reduction. We will have 80% power for assessing small to 
moderate differences of 0.35 SD in mean dose change.   
The secondary dose escalation outcome is defined as a proportional increase in daily dose of 
≥ 25% from baseline to 12 months. If 5-15% of participants meet this dose escalation 
outcome, we will have 80% power to detect between-group differences of 7-8%. 
In addition, we will assess between-group differences in the pain-related function, pain 
intensity, quality of life, fatigue and sleep, mental health measures, and physical symptoms 
over the follow-up period. We will fit separate repeated-measures linear regressions 
modelling change from baseline at the follow-up assessments using assigned intervention, 
assessment point and their interaction together with the respective baseline score and its 
interaction with assessment point as explanatory measures. Assessment points will be 
incorporated as random effects, with an unstructured covariance, to model potential 
correlation among outcomes for individuals. The primary assessment of an intervention 
effect on a particular outcome will use the model based 2-sided Wald test for a difference at 
the 12-month assessment together with the point and confidence interval estimates for the 
mean difference in change from baseline.  
We will examine variation in effects by sex, study site and over the course of enrollment, as 
well as moderation of effects by relevant covariates. Analyses will be similar to the subgroup 
analyses described above.  
7.6 Analysis of Tapering Strategies 
Among the subset of participants on high-dose opioid therapy at baseline we will modify the 
analyses discussed above by adding the tapering assignment as an explanatory measure to the 


CIRB Protocol #17-11 date   02/01/2022   42 
 
model structure in the same manner as the TCM/IPT measure is included in the models. We 
will use comparable testing and estimation approaches to assess whether the expanded 
tapering option results in better outcomes in this subpopulation.  
7.7 Analysis of Adverse Events 
Information about hospitalizations, ED visits, SUD admissions, and other adverse events will 
be extracted from VA administrative data. We will compare intervention arms with respect to 
the 1) proportion of individuals reporting any hospitalization, ED visit, and SUD admission 
and 2) number of hospitalization, ED visit, or SUD admissions per person at a) each 
assessment time-point and b) overall using, respectively, Pearson chi-square tests and, given 
the reasonable large sample in each arm, large sample normal approximation based z-tests. 
Similar comparisons will be made between other adverse events. We will also break these 
comparisons out by baseline dosage and assignment to the expanded taper options arm.  
8. PROJECT MANAGEMENT 
8.1 Project Management Overview 
The overall study structure includes a central study coordinating center located at the 
Minneapolis VA and ten VA sites where patients will be enrolled and receive the 
interventions. The coordinating center will manage core research activities including 
centralized recruitment and outcome assessment; engagement activities; data management, 
programming, and statistical analysis; data and safety monitoring; and regulatory 
compliance. Local sites will enroll patients and implement the interventions. Local site study 
personnel include local site investigators and at least one local site study coordinator. Local 
study coordinator absences or vacancies may be covered by other local approved study staff 
or coordinating center staff if needed. Intervention clinicians are VA employee volunteers 
who are being trained and evaluated; those who are not co-investigators will be considered 
research participants themselves.  
8.2 Study Application 
The coordinating center data team will create a customized web-based front end application 
to support research tasks. The “front end” is a secure web page on the VA intranet, but the 
actual data “back end” is stored on a secure VA server maintained and regularly backed up 
by Region 2 of VA Office of Information Technology. Only approved specific study 
personnel are granted access to this application.  
A user manual will be created as a guide for all study personnel. Contact information for 
patients selected for participation will be stored in the database. Additional tables will be 
created for scheduling and tracking study contacts. Coordinating center data team personnel 
will control access to the study application and provide access to research personnel at the 
coordinating center and local sites according to their research scope of practice. Study 
personnel will use the application to complete tasks including preparing recruitment 
mailings, conducting standardized eligibility screening, scheduling participant contacts, 
randomizing participants, and recording completed outcome assessments and adverse events. 
8.3 Local Site Facilitation  
During the start-up phase at each site, the study leadership team will support establishment of 
intervention clinical teams using an implementation facilitation approach. This will include 
the following activities:  


CIRB Protocol #17-11 date   02/01/2022   43 
 
• Assignment of each local site to a designated facilitator (Drs. Krebs, Seal, and Becker) 
for ongoing interactive problem-solving and support 
• Development of detailed local site implementation plans 
• Conduct of pre-implementation local site visits to accomplish the following objectives: 
o 
Describe rationale for the study and evidence for the interventions through 
research presentations and local stakeholder briefings 
o 
Develop relationships with local stakeholders and clinicians 
o 
Identify local site implementation challenges and opportunities 
o 
Refine local site implementation plans, including timetable 
• Establishment of cross-site collaborative groups to support local site clinical champions 
and clinician intervention teams 
8.4 Local Site Rollout 
Enrollment at individual local sites will be initiated on a rolling basis once sites have met all 
criteria for enrollment launch. We plan to initiate enrollment at 1-3 sites per month over 3-5 
months, with the order of launch depending on local site readiness.  
The PM will coordinate training for study coordinators and research assistants at all sites. 
The Minneapolis coordinating center team will use audio-visual resources to conduct “mock” 
consent sessions and share them with sites as a training tool. Ongoing training will be 
provided throughout the study as new personnel come onboard or if questions or issues arise 
at local sites. 
Prior to beginning enrollment at each site, the PI and overall study project manager (PM) will 
meet with the local site PIs and coordinators to ensure they fully understand informed 
consent, randomization, and data management procedures. A local site start-up checklist of 
required approvals and trainings will also be completed. Prior to initiating enrollment at any 
local site, all of the following criteria must be met:  
• Approvals obtained from the VA Central IRB (i.e., the Local Site Investigator 
application), the Research & Development committee of record, and any additional 
regulatory bodies as required at the local site (e.g., University IRB) 
• Site study coordinator and investigator(s) trained in study research protocols, 
including informed consent, randomization, adverse events reporting and other 
data/safety monitoring procedures 
• Intervention clinician teams established and trained in clinical background, 
intervention protocols, documentation templates, educational materials, study 
resources, and local site protocols for clinical coverage 
8.5 Cross-Site Communication 
Current protocol, informed consent, and study intervention documents will be maintained on 
the study SharePoint site. All amendments and modifications to the protocol, the informed 
consent form, and the HIPAA authorization will be promptly communicated to local sites by 
email. Regular cross-site study meetings will include discussion of any anticipated or recent 
changes to the study protocol and procedures.  


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8.6 Local Site Contingency Plans 
In case of significant delays in meeting enrollment launch criteria, despite facilitation efforts, 
site discontinuation and replacement will be considered. Consideration of site discontinuation 
or replacement will be discussed with engagement partners and PCORI staff prior to making 
a decision. If a decision is made to change a site, prior approval will be requested from 
PCORI as outlined in the contract for the funded research project.  
 
9. IMPLEMENTATION PROCESS EVALUATION  
9. 1 Process Evaluation Overview  
Goals of the implementation process evaluation are threefold: 1) to increase the relevance of 
the primary research findings to patients, clinicians, and health care decision-makers; 2) to 
increase the likelihood of timely translation of research findings into diverse practice 
settings; and 3) to generate information to guide interpretation of primary trial findings. In 
addition to scientific reports and manuscripts, products of this process evaluation will include 
an implementation toolkit (developed in collaboration with study partners) to support 
implementation of successful study interventions in diverse practice settings. 
 9.2 Process Evaluation Questions 
The RE-AIM and PARIHS frameworks related to dissemination/implementation were used 
to facilitate identification of questions related to the context of study sites and the process of 
implementing the interventions. Implementation process evaluation questions include the following: 
• What was the level of organizational readiness relative to the clinical interventions, 
including staff’s related perceptions/attitudes? 
•  What barriers or facilitators to the successful implementation of the study protocol were 
found (e.g., to what extent were clinic staff and leadership perceived as visibly supportive)? 
• How were the interventions received by patients (e.g., how many of the selected patients 
actually participated in the interventions and were they different from those who did not)?  
• How were the interventions received by patients who did participate actively (e.g., in 
terms of completion vs. drop-out rates and perceptions of usefulness to their treatment)? 
• Were the study interventions provided with high fidelity?  
• What, if any, recommendations do patients or clinicians have for changes to the 
interventions that they feel would improve the “fit” or effectiveness of the interventions? 
• To what extent did facilities plan to sustain the interventions following completion of the 
study? If they planned to sustain an intervention, what barriers did they anticipate? How did 
they plan to modify the intervention from the original study protocol to address those 
barriers? If they did not plan to sustain an intervention, what considerations or barriers led to 
that decision?  
9.3 Process Evaluation Methods  
Qualitative or basic quantitative data will be collected as appropriate to each question. 
Approaches include the following: 


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• Evaluation team observations: Each study site will have an assigned member of the 
implementation evaluation team to take observational notes of interactions as described in 
Section 6.4.2.  
• Information on patient recruitment and completion rates: Recruitment rates will provide 
an estimate of how appealing the interventions are to the targeted patients. Patients who 
decline study participation in the intervention will be asked their reason for declining. 
Intervention completion vs. drop-out rate will also provide information on acceptability of 
the interventions. Demographic and clinical data will be examined for the purpose of 
comparisons of decliners to enrollees and intervention completers to drop outs. 
• Fidelity monitoring: In the event of negative findings (no intervention effect) for an 
intervention arm, it is essential to rule out implementation failure as a cause. Fidelity will be 
assessed as described in Section 5.8. 
• Patient semi-structured interviews: A subset of participants enrolled in each study 
intervention will be interviewed at the end of their intervention participation as described in 
Section 6.4.1.  
• Semi-structured interviews with clinician participants and other VA employees: A sample 
of clinicians directly involved in the interventions and other VA clinical and administrative 
staff at enrolling sites will be interviewed at the end of the intervention period as described in 
Section 6.4.1.  
9.4 Qualitative Analysis 
Qualitative data from the evaluation team observational notes and the transcribed semi-
structured interviews will be analyzed by intervention evaluation team members, who are all 
experienced with qualitative data coding and analysis. They will review the transcripts and 
develop an initial coding list. They will each code an initial set of documents using the initial 
coding list, adding codes as new insights emerge. Consensus coding meetings will be held for 
review of consistency in coding. Inconsistencies will be resolved through mutual discussion. 
When evaluation team members have reached consistency in coding, remaining documents 
will be coded by one team member with 20% cross-coded by a second team member. 
Transcripts and codes will be entered into a software package designed to handle 
unstructured qualitative data (NVivo) to facilitate identification of themes and supporting 
quotations. Inductively derived themes will be compared with the elements identified by the 
PARIHS successful implementation model and RE-AIM dissemination model to further 
facilitate analysis and interpretation. All process data will then be triangulated, where 
appropriate, and used to answer the targeted questions and facilitate interpretation of 
summative findings. 
10. DATA & SAFETY MONITORING PLAN 
10.1 Overview of Data and Safety Monitoring Procedures 
The proposed study confers a low level of risk, similar to routine health care. All participants 
will be followed with regular clinical intervention visits that will include monitoring of 
treatment response, adherence, and side effects.  
At each site, intervention clinician teams will meet weekly to review participant progress, 
including pain and medication management, adherence, and adverse events. The study site 


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coordinator/research assistant (or in their absence, coordinating center staff or local site 
PI/co-investigator) will attend these meetings when possible to ensure adverse events and 
research-related problems and issues are appropriately identified and reported. Local site 
investigators and coordinators will meet regularly with the study leadership committee and 
coordinating center personnel. Local site study personnel will be expected to notify the study 
PI, PM, or other designated coordinating center personnel of serious adverse events, 
noncompliance, or other study related problems as soon as they are identified.   
Coordinating center personnel will ensure appropriate reporting of adverse events (AEs) and 
other problems to the IRB, DSMB, funder, and local sites. The study application will be used 
for tracking AEs and generating standard reports.  
10.2 Data and Safety Monitoring Board (DSMB) 
A DSMB will review and evaluate study data related to participant safety, data integrity, and 
study conduct during the active enrollment and intervention phases of the trial. The DSMB 
will be convened and the first meeting will be held within 60 days after enrollment of the 
first trial participant. A DSMB charter will be finalized and approved at the first meeting. 
Members will be four clinical investigators and experts and will include at least one 
physician investigator, at least one pharmacist, and at least one biostatistician. One DSMB 
member will serve as DSMB Chair. Subsequent meetings will be held approximately every 6 
months during the active intervention phase of the trial.  
The DSMB will review aggregate and individual participant data related to safety, data 
integrity, and overall conduct of the trial and will provide recommendations to continue, 
modify, or terminate the trial. Termination or modification may be recommended on the 
basis of serious safety concerns, non-compliance with human safety regulations, or serious 
protocol violations. The DSMB will not review interim analyses of effectiveness. 
10.3 Frequency of Data and Safety Monitoring 
Coordinating center personnel will compile a data and safety monitoring report every six 
months during the active enrollment and intervention phases of the study. Reports will be 
submitted to the DSMB two weeks prior to each meeting. Reports will include the following:  
• Description of serious adverse events, research-related problems, and protocol 
violations, including outcomes and follow-up 
• Summary report of all adverse events 
• Summary of recruitment outcomes, including rates of contact, refusal, and enrollment 
• Summary of study progress toward milestones, including enrollment and outcome 
assessment targets 
• Withdrawal rates, reasons for withdrawals 
• Fidelity to interventions overall and across sites 
• Study publications and reports 
10.4 Known Risks and Potential Harms 
Risks of interventions are similar to those in usual care. Medications and non-
pharmacological therapies will be selected based on individual needs in both arms and are 


CIRB Protocol #17-11 date   02/01/2022   47 
 
not experimental in nature. Only the buprenorphine rotation protocol (described in 5.6) is 
considered an experimental treatment. 
10.4.1 Known risks of study interventions 
Participants may experience adverse effects of pain medications prescribed in the course 
of the study. Medications are FDA-approved and have known adverse effects; benefits 
and risks of medication changes will be discussed with patients as in usual practice.  
Patients may experience withdrawal symptoms and other temporary discomfort due to 
reducing opioid doses or switching from one opioid medication to another. Intervention 
clinicians will educate participants about withdrawal symptoms, take precautions to 
prevent withdrawal, and manage symptoms if they occur.   
Participants may experience adverse effects of non-pharmacological pain management 
therapies recommended in the course of the study. Non-pharmacological therapies (e.g., 
yoga, home exercise programs, psychotherapy) have known adverse effects, most of 
which are mild and transient. Benefits and risks of recommended therapies will be 
discussed with patients as in usual practice. 
10.4.2. Known risks and potential harms associated with the underlying condition or study 
population 
All participants will have chronic pain and be on long-term moderate-to-high dose opioid 
therapy at baseline. Long-term opioid therapy is associated with physiologic adaptations, 
including tolerance, dependence, and a withdrawal syndrome. Opioids have serious 
known risks, including respiratory failure, opioid use disorder, and death. Higher doses of 
opioids are associated with greater risks of depressive disorder, opioid use disorder, 
respiratory failure, suicide, and overdose death. 
Chronic pain typically has a fluctuating course characterized by intermittent episodes of 
symptom exacerbation and improvement. 
The study population is also expected to have a substantial pre-existing burden of 
physical and mental health comorbidity.  
10.4.3 Known risks in pregnancy and lactation 
Because the study is comparing care delivery strategies and no specific medication or 
treatment is required in any arm, pregnant women will not be excluded. Medications used 
in this study have variable safety profiles in pregnancy and lactation. Opioid withdrawal 
during pregnancy may increase risk of miscarriage and preterm labor.  
 
For women under age 50, potential for pregnancy will be discussed prior to initiating 
medications or opioid tapers. If women are pregnant, lactating, or could possibly be 
pregnant, contraindicated medications will not be prescribed. Opioid tapering in women 
who are pregnant or suspected to be pregnant will be done in consultation with 
appropriate women’s health providers, such as the patient’s obstetrician. If indicated, 
intervention clinicians will facilitate pregnancy testing or initiation of effective 
contraceptive methods. Women who are pregnant or for whom pregnancy cannot be 
reasonably excluded will not be prescribed buprenorphine-naloxone. 


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10.5 Definitions of Potentially Reportable Events and Problems 
• An adverse event (AE) is any untoward physical or psychological occurrence in a human 
subject participating in research. An adverse event does not necessarily have to have a 
causal relationship with the research, or any risk associated with the research or the 
research intervention or research assessment. 
• A serious adverse event (SAE) is an AE that results in death, a life-threatening 
experience, inpatient hospitalization, prolongation of hospitalization, persistent or 
significant disability or incapacity, congenital anomaly, or birth defect, or for which 
medical, surgical, behavioral, social, or other intervention is needed to prevent such an 
outcome. 
• A serious problem is a problem in human research or research information security that 
may reasonably be regarded as a) presenting a genuine risk of substantive harm, to the 
safety, rights, or welfare of human research subjects, research personnel, or others, 
including their rights to privacy and confidentiality of identifiable private information; or 
b) substantively compromising a facility’s human research protection or research 
information security programs. Examples of such problems include the following:  
o Situations that require action to prevent immediate hazard to subjects or others 
o Problems described in a VA Pharmacy Benefits Management alert relevant to 
human subjects 
o Inappropriate access, loss, or theft of documents or equipment containing PHI  
o Unauthorized destruction of research records 
o Use or connection of unauthorized equipment (e.g., non-VA thumb drive, 
unauthorized personally owned equipment) to store, process, or transmit VA 
research-related PHI 
• An unanticipated or unexpected event or problem is an occurrence that is new or greater 
than previously known in terms of nature, severity, or frequency, given the procedures 
described in the protocol-related documents and the characteristics of the study 
population. 
• Related events or problems are occurrences that may reasonably be regarded as caused 
by, or probably caused by, the research. 
• An unanticipated problem involving risks to participants or others is an occurrence that 
meets all the following criteria: 1) unexpected (as defined above); 2) related to 
participation in the research (as defined above); and 3) suggests the research places 
participants or others at a greater risk of harm (including physical, psychological, 
economic, social, or legal harm) than previously known or recognized. 
• Serious noncompliance is a failure to adhere to requirements for conducting human 
research that may reasonably be regarded as a) presenting a risk of substantive harm to 
the safety, rights, or welfare of human research subjects, research personnel, or others; 
including their rights to privacy and confidentiality of identifiable private information; or 
b) substantively compromising a facility’s human research protection or human research 
oversight programs 


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• A protocol deviation or violation is an act of noncompliance with the VA Central IRB-
approved protocol or other requirements for conducting human research.  
10.5.1 Assessment of adverse events 
AEs will be systematically evaluated by study personnel at each site, with oversight by 
the coordinating center. In addition, medication-related symptoms and side effects will be 
extracted from templated intervention visit notes.  
10.5.1.1 Hospitalizations or deaths  
Local site PIs and site coordinators will monitor for hospitalizations and deaths using two 
main methods. First, site coordinators will enter enrolled patients in a personal CPRS 
patient list. Use of these lists generates automated notifications of VA hospital 
admissions, discharges, and deaths. Second, site coordinators/research assistants (or in 
their absence, coordinating center staff or local site PI/co-investigator) will attend weekly 
case review meetings and query clinicians at each meeting about any hospitalizations, 
deaths, or clinically-important AEs they learned about in the course of their clinical visits 
with participants.  
Clinicians will also be asked to notify their site coordinator or site investigator via 
telephone or encrypted email if they learn of a patient’s death (same business day), 
hospitalization, or other clinically-important AEs. If the coordinating center is notified by 
patient or family member of a hospitalization or death, coordinating center personnel will 
notify the applicable local site coordinator (via encrypted email) within one business day.   
Local site coordinators/research assistants (or in their absence, coordinating center staff) 
will obtain medical records as needed for investigators to determine the nature and 
severity of adverse events, as described in section 10.6. If a hospitalization occurs at a 
non-VA facility, study personnel will obtain non-VA records from CPRS or, if needed, 
contact the community-based hospital to request records associated with the event. 
Participants will be asked to sign a release of information form if records are needed from 
a non-VA facility.  
10.5.1.2 Assessment of treatment-related symptoms 
Participants will be asked about medication related symptoms at each research 
assessment interview (3, 6, 9, and 12 months).  
A checklist addressing common medication-related AE is incorporated into intervention 
follow-up note templates, along with an open field for reporting additional AE. 
Symptoms recorded in note templates will be retrievable for summary reporting.   
10.5.2 AE/SAE tracking 
Site coordinators/research assistants (or in their absence, coordinating center staff 
assisting site PI) will be responsible for entering AE information into a site-specific AE 
report tool on the study’s secure sharepoint site. Each site’s AE report tool is visible only 
to the local site PI and coordinator/research assistant, study leadership, and authorized 
coordinating center personnel. AEs will be updated in real time and coordinating center 
personnel may pull reports for all sites as needed. 


CIRB Protocol #17-11 date   02/01/2022   50 
 
10.6 Reporting of AEs and Research-Related Problems 
10.6.1 Unanticipated and related deaths 
Intervention clinicians and local site coordinators will notify the local site PI on the same 
business day (via encrypted email or phone) if they learn of a patient’s death by any 
cause.  Local site PIs will make the determination if a death is related to the research or is 
unanticipated. Local site PIs who are not physicians will consult with Dr. Krebs, Becker, 
or Seal for this determination for all participant deaths. In addition, any local site PI who 
is unsure whether a death is related to the research or unanticipated, will consult with Dr. 
Krebs, Becker, or Seal.  
Deaths that are unanticipated and related to the research will be reported by local site 
study personnel immediately to the Central IRB (by calling 877-354-3130). Written 
notification to the VA Central IRB must follow within 5 business days of becoming 
aware of the death. Additionally, the local site PI or local site coordinator will notify the 
coordinating center (via encrypted email or telephone) if they learn of any patient’s death, 
regardless of relationship to the research, and will add to their site’s AE reporting tool. 
These events must also be reported to PCORI within 10 days after reporting to the IRB. 
10.6.2 Unanticipated and related SAE 
Local site principal investigators and study coordinators will meet at least weekly. Local 
site PIs will determine whether events are related to the research or unanticipated. SAE 
that are unanticipated and related to the research will be reported in writing by local site 
study personnel to the VA Central IRB within 5 business days of becoming aware of the 
event. If a local site PI is unsure whether an event is related to the research or 
unanticipated, he/she will consult with Dr. Krebs, Seal, or Becker.   
These events must also be reported to PCORI within 10 days after reporting to the IRB. 
10.6.3 Serious and related unanticipated problems involving risks to participants or others  
Serious and related unanticipated problems will be entered into the site-specific adverse 
event report tool on the study’s secure sharepoint site. Each site’s report tool is visible 
only to the local site PI and site coordinator, study leadership, and authorized 
coordinating center personnel. Serious problems will be updated in real time, and 
coordinating center personnel may pull reports for all sites as needed. 
Serious problems that are both unanticipated and related to research will be reported in 
writing to the VA Central IRB within 5 business days of becoming aware of the event. If 
a local site PI is unsure whether an event is related to the research or unanticipated, 
he/she will consult with Dr. Krebs, Seal, or Becker.   
These events must also be reported to PCORI within 10 days after reporting to the IRB. 
10.6.4 Noncompliance and protocol deviations 
Noncompliance and protocol deviations the site-specific adverse event report tool on the 
study’s secure sharepoint site. Each site’s report tool is visible only to the local site PI 
and site coordinator, study leadership, and authorized coordinating center personnel. 
Deviations will be updated in real time, and coordinating center personnel may pull 
reports for all  sites as needed. 


CIRB Protocol #17-11 date   02/01/2022   51 
 
Apparent serious or continuing noncompliance will be reported in to the VA Central IRB 
within 5 business days of becoming aware of the event. Protocol deviations or other 
noncompliance that are likely to substantially adversely affect the rights, safety, or 
welfare of research participants; participants’ willingness to continue participation; or 
integrity of research data will be reported in writing to the VA Central IRB within 5 
business days of becoming aware of the event. If a local site PI is unsure whether an 
event is related to the research or unanticipated, he/she will consult with Dr. Krebs, Seal, 
or Becker.   
These events must also be reported to PCORI within 10 days after reporting to the IRB. 
10.6.5 Improper use or disclosure of research data 
Improper research data use or disclosure will be reported to local VA Information 
Security Officer (ISO) and Privacy Officers within one hour, regardless of whether the 
occurrence meets criteria for prompt IRB reporting.                         
10.6.6 Communication of prompt reports to local sites 
SAEs, serious problems, and protocol deviations that have the potential to affect 
implementation of the study at multiple sites will be communicated to all engaged 
participating sites using encrypted email or telephone calls to local site PIs and 
coordinators. Acknowledgement of receipt will be requested from local sites.  
10.6.7 Study termination or suspension 
This study has no pre-specified endpoints that would trigger immediate suspension of 
research. If termination or suspension is triggered by unexpected events (e.g., SAE, 
serious noncompliance, major information security violations, loss of funding), the PI 
will email notification to local site facility directors and to local site approving bodies 
(including local site IRB and R&D committees), along with Central IRB and PCORI, 
within 5 business days. Additionally, the PI will provide local sites with detailed 
information about procedures to ensure continuation of appropriate clinical care for 
research participants.  
10.7 Data Management 
10.7.1 Data Quality 
To maximize the reliability of outcome assessment and reduce the prevalence of missing 
data, a dedicated team of masked coordinating center personnel will conduct all follow-
up outcome assessments by telephone. Participant responses will be recorded on 
machine-readable paper questionnaire forms created using Teleform software. 
Questionnaires containing machine-readable patient-reported data will be scanned by 
research assessment personnel. Experienced data team members will train the outcome 
assessors and supervise the data scanning and verification process. Each completed form 
will be reviewed for completeness and stray marks before scanning. To ensure accuracy, 
each questionnaire form will be scanned twice, with verification performed by two 
people per document. Discrepancies will be resolved by comparing the different values 
against the survey document. Accuracy of completed datasets will be additionally 
verified by comparing values in the dataset to those on the original forms for randomly 
selected study identification numbers, representing 5% of all participants. Once accuracy 
is verified, SAS software will be used to generate databases. Consistency checks will be 
performed to check for out of range values and quantify the amount of missing data. 


CIRB Protocol #17-11 date   02/01/2022   52 
 
10.7.2 Privacy and Confidentiality 
All study procedures, including the consent process and face-to-face intervention visits, 
will occur in private areas at each participating VA facility. Telephone assessment 
interviews will be conducted by study personnel in research offices at the Minneapolis 
VA to ensure auditory privacy. 
To ensure confidentiality of data collected, we will assign patients unique study 
identifiers for tracking study data. Patient names, social security numbers, addresses, and 
other personal identifiers will be restricted to authorized personnel for limited necessary 
uses. The link between study identifiers and personal identifiers will also be protected 
and limited to authorized personnel. Only the study identification number will be used for 
data analysis and other uses of study data, such as reports to IRB.  
Study data will be reported only in aggregate in any reports or publications; no names or 
identifiable details of study participants will be used in any reports or publications 
resulting from this study.   
 
10.7.3 Information security 
All study personnel are trained on the protection of research data; only study authorized 
personnel will have access to records. Study personnel will be allowed research database 
and study application access only as needed to accomplish authorized study duties within 
their scope of practice. Authorized study personnel will be oriented to appropriate use of 
the study research application and database. Research data access will be removed 
promptly when authorized personnel leave the study.  
All electronic data will remain on secure VA servers, in secure electronic folders 
throughout the study. Study files are kept on secure servers within folders that are only 
accessible by IRB-approved personnel. Study files that contain any identifiable 
information are further secured to a smaller group of IRB-approved personnel who may 
see PHI.  These listings are regularly reviewed by the project manager. 
Cross-site communication involving PHI will be accomplished by using encrypted VA 
email or secure shared electronic folders whenever possible. Communication of PHI by 
fax will be used only when more preferred methods are infeasible.  
Local ISO and Privacy officers will be notified within one hour of improper research data 
use or disclosure, and will be consulted throughout the study if any issues or questions 
arise.   
Payments to patient participants will be in the form of a pre-paid debit card, issued via 
the University of Minnesota (UMN) Controller’s Office. The UMN pre-paid debit card 
program requires subjects’ first and last name, mailing address, and date of birth. This 
information is uploaded to the UMN vendor via a secure website (reviewed by VA ISOs).    
Paper files will be kept in locked cabinets within secured areas.   
10.8 Regulatory and Administrative Compliance 
10.8.1 Institutional Review Board (IRB) approvals 
The protocol and associated documents will be reviewed and approved by the VA Central 
IRB (CIRB) before trial recruitment begins. Prior to enrollment of patients at each local 


CIRB Protocol #17-11 date   02/01/2022   53 
 
site, approvals must be obtained from the CIRB (i.e., the Local Site Investigator 
application), the facility’s Research & Development committee of record, and any 
additional regulatory bodies as required at the local site (e.g., University IRB).  
All amendments to the project or changes in the informed consent will be submitted to 
the VA Central IRB for review and approval prior to implementation, except if necessary 
to avoid immediate hazard to participants. Any changes implemented as a result of an 
immediate hazard will be promptly reported to the VA Central IRB as a project deviation 
and an amendment submitted if determined necessary. All required local facility 
approvals will be obtained before amendments or modifications are implemented. 
10.8.2 ClinicalTrials.gov registration 
The study ClinicalTrials.gov identifier is NCT03026790. The PI is the responsible party 
for registering and updating the study record in the Protocol Registration and Results 
System (PRS). The record will be updated as follows:  
• Within 30 days of a change to recruitment status data elements 
• Within 30 days of a change to completion date  
• At least every 6 months, even if no changes  
10.8.3 Reporting to PCORI 
PCORI is the study funder and not a “sponsor.” Study documents will refer to PCORI as 
a funder, not a sponsor, of the research.  
10.8.3.1 Report submission 
The following reports will be submitted to PCORI, as outlined in the research funding 
contract: 
• Interim progress reports (every 6 months)  
• Draft final research report  
• Final research report 
• Final progress report  
10.8.3.2 Data and safety monitoring 
Approved minutes for each DSMB meeting will be submitted in interim progress 
reports, along with a summary of any significant data & safety monitoring issues that 
occurred in the reporting period.   
Serious unanticipated problems (e.g., serious adverse event, serious safety issue, or 
other serious problem) related to the research study will be reported to PCORI no 
later than 10 days after the problem is reported to the IRB.  
Any decision, finding, recommendation, action or direction of the IRB, DSMB, or 
other regulatory or oversight body relating to any serious unanticipated problem will 
be reported to PCORI within 10 days. 
10.8.3.3 Required notifications 
PCORI will be notified within 30 days of the following occurrences: 
• Absence of PI for > 3 continuous months 


CIRB Protocol #17-11 date   02/01/2022   54 
 
• Absence of Key Personnel for > 3 continuous months or change in overall effort ≥ 
25% of approved effort 
• Conflicts of interest that emerge during the contract term 
10.8.3.4 Changes requiring PCORI approval 
If any of the following changes are planned, a request will be submitted to PCORI 
prior to implementation:  
• Significant change in the scope, specific aims, protocol, or milestones 
• Significant change in approach, methodology, or number of participants 
• Transfer of PI 
• Significant new contracting or transferring project effort 
• Naming new key personnel or PI 
• Decrease in the annual percentage effort of a PI that exceeds a variance of 25% of 
the approved effort 
• Budget adjustments in salaries of Personnel or for Travel that exceed 25% of the 
total amount approved for the budget category 
• Deviation from PCORI Methodology Standards 
10.8.4 Research records retention 
All records will be retained in accordance with the VHA Records Control Schedule 10-1 
(May 2016) and will be destroyed in accordance with VHA regulations (under guidance 
of local Information Security Officer and Privacy Officers).   
10.8.5 Completion of local site engagement 
When study activities requiring local site participant interaction are complete, local site 
PIs, coordinators, and facility directors will be notified by email that the study no longer 
requires engagement of the local facility. A closeout meeting and checklist will be 
completed with local site PIs and coordinators at the time of closeout at each site.  
11. DISSEMINATION AND DATA SHARING 
11.1 Submission of Primary Study Results 
The PI will submit reports of primary analysis results to PCORI and to ClinicalTrials.gov, as 
outlined in the research funding contract. 
11.2 Peer-Reviewed Publications 
A study publication committee will coordinate planning, preparation, submission, and 
tracking of publications and will provide internal guidance on authorship. Electronic copies 
of accepted peer-reviewed manuscripts will be made publicly available on PubMed Central, 
consistent with the PCORI policy on Public Access to Journal Articles Presenting Findings 
from PCORI-Funded Research. 
PCORI will be notified prior to the publication/presentation date and within 30 days of 
acceptance of all presentations and peer-reviewed publications related to this research. 
VA will be notified at the time of acceptance of all scientific publications or presentations, in 
accordance with VHA Handbook 1200.19. 


CIRB Protocol #17-11 date   02/01/2022   55 
 
11.3 Results Reporting to Study Participants 
Study results will be reported directly to research participants by mailing a lay summary of 
results. This will be reviewed and approved by the study’s Veteran Engagement Panel prior 
to mailing. 
11.4 Dissemination of Additional Research Products 
Informational materials, intervention manuals, and other research products will be provided 
to PCORI as outlined in the research funding contract. The study team will strive to 
disseminate these products as widely as possible. 
11.5 Data Sharing Plan 
A complete, cleaned, de-identified copy of the final data set used in conducting the analyses 
will be made available within one year after the completion of the study, in accordance with 
ORD Data Management and Access Plan (DMAP) requirements of January 1, 2016. This 
relatively new requirement includes different ways to share research data; we plan to make 
available either a de-identified, anonymized dataset or a limited dataset that can be shared 
pursuant to a data use agreement appropriately limiting use of the dataset and prohibiting the 
recipient from identifying or re-identifying any individual whose data are included in the 
dataset.  
12. STUDY GOVERNANCE  
12.1 Leadership Committee 
Erin Krebs, Karen Seal, and William Becker constitute the leadership committee and will 
collaborate closely to ensure the ethical, timely, and scientifically rigorous conduct of the 
entire multi-site project.  
Primary and shared responsibilities are as follow:  
• Scientific direction and research protocol: Oversight and decision-making will be 
shared by all members of the leadership committee.  
• Administrative, regulatory, and technical matters: This includes human subjects and 
research regulatory compliance matters, coordinating center activities, and data 
management and statistical services. Oversight is the primary responsibility of Dr. 
Krebs, who will be responsible for day-to-day decision-making. Decisions about 
substantial changes or issues, such as those that may potentially affect scientific 
direction, protocol adherence, or ability to meet study milestones, will be made by 
the full leadership committee.  
• Budget: Dr. Krebs is primarily responsible for ensuring appropriate allocation of 
funds. Decisions about substantial changes or issues, such as those that may 
potentially affect scientific direction, protocol adherence, or ability to meet study 
milestones, will be made by the full leadership committee. 
Decisions of the leadership committee will be made by consensus. Disagreements will be 
resolved through discussion, including co-investigators and study personnel if appropriate. 
The PCORI program officer will be consulted in the case of any major disagreement related 
to the scientific direction, protocol adherence, or ability to meet study milestones. 


CIRB Protocol #17-11 date   02/01/2022   56 
 
12.2 Other Committees  
12.2.1 Engagement 
• Responsibilities: Recruiting, selecting, and interviewing patient engagement panel 
members. Identifying best practices for study initiating and sustaining stakeholder 
engagement and engagement evaluation. Other activities related to engagement. 
• Membership: Joseph Frank, Benjamin Morasco, Agnes Jensen, Erin Krebs 
• Reporting: Reports to leadership committee through Dr. Krebs 
12.2.2 Implementation evaluation 
• Responsibilities: Finalizing protocol for process evaluation (to be approved by 
leadership committee). Collecting process evaluation data through observation 
and interviews. Analyzing and interpreting results of process evaluation. 
Developing dissemination products. 
• Membership: Hildi Hagedorn, Karen Seal, Natalie Purcell 
• Reporting: Reports to leadership committee through Dr. Seal 
12.2.3 Data  
• Responsibilities: Finalizing data collection and management protocols. 
Monitoring study recruitment, enrollment, outcomes, and fidelity data. Reviewing 
data and statistical resources in relation to study milestones. Reviewing study data 
analysis plans.   
• Membership: David Nelson, Sean Nugent, Allyson Kats, Agnes Jensen, Erin 
Krebs 
• Reporting: Reports to leadership committee through Dr. Krebs 
12.3.4 Publications 
• Responsibilities: Establishing guidelines for authorship and for review, approval, 
and tracking of proposed data analysis plans, presentations, and publications. 
Reviewing study data analysis plans and presentation/publication drafts in 
collaboration with the data committee.   
• Membership: TBD 
• Reporting: Reports to leadership committee through Dr. Krebs 
 
 
 


CIRB Protocol #17-11 date   02/01/2022   57 
 
PROTOCOL REVISION HISTORY 
 
Version Number: 1.0 
Version Date: December 30, 2016 
 
Version Number: 2.0 
Version Date: May 15, 2017  
Summary of Revisions: Added information about local site recruitment (4.3.2), buprenorphine 
rotation protocol and IND exemption (5.6), qualitative data collection (6.4.1), local site rollout 
(8.3, 8.4, 8.6), process evaluation (9), ClinicalTrials.gov registration (10.8.2), and study 
governance (12). Removed certificate of confidentiality. Edited for clarity throughout. 
 
Version Number: 3.0  
Version Date: September 8, 2017 
Summary of Revisions: Changed title of study. Revised eligibility criteria and provided detail on 
consent visit (4.3.4-4.3.6); revised and clarified intervention details (5.1, 5.3, 5.4); added and 
revised buprenorphine rotation details (5.6.1-5.6.5); revised IPT fidelity monitoring (5.8.1) plan; 
clarified adverse event data collection and analysis for outcomes (6.2.3, 7.7) and assessment, 
tracking, and reporting for human subjects monitoring (10.5.1, 10.5.2, 10.6); added UPIRTSO 
definition (10.5); revised incentive payment data information (10.7.3). Edited for 
clarity/consistency of terminology throughout. 
 
Version Number: 4.0 
Version Date: November 20, 2017 
Summary of Revisions: Revised requirements for IPT team members (5.3, 5.6.3); 
simplified/revised description of patient-reported outcome assessment (6.4.5); changed baseline 
interview process (6.4). Edited for clarity/consistency throughout. 
 
Version Number: 5.0 
Version Date: March 6, 2018 
Summary of Revisions: Added travel pay for enrollment visit (4.3.6); edited section numbering 
(5.1 – 12.2). 
 
Version Number 6.0 
Version Date: June 22, 2018 
Summary of Revisions:  Minor inclusion criteria revision (4.1.); refined definition exclusion 
criteria (4.2); revised and reorganized content and subsections  to distinguish local and central 
recruitment procedures and improve clarity (4.3); revised enrollment visit and informed consent 
procedures to allow for VA Telehealth option (4.3.8); revised IPT visit schedule description for 


CIRB Protocol #17-11 date   02/01/2022   58 
 
clarity (5.4.2); revised protocol language throughout to clarify local tasks that may be done by 
local study personnel (rather than study coordinator specific).  
 
Version Number 7.0 
Version Date: February 5, 2019 
Summary of Revisions:  Added option to complete patient reported outcomes by mailed paper 
questionnaire (3.1 and 6.2). 
 
Version Number 8.0 
Version Date: April 12, 2019 
Summary of Revisions: Revised definitions of “moderate to high dose” opioid therapy from ≥ 50 
ME mg to ≥ 20 ME mg/day; revised “high dose” from ≥ 100 ME mg to ≥ 70 ME mg daily 
(Abstract, 1.2.1, 4.1, 4.3.3, 5.1).   
 
Version Number 9.0 
Version Date: September 13, 2019 
Summary of revisions: Removed “24 month period” from recruitment section (4.3.1); ; revised 
protocol language throughout to clarify tasks that may be done by coordinating center or other 
study personnel if local study staff are unavailable; clarified other local study staff authorized to 
obtain consent (5.6); updated buprenorphine management section to clarify approach to 
buprenorphine initiation may be individualized by prescribing clinician (5.6.3); added 
prescription monitoring program check and documentation of outside medications to transition 
of care process (5.9); added visual aids for follow-up outcome assessment interviews (6.2); 
added nominal token of appreciation prior to 12 month interview (6.2.1); made small word 
changes/edits for clarity.   
 
Version Number 10.0 
Version Date: November 25, 2019 
Summary of revisions: Updated number of sites from nine to 10 in multiple locations; revised 
estimated sample size and related power estimates (abstract, 7.1, 7.5); revised pre-specified 
subgroups (abstract, 1.2.1, 4.3.2).   
 
Version Number 11.0 
Version Date: May 28, 2020 
Summary of revisions: Added repeat core baseline interview if first intervention visit is delayed 
(section 6.2.1); added COVID-19 questions to assessments (section 6.2.3); added COVID test 
results to administrative data collection (section 6.3.1). 
 


CIRB Protocol #17-11 date   02/01/2022   59 
 
Version Number 12.0 
Version Date: October 20, 2020 
Summary of revisions:  Updated aim 2 outcome language consistent with previous changes in 
version 10.0 (abstract, section 1.1.2); clarified process for mailing signed documents when 
informed consent is not conducted in-person (sections 4.3.8, 4.3.9, 5.6.4); added telephone 
option for enrollment and intervention visits (sections 4.3.8, 5.1, 5.3.2, 5.4.2, 5.6.4, 5.6.5); 
clarified timing of qualitative interviews (section 6.4.1).  
 
Version Number 13.0 
Version Date: December 17, 2020 
Summary of revisions: Clarified issues related to delays receiving signed informed 
consent/HIPPA authorization forms after virtual enrollment visits (section 4.3.8); added 
allowance for less frequent case review meetings in final year of intervention (section 5.3.4 and 
5.4.4.); clarified processs for clinician reporting of adverse events (section 10.5.1.1).  
 
Version Number 14.0 
Version Date:  April 22, 2021 
Summary of revisions: Add patient interviews about COVID-19 pandemic-related experiences;  
add telehealth questions to clinician interviews  (section 6.4.1).   
 
Version Number 15.0 
Version Date:  August 16, 2021 
Summary of revisions: Add clinician interviews focused on buprenorphine (section 6.4.1).   
 
Version Number 16.0 
Version Date:  February 1, 2022 
Summary of revisions:  Clarification that baseline interview will be after the patient provides 
verbal informed consent and before randomization (section 6.2).  Written consent is required 
prior to randomization (section 4.3.9). 
 
 

ICF_001.pdf: 
 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 1 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
 
KEY SUMMARY INFORMATION ABOUT THIS STUDY 
 
You are being invited to take part in a research study funded by the Patient Centered Outcomes 
Research Institute (PCORI). Before you decide to take part, it is important for you to know why 
the research is being done and what it will involve. This includes any potential risks to you, as 
well as any potential benefits you might receive. Taking part in this study is completely 
voluntary.   
 
This study will compare two pain care delivery methods to determine which one helps more 
patients achieve improvement in pain. 
 
Read the information below closely and discuss it with family and friends if you wish. Ask one of 
the study staff if anything is not clear or if you would like more details. Take your time to decide.  
If you do decide to take part in this study, your signature on this consent form will show that you 
received all of the information below, and that you were able to discuss any questions and 
concerns you had with a member of the study team.   
WHAT IS THE STUDY ABOUT AND HOW LONG WILL IT LAST? 
This study will compare pain care delivery methods to determine which one helps more patients 
achieve improvement in pain. Your participation in this research will last one year.  
 
Patients who wish to enter the study will be assigned by chance to receive either “Pharmacist 
Pain Care” or “Integrated Pain Care” management for pain. Patients in the “Pharmacist Pain 
Care” group will have their pain managed by a pharmacist and a physician working together, but 
will have one-on-one appointments with the pharmacist, who has been specially trained in pain 
management.  Patients in the “Integrated Pain Care” group will work with a multi-disciplinary 
team of clinicians. All patients in the study will get personalized care to figure out what pain 
treatment plan works best for them as individuals. Also, for patients on high doses of opioid 
medication who want to cut down on their dose, the study will also test whether offering an extra 
medication option helps them succeed.  
 
• 
This research study is being conducted because many people who are treated with daily 
opioid medications (such as morphine and oxycodone) continue to have serious pain. 
Individualized treatment can help some people have less pain and/or lower opioid doses. 
This study is comparing two different ways of delivering individualized pain care.  
• 
This study is for patients who have moderate or severe pain despite treatment with 
medium or high doses of opioid pain medications.  


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 2 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
• 
By joining this study, you are agreeing to be assigned to receive care from Pharmacist 
Pain Care or Integrated Pain Care providers. You are not being asked to agree to any 
specific medication or pain treatment. Your assigned pain care provider(s) may 
recommend changes to your medications or pain treatments. Recommended treatments 
will be standard pain treatments, not experimental treatments.  
• 
The study will be conducted at 10 different VA sites, including [NAME OF LOCAL VA].   
• 
The Minneapolis VA Medical Center will operate as the coordinating center for the study.   
• 
The study will enroll approximately 1,000 people in total. 
• 
This study is funded by the Patient Centered Outcomes Research Institute (PCORI), an 
independent nonprofit, nongovernmental organization. 
WHAT ARE KEY REASONS YOU MIGHT CHOOSE TO VOLUNTEER FOR THIS STUDY? 
You may benefit from individualized pain care in this study and the information we get from this 
study may help us treat future patients and Veterans.   
WHAT ARE KEY REASONS YOU MIGHT CHOOSE NOT TO VOLUNTEER FOR THIS 
STUDY? 
You may feel stress when responding to interview questions, or committing to minimum number 
of study appointments and interviews (see below for details). For a complete description of 
risks, see pages 6-7. 
DO YOU HAVE TO TAKE PART IN THE STUDY? 
If you decide to take part in the study, it should be because you really want to volunteer. You will 
not lose any services, benefits or rights you would normally have if you choose not to volunteer.  
WHAT IF YOU HAVE QUESTIONS, SUGGESTIONS OR CONCERNS? 
• 
The person in charge of the study is  Local Site Investigator name} at the [insert name of VA 
facility.]   If you have questions, suggestions, or concerns regarding this study or you want to 
withdraw from the study his/her contact information is: [local site investigator: [NAME AND 
PHONE] 
 
 
 
 
 


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 3 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
DETAILED INFORMATION ABOUT THE STUDY 
WHAT IS THE PURPOSE OF THIS STUDY? 
This study will compare two pain care delivery methods to determine which one helps more 
patients achieve improvement in pain. 
HOW LONG WILL I BE IN THE STUDY? 
This research study is expected to take approximately 6 years.  Your individual participation in 
the project will take 1 year. 
WHAT WILL HAPPEN IF I TAKE PART IN THE STUDY? 
If you decide to take part in this study, this is what will happen:   
 
Randomization: The [local VA facility] study coordinator will randomly assign you to one of two 
treatment groups, either Pharmacist Pain Care or Integrated Pain Team.   
• 
You will be placed into a group based on computer program (like a flip of a coin, but 
computerized). Neither you, nor the study coordinator, can choose a specific group.   
• 
Both treatment groups provide active pain care from VA health care providers: 
o If you are assigned to the Pharmacist Pain Care group, you will have an initial 
appointment (in-person or by video if possible) at the start of the study. You will have 
telephone follow-up appointments at least every month for the first 2 months then at 
least every 3 months. You may have more appointments if needed.  
o If you are assigned to the Integrated Pain Care group, you will have at least two 
appointments (in-person or by video if possible) in the first 3 months of the study. 
You will have telephone follow-up appointments at least every month for the first 6 
months then at least every 2 months. 
• 
You, your primary care team, and the study team at [local VA facility] will know which group 
you are assigned to.  
 
Pain treatment: You will receive pain care in your assigned treatment group, either the 
Pharmacist Pain Care or Integrated Pain Care. 
 
• 
You will have your first appointment with your study health care provider(s) at [local VA 
facility] as soon as possible after you enroll. This will include discussion of your pain, pain 
treatment history, and treatment goals and preferences. The appointment will take about 
one hour. 
• 
You will receive information about pain treatment options. Your pain care provider(s) will 
work with you to develop a pain care plan.  


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 4 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
o Your pain care plan will be based on your individual needs. It can be adjusted during 
the study based on how you are doing and how your needs change. 
o Pain care plans will include FDA-approved medications and/or established therapies 
available in VA. They will not include experimental medications or other experimental 
treatments. 
• 
You will have regular follow-up appointments by telephone with your pain care provider(s). If 
you are assigned to the Integrated Pain Care group, you will have at least 2 face-to-face 
follow-up appointments if possible; telephone may be used for these appointments if 
needed. These appointments will usually take 20-30 minutes. 
• 
You may have additional face-to-face or telephone appointments depending on your needs 
and preferences.  
• 
When necessary or at your request, video or telephone appointments may be substituted for 
in-person visits.  
• 
If you wish to reduce your opioid medication, your pain care provider(s) will discuss options 
for how to do this. If you agree, they will help you reduce your dose safely and comfortably.  
• 
Your assigned Pharmacist Pain Care or Integrated Pain Care provider(s) will enter progress 
notes in your electronic medical record and coordinate care with your usual VA primary care 
team. 
• 
You may decide at any time that you do not wish to continue working with your assigned 
Pharmacist Pain Care or Integrated Pain Care provider(s). Please tell a research staff 
member if this is your decision. Your pain care will be transitioned back to your regular 
primary care provider.  
 
Possible recording of appointments:  
There are two instances where you may be audio-recorded for this study (audio recording only, 
no photographs or video recordings will occur). 
 
1. Monthly telephone coaching sessions will be recorded for Integrated Pain Care 
participants. As part of the study, the research team wants to ensure clinicians are 
following a similar protocol for these sessions. Researchers who are experts in 
counseling techniques listen to the recording of the sessions. If needed, the researchers 
may give feedback to clinicians to improve their techniques in future sessions. We will 
record only coaching sessions and not all appointments conducted by telephone. Your 
clinician will notify you at the beginning of the session if it will be audio-recorded.  
 
2. We will interview only a subset of participants after the 12-month study ends to ask 
about their experience. This one-time interview is voluntary and is recorded so that we 
can accurately document what was discussed. If you agree to be interviewed, you will be 
reminded at the beginning of the interview that you are being audio-recorded.               


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 5 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
 
Additional optional research protocol: Some people in this study will be asked if they want to 
take part in a second optional research protocol. The purpose of the optional protocol is to help 
people taking opioid medications reduce their opioid dose by switching to a different medication.  
 
• 
You may be offered this option if you are treated with a high daily dose of opioid medication 
AND the computer program selects you by random chance (like a flip of a coin, but 
computerized).  
• 
If you are offered this option, you will have the choice of whether or not to take part. You will 
be given time to decide. If you agree, you will be given a separate research consent form. 
Whether or not you choose to participate in the optional protocol will not affect your 
participation in the main study. 
 
Research outcome interviews: You will be asked to complete five research interviews by 
telephone over the course of the 12-month study. The main purpose of these interviews is to 
compare how effective the treatment groups are at improving pain. 
 
• 
Research assessments are conducted by study personnel at the Minneapolis VA study 
coordinating center. These interviewers are “blinded,” meaning they do not know which 
treatment group you are assigned to. It is important that you do not tell “blinded” study 
personnel which group you are in.  
• 
Interviews include questions about pain, daily activities, medication use, side effects, fatigue 
and sleep, mental health, and substance use. You may skip any questions you are not 
comfortable answering.  
• 
Research assessment interviews are conducted for research purposes only. They will not be 
shared with your [local VA facility] care providers or [local VA facility] pain care provider(s). 
• 
The first interview at the beginning of the study takes about 60 minutes to complete. Follow 
up interviews will be at 3 months (about 15 minutes), 6 months (up to 45 minutes), 9 months 
(about 15 minutes), and 12 months (up to 45 minutes).  
• 
You may be asked to participate in a one-time follow up interview to take place 
approximately three months after completing the study intervention. This interview will ask 
about your experiences during the study and your opinions about the study. The interview 
will be audio-recorded, and a transcript will be made of the recording for later review by the 
research team. Participation in this one-time interview is voluntary.  
• 
At the end of the 12-month interview, we will ask for your permission to re-contact you for 
other future interviews by the study team.  
• 
It is important for the science of the study to collect information about pain and other 
outcomes of all enrolled patients, even those who do not continue to get care from the 
assigned pain treatment group. We will contact you for research interviews and collect data 


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 6 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
unless you request to completely withdraw from the study. You are free to withdraw from the 
study at any time.  
 
Research findings: You will receive a summary of our research findings by mail at the end of 
this study. This may be a year or more after you complete your part in the study. 
WHAT IS EXPECTED OF ME IF I TAKE PART IN THIS STUDY? 
• 
Ask questions as you think of them. All questions are good questions! 
• 
Keep your study appointments or let us know right away if you need to reschedule. 
• 
Let us know if you move or have a change in your phone number. 
• 
Tell your Pharmacist Pain Care or Integrated Pain Care provider(s) if you might be having a 
side effect or have any concerns about study medications or treatment. 
• 
Tell your Pharmacist Pain Care or Integrated Pain Care provider(s) if you might be pregnant.  
• 
Keep medications in a safe place for your use only and away from children.  
• 
Tell the research staff if you change your mind about staying in the study. 
• 
While participating in this research study, do not take part in any other research project 
without approval. Taking part in another research study at the same time may interfere with 
study results. 
WHAT POSSIBLE RISKS OR DISCOMFORTS MIGHT I HAVE IF I TAKE PART IN THIS 
STUDY? 
Psychological or Social Risks 
• 
You may feel stress when responding to interview questions. Study staff will conduct 
interviews in a private setting. You may skip questions that make you uncomfortable.   
 
Risks from medications 
• 
Medication risks are the same as in usual care and are not risks of the research. No 
experimental drugs are offered in this study. Medications may be recommended by your 
pain care provider(s). You should discuss risks and benefits of any medication changes with 
your pain care provider(s). Those risks are not included in this consent form.  
• 
Some medications are not safe in pregnancy or breastfeeding. Let your pain care 
provider(s) know if you are pregnant, thinking about getting pregnant, or are breastfeeding.  
• 
Medications will be prescribed only if you agree. You may stop taking medications at any 
time if you have side effects or do not want to continue for any reason. Some medications 
must be reduced slowly (tapered) before stopping, so let your pain care provider(s) know if 
you want to stop. 
 
 


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 7 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
Risks from non-medication treatments 
• 
Pain treatment risks are the same as in usual care and are not risks of the research. No 
experimental treatments are offered in this study. Pain treatments may be recommended by 
your pain care provider(s). Risks of these treatments are mostly minor. For example, a new 
exercise could cause a temporary increase in muscle pain. You should discuss risks and  
benefits of any treatment changes with your pain care provider(s). Those risks are not 
included in this consent form.  
Unexpected or rare side effects could also occur. 
There is always a chance that any procedure can harm you.  The procedures in this study are 
no different.  In addition to the risks described above, you may experience a previously 
unknown risk or side effect. 
 
Risks of the usual care you receive are not risks of the research. Those risks are not included in 
this consent form. You should talk with your health care providers if you have any questions 
about the risks of usual care.   
WHAT ARE THE POSSIBLE BENEFITS OF THIS STUDY? 
You may benefit from individualized pain care in this study. We can’t promise that you will get 
any benefits from taking part in this research study. The information we get from this study may 
help us treat future patients.   
WHAT OTHER CHOICES DO I HAVE IF I DO NOT WANT TO JOIN THIS STUDY? 
You may choose not to participate in this study. If this is your decision, you may continue to get 
care from your current health care providers.  
 
You may discuss these options with your doctor.   
HOW WILL MY PRIVATE INFORMATION BE PROTECTED? 
We will include information about your study participation in your medical record. 
 
The research staff will ensure that measures are taken to maintain your confidentiality. 
However, participation in research always has a risk of the loss of privacy. Only approved study 
personnel will have access to the information from the outcome interviews. Information about 
you that is gathered during the research outcome interviews will be identifiable by a coded study 
identification number only. The study number will not be based on any information that could be 
used to identify you (for example, it will not be based on your social security number, initials, 


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 8 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
birth date, etc.) A master list matching your personal information with your study number will be 
kept separate from your personal information. 
 
All information collected about you will be double-locked in secure VA file cabinets and on 
encrypted VA computers. All research data for this study password-protected and accessible 
only by authorized study staff. All other research records will be stored in a confidential manner 
indefinitely in accordance with VHA’s record retention schedule 
(www1.va.gov/VHAPUBLICATIONS/RCS10/rcs10-1.pdf). 
 
Your identity will not be revealed in any reports or publications resulting from this study. 
Information about you will be combined with information from other people taking part in the 
study. We will write about the combined data we have gathered. Any talks or papers about this 
study will not identify you. Only authorized persons will have access to the information gathered 
in this study.  
 
If you agree to participate in a one-time follow up interview (within three months of completing 
the study intervention), it will be audio-recorded and a transcript will be made of the recording so 
researchers can review it. That recording will be transcribed by the VA’s Centralized 
Transcription Services Program. The recorded audio file will be sent to the them using a secure 
electronic portal and they will destroy the audio file at the end of the contract.   
 
There are times when we might have to show your records to other people. For example, 
someone from the Office of Human Research Protections, the Government Accountability 
Office, the Office of the Inspector General, the VA Office of Research Oversight, the VA Central 
IRB, the Food and Drug Administration (FDA), the Minneapolis VA Research Office, Research 
and Development Committee, and other study monitors may look at or copy portions of records 
that identify you.    
 
Study health care provider(s) or research personnel may disclose your confidential information 
without your permission in the event of an emergency or if you indicate imminent danger of 
hurting yourself or others. Health care provider(s) and research personnel are required to report 
if you are suicidal or planning to end your life. If this were to occur, we will assist you in 
contacting your local VA Urgent Care Triage, where you will be referred to appropriate services. 
If you refuse these services, the researcher will still call the Urgent Care line and relay your 
contact information for VA staff to follow up with you. You can also contact the Veteran’s Crisis 
Line at 1-800-273-8255 if you are concerned about your mental health or worried that you might 
hurt yourself.  
 
This is a ten site study. Your information will be shared between [local VA site] and VA study 
personnel at other sites using the VA secure internal computer network or secure intranet site.  


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 9 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
 
University of Minnesota and their payment contractor will be provided with your name, address, 
and date of birth to process payments (described below) using secure connections. 
 
Your identity will not be revealed to the study’s funder, the Patient Centered Outcomes 
Research Institute (PCORI). 
 
Your personal Identifiers may be removed from your private information, and that non-
identifiable information could be used for future research studies or distributed to another 
investigator for future research studies without additional consent from you. 
 
A description of this clinical trial is available on http://www.ClinicalTrials.gov as required by U.S. 
Law. This website will not include information that can identify you.  At most, the website will 
include a summary of the results. You can search this website at any time. 
WHAT ARE THE COSTS TO ME IF I TAKE PART IN THIS STUDY? 
You will not be charged for any treatments or procedures that are part of this study.  If you 
usually pay co-payments for VA care and medications, you will still pay these co-payments for 
VA care and medications that are not part of this study.   
 
Appointments may result in transportation costs and possible wages lost due to time missed 
from work. If personal devices are used for VA TeleHealth appointments using Video Connect 
app, data charges may apply.   
 
Payment Offered for Participation:   
You will be paid $50 in the form pre-paid debit card after each completed outcome interview at 
the beginning of the study and at 6 and 12 months.    
You will be paid $25 in the form of a pre-paid debit card after each completed outcome interview 
at 3 and 9 months. 
 
The total payment is up to $200 over the full year for outcome assessment interviews. 
Additionally, you will be paid up to [LOCAL SITE DOLLAR AMOUNT UP TO $50.00] to offset 
travel costs to today’s appointment if you traveled to a VA facility for this appointment. This 
travel payment will be paid in the form of the same pre-paid debit card, regardless of your 
decision to consent to study participation. 
 
 
 
 


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 10 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
IF LOCAL SITE OPTS TO USE TIERED SYSTEM:   
 
Travel payment is based on distance from your current home address to the [LOCAL SITE 
NAME AND ADDRESS]. If your address is <[LOCAL SITE LOWER MILEAGE TIER] miles, you 
will receive $[LOCAL SITE DOLLAR AMOUNT BETWEEN $20-25.00] and ≥[LOCAL SITE 
HIGHER MILEAGE TIER] miles will receive $[LOCAL SITE DOLLAR AMOUNT BETWEEN $40-
50.00]. If your visit today is at a VA clinic (not at the main facility address listed above), your 
travel mileage will be based on the distance from your home address to this VA clinic. 
 
The pre-paid debit card will be given to you today, with no value on the card. Within 7 days after 
completing the outcome interviews, your card will have the $50 or $25 loaded onto it. Your 
name, address, and birthdate will be shared with the University of Minnesota and their debit 
card contractor so they can process your payments. If the debit card is lost, damaged or stolen, 
the study team can replace it.   
 
If you agree to participate in the one-time follow up interview, you will be paid an additional $50 
on your pre-paid debit card.  
WHAT WILL HAPPEN IF I AM INJURED BECAUSE OF MY BEING IN THE STUDY? 
Every reasonable safety measure will be used to protect your well-being. If you are injured as 
result of taking part in this study, VA will provide necessary medical treatment at no cost to you 
unless the injury was due to your not following the study procedures. If you experience a 
research-related injury, please contact one of the following: 
 
For non-urgent matters: 
• 
The research coordinator at [local site]: [NAME AND PHONE] 
• 
The principal investigator at [local site]: [NAME AND PHONE] 
 
For urgent matters: 
• 
Your local VA 24-hour care line: (insert local VA number here) 
• 
Veteran Crisis hotline: 800-273-8255 Press 1  
 
You do not give up any of your legal rights and you do not release the VA from any liability by 
signing this form.    
 
 


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 11 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
DO I HAVE TO TAKE PART IN THE STUDY? 
It is up to you to decide whether or not to take part in this study. Choosing not to participate will 
not affect your current pain care. If you do decide to take part you may withdraw at any time. If 
you do not wish to be in this study, or if you decide to join and then withdraw, you will not lose 
any benefits to which you are entitled. If you don’t take part, you can still receive all usual care 
that is available to you. Your decision not to take part will not affect the relationship you have 
with your doctor or other staff, and it will not affect the usual care that you receive as a patient. 
 
If you choose to withdraw from the study at any point, please notify the study’s Principal 
Investigator in writing at: 
  
 
 
 
Erin Krebs, MD, MPH 
 
 
 
 
Minneapolis VA Medical Center (Code 152) 
 
 
 
 
1 Veterans Drive 
 
 
 
 
Minneapolis, MN 55417 
 
Or you may notify your local site investigator in writing at: 
 
 
 
 
[LOCAL PI NAME AND ADDRESS] 
 
 
 
 
VA Medical Center 
 
 
 
 
Street address 
 
 
 
 
City, STATE ZIP 
 
Any data that has already been collected, up to the point of your withdrawal, will be maintained 
with the project. However, no information can be collected from you after you choose to 
withdraw. 
WHO DO I CONTACT ABOUT THIS STUDY IF I HAVE QUESTIONS? 
If you have questions, complaints, or concerns about the research or related matters, please 
contact:   
 
• 
The research coordinator at [local site]: [NAME AND PHONE] 
• 
The investigator at [local site]: [NAME AND PHONE] 
• 
The patient advocate(s) at [local site]: [ PHONE] 
• 
The study project manager (at the Minneapolis VA): Agnes Jensen 612-629-7456 
 
If you have questions about your rights as a study participant, or you want to make sure this is a 
valid VA study, you may contact the VA Central Institutional Review Board (IRB). The VA 
Central IRB is responsible for overseeing the safety of participants in this study. You may call 


 
RESEARCH CONSENT FORM 
Version Date:     07/10/2020 
Participant Name:                                                                                                           Date:  _________ 
Title of Study:  Veterans’ Pain Care Organizational Improvement Comparative Effectiveness (VOICE) 
Principal Investigator:  _____________________________________ VA Facility: _________________  
Principal Investigator for Multisite Study: Erin Krebs MD, MPH; William Becker MD; Karen Seal MD,MPH 
 
  
                                                                      
  
 
 
 
  
 
                                               Page 12 of 12 
 
FOR VA CENTRAL IRB USE ONLY 
 
 
PI/SC Approval Date:   10/23/2020                          
 
LSI Approval Date:       N/A 
 
LSI Verification Date:   N/A 
                      
 
the VA Central IRB toll free at 1-877-254-3130 if you have questions, complaints or concerns 
about the study or if you would like to obtain information or offer input. 
WILL I BE TOLD NEW INFORMATION ABOUT THIS STUDY? 
Sometimes during the course of a research study, new information becomes available that 
might change a person’s decision to stay in the study. If this happens, your research coordinator 
will contact you to discuss with you whether you want to continue in the study. If at that point 
you decide to withdraw from the study, your pain care provider(s) will arrange for your medical 
care to continue with your primary care provider. If you decide to continue in the study, you 
might be asked to sign an updated informed consent form.   
 
FUTURE USE OF DATA AND RE-CONTACT  
An important part of this research is to save your data in a secure repository for other research 
studies in the future. The data will be stored at the study’s coordinating center (the Minneapolis 
VA) on encrypted VA computers. Access to non-identifiable study data will be restricted to 
authorized uses by VA and the study team.  At your final VOICE study research interview, you 
will be asked if you are willing to be contacted for future research. 
 
AGREEMENT TO PARTICIPATE IN THE RESEARCH STUDY 
The designated research staff member has explained the research study to you.  You have 
been told of the risks or discomforts and possible benefits of the study. You have been told of 
other choices of treatment available to you.  You have been given the chance to ask questions 
and obtain answers.   
 
By signing this document below, you voluntarily consent to participate in this study.  You also 
confirm that you have read this consent, or it has been read to you.  You will receive a copy of 
this consent after you sign it.  A copy of this signed consent will also be put in your medical 
record. 
 
I agree to participate in this research study as has been explained in this document. 
 
 
 
_________________________ 
Participant’s Name 
____________________________ 
Participant’s Signature 
___________ 
Date