Conditions: End Stage Renal Disease Chronic Pain Opioid Dependence
Keywords: hemodialysis pain opioids pain coping skills
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 643
Healthy volunteers: no

Brief summary:
HOPE is a randomized clinical trial that will evaluate approaches to reducing pain and opioid use among patients with chronic pain who are receiving maintenance hemodialysis for end-stage renal disease. The hypothesis is that pain coping skills training will be effective at reducing pain and opioid use, and that buprenorphine will be acceptable and tolerable as an approach to managing physical dependence on opioids in this patient population.

Detailed description:

Arms:
arm 1: The PCST intervention will focus primarily on reducing pain interference in daily activities and improving pain self-management skills. For participants with recent or current opioid use, the PCST intervention will include motivational interviewing aimed at reducing opioid use. During Weeks 1 - 12 the PCST will be delivered by coaches via telehealth (video). During Weeks 13 - 24, the Interactive Voice Response (IVR) will be delivered via telephone. The telehealth component will consist of weekly sessions, each lasting 45-50 minutes. The IVR content, intended to enhance and sustain the effects of the coach-led session, will be delivered with daily telephone interactions, each lasting approximately 5 minutes. Both components of the intervention will be available in English and Spanish. arm 2: Participants in the Usual Care arm will be provided with written educational material about chronic pain and opioid medications, and available resources for treatment.

Interventions: intervention 1: Pain Coping Skills Training (PCST) intervention 2: Buprenorphine
Intervention descriptions: intervention 1: The PCST intervention will focus primarily on reducing pain interference in daily activities and improving pain self-management skills. For participants with recent or current opioid use, the PCST intervention will include motivational interviewing aimed at reducing opioid use. During Weeks 1 - 12 the PCST will be delivered by coaches via telehealth (video). During Weeks 13 - 24, the Interactive Voice Response (IVR) will be delivered via telephone. The telehealth component will consist of weekly sessions, each lasting 45-50 minutes. The IVR content, intended to enhance and sustain the effects of the coach-led session, will be delivered with daily telephone interactions, each lasting approximately 5 minutes. Both components of the intervention will be available in English and Spanish. intervention 2: At Week 24, participants who meet the eligibility criteria for the buprenorphine intervention will be encouraged to switch from their current full agonist opioid medication to the partial opioid agonist, buprenorphine. Participants who switch to Buprenorphine will be provided with individualized buprenorphine treatment recommendations. Individualized buprenorphine treatment recommendations will be made by the study buprenorphine physician based on current opioid use and other relevant factors. Participants who do not meet the Phase 2 eligibility criteria will not be offered buprenorphine. All participants will continue to be followed from Week 24 until Week 36 for ascertainment of pain, opioid use, and other outcomes to address durability of the effects of PCST, and, for those who switch to buprenorphine, to assess buprenorphine acceptability, tolerability, and efficacy as exploratory outcomes.

Protocol document:
Prot_SAP_001.pdf: 
THIS IS A CONFIDENTIAL DOCUMENT AND SHOULD NOT BE DISTRIBUTED 
 
HOPE Consortium Trial to Reduce Pain and Opioid Use 
in Hemodialysis 
 
A Randomized Clinical Trial to Evaluate Non-Pharmacologic and Pharmacologic 
Approaches for Reducing Pain and Opioid Use Among Patients Treated with 
Maintenance Hemodialysis 
A National Institutes of Health HEAL Initiative Trial 
 
 
Funding Sponsor: 
National Institutes of Diabetes and Digestive 
and Kidney Diseases 
National Institutes of Health 
2 Democracy Plaza 
6707 Democracy Boulevard 
Bethesda, MD  20892-5458 
 
Study Product: 
Buprenorphine 
Protocol Number: 
843471 
IND Number:  
151345 
Protocol Version: 
V1.7; July 7, 2023 
 


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Table of Contents 
PRINCIPAL INVESTIGATOR SIGNATURE ........................................................................................................ 6 
1. 
Study Summary ................................................................................................................................... 8 
1.1. 
Synopsis ............................................................................................................................................. 8 
1.2. 
Key Roles and Study Governance .................................................................................................... 10 
1.3. 
Study Schema ................................................................................................................................... 11 
2. 
Introduction and Rationale ................................................................................................................ 12 
2.1. 
Study Rationale ................................................................................................................................ 12 
2.2. 
Background ...................................................................................................................................... 12 
2.2.1. Prevalence of Pain among Patients Treated with Hemodialysis................................................. 12 
2.2.2. Complexity of Pain Management among Patients Treated with Hemodialysis.......................... 13 
2.2.3. Potential Harms from Long Term Opioid Therapy ...................................................................... 14 
2.2.4. The Need for Non-Pharmacologic Approaches to Pain Management and Opioid Reduction in 
the Setting of Maintenance Hemodialysis .................................................................................. 14 
2.2.5. Rationale for a Pain Coping Skills Training Intervention to Address Pain and Opioid Use ......... 14 
2.2.6. Rationale for a Buprenorphine Intervention to Address Opioid Physical Dependence in 
Hemodialysis Patients ................................................................................................................. 16 
2.3. 
Risk / Benefit Assessment for the HOPE Trial Interventions ........................................................... 17 
2.3.1. Known Potential Risks of Trial Interventions .............................................................................. 17 
2.3.2. Known Potential Benefits of Trial Interventions ......................................................................... 18 
2.3.3. Assessment of the Balance between Risks and Benefits ............................................................ 18 
3. 
Study Objectives ................................................................................................................................ 19 
4. 
Study Design and Outcomes .............................................................................................................. 20 
4.1. 
Trial Design and Rationale ............................................................................................................... 20 
4.2. 
Outcomes ......................................................................................................................................... 20 
4.2.1. Primary Outcome: Pain Interference .......................................................................................... 21 
4.2.2. Secondary Outcomes .................................................................................................................. 21 
4.2.3. Patient-Reported Outcome (PRO) Ascertainment Approach ..................................................... 23 
4.2.4. Timing of Ascertainment of Primary Outcome ........................................................................... 24 
5. 
Study Population ............................................................................................................................... 25 
5.1. 
Inclusion Criteria .............................................................................................................................. 25 
5.2. 
Exclusion Criteria.............................................................................................................................. 25 
5.3. 
Subgroup with Current or Recent Opioid Use ................................................................................. 25 
5.4. 
Participant Recruitment and Eligibility Screening............................................................................ 26 
5.5. 
Re-Screening for Eligibility ............................................................................................................... 26 
6. 
Study Interventions ........................................................................................................................... 27 
6.1. 
Pain Coping Skills Training Intervention (PCST) ............................................................................... 27 
6.1.1. Rationale for Using Telehealth and IVR as Delivery Modes for PCST ......................................... 27 
6.1.2. Telehealth Implementation ........................................................................................................ 28 
6.1.3. IVR Implementation .................................................................................................................... 28 
6.1.4. Structure and Content of PCST Telehealth Intervention (Weeks 1 - 12) .................................... 28 
6.1.5. Structure and Content of IVR Booster (Weeks 13-24) ................................................................ 29 
6.1.6. Qualifications and Training of the PCST Coaches........................................................................ 31 
6.2. 
Buprenorphine Intervention ............................................................................................................ 32 


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6.2.1. Overview ..................................................................................................................................... 32 
6.2.2. Eligibility for Buprenorphine Intervention: Inclusion Criteria ..................................................... 32 
6.2.3. Eligibility for Buprenorphine Intervention: Exclusion Criteria .................................................... 32 
6.2.4. Buprenorphine Formulations ...................................................................................................... 33 
6.2.5. Buprenorphine Regulatory Issues ............................................................................................... 34 
6.2.6. Buprenorphine Prescribing and Dispensing ................................................................................ 34 
6.2.7. Buprenorphine Initiation ............................................................................................................. 34 
6.2.8. Buprenorphine Dosing Regimens................................................................................................ 36 
6.2.9. Buprenorphine Maintenance During and After the Trial ............................................................ 37 
6.2.10. Monitoring for Changes in Concomitant Medications During Treatment with Buprenorphine 
with Particular Attention to Medications that Affect Cyp3A4 Enzyme Activity ......................... 37 
6.3. 
Usual Care ........................................................................................................................................ 38 
6.4. 
Intervention Fidelity ......................................................................................................................... 38 
6.5. 
Clinical Management of Trial Participants ....................................................................................... 39 
6.5.1. Concomitant Therapy .................................................................................................................. 39 
6.5.2. Opioid Adherence Problems ....................................................................................................... 39 
6.5.3. Clinical Management of OUD or other Substance Use Disorders ............................................... 39 
6.5.4. Clinical Management of Suicidality ............................................................................................. 40 
7. 
Study Procedures and Assessments .................................................................................................... 41 
7.1. 
Pre-screening and Screening ........................................................................................................... 41 
7.2. 
Baseline Data Collection and PRO Ascertainment – (within 4 weeks of Screening)........................ 41 
7.3. 
Randomization for Phase 1 (within 1 week of Baseline) ................................................................. 42 
7.4. 
Phase 1 Intervention Administration, Data Collection, and Research Team Contacts 
(Weeks 1 - 24) .................................................................................................................................. 43 
7.4.1. Intervention Administration (Weeks 1 - 24) ............................................................................... 43 
7.4.2. Contacts with the Research Team (Weeks 4, 8, 12, 16, and 20) ................................................. 43 
7.4.3. Follow-Up PROs (Week 12) ......................................................................................................... 43 
7.4.4. End of Phase 1 Intervention, Week 24 PROs, and Determination of Eligibility for 
Buprenorphine (Week 24) .......................................................................................................... 44 
7.5. 
Phase 2 Intervention Administration, Data Collection, and Research Team Contacts  (Weeks 24 - 
36) .................................................................................................................................................... 45 
7.5.1. Intervention Administration (Weeks 24 - 36) ............................................................................. 45 
7.5.2. Contacts with the Research Team (Weeks 28, 32, and 36) ........................................................ 45 
7.5.3. Planning for End-of-Trial (Weeks 32 - 36) ................................................................................... 45 
7.5.4. Follow-Up PROs (Week 36) ......................................................................................................... 45 
7.5.5. End of Phase 2 / End of Study (Week 36) ................................................................................... 46 
7.5.6. Buprenorphine Qualitative Interviews (After Study Participation has been Completed) .......... 46 
8. 
Discontinuation of Study Interventions and Study Participation .......................................................... 47 
8.1. 
Discontinuation of Study Interventions ........................................................................................... 47 
8.2. 
Participant Withdrawal / Discontinuation from the Study .............................................................. 47 
9. 
Adverse Event Ascertainment and Reporting ...................................................................................... 48 
9.1. 
Definitions ........................................................................................................................................ 48 
9.1.1. Adverse Event ............................................................................................................................. 48 
9.1.2. Serious Adverse Event ................................................................................................................. 48 
9.1.3. Unanticipated Problem Involving Risk to Participants or Others ............................................... 48 
9.1.4. Pre-Existing Condition ................................................................................................................. 49 


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9.1.5. Adverse Event Reporting Period ................................................................................................. 49 
9.2. 
Adverse Events of Interest ............................................................................................................... 49 
9.3. 
Anticipated SAEs .............................................................................................................................. 50 
9.4. 
Reporting of AEs of Interest, SAEs, and Unanticipated Problems ................................................... 50 
9.4.1. Reporting AEs of Interest ............................................................................................................ 50 
9.4.2. Reporting SAEs ............................................................................................................................ 51 
9.4.3. Reporting Unanticipated Problems ............................................................................................. 51 
9.5. 
Reporting to the IRB ......................................................................................................................... 51 
9.5.1. Reporting Process ....................................................................................................................... 52 
9.5.2. Other Reportable Events ............................................................................................................. 52 
9.5.3. SDRC Notifications to Participating Investigators ....................................................................... 53 
10. Statistical Considerations ................................................................................................................... 54 
10.1. 
Endpoints, Objectives, and Trial Questions ..................................................................................... 54 
10.2. 
Statistical Considerations for the Phase 1 Randomization .............................................................. 56 
10.2.1. Sample Size and Power Analysis for the Primary Objective ....................................................... 56 
10.2.2. Statistical Analyses ...................................................................................................................... 57 
10.2.3. Planned Interim Efficacy and Futility Analyses for the Phase 1 Randomization ......................... 60 
10.3. 
Statistical Considerations for the Phase 2 Intervention .................................................................. 62 
10.3.1. Acceptability ................................................................................................................................ 63 
10.3.2. Tolerability .................................................................................................................................. 63 
10.3.3. Efficacy ........................................................................................................................................ 64 
10.4. 
Safety Analyses ................................................................................................................................ 65 
10.5. 
Tabulation of Individual Participant Data ........................................................................................ 65 
10.6. 
Populations for Analyses .................................................................................................................. 65 
11. Regulatory, Ethical, and Oversight Considerations .............................................................................. 67 
11.1. 
Informed Consent Process and Participant Compensation ............................................................. 67 
11.2. 
Study Discontinuation and Closure .................................................................................................. 67 
11.3. 
Confidentiality and Privacy .............................................................................................................. 68 
11.3.1. Certificate of Confidentiality ....................................................................................................... 68 
11.4. 
Future Use of Data ........................................................................................................................... 68 
11.5. 
Safety Oversight ............................................................................................................................... 69 
11.5.1. Clinical Center Medical Monitoring ............................................................................................ 69 
11.5.2. Internal Safety Committee .......................................................................................................... 69 
11.5.3. Independent Data and Safety Monitoring Board (DSMB) .......................................................... 69 
11.6. 
Quality Assurance and Quality Control ............................................................................................ 70 
11.7. 
Data Handling and Record Keeping ................................................................................................. 71 
11.7.1. Study Records Retention ............................................................................................................. 71 
11.8. 
Protocol Deviations .......................................................................................................................... 71 
11.9. 
Publications and Data Sharing ......................................................................................................... 73 
11.10. Conflict of Interest Policy ................................................................................................................. 73 
12. Protocol Amendment History ............................................................................................................. 74 
13. References ........................................................................................................................................ 79 
14. Appendix ........................................................................................................................................... 84 
14.1. 
Schedule of Procedures ................................................................................................................... 85 
14.2. 
PRO Questionnaire Schedule and Activities During Research Team Contacts ................................ 86 
14.3. 
Data Safety and Monitoring Board (DSMB) Charter ........................................................................ 88 


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Table 2.1. Systemic Pharmacologic Options for Pain in Hemodialysis: Benefits and Llimitations20, 21 ................. 13 
Table 3.1. Trial Objectives and Outcomes ............................................................................................................. 19 
Table 4.1. Secondary Outcomes: Pain and Opioid Use ......................................................................................... 21 
Table 4.2. Composite Outcome of Pain Interference and Opioid Use: Success (+) or No-Success (−) ................. 21 
Table 4.3. Secondary Outcomes Reflecting Conditions or Symptoms Associated with Pain and/or Opioid Use . 22 
Table 6.1. PCST Telehealth Sessions ..................................................................................................................... 29 
Table 6.2. Buprenorphine Dosing .......................................................................................................................... 37 
Table 9.1. Reporting to the Single IRB of Record .................................................................................................. 52 
Table 10.1. Scientific Questions that can be Addressed with the Trial Design ..................................................... 55 
Table 10.2. Minimum Detectable Differences between the PCST and Usual Care Groups in the Change  from 
Baseline to Week 12 in the BPI Interference Score ........................................................................... 56 
Table 10.3. Stopping Boundaries of Efficacy and Futility for a Power of 90% and at a Two-Sided Type 1  Error of 
5% for an Interim Analysis with One Look at 50% Information Time................................................ 61 
Table 10.4. Stopping Boundaries of Efficacy and Futility for a Power of 90% and at a Two-Sided Type 1 Error of 
5% for an Interim Analysis with Two Looks at 50% and 75% Information Time ............................... 62 
Table 10.5. Minimum Detectable Differences between the PCST and Usual Care Groups in the Change from 
Baseline to Week 12 in the BPI Interference ..................................................................................... 62 
Table 10.6. 95% Confidence Intervals for % of Participants Willing to Switch from a Full Agonist Opioid  to 
Buprenorphine ................................................................................................................................... 63 
Table 10.7. 95% Confidence Intervals for % of Participants who Continue Buprenorphine Until the End of the 
Study (Week 36) ................................................................................................................................ 64 
Table 10.8. 95% Confidence Intervals for the Change in BPI Interference Score between Weeks 24 and 36 ..... 65 
Figure 1.1. Trial Design .......................................................................................................................................... 11 
 


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PRINCIPAL INVESTIGATOR SIGNATURE 
STUDY SPONSOR: 
National Institute of Diabetes and Digestive and Kidney Diseases 
STUDY TITLE: 
HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis 
STUDY ID 
PROTOCOL 
VERSION 
843471 
V1.7; July 7, 2023 
I have read the referenced protocol. I agree to conduct the study in accordance to this protocol, in 
compliance with the Declaration of Helsinki, Good Clinical Practices (GCP), and all applicable 
regulatory requirements and guidelines. 
Principal 
Investigator Name  
 
 
Signature 
 
Affiliation: 
 
 
Date 
 
 
 
 
 
 
 


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Abbreviations 
ACP 
American College of Physicians 
AE 
adverse event 
BPI 
Brief Pain Interference Scale 
BUP 
Buprenorphine 
CATI 
computer-assisted telephone interviewing  
CDC 
The Centers for Disease Control and Prevention 
COPES 
Cooperative Pain Education and Self-Management 
CSQ 
Coping Strategies Questionnaire 
CRF 
case report form 
DSMB  
Data and Safety Monitoring Board 
ESRD 
end-stage renal disease 
GAD-7 
Generalized Anxiety Disorder – 7 
GCP 
Good Clinical Practices 
HIPAA 
Health Insurance Portability and Accounting Act 
HOPE 
Hemodialysis Pain Reduction Effort 
IRB 
Institutional Review Board 
ICC 
intra-cluster correlation coefficient 
IVR 
interactive voice response 
MME  
morphine milligram equivalents  
MOP 
Manual of Procedures 
MSPSS 
Multidimensional Scale of Perceived Social Support 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
NIH 
National Institutes of Health 
NSAIDS 
non-steroidal anti-inflammatory drugs 
OHRP 
Office of Human Research Protections 
OUD 
opioid use disorder 
PA 
physician assistant 
PCS 
Pain Catastrophizing Scale 
PCST 
pain coping skills training 
PGIC 
Patient Global Impression of Change 
PHI 
protected health information 
PHQ-9 
Patient Health Questionnaire – 9 
PRO 
patient reported outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QOL 
Quality of Life 
MQOL 
McGill Quality of Life 
SAE 
serious adverse event 
SDRC 
Scientific and Data Research Center 
SIS 
Single-item scale 
SSRIs 
selective serotonin reuptake inhibitors 
SNRIs 
serotonin-nor-epinephrine reuptake inhibitors 
SUD 
substance use disorder 
TAPS 
Tobacco, Alcohol, Prescription medication, and other Substance use Tool 
TLFB 
Timeline Followback 
UPenn 
University of Pennsylvania 
U.S. 
United States 
 


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1. 
STUDY SUMMARY 
1.1. 
Synopsis 
Title 
HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis 
Short Title 
HOPE Trial 
Study Description 
HOPE is a randomized clinical trial that will evaluate approaches to reducing pain 
and opioid use among patients with chronic pain who are receiving maintenance 
hemodialysis for end-stage renal disease. The hypotheses are: 1) pain coping skills 
training is effective at reducing pain and opioid use, and 2) buprenorphine is 
acceptable and tolerable as an approach for managing opioid physical dependence. 
Objectives 
Primary Objective 
• To evaluate the effectiveness of pain coping skills training compared with usual 
care for reducing pain interference (primary outcome), and for improving other 
pain outcomes, opioid use, and associated conditions (all secondary outcomes) 
among patients with end-stage renal disease receiving treatment with 
maintenance hemodialysis  
 
Secondary Objective 
• To explore acceptability, tolerability, and efficacy of buprenorphine in a 
subgroup of trial participants prescribed moderate to high-dose long-term 
opioid therapy for chronic pain 
Primary Outcome 
Pain interference as measured by the Brief Pain Inventory Interference Scale 
Secondary 
Outcomes 
• Pain intensity 
• Pain catastrophizing 
• Opioid use 
• Composite of pain interference and opioid use 
• Quality of life 
• Physical functioning 
• Depression  
• Anxiety 
• Coping 
• Self-efficacy 
• Sleep quality 
• Fatigue 
• Other symptoms 
• Satisfaction with treatment 
• Social support 
• Family intrusion 


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• Discrimination 
• Falls  
• Hospitalizations 
• Death 
• Buprenorphine acceptability  
• Buprenorphine tolerability  
Study Population 
640 patients being treated with maintenance hemodialysis for end-stage renal 
disease who have chronic pain, at least 300 of whom have prescription opioid use.  
Phase or Trial Type 
Effectiveness (PCST intervention); Exploratory (buprenorphine intervention)  
Description of 
Sites/Facilities 
Enrolling 
Participants 
Participants are enrolled from multiple dialysis units affiliated with the following  
8 Clinical Centers, some of which involve collaborations across multiple medical 
centers:  
• Hennepin Health Care 
• Massachusetts General Hospital 
• New York University 
• University of Illinois-Chicago 
• University of Pittsburgh; University of Pennsylvania 
• University of Washington; University of New Mexico; Rogosin Institute 
• Vanderbilt University Medical Center; West Virginia University 
• Yale University; Multiple Veterans Affairs Healthcare Systems 
 
The Scientific and Data Research Center is based at the University of Pennsylvania. 
Description of Study 
Intervention 
1. Pain Coping Skills Training (PCST): Participants will complete a structured, 
standardized, interactive program designed to reduce pain interference, opioid 
use, and comorbid symptoms of depression, anxiety, and sleep disturbance. The 
program is adapted for the hemodialysis patient population, and is delivered 
using live coaches via video telehealth and with interactive voice response via 
telephone. 
2. Usual Care: Participants will be given educational materials and resources about 
alternatives to opioid pain medications. These materials will also be provided to 
participants in the PCST group. 
3. Buprenorphine: In a second phase of the trial, participants in both the PCST and 
Usual Care groups who meet eligibility criteria, including use of moderate to 
high-dose prescribed opioid therapy, will be offered  buprenorphine as an 
alternative to a full-agonist opioid pain medication. 
Study Duration 
44 months 
Participant Duration 
36 weeks 


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1.2. 
Key Roles and Study Governance 
Sponsor  
Scientific and Data Research Center 
National Institute of Diabetes and Digestive and 
Kidney Diseases / National Institutes of Health 
Perelman School of Medicine;  
University of Pennsylvania 
Project Scientist:  Paul L. Kimmel, MD 
Principal Investigator:  Laura M. Dember, MD 
Address: 
2 Democracy Plaza 
6707 Democracy Boulevard 
Bethesda, MD  20892-5458 
 
Address:  
920 Blockley Hall 
423 Guardian Drive 
Philadelphia, PA 19104 
Phone Number: 301-594-7717 
Phone Number 215-573-5264 
Email: kimmelp@extra.niddk.nih.gov 
Email: ldember@pennmedicine.upenn.edu 
The HOPE Trial Steering Committee includes the Contact Principal Investigator of each of the Clinical Centers 
and the Scientific and Data Coordinating Center, the NIDDK Project Scientist, the Steering Committee Chair 
(TBD), and patients. Additional HOPE Consortium committees include: 1) Protocol Committee and Working 
Groups, 2) Safety Committee, 3) Quality Control Committee, 4) Recruitment and Retention Committee, 5) 
Publications Committee, and 6) Stakeholder Advisory Committee composed of patients and representatives 
from dialysis provider organizations.  
The external Data and Safety Monitoring Board (DSMB), serves as a protocol review committee and a trial 
monitoring committee. The members and chair of the DSMB are appointed by the NIDDK. 
 
 


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1.3. 
Study Schema 
 
 
Figure 1.1. Trial Design 
The trial uses a sequential multiple assignment design with a randomized component (Phase 1) and a non-
randomized component (Phase 2). Patients undergoing treatment with maintenance hemodialysis who have 
chronic pain, a subset of whom are using prescribed opioid medications, are randomized in equal proportions 
to the Phase 1 intervention: Pain Coping Skills Training (PCST) or Usual Care for 24 weeks. The PCST 
intervention has two components each taking place over 12 weeks: 1) weekly telehealth sessions with a PCST 
coach, and 2) daily interactive voice response (IVR) sessions via telephone. The primary outcome of pain 
interference will be ascertained at Week 12 coinciding with the end of the PCST weekly coaching sessions. At 
Week 24, participants in either of the randomized groups who are taking opioids at a dose of ≥ 20 morphine 
milligram equivalents (MME)/day will be assessed for eligibility for the Phase 2 intervention. Participants who 
meet eligibility criteria for the Phase 2 intervention will be encouraged to switch from their current full agonist 
opioid medication to the partial opioid agonist, buprenorphine, as an approach to addressing physical 
dependence on prescribed opioids. Participants who do not meet the Phase 2 eligibility criteria will not be 
offered buprenorphine. All participants will continue to be followed from Week 24 until Week 36 for 
ascertainment of pain, opioid use, and other outcomes to address durability of the effects of PCST, and, for 
those who switch to buprenorphine, to assess buprenorphine acceptability, tolerability, and efficacy as 
exploratory outcomes. 


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2. 
INTRODUCTION AND RATIONALE 
2.1. 
Study Rationale 
With the recognition that many patients with end-stage renal disease (ESRD) prioritize how they feel and 
function over how long they live, there has been increased effort to address the tremendous symptom burden 
that accompanies ESRD.1 Pain is among the most common of these symptoms with approximately 60% of 
dialysis patients reporting pain that is usually described as moderate or severe.2 The causes and types of pain 
in this patient population are numerous and medical management is complicated by altered pharmacokinetic 
and pharmacodynamic properties of analgesic agents in the setting of kidney failure. Due to both the high 
prevalence of pain and the limited options for its management, use of opioid medications is common in this 
population. In 2010, as many as 20% of hemodialysis patients in the United States (U.S.) received prescribed 
opioids for 90 days or longer.3 Long term opioid therapy is of questionable benefit for chronic pain,4, 5 and, 
among the general population, is associated, in a dose-dependent manner, with an increased likelihood of 
serious harms including declining functional status, infection, hypogonadism, overdose, and opioid use 
disorder (OUD).6, 7 Among hemodialysis patients, long term opioid use is associated with increased rates of 
falls, hip fractures, hospitalizations, dialysis withdrawal, and death.3, 8 Patients treated with hemodialysis 
generally have low levels of physical activity and high rates of insomnia and depression,9 all of which can 
exacerbate chronic pain, complicate its management, and be potentiated by opioid use.10 Non-pharmacologic 
approaches such as cognitive behavioral therapy, mindfulness, and acceptance and commitment therapy, have 
demonstrated efficacy for chronic pain in the general population, but have not been studied in ESRD. 
Buprenorphine, a partial opioid agonist with an improved safety profile compared to other opioids, may be an 
effective option for reducing opioid use among patients treated with hemodialysis, but there is limited 
experience with this drug in the ESRD population. Thus, the primary objective of this 36-week trial is to 
evaluate the effectiveness of a cognitive behavioral therapy-based intervention called pain coping skills 
training (PCST) for improving pain and reducing opioid use among patients on hemodialysis with chronic pain. 
A secondary objective is to explore acceptability, tolerability, and efficacy of buprenorphine among patients 
who are using prescribed moderate to high-dose opioid therapy. 
2.2. 
Background 
2.2.1. 
Prevalence of Pain among Patients Treated with Hemodialysis 
In the U.S. chronic pain has a prevalence of 11% among adults and was estimated in 2016 to have an annual 
cost of $635 billion.11 Due to a high comorbidity burden, chronic pain is even more common among patients 
undergoing treatment with maintenance hemodialysis.12 13 More than half of hemodialysis patients have 
diabetes mellitus,14 often with accompanying painful neuropathy, and most patients have ESRD-associated 
mineral metabolism disorders that predispose to chronic musculoskeletal pain,15 and to a fracture risk that is 
2- to 4-fold higher than that for the general population.16 Falls are also common among hemodialysis patients; 
recent reports indicate that 25-30% of hemodialysis patients experience at least one fall per year and 57% of 
these individuals reported multiple falls.17  


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Pain in the setting of ESRD and hemodialysis has some key differences from that experienced by the general 
population. In addition to chronic pain, patients often experience acute pain associated with recurring 
hemodialysis sessions (typically 3 per week). Sources of hemodialysis-associated pain include severe muscle 
cramping resulting from fluid removal, needle infiltrations, vascular steal syndrome and other complications of 
hemodialysis vascular access, and a “washed out” feeling with substantial fatigue and headaches that may 
persist for up to 12 hours after dialysis sessions. One recent systematic review estimated that 33-82% and  
21-92% of dialysis patients have acute and chronic pain, respectively.18 An earlier systematic review quantified 
this as a mean prevalence of pain of 47% across 60 studies, with pain during the hemodialysis treatments, 
including vascular access pain, headache, neuropathic pain, and musculoskeletal pain, occurring most 
frequently.12 
2.2.2. 
Complexity of Pain Management among Patients Treated with Hemodialysis 
Pharmacologic options to treat pain are limited for patients receiving maintenance dialysis because of a 
difficult balance between efficacy and safety for many types of medications (see Table 2.1). The high risk-to-
benefit ratio results from reduced clearance of agents that are metabolized by the kidneys and from side 
effects that are of particular significance in the presence of kidney failure. Despite limited evidence for 
efficacy,19 long-term opioid therapy, defined as ≥ 90 days of opioid analgesics, has emerged as a dominant 
treatment paradigm for chronic pain, particularly among maintenance hemodialysis patients.3 The challenges 
associated with long-term use of opioid medications, discussed in Section 2.2.3, have resulted in a critical need 
in the dialysis population for better pharmacologic strategies as well as approaches that combine 
pharmacologic and non-pharmacologic interventions to reduce pain and its deleterious effects.  
Table 2.1. Systemic Pharmacologic Options for Pain in Hemodialysis: Benefits and Llimitations20, 21 
Class 
Benefits 
Limitations 
Non-steroidal anti-inflammatory 
drugs (NSAIDS) 
Effective pain control; inexpensive; 
no central nervous system effects 
May accelerate loss of residual kidney 
function; gastrointestinal bleeding 
COX-2 Inhibitors 
Effective pain control; no CNS effects 
May accelerate loss of residual kidney 
function; pro-thrombotic 
Acetaminophen 
Safe; inexpensive 
Often insufficient analgesia; liver toxicity 
Tricyclic antidepressants 
Likely effective for treating 
neuropathic pain 
Anticholinergic adverse effects, 
particularly in the elderly 
Selective serotonin reuptake 
inhibitors / serotonin-nor-
epinephrine reuptake inhibitors  
May be effective for treating 
neuropathic and headache pain 
Dosing considerations for some agents; 
may worsen restless leg syndrome; QT 
prolongation with some agents 
Gabapentin / Pregabalin 
Likely effective for neuropathic pain 
High toxicity risk including mental status 
changes, somnolence, and hypotension 
Opioids 
May be effective for treating pain in 
some patients (mixed evidence);  
Addiction potential; constipation, 
mental status changes, somnolence, 
respiratory depression; mixed evidence 
for efficacy for chronic pain 


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2.2.3. 
Potential Harms from Long Term Opioid Therapy  
In the non-dialysis population, observational data and limited clinical trial data suggest that long-term opioid 
therapy is associated with potential harms without significant improvements in chronic pain. In addition to a 
higher risk of overdose death among long-term opioid recipients,22 accumulating data show dose-dependent 
associations with hypogonadism, infection,6 osteoporosis, falls, fractures, motor vehicle accidents, opioid use 
disorder (OUD), and intermittent withdrawal symptoms,7 and, additionally, among hemodialysis patients, with 
increased rates of hospitalizations, dialysis withdrawal, and death.3 For the general population, the Centers for 
Disease Control and Prevention (CDC) recommends using non-opioid medications instead of opioids for 
chronic pain. For patients already taking opioids, the CDC recommends that providers use caution if increasing 
opioid doses above 50 MME/day and avoid dose escalations to beyond 90 MME/day.23 For the dialysis patient 
population, data to guide opioid dosing and alternative pain management strategies are lacking.21 For 
example, because of its hepatic metabolism and elimination, methadone is a favored opioid in the setting of 
kidney failure;24 however, methadone has multiple drug interactions and prolongs the QT interval which may 
have important implications given the high rates of sudden cardiac death among hemodialysis patients. 
2.2.4. 
The Need for Non-Pharmacologic Approaches to Pain Management and Opioid Reduction in 
the Setting of Maintenance Hemodialysis 
Individuals receiving maintenance hemodialysis are an exceedingly vulnerable population. Mortality rates are 
similar to those for metastatic cancer,25 the burden of pain, prevalence of frailty, and rates of physical and 
cognitive impairment are high, and there are few well-studied strategies for managing symptoms. As is evident 
in Table 2.1, pain management is challenging in the setting of kidney failure. Non-steroidal anti-inflammatory 
drugs are often contraindicated because of the need to maintain residual kidney function and the risk of 
gastrointestinal bleeding, and the use of other agents, such as gabapentin and pregabalin,26 is limited by 
toxicities including orthostasis, encephalopathy, somnolence, and falls. Many opioids are metabolized and 
cleared differently when kidney function is reduced, increasing the risk of adverse effects of some agents. 
Patients with dialysis-dependent ESRD may be more vulnerable to the neurocognitive, endocrine and 
infectious complications of opioids, but they may also be more vulnerable to the complications associated with 
non-opioid based pain regimens and, in the absence of pain control, may become increasingly debilitated. 
Accordingly, safely minimizing the toxicities of pain management strategies while maximizing overall levels of 
functioning is a critical goal for this patient population. These complexities underscore the need for targeted 
strategies to incorporate non-pharmacological approaches to pain management.  
2.2.5. 
Rationale for a Pain Coping Skills Training Intervention to Address Pain and Opioid Use 
Cognitive behavioral therapy directed at pain coping skills has a strong evidence base and is among the most 
widely studied non-pharmacological treatments for chronic pain.27 Providing cognitive behavioral coping skills 
training is an attractive adjunct or alternative to pharmacological treatments because its effects can persist 
after treatment is discontinued without the negative side effects and potential harms of pharmacological 
treatments such as opioids. The goal of a cognitive behavioral pain coping skills intervention is to help patients 
develop skills to manage pain, and its associated disability and emotional distress, as a means to improve 
functioning and quality of life.28 Skills include reframing maladaptive cognitive processes (e.g., catastrophizing) 


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and promoting adaptive behaviors (e.g., relaxation). Cognitive behavioral interventions have been 
recommended by the CDC23 and American College of Physicians (ACP)29 as a first-line treatment to reduce pain 
and improve function. 
Newer treatments such as mindfulness and acceptance and commitment therapy share commonalities in their 
underlying rationale and treatment strategies with standard cognitive behavioral therapy. Because of these 
commonalities and lack of single universally accepted protocol for these treatments for pain, many 
interventions for chronic pain combine techniques from all of these treatments.   
2.2.5.1. 
Efficacy of Interactive Voice Response for Chronic Pain Cognitive Behavioral Interventions 
In addition to providing pain coping skills training through telehealth-delivered real-time sessions between a 
coach and a patient, the cognitive behavioral intervention for this trial includes an interactive voice response 
(IVR) component that is based on the recently developed and tested COPES (Cooperative Pain Education and 
Self-Management) program.30 In a non-inferiority trial that compared an in-person cognitive behavioral 
intervention to COPES in a non-ESRD patient population, post-treatment statistically significant improvements 
in physical functioning, sleep quality, and physical quality of life relative to baseline occurred with both 
treatments, with no significant advantage for either treatment.30 Additionally, patients were equally satisfied 
with COPES and the in-person intervention. Importantly, work by Naylor and colleagues demonstrated that 
IVR-based booster sessions, similar to those that will be used in this trial, following a traditional cognitive 
behavioral intervention produced maintenance of treatment gains and continued reduction in opioid 
medication use.31   
The IVR treatment infrastructure that has been developed and tested in prior trials will provide foundational 
resources for this trial. In prior studies, participants completed 85-90% of scheduled daily calls. The COPES 
manual includes an extensive library of feedback scripts that have been refined based on post-treatment 
participant interviews and feedback with participants from the original COPES trial. These feedback scripts will 
serve as the basis for the personalized feedback in the planned IVR booster intervention.  
2.2.5.2. 
Adaptation of Pain Coping Skills Training Interventions to the Hemodialysis Population 
Patients undergoing hemodialysis have high rates of depression, and the presence of depressive symptoms is 
known to be associated with dialysis withdrawal, hospitalization, mortality, and non-adherence with dialysis 
treatments.32-34 Additionally, low rates of physical activity, poor sleep, and quality of life are well-documented 
in this population.35-37 Cognitive behavioral skills may be effective for improving depression, quality of life, and 
sleep, and increasing physical activity and adherence behaviors among patients treated with hemodialysis.38 
For the HOPE Trial, the Pain Coping Skills Training (PCST) intervention will retain the critical components of 
traditional behavioral pain management skills but will be expanded to include skills for mood regulation, sleep 
improvement, and anxiety management, all core issues for this patient population. A focus will be on 
highlighting how these conditions and their treatment overlap and interact, e.g., walking improves pain and 
physical function, or cognitive restructuring can address pain catastrophizing as well as beliefs that impede 
hemodialysis adherence or maintain depressive symptoms. Additionally, the intervention will promote use of 


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skills such as guided mindfulness and progressive muscle relaxation during hemodialysis sessions, a setting 
well-suited for these types of interventions.  
2.2.6. 
Rationale for a Buprenorphine Intervention to Address Opioid Physical Dependence in 
Hemodialysis Patients 
Buprenorphine is a partial opioid agonist with analgesic properties similar to those of full-agonist opioids. 
Various formulations of buprenorphine are available for the treatment of opioid use disorder and for pain. 
Because buprenorphine causes less respiratory depression than full agonist opioids, it is considered to be safer 
and is designated as a schedule III controlled substance, in contrast to schedule II full agonists such as 
oxycodone, hydrocodone and others.39, 40 Among patients on long-term opioid therapy for chronic pain, higher 
prescribed opioid daily doses (compared with lower daily doses) are associated with worse pain-related 
function and more frequent adverse outcomes. Limited evidence suggests that opioid dose reduction can 
improve pain, function, and quality of life; however, physical dependence makes it difficult for many patients 
prescribed long-term opioids to reduce their opioid use. Buprenorphine addresses physical dependence by 
preventing withdrawal symptoms and reducing cravings. Patients who have transitioned from high-dose 
opioids to buprenorphine often have improved pain/function and decreased opioid-related adverse effects.41, 
42 In a large controlled case series, buprenorphine was effective for successful discontinuation of full-agonist 
opioids by patients on long-term opioid therapy for pain; due to marked physical opioid dependence, patients 
in this study used higher dose buprenorphine formulations approved for treating opioid use disorder,43 as 
opposed to the lower dose formulations approved for pain. Benefits of switching from full-agonist opioids to 
buprenorphine are hypothesized to be due to effective management of physical dependence, which allows 
patients to more easily reduce their overall opioid use. Buprenorphine may also have fewer adverse cognitive 
and emotional effects than other opioids. Patients receiving maintenance hemodialysis for kidney failure may 
be especially vulnerable to adverse effects associated with use of long-term opioids and may experience these 
adverse effects at lower daily dosages than other patients. Thus, strategies are needed to help this patient 
population reduce opioid use and, ultimately, reduce pain interference and opioid adverse effects. The HOPE 
Consortium trial will evaluate, in an exploratory manner, the acceptability, tolerability, and potential efficacy of 
buprenorphine for physical dependence on opioids in hemodialysis patients on moderate to high-dose long-
term opioid therapy. 
2.2.6.1. 
Buprenorphine Pharmacokinetics, Pharmacodynamics, and Toxicology 
Buprenorphine taken orally undergoes extensive first-pass metabolism but its bioavailability with sublingual 
administration makes this a feasible route of administration. The mean time to maximum plasma 
concentration of buprenorphine following sublingual administration is variable, ranging from 40 minutes to 3.5 
hours. Buprenorphine has a large volume of distribution and is highly protein bound (96%). The drug is 
extensively metabolized by N-dealkylation to norbuprenorphine, primarily through cytochrome P450 (CYP) 3A4 
(i.e., liver, not renal, metabolism). The terminal elimination half-life of sublingually administered 
buprenorphine is 22 to 44 hours. Approximately 10-30% of buprenorphine is excreted in the urine. Some 
formulations of buprenorphine include naloxone as a deterrent to misuse via injection, but naloxone is inert 
when buprenorphine/naloxone is used as directed. Naloxone does not appear to influence the 


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pharmacokinetics of buprenorphine when the combination buprenorphine/naloxone product is taken as 
prescribed (sublingually). Buprenorphine crosses the placenta during pregnancy and also crosses into breast 
milk. It is not necessary to modify dosing of buprenorphine in kidney failure, and the safety of buprenorphine 
in ESRD and compatibility with hemodialysis are established.44,45 The half-life of buprenorphine may be 
prolonged in individuals with severe chronic liver disease because of reduced CYP3A4 activity. Buprenorphine 
is not removed by dialysis.45 
2.3. 
Risk / Benefit Assessment for the HOPE Trial Interventions 
2.3.1. 
Known Potential Risks of Trial Interventions 
The PCST intervention may increase distress for participants if sensitive topics are raised during the telehealth 
or IVR sessions. All prescribing decisions for participants will be made by the treating physicians rather than by 
the research team. Participants in both the PCST and Usual Care groups may have adverse effects from the 
non-opioid pain medications that are prescribed by treating (non-study) clinicians during the course of the 
study. Patients may experience withdrawal symptoms and other temporary discomfort due to reducing opioid 
doses, switching from one opioid medication to another, or transitioning to non-opioid medications. Because 
opioids may reduce the symptoms of restless leg syndrome in hemodialysis patients, reducing or discontinuing 
opioids may worsen this condition. Intervention clinicians will educate participants about withdrawal 
symptoms, take precautions to prevent withdrawal, and manage symptoms if they occur.  
Common adverse effects of buprenorphine, the Phase 2 intervention, are similar to those of other opioids and 
include dizziness, headache, sedation, dry mouth, mouth numbness, constipation, insomnia, abdominal pain, 
drowsiness, fatigue, and numbness or tingling. An FDA report issued on January 12, 2022 identified dental 
issues such as tooth decay, cavities, oral infections, and loss of teeth, as newly recognized possible adverse 
effects of buprenorphine delivered via buccal or sublingual approaches. The FDA advises that these dental 
problems have been reported even in patients with no history of dental issues.   The risk of these dental 
problems can be reduced by rinsing the mouth with water after using the drug, waiting at least an hour before 
teeth brushing, visiting a dentist shortly after starting buprenorphine, and having regular dental checkups.  The 
FDA maintains that despite these risks, the benefits of buprenorphine medicines clearly outweigh the risks.  As 
for all opioids, additive or synergistic interactions can occur between buprenorphine and central nervous 
system depressants including benzodiazepines and alcohol. Active, untreated substance use disorder is an 
exclusion criterion for the trial. Study investigators will educate participants eligible for the buprenorphine 
intervention about withdrawal symptoms, take precautions to prevent withdrawal, and manage symptoms if 
they occur.  
The trial will not exclude people who are pregnant. Pregnancy is rare in patients undergoing maintenance 
hemodialysis. The PCST intervention does not require any specific medications or activities with pregnancy-
associated risks, and for participants who are pregnant, lactating, or could possibly be pregnant, 
contraindicated medications will not be recommended by the research teams. People who are pregnant or 
people with child-bearing potential who are not willing to use acceptable forms of contraception will not be 
eligible for the buprenorphine intervention (see Study Schema in Section 1.2) since opioid withdrawal during 
pregnancy may increase the risk of miscarriage and preterm labor.  


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2.3.2. 
Known Potential Benefits of Trial Interventions 
As described above, demonstrated benefits of CBT-based interventions in the non-ESRD setting include 
reduced pain interference and pain intensity, reduced opioid use, and improved quality of life. In the ESRD 
setting, CBT has been shown to be an effective treatment for depression.46 Buprenorphine improves function 
and quality of life in individuals with opioid dependence and has demonstrated analgesic efficacy. 
Buprenorphine has a markedly lower risk of overdose compared to full agonist opioids so its use could 
decrease long-term overdose risk.  
2.3.3. 
Assessment of the Balance between Risks and Benefits 
Risks of the trial interventions, described above, are similar to those in routine clinical care. Benefits and risks 
of recommended therapies will be discussed with patients as in clinical practice. To address the potential for 
increased distress from discussing sensitive topics in the PCST arm, the PCST coaches will be trained to manage 
such distress in accordance with accepted standard practices, and there will be a protocol in place for 
protective transfer should greater intensity of services be indicated. Buprenorphine is an FDA-approved 
medication for which there is more than 15 years of post-marketing data, and a risk profile that is similar 
among patients with and without impaired kidney function. Buprenorphine is a schedule III controlled 
substance, meaning its risk for abuse is considered by the DEA to be lower than the risk with the opioid 
medications likely to be used by patients enrolled in the trial (mostly schedule II opioids). Eligibility for the 
buprenorphine component of the trial intervention will be based on specific criteria assessed at Week 24 and 
use of buprenorphine will require additional informed consent. 
Overall, the benefits of trial participation outweigh the risks based on the following considerations: 1) there 
are substantial potential benefits including improved pain management, decreased opioid-related adverse 
effects, and improved safety, and 2) the known risks will be minimized through individualized care decisions 
consistent with standards of care.   


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3. 
STUDY OBJECTIVES 
The overall objective of the trial is to evaluate the effectiveness of approaches to reducing pain and opioid use 
among individuals receiving treatment with maintenance hemodialysis for ESRD. The specific objectives and 
outcomes are summarized in Table 3.1. Additional information about the outcomes and methods for their 
ascertainment is provided in Section 4.3. 
Table 3.1. Trial Objectives and Outcomes 
Objectives 
Outcomes 
Justification for Outcomes 
Primary 
To evaluate the effectiveness of pain 
coping skills training compared with 
usual care for reducing pain 
interference, opioid use, and related 
outcomes among patients with end-
stage renal disease receiving treatment 
with maintenance hemodialysis 
The primary outcome is reduction in pain 
interference, as measured by the Brief Pain 
Inventory Interference scale. 
Secondary outcomes include:  
• Pain intensity 
• Composite of pain interference and 
opioid use 
• Opioid use 
• Pain catastrophizing 
• Quality of life 
• Depression 
• Anxiety 
• Coping 
• Self-efficacy 
• Sleep quality 
• Fatigue 
• Other symptoms 
• Satisfaction with treatment 
• Social  support 
• Family intrusion 
• Discrimination 
• Falls  
• Hospitalization rate 
• Death 
The primary outcome, pain 
interference, is important 
both patients and providers, 
and has been recommended 
by expert consensus groups 
as one of the most important 
measures for chronic pain 
trials.  
 
The secondary outcomes 
include conditions or 
symptoms often associated 
with chronic pain and/or 
opioid use, or clinical events 
that can result from 
medications used to manage 
pain. 
 
Exploratory 
To explore acceptability, tolerability, 
and efficacy of buprenorphine among 
hemodialysis patients receiving 
moderate to high-dose long-term 
opioid therapy for chronic pain 
• Acceptability to patients, as measured 
by the proportion of participants who 
initiate buprenorphine from among 
those participants who are offered 
buprenorphine.   
• Tolerability, as measured by the 
proportion of participants who do not 
discontinue buprenorphine due to 
adverse effects or intolerance. 
• Efficacy, as assessed by the Brief Pain 
Inventory Interference scale  
Assessment of acceptability 
and tolerability of 
buprenorphine is needed 
before conducting definitive 
large scale trials of 
buprenorphine in the 
hemodialysis patient 
population. 
 


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4. 
STUDY DESIGN AND OUTCOMES 
4.1. 
Trial Design and Rationale  
The primary trial hypothesis is that pain coping skills training will improve pain and opioid use outcomes more 
than usual clinical care. The design is a multicenter, sequential, multiple assignment trial with a randomized 
component (Phase 1) and a non-randomized component (Phase 2).  In Phase 1 (Weeks 1 - 24), participants will 
be randomized into one of two treatment groups: 1. Pain Coping Skills Training (PCST) for 24 weeks, or 2. Usual 
Care.  The PCST intervention has two sequential components each taking place over 12 weeks: 1) weekly 
telehealth sessions with a PCST coach, and 2) daily interactive voice response (IVR) sessions via telephone. The 
primary outcome of pain interference will be ascertained at Week 12 which coincides with the end of the PCST 
weekly coaching sessions. In Phase 2, beginning at Week 24, participants in both randomized groups will be 
assessed for eligibility for a second intervention, buprenorphine, as an alternative to full agonist opioid pain 
medication.  The main eligibility criterion for the buprenorphine intervention is current use of prescribed 
opioids at an average dose of ≥ 20 morphine milligram equivalents (MME)/day. Participants who meet the 
buprenorphine eligibility criteria will be  encouraged, but not required, to switch from their current opioid 
medication to buprenorphine to explore buprenorphine as an approach to addressing physical opioid 
dependence in patients receiving maintenance hemodialysis. Participants who do not meet the buprenorphine 
eligibility criteria will not be offered buprenorphine. All participants will continue to be followed from Week 24 
until Week 36 (Phase 2) for ascertainment of pain, opioid use, and other outcomes to address durability of the 
effects of PCST, and, for those who switched to buprenorphine, to assess buprenorphine acceptability, 
tolerability, and efficacy as exploratory outcomes.  
Randomization will be performed at the level of the individual participant using permuted blocks with 
stratification by enrolling site and by the presence or absence of opioid use using the criteria provided in 
Section 5.3 for the Phase 1 randomization. Treatment assignments will not be masked to participants or 
research team members because of 1) impracticability, and 2) an interest in implementing the interventions as 
they would be outside of a trial setting. The trial includes a control group that does not receive an active 
intervention beyond usual clinical care so it is possible to determine whether changes observed in the active 
treatment groups are the result of the interventions or the result of either increased attention that 
accompanies trial participation or the natural history of the condition. Bias will be minimized by performing 
randomization after collection of baseline data, concealing the allocation order, and ascertaining the patient-
reported outcomes, including the primary outcome, using standardized, centrally administered questionnaires 
by research personnel blinded to treatment assignment.  Safety and tolerability will be evaluated through 
ascertainment of specific adverse events of interest and serious adverse events throughout the duration of the 
trial. 
4.2. 
Outcomes 
Citations and references for the instruments or questionnaires used for the outcome ascertainment are 
provided in Appendix 14.2 and Section 13, respectively. 


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4.2.1. 
Primary Outcome: Pain Interference  
Pain interference will be measured by the Brief Pain Inventory Interference Scale (BPI Interference)47 which has 
a 7-day look-back period. The BPI is a multidimensional measure developed for cancer pain, but subsequently 
validated in diverse populations, including patients with chronic pain.47, 48 BPI is composed of the severity 
subscale (four pain intensity items) and the interference subscale (seven pain interference items). Pain 
interference has been recommended by expert consensus groups as a key outcome measure in chronic pain 
trials.49 Interference, or the degree to which pain interferes with various domains of function, is thought to 
have greater salience with patients and greater generalizability across populations than pain intensity.47, 50-53 
The BPI Interference scale, specifically, has demonstrated responsiveness to change in numerous clinical 
trials.54-56 
4.2.2. 
Secondary Outcomes  
The secondary outcomes will include: 1) patient-reported indicators of pain and opioid use, 2) patient-reported 
indicators of conditions or symptoms that often accompany pain and/or opioid use, 3) clinical outcomes, and 
4) acceptability and tolerability outcomes. 
4.2.2.1. 
Secondary Pain and Opioid Use Outcomes 
As secondary outcomes, pain and opioid use will be assessed using the instruments or methods shown in  
Table 4.1 and analyzed as continuous measures.  
Table 4.1. Secondary Outcomes: Pain and Opioid Use 
 
Domain 
 
Instrument or Data Source 
 
Look-Back Period 
Time-Points for 
Assessment 
Pain intensity 
Brief Pain Inventory (BPI) Severity 
7 days 
Weeks 0, 12, 24, 36 
Pain catastrophizing 
Pain Catastrophizing Scale – SF 6 
None 
Weeks 0, 12, 24, 36 
Opioid use 
Timeline Followback 
14 days 
Weeks 0, 12, 24, 36 
Composite of pain and opioid use  
BPI Interference / Timeline Followback 
7 days/14 days 
Weeks 0, 12, 24, 36 
4.2.2.1.1. 
Composite Outcome of Pain and Opioid Use 
One of the secondary outcomes is a composite outcome of pain and opioid use as shown in Table 4.2. Both a 
reduction in pain interference with stable or decreased opioid use, and a reduction in opioid use with stable or 
decreased pain interference will be categorized as success. 
Table 4.2. Composite Outcome of Pain Interference and Opioid Use: Success (+) or No-Success (−) 
 
Pain Less 
Pain Stable 
Pain More 
Opioid Use Less 
+ 
+ 
− 
Opioid Use Stable 
+ 
− 
− 
Opioid Use More 
− 
− 
− 


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Criteria for Less, Stable, and More Pain 
For the composite outcome of pain and opioid use, the criteria for less, stable, and more pain are based on the 
change from the baseline BPI Interference score using the following thresholds:57 
Pain Less: Decrease in BPI Interference score of > 1 point 
Pain Stable: Change in BPI Interference by 0 – 1 point in either direction 
Pain More: Increase in BPI Interference by > 1 point 
Criteria for Less, Stable, and More Opioid Use 
For the composite outcome of pain and opioid use, the criteria for less, stable, and more opioid use are based 
on the difference from baseline in average MME/day using the following thresholds: 
Opioid Use Less: ≥ 25% reduction in average MME/day 
Opioid Use Stable: < 25% reduction and < 10% increase in average MME/day 
Opioid Use More: ≥ 10% increase in average MME/day 
The rationale for considering an increase in MME/day of up to < 10% as stable opioid use is to account for 
sporadic, unpredictable acute pain events or clinically unimportant increases in chronic opioid use. 
4.2.2.2. 
Secondary Outcomes Reflecting Conditions or Symptoms Associated with Pain and/or 
Opioid Use 
The effects of the interventions on several conditions or symptoms often associated with pain and/or opioid 
use will be evaluated through ascertainment of a set of patient-reported outcomes using validated 
instruments (see Table 4.3).  
Table 4.3. Secondary Outcomes Reflecting Conditions or Symptoms Associated with Pain and/or Opioid Use 
Domain 
Instrument or Data Source 
Time-Points for 
Assessment 
Depression 
Patient Health Questionnaire (PHQ)-9 
Weeks 0, 12, 24, 36 
Anxiety 
Generalized Anxiety Disorder (GAD)-7 
Weeks 0, 12, 24, 36 
Sleep quality 
PROMIS Sleep Disturbance 6a + Sleep Duration Question 
Weeks 0, 12, 24, 36 
Fatigue 
PROMIS Fatigue SF 6a 
Weeks 0, 12, 24, 36 
Other symptoms 
Dialysis Symptom Index 
Weeks 0, 12, 24, 36 
Physical functioning 
PROMIS Physical Functioning SF 6b 
Weeks 0, 12, 24, 36 
Quality of life 
Single-Item QOL Scale [SIS] from McGill Quality of Life (MQOL) 
Weeks 0, 12, 24, 36 
Coping 
Coping Strategies Questionnaire: 1-item version 
Weeks 0, 12, 24, 36 
Self-efficacy 
PROMIS Self-Efficacy for Managing Chronic Conditions – Managing 
Symptoms – Short Form 8A + single item targeting self-efficacy for pain 
Weeks 0, 12, 24, 36 
Discrimination 
Everyday Discrimination Scale 
Weeks 0, 36 
Satisfaction with treatment 
Patient Global Impression of Change 
Weeks 0, 12, 24, 36 
Family intrusion 
PROMIS Satisfaction with Social Roles and Activities 
Weeks 0, 12, 24, 36 
Social support  
Multidimensional Scale of Perceived Social Support (MSPSS) 
Weeks 0, 12, 24, 36 


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4.2.2.3. 
Secondary Outcomes: Clinical Events  
The trial interventions are hypothesized to reduce the frequency of several clinical events that will be treated 
as secondary outcomes.  
• 
Falls 
• 
Hospitalizations 
• 
Deaths 
4.2.2.4. 
Exploratory Outcomes: Acceptability and Tolerability of Buprenorphine 
Participants who meet the eligibility criteria for buprenorphine will be encouraged, but not required, to initiate 
buprenorphine. The buprenorphine acceptability and tolerability outcomes are: 
Acceptability 
1. The proportion of participants who initiate buprenorphine among those who are offered the 
buprenorphine intervention. 
2. Reasons for not initiating buprenorphine will be ascertained via questionnaire. 
Tolerability 
1. The proportion of participants who do not discontinue buprenorphine due to adverse effects among those 
who initiate buprenorphine  
2. Medication-related side effects assessed via questionnaire. 
4.2.3. 
Patient-Reported Outcome (PRO) Ascertainment Approach 
The primary and secondary patient-reported outcomes for participants at each of the clinical sites will be 
captured using computer-assisted telephone interviewing (CATI), administered by a centralized team who will 
be masked to patient treatment assignments. 
CATI is a highly reproducible approach for patient-reported outcomes with successful implementation in 
several multi-center clinical trials in hemodialysis including the Frequent Hemodialysis Network studies and 
ASCEND,46 and is currently being used for SLEEP-HD (NCT03534284) and the Hemodialysis Novel Therapies 
ACTION trial (NCT03141983). The approach allows for participation of patients with a wide range of health 
literacy and limitations in vision and manual dexterity, and reduces bias in assessing patient-reported 
outcomes. An interviewer blinded to the treatment assignment will administer the English or Spanish versions 
of the patient-reported outcome measures made available to the interviewer through the web-based study 
portal in sequential screens in a fixed sequence starting with the Brief Pain Inventory Interference scale. The 
study coordinator at each site will schedule the date and time for the participant to receive a phone call for 
outcome ascertainment. The participant will choose whether to receive the phone call at home on a non-
dialysis day (preferred) or at the dialysis unit. Efforts will be made to ensure that all subsequent calls occur at 
the same site as the baseline assessment. The research team at each site will be equipped with mobile phones 
that can be made available to participants for the calls, if needed. Each call is expected to last approximately 
45 minutes (see Appendix 14.1 for the instruments included in the full and partial sets of PROs).  


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The CATI team will be represented on the regular teleconferences of the Steering Committee, Recruitment and 
Retention Committee, and Quality Control Committee, and will review data capture bi-weekly with the SDRC. 
A data tracking and scheduling report will be established by the SDRC. The report will prompt the clinical sites 
to update contact information and vital status prior to data collection calls. To the extent possible, the calls will 
be performed within a 10-day window around the target date. 
4.2.4. 
Timing of Ascertainment of Primary Outcome 
The primary outcome for the trial will be ascertained at Week 12 which coincides with the end of the PCST 
weekly coaching sessions. The rationale for ascertaining the primary outcome at the end of the weekly 
coaching sessions, rather than after the IVR component of PCST, is as follows: 
1. The initial component of the PCST intervention that is administered by a live coach using a cognitive 
behaviorally oriented approach is the component of the PCST intervention that has established 
efficacy in other patient populations. 
2. The initial component of the PCST intervention is more readily implemented in clinical practice than is 
the IVR component due to shorter duration and lack of need for additional technical resources. 
3. Assessment of the primary outcome at Week 12 rather than Week 24 protects against loss to 
follow-up because of kidney transplantation, medical events, or death. 


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5. 
STUDY POPULATION 
The eligibility criteria for trial participation are provided in Sections 5.1 and 5.2. The criteria for the 
buprenorphine intervention are provided in Section 6.3.2. 
5.1. 
Inclusion Criteria 
1. Age ≥ 18 years 
2. Undergoing in-center maintenance hemodialysis for ≥90 days 
3. English- or Spanish-speaking 
4. Chronic pain defined as a response of “Most days” or “Every day” to the following question: “In the 
past 3 months, how often have you had pain?” Answer options: Never, Some days, Most days, 
Every day 
5. Current PEG58 score ≥ 4  
6. Willing to provide informed consent 
7. Willing to allow research team to obtain opioid pharmacy refill data 
8. Willing to allow research team to contact and work with their opioid prescriber  
5.2. 
Exclusion Criteria 
1. Current opioid use disorder 
2. Current use of heroin 
3. Current non-opioid substance use disorder with the exception of tobacco use disorder 
4. Current use of methadone, buprenorphine, or naltrexone for opioid use disorder 
5. Current receipt of hospice care 
6. Cognitive impairment that, in the judgement of the research team, precludes trial participation  
7. Active suicidal intent based on an initial screening with PHQ-9 question #9 followed by further 
assessment when indicated (see Section 6.5.4.) 
8. Unstable bipolar disorder, schizophrenia, post-traumatic stress disorder, or other psychotic disorder 
9. Life expectancy < 6 months 
10. Expected to receive a kidney transplant, transfer to another dialysis facility, or transition to home 
dialysis within 6 months 
11. Current incarceration 
12. Any other condition that the investigator considers precludes participation in the clinical trial 
5.3. 
Subgroup with Current or Recent Opioid Use  
During eligibility screening all potential participants will have opioid use ascertained using the timeline follow 
back approach. The trial will enroll at least 300 participants (among the 640 total study participants) with 
current or recent opioid use defined as patient-reported prescription opioid use during at least 3 of the past 6 
months. The number of participants in the opioid use subgroup will be monitored throughout the trial 
enrollment period. If the rate of enrollment into the opioid use subgroup is lower than targeted, trial 
enrollment will be restricted to individuals meeting the opioid use criteria as long as this restriction will not 
compromise the ability of the trial to meet its overall enrollment goal by the target completion date.  


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5.4. 
Participant Recruitment and Eligibility Screening 
Patients being treated in participating dialysis facilities will be invited to complete a brief pre-screening survey. 
They will be informed that the purpose of the survey is to identify people who might be appropriate for 
subsequent screening for trial participation. The pre-screening survey will include one item about chronicity of 
pain, the PEG 3-item scale and a request for basic contact information (name and phone number). Patients will 
have the option to opt-out of the pre-screening. The survey also provides an opportunity to indicate a 
preference to not be contacted about the trial in the future. Completion of the pre-screening survey is not 
required for study participation. Patients may be approached for consent and subsequent screening activities 
without having completed the pre-screening survey. 
All patients meeting the pain chronicity criterion will be approached for their willingness to undergo screening 
activities for participation in the clinical trial. Patients who agree to undergo screening will be asked to sign the 
trial consent form for the 36-week trial (Phases 1 and 2) prior to any further research-related activities. Dialysis 
unit laboratory studies, medical records at Clinical Centers, and treatment or history records at local dialysis 
units may be reviewed as part of the screening process. Informational materials may be disseminated at 
participating dialysis units in order to allow potential participants to learn about the study and to contact 
investigators if interested. All study material must be approved by local IRBs before dissemination to potential 
study participants.   
5.5. 
Re-Screening for Eligibility 
Individuals who do not meet the eligibility criteria for one or more reasons can be screened again after  
30 days. There is no limit to the number of times an individual can be screened for participation in the trial.  


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6. 
STUDY INTERVENTIONS 
 
Figure 1.1 and described in Section 4.1, participants will be initially randomized to Pain Coping Skills Training 
for 24 weeks, or Usual Care. At Week 24, all participants will be assessed for eligibility for the buprenorphine 
intervention. Buprenorphine-eligible participants – determined by current opioid use, will be encouraged, but 
not required, to switch from their full agonist opioid medication to buprenorphine.  
6.1. 
Pain Coping Skills Training Intervention (PCST) 
The PCST intervention will focus primarily on reducing pain interference in daily activities as well as other 
factors associated with pain, such as negative emotions and sleep disturbance, and will incorporate a strong 
emphasis on improving pain self-management skills. For participants who have recent or current opioid use, 
the PCST intervention will include motivational interviewing aimed at reducing opioid use. For participants who 
do not have recent or current opioid use, motivational interviewing skills will be focused on any identified 
adherence goals or a value-based skill that the participant is interested in acquiring. Although many 
components of PCST will be delivered in a structured manner, the approach will allow flexibility to adjust to a 
participant’s personal circumstances.  
The PCST training will be delivered by coaches using telehealth during Weeks 1 - 12 and Interactive Voice 
Response (IVR) during Weeks 13 - 24. The telehealth component will consist of weekly sessions, each lasting  
45-50 minutes. The IVR content, intended to serve as booster sessions, will be delivered with daily telephone 


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interactions, each lasting 5 minutes. Both components of the intervention will be available in English and 
Spanish. 
6.1.1. 
Rationale for Using Telehealth and IVR as Delivery Modes for PCST 
The rationale for using telehealth and IVR rather than in-person visits or a fully computerized approach to 
deliver the PCST intervention is based on the following considerations: 
1. Access to traditional in-office behavioral therapy is challenging for patients treated with hemodialysis 
because of the substantial time commitment required for dialysis treatments, the high symptom 
burden associated with ESRD, the high frequency of complications during dialysis treatments, and 
transportation challenges.  
2. Using “chair-side” in-person sessions at the dialysis unit during dialysis treatments is resource 
intensive, inefficient for the coaches due to time involved in driving to dialysis units, and poses 
challenges for maintaining privacy.  
3. Based on prior experience, it is anticipated that fully computerized cognitive behavioral skills training 
programs will be challenging for a substantial proportion of trial participants due to limited comfort 
with technology and/or low vision or manual dexterity.   
4. Telehealth using live video interaction via tablets maximizes treatment efficiency and fidelity, while 
preserving the engagement and alliance-formation that occurs with in-person interactions.   
5. IVR provides reinforcement of skills learned during the telehealth sessions with minimal time or 
technology burden for participants.  
6.1.2. 
Telehealth Implementation  
The following tiered approach to telehealth implementation will be used: 
1. Skill sessions will be conducted individually through face-to-face interactions with patients via a fully 
interactive Health Information Portability and Accountability Act (HIPAA) compliant video telehealth 
platform on the patient’s own device. For a subset of participants, the audio portions of the sessions 
will be recorded. Participants will receive the intervention at the location of their choice – at a dialysis 
facility while undergoing hemodialysis, at their home, or at any location of their choice. 
2. If the participant does not have a video-enabled device, a tablet computer will be provided by the 
study team for use in the hemodialysis facility.  
3. If the participant cannot or will not engage in the intervention, or a particular session, through a video 
telehealth platform, the live interaction will be done via the participant’s telephone. 
4. If the participant does not have a telephone for use for the study, one will be provided by the study. 
Video and audio sessions will be conducted using secure, HIPAA compliant telehealth portals routinely used for 
clinical care and research. For sessions conducted during hemodialysis treatments, the tablets will be pre-
programmed to connect to the secure Wi-Fi, and configured to enable a simple one-touch connection. To 
ensure privacy, highly sensitive microphones attached to a headphone set are used, so that patients can talk 
softly and privacy is increased. Sensitive questions will be framed in a way that allows participants to respond 
using few words. Safety is ensured by reminding patients during sessions not to move the access arm with the 
vascular access and providing optional stands clipped to the dialysis chair arm rest. Devices provided to 


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participants by the study will be placed in a fresh, transparent plastic cover for each session to prevent 
nosocomial transmission of infections.  
6.1.3. 
IVR Implementation 
The IVR system will facilitate collection of patient-reported data, provision of treatment skill information, 
facilitation of skill practice, and provision of coach feedback. Participants will interact with the IVR system 
using a touch-tone telephone (smart or other cell phone or land line). Participants will use their telephone 
keypad to enter data or listen to pre-recorded messages. Coaches will log into a web-based portal where the 
participant’s IVR data will be summarized and displayed to facilitate provision of feedback. Coaches will use 
the IVR system to deliver the feedback in the form of a voice message that participants can retrieve during a 
scheduled IVR assessment call. Alternatively, participants may initiate a call into the system using the system 
toll free telephone number. 
6.1.4. 
Structure and Content of PCST Telehealth Intervention (Weeks 1 - 12)  
The intervention has been designed to reduce pain interference, and address opioid use, symptoms of 
depression, anxiety and sleep disturbance, as appropriate. Skills are from the cognitive behavioral therapy 
family of interventions, including acceptance and commitment therapy, motivational interviewing and 
mindfulness (see Table 6.1).  
General Structure of Sessions (45 minutes): 
1. Check in (5 minutes) 
2. Agenda/Homework review (5 minutes) 
3. Key content (10 minutes) 
4. Experiential practice (15 minutes) 
5. Motivational interviewing (5 minutes) 
6. Homework assignment (5 minutes) 
Table 6.1. PCST Telehealth Sessions 
Session 
Key skills 
Experiential Activity 
Assigned Homework 
1 
Socialization to skills training;  
Thinking about pain 
Patient narrative 
Pain questionnaire 
2 
Strategies to manage pain; 
Mindfulness of opioid cues  
Guided imagery 
Pain tracking  
3 
Relaxation training 
Progressive muscle relaxation 
& diaphragmatic breathing 
Relaxation practice log 
4 
Exercise and pacing; 
MI - Introduction 
Activity pacing  
Relaxation practice log  
Activity pacing 
5 
Pleasant activities 1: Identification of activities; 
MI - Opioid reduction 
ACT Values/Goal setting 
Activity scheduling 
Activity scheduling 
6 
Pleasant activities 2: Implementation of activities; 
MI - Opioid reduction/Goal acquisition 
Activity scheduling 
Activity scheduling 


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Session 
Key skills 
Experiential Activity 
Assigned Homework 
7 
Cognitive coping 1; 
MI – Opioid reduction/Goal acquisition 
Thought/feeling/behavior 
connectome 
Thought log 1 
8 
Cognitive Coping 2; 
MI – Opioid reduction/Goal acquisition 
Skills to challenge one’s 
thinking style  
Thought log 2 
9 
Problem solving to minimize pain interference; 
IVR introduction; 
MI – Opioid reduction/Goal acquisition 
Problem solving exercise 
Sleep diary 
10 
Sleep health, IVR feedback; 
MI - Opioid reduction/Goal acquisition  
Sleep Hygiene 
Sleep diary 
11 
Anxiety management skills; 
MI - Opioid reduction/Goal acquisition 
Worry control 
Anxiety tracking 
12 
Relapse prevention; 
IVR hand-off; 
MI - Opioid reduction/Goal acquisition 
Highlights  
 
Abbreviations: MI, motivational interviewing; IVR, interactive voice response; ACT, acceptance and commitment therapy 
6.1.5. 
Structure and Content of IVR Booster (Weeks 13-24) 
Following 12 weeks of coach-led pain coping skills training, participants will receive an IVR booster intervention 
for an additional 12 weeks. The booster intervention will promote continued practice of the skills taught in the 
pain coping skills training with the goal of maintaining or improving gains made during the initial 12 weeks of 
the intervention.  
6.1.5.1. 
Daily IVR Calls  
Participants will receive daily IVR assessments of self-efficacy, pain intensity, pain interference, sleep quality, 
sleep duration, stress, and anxiety and weekly assessment of opioid use, values-based goal attainment, and 
pain coping skill practice for the duration of the 12-week booster treatment to provide ongoing feedback to 
the coach. Patient-reported data collected on the IVR assessment calls will form the basis for the coach’s 
weekly feedback, but in distinction to the trial-wide CATI assessments, the IVR data will not be used as 
outcomes. Participants will receive automated calls daily for the duration of the booster treatment. After 
listening to their weekly coach feedback, participants may leave a message that their coach will access during 
regular business hours. 
6.1.5.2. 
Didactic Skill Review 
Participants will be able to access a verbal review of the pain management skills they learned during the 
telehealth component of the pain coping skills training. Skill review recordings will be brief (1-4 minutes) and 
can be accessed at any time. The skill review recordings will include: 
• 
Explanation of pain model  
• 
Deep breathing 
• 
Progressive muscle relaxation 
• 
Pacing 


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• 
Values-based goals 
• 
Pleasant activities 
• 
Relationship between thoughts, feeling, and behavior  
• 
Challenging unhelpful thoughts 
• 
Healthy sleep 
• 
Anxiety 
• 
Relapse prevention and problem solving 
6.1.5.3. 
Guided Practice Sessions of Pain Coping Skills 
Participants will be able to access the pre-recorded voice of a coach guiding them through behavioral 
rehearsals of the coping skills taught during the telehealth portion of the pain coping skills training. Coping 
skills will include: 
• 
Deep breathing 
• 
Progressive muscle relaxation 
• 
Pacing 
• 
Setting values-based goals 
• 
Scheduling pleasant activities 
• 
Identifying and countering unhelpful thoughts 
• 
Problem solving 
• 
Healthy sleep 
• 
Managing anxiety 
Additional skills not presented in telehealth CBT 
• 
Mindfulness meditation 
6.1.5.4. 
Values-based Goal 
Participants will learn the basics of values-based goal setting in the telehealth portion of the pain coping skills 
training. Using the “value-based goal setting” guided practice module participants can set a goal for 
themselves. If they choose this option, the participant will report their goal using the audio recording function 
during the automated IVR daily call. One week later the participant will be asked to report on the degree to 
which they made progress toward this goal via the IVR system. This information will be made available to their 
coach and incorporated into their weekly feedback message.  
6.1.5.5. 
Coach-Provided Feedback Message 
Coaches will use data collected from daily IVR assessment calls to inform a 2-4 minute personalized feedback 
message for each participant. The message will be pre-recorded and left on the final day of each treatment 
week. Feedback will be guided by scripts that provide step-by-step instructions for feedback. Procedures for 
developing feedback scripts, feedback script examples, and suggestions for common patient circumstances 
have been developed in prior trials that have used IVR. Feedback is personalized based on participant’s IVR 


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reports with insight into possible relationships between use of coping skills, anxiety, stress, and pain levels, 
suggestions for new pain management coping skills other than medication, and reminders about underutilized 
coping skills learned in the telehealth component of PCST. 
6.1.6. 
Qualifications and Training of the PCST Coaches 
PCST coaches will have masters-level training in a healthcare service delivery field with prior coursework and 
clinical experience in coaching patients with regard to health behaviors. The coaches will have comfort and 
familiarity in working remotely with people with chronic medical conditions. For both telehealth and IVR, the 
coaches will be trained in administration of the components of the intervention before the trial begins, and 
will be supervised during the trial as detailed in the Manual of Procedures. 
For the telehealth component of the intervention, following the completion of training, each coach will be 
required to complete mock complete telehealth sessions prior to implementing trial sessions. These mock 
sessions will be video/audio recorded and will be reviewed using a structured fidelity adherence form.  
Training of coaches for the IVR component of the intervention will include a review of the intervention manual, 
review of IVR data and feedback creation for practice patients followed by feedback and discussion with a 
seasoned IVR practitioner, and supervision on their active cases. IVR coaches will work with a trainer with 
experience providing pain coping skills training and delivering IVR-based treatments. Coaches will review 
example IVR feedback scripts and listen to audio recordings of examples of IVR feedback. The coaches will be 
given practice data and asked to generate six monthly feedback scripts using the script templates provided in 
the coach manual. Feedback scripts will be reviewed by the trainer one at a time with written or verbal 
feedback before the coach proceeds to generating the next feedback script. Additional practice may be 
assigned based on the judgment of the trainer until the coach is cleared to deliver the intervention to study 
participants. After clearance, the trainer will review feedback scripts. The training sessions for telehealth and 
IVR will be video recorded and used to supplement the training of coaches who join the study team after the 
trial is underway. 
6.2. 
Buprenorphine Intervention 
6.2.1. 
Overview 
At Week 24, participants who meet the eligibility criteria for the buprenorphine intervention will be provided 
with individualized buprenorphine treatment recommendations and encouraged to initiate treatment; 
however, they will not be required to initiate buprenorphine. Participants who agree to switch to 
buprenorphine will sign an informed consent document. Individualized buprenorphine treatment 
recommendations will be made by the study buprenorphine physician based on current opioid use and other 
relevant factors. 
6.2.2. 
Eligibility for Buprenorphine Intervention: Inclusion Criteria 
Participants must meet the following inclusion criteria at Week 24 to be eligible for the Phase 2 buprenorphine 
intervention:  


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1. Current use of prescribed opioids at an average dosage of ≥ 20 MME/day  
2. For participants of childbearing potential, a negative serum pregnancy test and willingness to use an 
effective form of contraception or remain abstinent from sexual intercourse with partners of the opposite 
sex during the buprenorphine administration period. See Section 6.2.3.1 for the definition of childbearing 
potential and effective forms of contraception. 
6.2.3. 
Eligibility for Buprenorphine Intervention: Exclusion Criteria 
1. Current active addiction to substances other than tobacco, defined as probable moderate-severe 
substance use disorder for which evidence-based addiction treatment is indicated. This criterion may be 
identified by any of the following: 
• Patient self-report on eligibility interview 
• Documentation of probable substance use disorder during initial 24 weeks of study 
• Probable substance use disorder based on available clinical information and standardized assessment 
using the TAPS tool59  
2. ALT, AST, or total bilirubin >2X the upper limit of normal based on the most recent available laboratory 
studies obtained within the preceding 12 weeks. 
3. History of long QT syndrome, family history of long QT syndrome, or use of Class IA or Class III anti-
arrhythmic medications. Class 1A anti-arrhythmic medications used in the outpatient setting include 
quinidine, procainamide, and disopyramide. Class III anti-arrhythmic medications include amiodarone, 
sotalol, dofetilide, and dronedarone. 
4. Known allergy or prior intolerance to buprenorphine 
5. Current use of buprenorphine 
6.2.3.1. 
Childbearing Potential 
A person of childbearing potential has experienced menarche and has not undergone successful sterilization or 
is not postmenopausal. Postmenopausal is defined as amenorrhea for ≥ 12 consecutive months without 
another cause. 
Acceptable forms of contraception include: 
• Intrauterine device or hormonal contraceptive implant 
• Consistent use of hormonal contraception (depot medroxyprogesterone, combined oral contraceptive; 
contraceptive patch or ring) 
• Consistent use of a barrier method with spermicide (diaphragm, condom, cervical cap) 
• Partner who has undergone surgical sterilization 
• Abstinence from sexual intercourse 
6.2.4. 
Buprenorphine Formulations 
Multiple buprenorphine formulations are FDA-approved for either pain or OUD. Formulations approved for 
pain (buccal and transdermal buprenorphine) are generally lower strength than those approved for OUD. 


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Because patients enrolled in this study are expected to be using opioids at a wide range of dosages, more than 
one buprenorphine formulation will be included as treatment options: sublingual buprenorphine/naloxone 
and buccal buprenorphine.  
6.2.4.1. 
Sublingual Buprenorphine/Naloxone (Suboxone or Generic Equivalent) 
Sublingual buprenorphine/naloxone (Suboxone and generic equivalents) is approved for opioid 
dependence/OUD. Naloxone is included to deter abuse of the medication by injection, but is inactive when the 
medication is taken sublingually as directed. Advantages of sublingual buprenorphine/naloxone over buccal (or 
transdermal buprenorphine) include wide availability with multiple generic products, relatively low cost, ability 
to efficiently titrate to higher dosages as needed for patients with a high degree of opioid 
tolerance/dependence, and widespread prescriber experience with this formulation.  
6.2.4.2. 
Buccal Buprenorphine (Belbuca) 
Buccal buprenorphine (Belbuca) is approved for moderate to severe chronic pain requiring around-the-clock 
opioid therapy. Advantages include low starting dosages. Disadvantages include relatively low upper dosages, 
higher cost, limited insurance coverage, and the time-consuming recommended approach to initiation for 
patients on high baseline opioid daily doses.  
For the trial, buccal buprenorphine will be used for participants on full agonist opioids of <60 MME/day at the 
time of buprenorphine initiation, those who are anticipated to have low daily buprenorphine dosage 
requirements, or those who have other reasons for buccal buprenorphine to be preferred. Sublingual 
buprenorphine/naloxone will be the preferred formulation for participants on ≥60 MME/day at the time of 
buprenorphine initiation, those who are thought to have higher daily dosage requirements, or those with 
other reasons for sublingual buprenorphine to be preferred, such as insurance coverage anticipated to restrict 
access to alternatives after trial participation ends. In determining the initial medication selection and 
subsequent medication adjustments, individual clinical factors will be considered together with drug cost and 
factors that would affect availability to the participant after trial participation is completed.  
6.2.5. 
Buprenorphine Regulatory Issues 
With few exceptions, federal regulations prohibit clinicians from prescribing opioids for the purpose of treating 
OUD. One exception is for sublingual buprenorphine, which is FDA-approved for the treatment of OUD. 
Physicians and advanced practice providers may complete specific training and apply for a waiver through the 
DEA that authorizes them to prescribe sublingual buprenorphine for OUD. Importantly for this trial, the DEA 
clarified in 2004 that clinicians may prescribe sublingual buprenorphine “off-label” without a waiver. Use of 
sublingual buprenorphine in this protocol is for physical dependence due to prescribed long-term opioid 
therapy for pain, not for OUD; therefore, study prescribers are not required to have a waiver regardless of 
which buprenorphine formulation is prescribed.  


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6.2.6. 
Buprenorphine Prescribing and Dispensing 
Each enrolling site will designate at least two study physicians as buprenorphine prescribers. Study physicians 
will prescribe buprenorphine for participants who are eligible for and elect to switch to buprenorphine after 
obtaining informed consent specifically for buprenorphine. Buprenorphine prescriptions written by authorized 
study prescribers will be transmitted to the central investigational pharmacy and the medication will be mailed 
by the investigational pharmacy to the participant in specified intervals throughout the study period. 
Participants will use study-provided mailers to return medication containers to the investigational pharmacy 
for dose counting and return of unused drug. For participants enrolled from the Veterans Affairs (VA) 
Healthcare System sites, all of the activities described above will be completed by the local VA pharmacy for 
each site.  
6.2.7. 
Buprenorphine Initiation  
Decisions about how to initiate buprenorphine will be individualized based on the participant’s needs and 
preferences as well as the prescriber’s experience and local resources. Participants may initiate buprenorphine 
at home or in the study physician’s office. There are two methods for switching from full-agonist opioids to 
either buccal or sublingual buprenorphine: a traditional method and a newer crossover titration method.60 The 
approach used for individual participants will be at the discretion of the study physician prescribing the 
buprenorphine; however, in general, the crossover titration method is preferred, and required for participants 
using long-acting opioid medications. 
6.2.7.1. 
Traditional Method for Initiating Buprenorphine 
For the traditional method, full-agonist opioids are stopped entirely prior to starting buprenorphine. The 
interval between last dose of the full-agonist opioid and the first dose of buprenorphine 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 (approximately 18-24 hours for morphine SA). 
Patients using the traditional method for switching to buprenorphine will be advised that they will experience 
opioid withdrawal symptoms during the interval after stopping full-agonist opioids and before starting 
buprenorphine. For participants using long-acting opioids (e.g., oxycodone controlled-release, morphine 
controlled-release tablet or capsule, oxycodone controlled-release, oxymorphone extended-release 
hydromorphone extended-release, fentanyl transdermal), the crossover method will be used rather than the 
traditional method in order to avoid the need for prolonged periods without use of either the full agonist 
opioid or buprenorphine. 
6.2.7.2. 
Crossover Titration Method for Initiating Buprenorphine 
For the crossover titration method, buprenorphine is started at very low doses several days before the full-
agonist opioid is stopped. Buprenorphine is titrated up over several (typically 3-5) days and the full-agonist 
opioid is discontinued once the buprenorphine is at a therapeutic dose. Case series demonstrate that the 
crossover titration method is well-tolerated,60 and clinical experience indicates that some patients on long-
term opioid therapy for pain prefer this approach because they do not have to experience opioid withdrawal 


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symptoms before initiating buprenorphine. Belbuca will be used as the buprenorphine formulation for the 
crossover titration method. Once the participant has up-titrated the Belbuca and discontinued the full agonist 
opioid, either Belbuca or buprenorphine/naloxone will be used as the maintenance buprenorphine 
formulation based on the considerations described in Section 6.2.4.  
6.2.7.3. 
Information for Participants About Initiation of Buprenorphine 
Precipitated opioid withdrawal is the main potential adverse effect of switching to buprenorphine; however, 
this can be avoided by adhering to the initiation protocol. When using the traditional method for switching to 
buprenorphine, the most critical point patients need to understand is that the full agonist opioids must be 
sufficiently cleared from the body before buprenorphine initiation. This means that participants must wait for 
the onset of at least moderate withdrawal symptoms. When using the crossover 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.  
6.2.7.4. 
Initial Visit with Buprenorphine Prescriber 
Participants who meet eligibility criteria for the Phase 2 buprenorphine intervention will be scheduled as soon 
as convenient for a visit (in-person or by video) with a study physician who will prescribe the buprenorphine. 
Substance use testing using saliva will be performed prior to the initial visit with the buprenorphine prescriber.  
The initial buprenorphine visit will be an in-person or video-based visit with the study buprenorphine 
prescriber, as described above. First visit tasks include the following:  
• 
Obtain history of prescription and non-prescription opioid use and substance (alcohol, drug) use and 
assess for substance use disorder; assess buprenorphine risk factors (including risk for pregnancy if 
applicable) 
• 
Provide standardized buprenorphine educational materials and resources 
• 
Discuss benefits and risks of buprenorphine use and provide instructions to reduce risks such as dental 
problems  
• 
Recommend buprenorphine and use shared decision-making to establish a plan for buprenorphine 
initiation and follow up; provide information about who should be contacted if problems or concerns 
occur between visits 
• 
Complete informed consent process for initiating buprenorphine 
Buprenorphine administration will not occur at the initial buprenorphine visit. After the initial visit has been 
completed and written informed consent is obtained, the study physician will prescribe buprenorphine, which 
will be mailed to the patient’s home. Patients will self-administer buprenorphine, typically at home, as 
described above. 
Following buprenorphine initiation, structured follow-up will occur at multiple time points within the first 3 
weeks after buprenorphine initiation. These follow-up visits will occur at 2-3 days, 1 week, 2 weeks, and 3 
weeks after initiation, but the timing can be modified based on the judgement of the buprenorphine 


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prescriber. These visits will be conducted by the buprenorphine-prescribing study physician. Most visits will be 
conducted by telephone, but they may be conducted in-person or by video if preferred. After these four 
structured visits, follow up will occur at a frequency determined by the buprenorphine prescriber but will 
include follow-up at Weeks 32 and 36 during which plans for post-trial pain management will be discussed (see 
Section 6.2.9). 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 or counseling as needed 
• 
Perform substance use testing using saliva at the discretion of the buprenorphine prescriber in a 
manner consistent with standard clinical care  
• 
Plan for post-trial pain management (Week 32 and Week 36 visits) 
6.2.8. 
Buprenorphine Dosing Regimens  
Dosages and dosing regimens for Belbuca and sublingual buprenorphine/naloxone are shown in Table 6.2. For 
participants using the crossover titration approach to transitioning to buprenorphine, Belbuca will be used to 
initiate the crossover titration. After the transition, Belbuca will be used for all participants who had been 
using a full agonist opioid at a dose of <30 MME/day. Belbuca will also be used for participants who had been 
using a full agonist opioid at a dose of 30-35 MME/day, unless the maximal dose of Belbuca (450 mcg twice 
daily) is insufficient to manage their symptoms. As detailed in the Buprenorphine Manual of Procedures, the 
dose of buprenorphine will be adjusted (increased or decreased) based on adequacy of pain control, 
withdrawal symptoms, and tolerability.  
For participants using the traditional approach to transitioning to buprenorphine, either Belbuca or 
buprenorphine/naloxone can be used as the initial buprenorphine formulation depending on the full agonist 
opioid MME/day, in accordance with the guidelines in the Buprenorphine Manual of Procedures. 
Table 6.2. Buprenorphine Dosing 
Formulation 
Formulation-Specific Exclusions1 
Dosage Forms 
Typical Dosing Regimens 
Buprenorphine buccal 
film (Belbuca) 
1. Use of full agonist opioid at dose 
>160 MME/day 
• 75 mcg buccal film 
• 150 mcg buccal film 
75 mcg – 450 mcg two 
times per day 
Buprenorphine/naloxone 
sublingual film 
(Suboxone or generic 
equivalent) 
1.  Use of full agonist opioid at dose 
<30 MME/day 
2. Known hypersensitivity to 
naloxone 
• 2 mg/0.5 mg 
sublingual film 
• 8 mg/2 mg 
sublingual film 
2 mg/0.5 mg – 8 mg/2 mg 
two to three times per day, 
not to exceed a total dose 
of 24 mg/6 mg per day 
1These exclusions are in addition to the overall exclusion criteria for the buprenorphine intervention listed in Section 
6.2.3. Note that these exclusions apply to the anticipated buprenorphine formulation that will be used immediately 
following the transition from the full agonist opioid. The exclusion does not apply to dose modifications required after a 
participant has been transitioned to buprenorphine. 


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6.2.9. 
Buprenorphine Maintenance During and After the Trial 
Most participants should achieve a stable dosage of buprenorphine within a month of starting the medication. 
For either sublingual or buccal buprenorphine, dosing may be 2 to 3 times per day. Decisions about 
buprenorphine maintenance during and after the study will be made on an individual basis. Factors that will be 
considered include outcomes of therapy and participant preferences. Options for participants during and after 
completion of study participation include the following:  
• 
Continue buprenorphine indefinitely; 
• 
Taper off buprenorphine and completely discontinue opioids; or 
• 
Rotate back to a full-agonist opioid at a lower dose. If participants rotate back to a full-agonist opioid 
after achieving stability on buprenorphine, the full-agonist opioid will be restarted at a lower dose to 
account for incomplete cross-tolerance. 
6.2.10. Monitoring for Changes in Concomitant Medications During Treatment with Buprenorphine 
with Particular Attention to Medications that Affect Cyp3A4 Enzyme Activity 
For patients receiving treatment with buprenorphine as a study intervention, in addition to the medication 
review that takes place every 4 weeks as a component of the regular interactions with the research team (see 
Sections 7.4.2 and 7.5.2), participants will be asked to contact the research team at any time that there is a 
change in their concomitant medications including initiations, discontinuations, or dose changes. The research 
team will review all medication changes that are identified either through scheduled interactions or through 
notifications by participants, to determine whether there have been changes in medications that affect (either 
increase or decrease) the activity of the Cyp3A4 enzyme. The research teams will be provided with lists of 
medications that affect Cyp3A4 activity to facilitate the review. 
If there are changes to medications that affect Cyp3A4 activity, the research team will inquire about the 
following symptoms that might occur as a result of Cyp3A4-associated changes in in buprenorphine blood 
concentrations: increased pain, withdrawal symptoms, sedation, or respiratory depression. The initial 24 – 72 
hours following the medication change will be of particular interest. Participants will be instructed to report 
symptoms to the research team. If symptoms occur, the dose of buprenorphine can be increased or decreased 
by the study buprenorphine prescriber as needed. 
6.3. 
Usual Care 
Participants in the Usual Care arm will be provided with written educational material about chronic pain and 
opioid medications, and available resources for treatment. Information will also be provided to the 
participant’s treating clinicians that describes the trial and indicates the participant’s randomized assignment. 
The same participant and prescriber informational materials will be used for the PCST intervention.  
Participants randomized to Usual Care will be assessed for eligibility for the Buprenorphine intervention at 
Week 24 using the same approach as for participants randomized to the PCST intervention. 


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6.4. 
Intervention Fidelity 
Throughout the duration of the trial, the fidelity of the interventions will be monitored through ongoing review 
of both participant adherence and research team implementation. Efforts to maximize adherence will be 
implemented by the Clinical Center research teams with guidance and assistance from the trial’s Quality 
Control Committee. 
For the coach-led telehealth component of the PCST intervention, adherence will be based on the number of 
telehealth sessions completed (out of 12 prescribed sessions) and categorized as minimal (< 3 session), some 
(3-9 sessions), and most (10-12). Additional adherence data will include the duration of sessions, completion of 
PCST homework, utilization of symptom management skills, and utilization of opioid reduction strategies. For 
the IVR component of the PCST intervention, the proportion of calls completed and duration of IVR will be 
indicators of adherence.  
To ensure that the PCST intervention is delivered as intended there will be regular interactions between 
coaches and the relevant supervisory team, during which implementation and clinical issues will be reviewed. 
For each coach, the audio recordings of all PCST sessions for a minimum of one participant will be reviewed to 
provide ratings for treatment fidelity using forms that capture the core skills and intervention components. In 
addition to the review of all sessions for a minimum of one participant per coach, a random sample of 
subsequent telehealth sessions will be reviewed and scored for fidelity to the intervention. This will allow 
coaches to receive support and real-time feedback to ensure the highest standards for delivering the 
intervention. Ongoing supervision for the IVR component will also be provided during weekly meetings. 
Enactment fidelity, i.e., the degree to which participants implement and use the intervention skills, will be 
assessed post-treatment by the coach using a checklist. 
For the buprenorphine intervention, participants who meet eligibility criteria will be encouraged, but not 
required, to initiate buprenorphine. The proportion of participants offered the drug who initiate 
buprenorphine is one of the exploratory outcomes for the intervention. Rates of completion of the structured 
follow-up contacts and subsequent monthly contacts will serve as indicators of implementation fidelity.  
6.5. 
Clinical Management of Trial Participants 
6.5.1. 
Concomitant Therapy 
The following approach will be taken regarding concomitant therapies: 
1. Doses and frequency of use of non-opioid analgesics, antidepressants, anxiolytic and sedatives/hypnotics 
will be recorded at baseline and Weeks 4, 8, 12, 16, 20, 24, and 36.  
2. Use of non-study behavioral therapy or any other non-pharmacological therapy for pain (such as 
acupuncture, physical therapy, etc.) will be recorded at baseline and Weeks 4, 8, 12, 16, 20, 24, and 36.  
3. With the exception of the buprenorphine intervention, opioid medications will not be prescribed or 
managed by the study.   


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6.5.2. 
Opioid Adherence Problems 
For participants who are not receiving the buprenorphine intervention, opioid adherence problems will be 
managed by the participant’s clinical care providers. During Weeks 24 – 36, for participants receiving the 
buprenorphine intervention, the study physician prescribing the buprenorphine will be responsible for 
addressing buprenorphine or opioid adherence problems. If issues are identified, they will be addressed with 
the goals of improving safety. An 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 visits; d) review of state Prescription Drug Monitoring Program database; e) 
blood or saliva drug testing; f) shorter prescription intervals; or g) referral to a mental health or addiction 
clinician.  
6.5.3. 
Clinical Management of OUD or other Substance Use Disorders 
Previously undiagnosed moderate-severe OUD or other substance use disorders may become clinically 
apparent during the course of the trial. Participants with symptoms or signs of OUD or other substance use 
disorders will be evaluated by a study clinician with appropriate expertise or referred to appropriate local  
non-study clinicians to establish a diagnosis. Study clinicians and coordinators will facilitate access to evidence-
based addiction treatment for participants who are diagnosed with OUD or other substance use disorder 
during the study.  
Participants who are diagnosed with OUD or other substance use disorders after randomization should not be 
withdrawn from the study and may continue to receive treatment in the PCST or Usual Care group if the 
interventions are compatible with the care they receive for the substance use disorder. The buprenorphine 
intervention is not intended as medication treatment for OUD. If a participant receiving the Phase 2 
buprenorphine intervention is diagnosed with moderate-severe OUD, study clinicians should facilitate transfer 
of buprenorphine prescribing to a DEA-certified prescriber of medications for OUD and the patient’s 
participation in the buprenorphine intervention should be discontinued. However, the participant will continue 
to be followed for data collection and outcome ascertainment. 
6.5.4. 
Clinical Management of Suicidality 
It is possible that suicidal ideation will be evident from responses to question #9 of the PHQ-9 survey used 
during eligibility screening or during ascertainment of the patient reported outcomes throughout the course of 
trial participation. Participants will be considered to have possible elevated risk of suicide based on a response 
of “1”, “2”, or “3” to the PHQ-9 Question 9:  Over the last 2 weeks how often have you been bothered by 
thoughts that you would be better off dead or of hurting yourself in some way: 0 = not at all, 1 = several days, 
2 = more than half the days, or 3 = nearly every day.  
If during eligibility screening, based on the response to the PHQ-9 Question 9, a participant is considered to a 
possible elevated risk of suicide, the research coordinator will administer two specific follow-up questions 
about suicidal ideation. If the responses to these questions support possible suicidal intent the research 
coordinator will stop the screening procedures and contact a designated member of the enrolling site’s 


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research team to perform an immediate further assessment of suicidal intent. The patient will be provided 
with appropriate support and resources, including arrangement for emergency care and/or referral to mental 
health specialists, as needed, based on the assessment by the designated research team member. The 
research team will inform the participant’s treating nephrologist and primary care provider about the events 
that transpired, and will document the follow-up procedures. If the research team deems that the participant 
is safe to proceed with screening procedures and possible randomization into the trial, the screening process 
will be resumed. 
Management of elevated risk of suicide identified during the PRO ascertainments will be addressed using a 
similar approach. The personnel at the centralized PRO assessment center (CATI Center) will have emergency 
telephone numbers for 3 members of the research team at each enrolling site. If a participant indicates 
increased risk of suicide based on a response of “1”, “2”, or “3” to question 9 of the PHQ-9 survey, the CATI 
team member will ask two specific follow-up questions (the same questions used during screening). If the 
responses to the two follow-up questions support possible suicidal intent the CATI team member will inform 
the participant that the research team will contact the participant to provide follow-up and any necessary 
resources and will end the call. The CATI team will immediately contact the research team at the participant’s 
enrolling site to inform them of the participant’s elevated suicide risk. A designated person on the research 
team will immediately contact the participant, assess the participant’s level of possible suicidal ideation, and, 
based on the results, provide appropriate support and resources, including arrangement for emergency care 
and/or referral to mental health specialists as needed. The enrolling site’s research team will inform the 
participant’s treating nephrologist and primary care provider about the events that transpired. The 
administration of the remaining PRO questionnaires will be deferred until a later date after the management 
of suicidal intent has been completed. The CATI team member will notify the SDRC about the event 
electronically using the participant’s study ID. The research team will document the follow-up procedures. 


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7. 
STUDY PROCEDURES AND ASSESSMENTS 
A schedule of study visits and procedures is provided in Appendix 14.1. To the extent possible, in-person study 
visits will take place at the dialysis unit during scheduled dialysis sessions. 
7.1. 
Pre-screening and Screening  
The pre-screening and screening activities include: 
1. Pre-screening  
2. Obtaining informed consent for those who meet pre-screening criteria 
3. Performing screening activities to determining eligibility  
Patients at participating dialysis units will be pre-screened for chronic pain as described in Section 5.4. Those 
who meet the criteria for Screening will be approached in person to determine interest in trial participation. 
Study personnel will discuss the study goals and procedures with the potential participant and assess 
understanding of the content in the consent form before obtaining informed consent from the participant. The 
consenting process will be performed by a qualified investigator or study site designee. Informed consent will 
be obtained and documented before any Screening procedures are performed.  
Eligibility will be determined through interaction with the participant, review of medical records, and 
interaction with treating clinicians. Review of the inclusion and exclusion criteria will be performed and 
documented in the data management system for all consented participants, including those who are found to 
be ineligible. 
7.2. 
Baseline Data Collection and PRO Ascertainment – (within 4 weeks of Screening) 
Baseline data includes demographic information, medical history via checklist, dialysis history, substance use 
history, pain history, prescribed and over-the-counter medications, and use of behavioral or other non-
pharmacologic interventions for pain.  
PRO questionnaires will be administered by telephone by a centralized CATI team (see Section 4.2.3). The 
order of preference for the day of the week for completing CATI, from optimal to the least preferred, is as 
follows: 
1. The day following the first dialysis treatment of the week: Tuesday for patients on a Monday-Wednesday-
Friday schedule, or Wednesday for patients on a Tuesday-Thursday- Saturday schedule, or Monday for 
patients on a Sunday-Tuesday-Thursday schedule. The first dialysis treatment of the week is defined as 
the treatment following the 72-hour dialytic interval. 
 
2. The day following the second dialysis treatment of the week: Thursday for patients on a Monday-
Wednesday-Friday schedule, or Friday for patients on a Tuesday-Thursday-Saturday schedule, or 
Wednesday for patients on a Sunday-Tuesday-Thursday schedule. 
 
3. Preferably, within the first hour of the 2nd dialysis session of the week which is Wednesday for patients on 
a Monday-Wednesday-Friday schedule, or Thursday for patients on a Tuesday-Thursday-Saturday 
schedule, or Tuesday for patients on a Sunday-Tuesday-Thursday schedule.  


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To the extent possible, the timing with respect to dialysis will be kept consistent throughout the duration of 
the trial.  
If all attempts to complete a follow up CATI call are unsuccessful, the Clinical Center Principal Investigator may 
authorize the site study coordinator to complete the PROs using paper forms chairside during dialysis. This 
approach is expected to be used only under exceptional circumstances.  
The baseline PRO questionnaires include*: 
• Brief Pain Inventory 7-item Interference (BPI-Interference) 
• Brief Pain Inventory 4-item Severity (BPI-Severity) 
• Pain Catastrophizing Scale (PCS) SF6 
• Opioid Use Timeline Follow-Back (TLFB) 
• Pain Mapping Questionnaire 
• Single Item Quality of Life Scale [SIS] from the McGill Quality of Life (MQOL) Questionnaire 
• Patient Health Questionnaire (PHQ-9) 
• Generalized Anxiety Disorder (GAD-7) 
• Coping Strategies Questionnaire 24 (CSQ-24) 
• Single item targeting self-efficacy for pain 
• PROMIS Self-Efficacy for Managing Chronic Conditions – Managing Symptoms – Short Form 8A 
• PROMIS Sleep Disturbance 6a + Sleep duration 
• PROMIS-Fatigue SF 6a 
• PROMIS Physical Functioning SF 6b 
• Multidimensional Scale of Perceived Social Support (MSPSS) 
• Dialysis Symptom Index 
• PROMIS Satisfaction with Social Roles and Activities 
• Everyday Discrimination Scale 
 
*Citations for PRO references can be found in Appendix 14.2. 
7.3. 
Randomization for Phase 1 (within 1 week of Baseline) 
Randomization to the Phase 1 treatment group will take place after determination of eligibility, baseline data 
collection, and baseline PRO ascertainment. Randomization will be performed via the centralized Data 
Management System. Recruitment of new participants will conclude once 640 participants have been 
randomized. At the time of the 640th randomization, participants who are “in the pipeline” (participants who 
provided consent and have been screened eligible but have not yet been randomized) will also be randomized 
and continue in the study.  


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7.4. 
Phase 1 Intervention Administration, Data Collection, and Research Team Contacts 
(Weeks 1 - 24) 
7.4.1. 
Intervention Administration (Weeks 1 - 24) 
The PCST and Usual Care interventions will be administered during Weeks 1 - 24 as described in Sections 6.1, 
6.2, and 6.4, respectively. 
7.4.2. 
Contacts with the Research Team (Weeks 4, 8, 12, 16, and 20) 
Participants in both randomized groups will be contacted by research coordinators either in person or by 
telephone every 4 weeks during Phase 1. These contacts will be used for the following: 
• Ascertainment of hospitalizations (secondary outcome) 
• Ascertainment of falls (secondary outcome) 
• Ascertainment of Adverse Events of Interest and SAEs 
• Documentation of any change in the participant’s opioid prescriber(s) 
• Documentation of non-opioid analgesics, antidepressants, anxiolytic and sedatives/hypnotics 
• Review of concomitant medications with documentation of initiation of new medications or 
discontinuation of prior medications 
• Documentation of use of non-study behavioral or other non-pharmacologic treatments for pain 
• Scheduling of Week 12 or Week 24 CATI calls  
7.4.3. 
Follow-Up PROs (Week 12)  
Follow-up PRO questionnaires will be administered by telephone by a centralized CATI team. To the extent 
possible, the surveys should be performed using the same timing with respect to dialysis as was used for the 
Baseline PROs. The Week 12 PRO ascertainment will provide the data for the primary outcome.  
The follow-up PRO questionnaires performed at Week 12: 
• Brief Pain Inventory 7-item Interference (BPI-Interference) – primary outcome 
• Brief Pain Inventory 4-item Severity (BPI-Severity) 
• Pain Catastrophizing Scale (PCS) SF6 
• Opioid Use Timeline Follow-Back (TLFB) 
• Single Item Quality of Life Scale [SIS] from the McGill Quality of Life (MQOL) Questionnaire 
• Patient Health Questionnaire (PHQ-9) 
• Generalized Anxiety Disorder (GAD-7) 
• Coping Strategies Questionnaire (CSQ) 1-item 
• Single item targeting self-efficacy for pain 
• PROMIS Self-Efficacy for Managing Chronic Conditions – Managing Symptoms – Short Form 8A 
• PROMIS Sleep Disturbance 6a + Sleep duration 
• PROMIS-Fatigue SF 6a 
• PROMIS Physical Functioning SF 6b 
• Multidimensional Scale of Perceived Social Support (MSPSS) 
• Dialysis Symptom Index 


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• Patient Global Impression of Change (PGIC) 
• PROMIS Satisfaction with Social Roles and Activities 
7.4.4. 
End of Phase 1 Intervention, Week 24 PROs, and Determination of Eligibility for 
Buprenorphine (Week 24) 
Follow-up PRO questionnaires will be administered by telephone by a centralized CATI team. To the extent 
possible, the surveys should be performed using the same timing with respect to dialysis as was used for the 
Baseline PROs. 
The follow-up PRO questionnaires performed at Week 24 include: 
• Brief Pain Inventory 7-item Interference (BPI-Interference) 
• Brief Pain Inventory 4-item Severity (BPI-Severity) 
• Pain Catastrophizing Scale (PCS) SF6 
• Opioid Use Timeline Follow-Back (TLFB) 
• Single Item Quality of Life Scale [SIS] from the McGill Quality of Life (MQOL) Questionnaire 
• Patient Health Questionnaire (PHQ-9) 
• Generalized Anxiety Disorder (GAD-7) 
• Coping Strategies Questionnaire (CSQ) 1-item 
• Single item targeting self-efficacy for pain 
• PROMIS Self-Efficacy for Managing Chronic Conditions – Managing Symptoms – Short Form 8A 
• PROMIS Sleep Disturbance 6a + Sleep duration 
• PROMIS-Fatigue SF 6a 
• PROMIS Physical Functioning SF 6b 
• Multidimensional Scale of Perceived Social Support (MSPSS) 
• Dialysis Symptom Index 
• Patient Global Impression of Change (PGIC) 
• PROMIS Satisfaction with Social Roles and Activities 
• Internalized Stigma in Chronic Pain Scale 
After the Week 24 PROs have been ascertained, participants in the 2 randomized groups will proceed to  
Phase 2. Participants in the PCST group will be told that the Phase 1 intervention has been completed.  
All participants in both randomized groups will undergo eligibility determination for the buprenorphine 
intervention (see Sections 6.3.2 and 6.3.3 for the Buprenorphine Inclusion and Exclusion Criteria). 


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7.5. 
Phase 2 Intervention Administration, Data Collection, and Research Team Contacts  
(Weeks 24 - 36) 
7.5.1. 
Intervention Administration (Weeks 24 - 36) 
Participants who are eligible for buprenorphine will receive recommendations and instructions for switching 
from their full agonist opioid medication to buprenorphine. Written informed consent will be required before 
initiating buprenorphine. The buprenorphine will be administered as detailed in Sections 6.3.4 – 6.3.8. 
7.5.2. 
Contacts with the Research Team (Weeks 28, 32, and 36) 
All participants will be contacted by research coordinators either in person or by telephone every 4 weeks 
during Phase 2. These contacts will be used for the following: 
• Ascertainment of hospitalizations (secondary outcome) 
• Ascertainment of falls (secondary outcome) 
• Ascertainment of Adverse Events of Interest and SAEs 
• Documentation of any change in the participant’s opioid prescriber(s) 
• Documentation of non-opioid analgesics, antidepressants, anxiolytic and sedatives/hypnotics 
• Review of concomitant medications with documentation of initiation of new medications or 
discontinuation of prior medications. For participants being treated with buprenorphine as a trial 
intervention, medications will also be reviewed for initiation, discontinuation, or change in dose for 
medications that increase or decrease Cyp3A4 enzyme activity (see Section 6.2.10 for additional 
information about monitoring for changes in medications with effects on Cyp3A4). 
• Documentation of use of non-study behavioral or other non-pharmacologic treatments for pain 
• Scheduling of Week 36 CATI call 
7.5.3. 
Planning for End-of-Trial (Weeks 32 - 36) 
For participants taking buprenorphine, during Weeks 32 - 36, the study buprenorphine prescriber will develop 
a plan for continued use or discontinuation of buprenorphine with the participant and their usual opioid 
prescriber after the trial ends (see Section 6.2.8 for post-trial options). 
7.5.4. 
Follow-Up PROs (Week 36)  
Follow-up PRO questionnaires will be administered by telephone by a centralized CATI team at Week 36. To 
the extent possible, the surveys should be performed using the same timing with respect to dialysis as was 
used for the Baseline PRO. 
The follow-up PRO questionnaires performed at Week 36 include: 
• Brief Pain Inventory 7-item Interference (BPI-Interference) 
• Brief Pain Inventory 4-item Severity (BPI-Severity) 
• Pain Catastrophizing Scale (PCS) SF6 
• Opioid Use Timeline Follow-Back (TLFB) 


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• Single Item Quality of Life Scale [SIS] from the McGill Quality of Life (MQOL) Questionnaire 
• Patient Health Questionnaire (PHQ-9) 
• Generalized Anxiety Disorder (GAD-7) 
• Coping Strategies Questionnaire (CSQ) 1-item 
• Single item targeting self-efficacy for pain 
• PROMIS Self-Efficacy for Managing Chronic Conditions – Managing Symptoms – Short Form 8A 
• PROMIS Sleep Disturbance 6a + Sleep duration 
• PROMIS-Fatigue SF 6a 
• PROMIS Physical Functioning SF 6b 
• Multidimensional Scale of Perceived Social Support (MSPSS) 
• Dialysis Symptom Index 
• Patient Global Impression of Change (PGIC) 
• PROMIS Satisfaction with Social Roles and Activities 
• Everyday Discrimination Scale 
7.5.5. 
End of Phase 2 / End of Study (Week 36)  
Trial participation will end at Week 36. For participants taking buprenorphine, continuation or transition off 
buprenorphine will be handled as described in Sections 6.3.8 and 7.6.3. 
7.5.6. 
Buprenorphine Qualitative Interviews (After Study Participation has been Completed)  
Approximately 25 participants who were offered the Phase 2 buprenorphine intervention will be asked to 
complete a one-time qualitative interview by telephone. The purpose of the interviews is to understand why 
participants were willing or were not willing to switch from their full agonist opioids to buprenorphine when it 
was offered to them as part of the HOPE Trial. The interviews will be approximately 30 minutes in duration and 
will be conducted by researchers at the University of Pittsburgh. All interviews will be audio-recorded and 
transcribed for analysis. The audio recordings will be destroyed after all analyses are completed. Informed 
consent will be obtained prior to performing the interviews using an informed consent form that is specific to 
the buprenorphine qualitative interviews. The consent will be obtained under a waiver of consent 
documentation since not all participants will be able to complete the consent process in person. Participants 
will have concluded all other elements of study participation before being contacted for possible participation 
in this interview.   


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8. 
DISCONTINUATION OF STUDY INTERVENTIONS AND STUDY PARTICIPATION 
8.1. 
Discontinuation of Study Interventions 
For all of the trial interventions, participants will be encouraged to continue for the duration indicated by the 
protocol, but they will have the right to discontinue at any time based on preference. Interruptions in the PCST 
intervention may be necessary because of hospitalizations or other inter-current events; if so, the intervention 
will be resumed as soon as it is possible based on the judgement of the research team. Every effort will be 
made to continue buprenorphine during hospitalizations just as would be done in clinical care. As with any 
medication, buprenorphine may induce intolerable side effects, or, in rare cases, allergic reactions that will 
necessitate its discontinuation by the study physician. In these cases, the study physician will use clinical 
judgment to decide whether the participant should be switched back to full agonist opioids or discontinued 
from opioids altogether. Participants who switch back to full agonist opioids will remain in the buprenorphine 
arm. The study buprenorphine prescriber will be responsible for ensuring that the participant has continued 
access to pain medication either through their clinical opioid prescriber or through the study buprenorphine 
prescriber.  
Participants who are not willing or able to continue trial interventions will be encouraged to remain in the trial 
and continue data collection, adverse event monitoring, and outcome ascertainment.  
8.2. 
Participant Withdrawal / Discontinuation from the Study 
Participants will be free to withdraw from participation in the study at any time. If a participant indicates a 
desire to withdraw, the research team will discuss the request with the participant and determine whether the 
participant is willing to allow ongoing data collection for outcome ascertainment or adverse event monitoring. 
An investigator may discontinue or withdraw a participant from the study if any clinical adverse event, 
laboratory abnormality, or other medical condition or situation occurs such that continued participation in the 
study would not be in the best interest of the participant. The reason for participant withdrawal or 
discontinuation from the study will be recorded on a Withdrawal case report form.  


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9. 
ADVERSE EVENT ASCERTAINMENT AND REPORTING 
9.1. 
Definitions 
Definitions are per the January 2007 Guidance on Reviewing and Reporting Unanticipated Problems Involving 
Risks to Participants or Others and Adverse Events, Office on Human Research Protection (OHRP) Guidance. 
http://www.hhs.gov/ohrp/policy/advevntguid.html  
9.1.1. 
Adverse Event 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human study participant, 
including any abnormal sign (for example, abnormal physical examination or laboratory finding), symptom, or 
disease, temporally associated with the participant’s involvement in the research, whether or not considered 
related to the participant’s participation in the research. 
9.1.2. 
Serious Adverse Event 
A serious adverse event (SAE) is any AE that is:  
• fatal or results in death 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• results in congenital anomalies or birth defects 
• an important medical event* 
*Important medical events are those that may not be immediately life threatening but are clearly of major 
clinical significance. 
9.1.3. 
Unanticipated Problem Involving Risk to Participants or Others  
An Unanticipated Problem is any incident, experience, or outcome that meets all of the following criteria: 
• It is unexpected (in terms of nature, severity, or frequency) given the research procedures that are 
described in the IRB-approved research protocol and informed consent document and the characteristics 
of the participant population being studied; 
• It is related or possibly related to participation in the research; possibly related means that there is a 
reasonable possibility that the incident, experience or outcome may have been caused by the procedures 
involved in the research, and 
• It suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) related to the research than was previously known or 
recognized. 


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9.1.4. 
Pre-Existing Condition 
A pre-existing condition is one that is present at the start of the study. A pre-existing condition will be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during the 
study period. 
9.1.5. 
Adverse Event Reporting Period 
The study period during which adverse events must be tracked and reported is defined as the period from the 
initiation of study procedures to study completion. Participants who undergo screening and are ineligible for 
the trial will no longer be followed for adverse events. If a participant is rescreened, adverse event 
monitoring/reporting will resume and continue until the end of trial participation or until he/she is determined 
to be ineligible for the trial.  
9.1.5.1. 
Post-Study Adverse Events 
All unresolved adverse events will be followed by the investigator until the events are resolved, the participant 
is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled visit, the investigator will 
instruct each participant to report any subsequent event(s) that the participant, or the participant’s personal 
physician, believes might reasonably be related to participation in this study. The investigator will notify the 
SDRC of any death or adverse event occurring after a participant has discontinued or terminated study 
participation that may reasonably be related to the study.  
9.2. 
Adverse Events of Interest 
The following adverse events are anticipated in patients with chronic pain, opioid use, or treatment with the 
trial interventions, and will be considered AEs of Interest.  
• Development of suicidality – based on response to question 9 of the PHQ-9 
• Development of opioid use disorder or other substance use disorder 
• Adverse effect from a medication started during the trial (including buprenorphine) to treat pain, opioid 
dependence, depression, or anxiety 
• Falls  
• Withdrawal symptoms  
• Dental events in participants who have switched to buprenorphine 
AEs of Interest will be ascertained during the contacts between the research coordinator and the participant 
that occur every 4 weeks through specific questioning and, as appropriate, by review of medical records. 
Information about the events will be recorded on the Adverse Event of Interest case report form (CRF) and 
entered into the data management system.  


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9.3. 
Anticipated SAEs 
The following serious adverse events are anticipated in the hemodialysis population and are not considered 
Unanticipated Problems. Note that the designation as “Anticipated” does not imply that the event is not an 
SAE but relates to the regulatory definition of Unanticipated Problems as provided in Section 9.1.3. 
• 
Death 
• 
Coronary Ischemia including: 
− Unstable angina 
− Acute MI 
− Coronary revascularization 
• 
Heart failure hospitalization or exacerbation 
• 
Cardiac arrest 
• 
Cardiac arrhythmia (ventricular or atrial) 
• 
Peripheral vascular revascularization 
• 
Amputation 
• 
Hypotension 
• 
Hypertension 
• 
Nausea or vomiting 
• 
Vascular Access Events including: 
− Catheter exchange, removal, or thrombolysis 
− Arteriovenous graft or fistula complications 
▪ Thrombosis 
▪ Stenosis 
▪ Revascularization 
▪ Infection 
• 
Infections including: 
− Pneumonia 
− Bacteremia 
− Hemodialysis vascular access infection  
9.4. 
Reporting of AEs of Interest, SAEs, and Unanticipated Problems 
9.4.1. 
Reporting AEs of Interest 
AEs of Interest will be documented on CRFs and entered into the Data Management System as they are 
ascertained. If the Adverse Event of Interest meets the criteria for an SAE it will be also documented on an SAE 
form and reported to the SDRC using the same approach as for any other SAE. 


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9.4.2. 
Reporting SAEs 
SAEs will be reported to the SDRC within 1 business day of first knowledge of the event. An SAE form will be 
completed by the Clinical Center research team and sent by electronic mail to the SDRC. At the time of the 
initial report, the following information will be provided: 
▪ 
Study identifier 
▪ 
Study Center 
▪ 
Participant number 
▪ 
A description of the event 
▪ 
Date of onset 
▪ 
Current status 
▪ 
Whether study treatment was discontinued 
▪ 
The reason why the event is classified as serious 
▪ 
Investigator assessment of the association 
between the event and study participation 
Additional information will be provided on a follow-up SAE form and mailed electronically to the SDRC typically 
within 7 calendar days of first knowledge of the SAE. Significant new information on ongoing serious adverse 
events will be provided promptly to the SDRC until the event is resolved (i.e., no longer ongoing). SAE forms 
can be completed by research coordinators but must be signed by a Clinical Center investigator. 
If a participant becomes pregnant while receiving buprenorphine, this will be reported as an SAE. Pregnancy 
outcomes will be collected, including the outcome of the infant and whether the pregnancy was terminated. 
This information will be submitted to the IRB. 
SAEs that are still ongoing at the end of the trial participation will be followed to determine the final outcome. 
The SDRC will facilitate the timely medical review and reporting of SAEs, and provide reports to the NIDDK and 
the Data and Safety Monitoring Board (DSMB) in accordance with DSMB-approved study policies and 
regulatory requirements (see Section 11.5.3 for information about the DSMB). 
9.4.3. 
Reporting Unanticipated Problems 
Unanticipated problems will be reported by the Clinical Center to the SDRC within one calendar day of first 
knowledge of the event. Additional information will be provided to the SDRC as it becomes available. The SDRC 
will inform the NIDDK and the DSMB about Unanticipated Problems and will report the events to the IRB as 
described in Section 9.5.  
9.5. 
Reporting to the IRB  
The University of Pennsylvania (UPenn) Institutional Review Board is the Single IRB of Record for the trial for all 
sites other than the VA sites. The VA Central Institutional Review Board (CIRB) will serve as the IRB of Record 
for VA sites. The SDRC will report events that occur at either the Clinical Centers or the SDRC to the UPenn IRB 
in accordance with the reporting requirements of the IRB shown in Table 9.1. The VA sites will be responsible 
for reporting to the VA CIRB.  
 
 


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Table 9.1. Reporting to the Single IRB of Record 
Relatedness 
Expectedness 
Reportable to IRB? 
Timeframe for Reporting 
Unrelated or Unlikely related 
Expected or 
Unexpected 
No report 
N/A 
Possibly, Probably, or 
Definitely related 
Expected 
No report 
N/A 
Possibly related 
Unexpected 
Yes (includes Serious and Non-Serious), 
only if the event suggests that the 
research placed participants at greater 
risk than was previously known or 
recognized (i.e., changes to the study 
conduct are required to mitigate risk 
and/or participants’ willingness to 
participate may be adversely impacted) 
Expedited reporting 
within 10 business days 
and summarized at 
Continuing Review  
Probably or Definitely related;  
No death 
Unexpected 
Yes (includes Serious and Non-Serious) 
Expedited reporting 
within 10 business days 
and summarized at 
Continuing Review 
Probably or Definitely related 
death 
Unexpected 
Yes 
Expedited reporting 
within 3 calendar days 
and summarized at 
Continuing Review 
9.5.1. 
Reporting Process 
Unanticipated problems will be reported using the appropriate IRB-designated form or as a written report of 
the event (including a description of the event with information regarding its fulfillment of the above criteria, 
follow-up/resolution and need for revision to consent form and/or other study documentation). 
Copies of each report and documentation of IRB notification and receipt will be maintained by the SDRC and in 
the Clinical Center’s study file. 
9.5.2. 
Other Reportable Events 
• Any adverse event that would cause the study’s Steering Committee to modify the protocol or informed 
consent form or would prompt other action by the IRB to assure protection of human participants. 
• Information that indicates a change to the risks or potential benefits of the research, in terms of severity or 
frequency.  
• Breach of confidentiality 
• Change to the protocol made without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
• Incarceration of a participant when the research was not previously approved under 45 CFR part 46 
subpart C and the investigator believes it is in the best interest of the participant to remain in the study. 


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• Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be 
resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB approved protocol) that 
in the opinion of the investigator placed one or more participants at increased risk, or affects the rights or 
welfare of participants. 
9.5.3. 
SDRC Notifications to Participating Investigators 
The SDRC will notify the Contact Principal Investigator at each Clinical Center, in a written safety report, of any 
event from any of the Clinical Centers or SDRC that meets the criteria for reporting to the Single IRB of Record. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. Endpoints, Objectives, and Trial Questions 
Scientific questions that will be addressed with the trial design, and the relevant comparison groups, 
outcomes, and analytic approaches are depicted in Table 10.1. 
• The primary endpoint is based on a continuous outcome, the BPI Interference score. The endpoint for the 
primary analyses is based on the BPI Interference score at Week 12 (see Section 4.2.4 for the rationale for 
the Week 12 time point).  
• The primary objective is to determine whether initial component of the PCST intervention, which consists 
of 12 weekly, live, coach-led sessions, reduces pain interference for hemodialysis-dependent patients 
with chronic pain. The null hypothesis is that changes in the BPI Interference score from baseline to 12 
weeks are the same for the PCST and Usual Care groups. The alternative hypothesis is that changes in the 
BPI Interference score from baseline to 12 weeks differ between the randomized groups. 
• Secondary endpoints include pain severity, pain catastrophizing, opioid use, other PROs that capture 
conditions associated with chronic pain, and clinical outcomes. 
• A secondary objective is to determine whether the full PCST intervention, which consists of weekly, live, 
coach-led sessions for 12 weeks followed by IVR for 12 weeks, reduces pain interference for 
hemodialysis-dependent patients with chronic pain. The null hypothesis is that changes in BPI 
Interference scores between baseline and 24 weeks are the same for the PCST and Usual Care groups. 
The alternative hypothesis is that changes in the BPI Interference scores between baseline and 24 weeks 
are different between the randomized groups. 
• An exploratory objective is to learn about the acceptability, tolerability, and efficacy of buprenorphine by 
evaluating the proportion of participants who initiate buprenorphine among those who are offered 
buprenorphine, the proportion of participants who do not require discontinuation of buprenorphine 
because of adverse effects among those who initiate buprenorphine, and the change in BPI-Interference 
from Week 24 to Week 36 among those who initiate buprenorphine. For this exploratory objective, the 
purpose is to generate preliminary estimates and signals. 
 


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Table 10.1. Scientific Questions that can be Addressed with the Trial Design 
Scientific Question 
Contrast  
of Interest 
Outcome(s) 
Analytic Approach 
1. Does PCST consisting of 
weekly, live, coach-led 
sessions improve outcomes 
at 12 weeks?  
This is the primary trial 
question. 
PCST vs Usual Care;  
baseline to Week 12 
• Primary: BPI Interference 
• Secondary: pain severity, pain 
catastrophizing, opioid use, 
other PROs, and clinical 
outcomes 
• Linear mixed effects models for 
continuous outcomes; 
• Generalized linear mixed effects 
models for binary outcomes;  
• Time to event models accounting 
for semi-competing risk of death 
(where relevant) 
2. Does PCST consisting of 
weekly, live, coach-led 
sessions followed by IVR 
improve outcomes at 24 
weeks?  
This is a secondary question 
and findings will be 
interpreted as such. 
PCST vs Usual Care;  
baseline to Week 24  
• Primary: BPI Interference 
• Secondary: pain severity, pain 
catastrophizing, opioid use, 
other PROs, and clinical 
outcomes 
• Linear mixed effects models for 
continuous outcomes; 
• Generalized linear mixed effects 
models for binary outcomes;  
• Time to event models accounting 
for semi-competing risk of death 
(where relevant) 
3. Are the effects of PCST 
sustained?  
This is a secondary question 
and findings will be 
interpreted as such. 
PCST vs Usual Care;  
baseline to Week 36 
• Primary: BPI Interference 
• Secondary: pain severity, pain 
catastrophizing, opioid use, 
other PROs, and clinical 
outcomes 
• Linear mixed effects models for 
continuous outcomes; 
• Generalized linear mixed effects 
models for binary outcomes;  
• Time to event models accounting 
for semi-competing risk of death 
(where relevant) 
Exploratory Questions Addressed with the Phase 2 Intervention 
4. Is buprenorphine acceptable 
to patients? 
Single group  
• % Initiating buprenorphine 
• Reasons for non-initiation of 
buprenorphine 
Summary statistics: frequency, 
percentage  
 
5. How well tolerated is 
buprenorphine? 
Single group  
• % who do not discontinue 
buprenorphine due to adverse 
effects 
• Adverse effects 
Summary statistics: frequency and 
percentage 
6. Does buprenorphine 
improve outcomes for 
patients using full agonist 
opioids for pain? 
Single group 
• BPI Interference 
• Opioid use, pain severity, pain 
catastrophizing, other PROs 
• Linear mixed effects models for 
continuous outcomes; 
• Generalized linear mixed effects 
models for binary outcomes;  
 


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10.2. Statistical Considerations for the Phase 1 Randomization 
10.2.1. Sample Size and Power Analysis for the Primary Objective 
The primary objective for Phase 1 is to compare changes from baseline to 12 weeks in the BPI Interference 
scores between the PCST and Usual Care groups. The null hypothesis is that the change in BPI Interference 
score is the same in the PCST and Usual Care groups.  
Table 10.2 depicts the minimum detectable difference between the PCST and Usual Care groups in the change 
in BPI Interference score, for a power of 90%, a type 1 error of 5%, an attrition rate of 20%, standard 
deviations of change of 2 and 3, a total number of participants ranging from 480 – 800 (participant numbers 
per Clinical Center ranging from 60 to 100), intra-class correlation coefficients of 0 and 0.02, and an interim 
analysis of one look at 50% information time. Details of the interim analysis are described in Section 10.2.3. All 
calculations are based on two-sample t tests. As one example, if the total sample size is 640, the number of 
participants per Clinical Center is 80, the ICC is 0 (i.e., no clustering effect), and the standard deviation of the 
change in BPI Interference score is 2, the BPI Interference score for PCST would need to decrease by at least 
0.62 points if the change in BPI Interference score for Usual Care were 0 (Table 10.2, Row #2). As another 
example, again using the parameters in Table 10.2, Row #2, the change in the BPI Interference score would 
need to decrease by 1.02 in the PCST group if the score decreased by 0.40 in the Usual Care group.  
Table 10.2. Minimum Detectable Differences between the PCST and Usual Care Groups in the Change  
from Baseline to Week 12 in the BPI Interference Score 
Row 
Total 
N 
Clinical 
Center 
n 
ICC 
Minimum Detectable Between-Group Difference 
 in Change in BPI Interference Score1 
If SD = 2 
If SD = 3 
1 
800 
100 
0 
0.56 
0.83 
2 
640 
80 
0 
0.62 
0.93 
3 
480 
60 
0 
0.72 
1.08 
4 
800 
80 
0.02 
0.73 
1.10 
5 
640 
80 
0.02 
0.78 
1.17 
6 
480 
60 
0.02 
0.86 
1.29 
1Effect sizes determined for a power of 90%, at a type 1 error of 5%, an attrition rate of 20%, standard deviations 
of change of 2 and 3, and an interim analysis of one look at 50% information time, using two-sample t tests. 
Each of eight Clinical Centers aims to recruit "𝑚" participants. The University of Washington Clinical Center 
consists of three recruitment sites: University of Washington, Rogosin Institute, and University of New Mexico. 
The University of Washington and Rogosin will each recruit 43.75% of the Clinical Center’s target, and the 
University of New Mexico will recruit 12.5% of the target. The University of Pittsburgh Clinical Center consists 
of two recruitment sites: University of Pittsburgh and University of Pennsylvania. The University of Pittsburgh 
site will recruit two thirds of the Clinical Center’s target and the University of Pennsylvania site will recruit one 
third of the target. The Vanderbilt Clinical Center consists of two recruitment sites: Vanderbilt University 
Medical Center and West Virginia University. Vanderbilt University Medical Center will recruit two thirds of the 


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Clinical Center’s target, and West Virginia University will recruit one third of the target. The Yale University 
Clinical Center consists of three recruitment sites in Veterans Affairs Healthcare Systems; each site will recruit 
one third of the target. Therefore, there are 14 recruitment sites. When clustering at the recruitment site level 
is considered in the power calculation, the average cluster size per recruitment site per arm is 𝑚̅ =
0.571 ×
𝑚
2 = 0.286𝑚, and the standard deviation of cluster size is 𝑠𝑚= 0.313 ×
𝑚
2 = 0.156𝑚. This will yield 
the design effect of 1 + ICC × [{(
𝑠𝑚
𝑚̅ )
2
+ 1} × 𝑚̅ −1]. For example, for 𝑚= 80 and ICC = 0.02, 𝑚̅ is 22.88, 
𝑠𝑚 is 12.48, and the design effect is 1.574. Thus, the sample size per arm in the power calculation is around 
139 (
80×8
2
×
1
1.574 × {1 −0.2} ×
1
1.173 ≅139) after taking into account the design effect (1.574), the attrition 
rate (0.2) and the inflation factor of the interim analysis (1.173). 
10.2.1.1. Rationale for the Selected Sample Size 
The trial will aim to enroll 640 participants. Based on the minimum detectable differences in changes of BPI 
Interference scores under a range of assumptions provided in Table 10.2, for the primary objective of 
comparing PCST with Usual Care in Phase 1, this sample size will allow detection of a difference in the change 
in BPI Interference score of 0.62 if there is no intra-cluster correlation and a standard deviation of change of 2, 
or 1.17. under the conservative assumptions of an intra-cluster correlation coefficient (ICC) of 0.02 and a 
standard deviation of change of 3 (which is larger than the SD of change observed in studies of chronic pain in 
non-ESRD patient populations57). Based on a review of the literature, the Initiative on Methods, Measurement, 
and Pain Assessment in Clinical Trials identified 1 as the minimal clinically important change for individuals on 
the BPI Interference scale.57 However, this group also recognized a critical tenet of randomized trials with 
between group comparisons: “…criteria for clinically important change in individuals cannot be directly applied 
to the evaluation of clinically important group differences.” Determination of the importance of group 
differences must be established in the broader context of the disease being treated, the currently available 
treatments, and the overall risk-benefit evaluation of the treatment. Our proposed sample size will allow us to 
detect a between-group difference as small as the ranges listed above. We hypothesize that the actual 
observed difference will be larger because we are testing an adaptation of an evidence-based intervention that 
has had moderate effect sizes in other populations and settings.27-29 
10.2.2. Statistical Analyses 
General Approach. The following descriptive statistics will be used: number of observations, mean, standard 
deviation, median, minimum and maximum for continuous variables; frequencies and proportions for 
categorical variables; number of events and rates for count variables. Results will be reported in accordance 
with the extended CONSORT guidelines for pragmatic clinical trials61 using two-sided statistical tests and 
confidences intervals. For all analyses, the overall level of significance will be set at 0.05. Methods for multiple 
comparisons such as Bonferonni, false discovery, or others, will be implemented to maintain the overall 0.05 
level of significance. All analyses will be adjusted for site and the presence or absence of opioid use using the 
criteria provided in Section 5.3. All analyses will be performed using SAS v9.4 (SAS Institute, Cary, NC) or the 
latest version of R (currently 3.6.1; https://cran.r-project.org/). 


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Baseline Descriptive Statistics. Randomization adequacy will be assessed by comparing the distributions of 
baseline demographic and clinical characteristics between the PCST and Usual Care groups. Comparability for 
continuous variables will be examined graphically and by summary statistics: mean, standard deviation, 
median, minimum, and maximum for continuous variables, and frequency and proportion for and categorical 
variables. If statistically and/or clinically meaningful differences are found in baseline characteristics (i.e., 
baseline characteristics are not balanced between the PCST and Usual Care groups), sensitivity analyses will be 
conducted with covariate adjustment. 
10.2.2.1. Analyses of the Primary Endpoint for the Phase 1 Randomization 
Question 1 (Table 10.1): Does a PCST intervention consisting of weekly, live, coach-led sessions improve 
outcomes at 12 weeks?  
Question 1 addresses the primary trial hypothesis. The primary efficacy endpoint, the change in BPI 
Interference between baseline and 12 weeks, and will be analyzed using a linear mixed effects model.62 The 
linear mixed effects model will include fixed effects of intervention, time, and interactions between 
intervention and time, taking into account the repeated measures over time and clustering of recruitment sites 
via random effects. All repeated measures of the BPI Interference scores at baseline and 12 weeks will be 
included in the model as the dependent variable. The linear mixed effects model is expressed as 
𝑦𝑖𝑗𝑘= 𝛽0 + 𝛽1𝑋𝑖𝑗+ 𝛽2𝐼(𝑇𝑖𝑗𝑘= 12) + 𝛽3𝑋𝑖𝑗𝐼(𝑇𝑖𝑗𝑘= 12) + 𝜸𝑻𝑾𝑖𝑗+ 𝜃𝑖+ 𝛼𝑖𝑗+ 𝜀𝑖𝑗𝑘, 
where 𝑦𝑖𝑗𝑘 is the BPI Interference score for participant ij (i = 1, 2, …, 14; j = 1, 2, …, ni; ni is number of 
participants from recruitment site i) at time point k (k = 1, 2), 𝑋𝑖𝑗 is the binary intervention indicator (𝑋𝑖𝑗= 1 if 
PCST; 𝑋𝑖𝑗= 0 if Usual Care) for participant ij, 𝑇𝑖𝑗𝑘 is the study weeks for participant ij at time point k (𝑇𝑖𝑗1 = 0 
and 𝑇𝑖𝑗2 = 12), 𝐼(∙) is an indicator function returning 1 (0) if the event is true (false), 𝑾𝑖𝑗 is a vector of 
baseline measures, including the stratification factors, for participant ij, 𝛽’s and 𝜸 are regression parameters 
for the fixed effects, 𝜃𝑖 and 𝛼𝑖𝑗 are the regression parameters for the random effects for recruitment site i and 
participant ij, respectively, and 𝜀𝑖𝑗𝑘 is the random error for participant ij at time point k. Model diagnostics will 
be conducted to examine the assumption of normality. If there are potential violation of the assumptions, 
transformations of the data beginning with a log transformation will be explored. The primary efficacy 
estimand is the contrast of PCST and Usual Care for the change at the 12-week time point; i.e., 𝛽3. Differences 
in changes, their 95% confidence intervals, and p-values will be presented. 
Question 2 (Table 10.1): Does a PCST intervention consisting of weekly, live, coach-led sessions for 12 weeks 
followed by IVR for 12 weeks improve outcomes at 24 weeks? 
To answer this question, the aforementioned linear mixed effects model is revised by adding the BPI 
Interference score at 24 weeks to the dependent variable. The linear mixed effects model is expressed as 
𝑦𝑖𝑗𝑘= 𝛽0
′ + 𝛽1
′𝑋𝑖𝑗+ 𝛽2
′𝐼(𝑇𝑖𝑗𝑘= 12) + 𝛽3
′𝐼(𝑇𝑖𝑗𝑘= 24) + 𝛽4
′𝑋𝑖𝑗𝐼(𝑇𝑖𝑗𝑘= 12) + 𝛽5
′𝑋𝑖𝑗𝐼(𝑇𝑖𝑗𝑘= 24) + 𝜸′𝑻𝑾𝑖𝑗+ 𝜃𝑖
′ + 𝛼𝑖𝑗
′ +
𝜀𝑖𝑗𝑘
′ , 
where 𝑦𝑖𝑗𝑘 is the BPI Interference score for participant ij at time point k (k = 1, 2, 3) and 𝑇𝑖𝑗3 = 24. The 
estimand for Question 2 in Table 10.1 is the contrast of PCST and Usual Care for the change at the 24-week 
time point; i.e.,𝛽5
′. Differences in changes, their 95% confidence intervals, and p-values will be presented. 


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Question 3 (Table 10.1): Are the effects of PCST sustained? 
To answer this question, the aforementioned linear mixed effects model is revised by adding the BPI 
Interference score at 36 weeks to the dependent variable. The linear mixed effects model is expressed as 
𝑦𝑖𝑗𝑘= 𝛽0
′′ + 𝛽1
′′𝑋𝑖𝑗+ 𝛽2
′′𝐼(𝑇𝑖𝑗𝑘= 12) + 𝛽3
′′𝐼(𝑇𝑖𝑗𝑘= 24) + 𝛽4
′′𝐼(𝑇𝑖𝑗𝑘= 36) + 𝛽5
′′𝑋𝑖𝑗𝐼(𝑇𝑖𝑗𝑘= 12) + 𝛽6
′′𝑋𝑖𝑗𝐼(𝑇𝑖𝑗𝑘= 24) +
𝛽7
′′𝑋𝑖𝑗𝐼(𝑇𝑖𝑗𝑘= 36) + 𝜸′′𝑻𝑾𝑖𝑗+ 𝜂′′𝑉𝑖𝑗𝐼(𝑇𝑖𝑗𝑘≥24) + 𝛿′′𝑍𝑖𝑗𝐼(𝑇𝑖𝑗𝑘≥24) + 𝜃𝑖
′′ + 𝛼𝑖𝑗
′′ + 𝜀𝑖𝑗𝑘
′′ , 
where 𝑦𝑖𝑗𝑘 is the BPI Interference score for participant ij at time point k (k = 1, 2, 3, 4), 𝑇𝑖𝑗4 = 36, 𝑉𝑖𝑗 is the 
binary buprenorphine eligibility indicator (𝑉𝑖𝑗= 1 if buprenorphine eligible; 𝑉𝑖𝑗= 0 if not buprenorphine 
eligible), 𝑍𝑖𝑗 is the binary buprenorphine indicator (𝑍𝑖𝑗= 1 if initiated buprenorphine; 𝑍𝑖𝑗= 0 if declined 
buprenorphine), and 𝜂′′ and 𝛿′′ are regression parameters for the fixed effects. The estimand for Question 3 
in Table 10.1 is the contrast of PCST and Usual Care for the change at the 36-week time point; i.e.,𝛽7
′′. 
Differences in changes, their 95% confidence intervals, and p-values will be presented. 
10.2.3.2 
Analyses of the Secondary Endpoints 
The secondary endpoints include pain severity, pain catastrophizing, opioid use, other PROs, hospitalizations, 
falls and mortality. 
For continuous endpoints, such as pain severity, pain catastrophizing, and opioid use expressed as MME/day., 
similar methods as described for the primary outcome will be used to compare differences in changes of the 
endpoints between PCST and Usual Care at 12 (Table 10.1; Question 1), 24 (Table 10.1; Question 2), and 36 
(Table 10.1; Question 3) weeks; i.e., linear mixed effects models with adjustment for baseline measures (and 
additional adjustment for buprenorphine eligibility and initiation of buprenorphine for Question 3 in Table 
10.1), taking into account the repeated measures over time and clustering of recruitment sites via random 
effects. 
For binary endpoints, such as the composite of pain interference and opioid use, generalized linear mixed 
effects models with a binomial distribution and a log link adjusting for baseline measures (additionally 
adjusting for buprenorphine eligibility and initiation of buprenorphine for Question 3 in Table 10.1), taking 
into account the repeated measures over time and clustering of recruitment sites via random effects, will be 
used to compare relative risks between PCST and Usual Care at 12 (Table 10.1; Question 1), 24 (Table 10.1; 
Question 2), and 36 (Table 10.1; Question 3) weeks. 
For recurrent endpoints (counts) such as number of hospitalizations and falls, participants will be followed 
from baseline to 36 weeks, loss-to-follow-up, or death, whichever comes first. Generalized linear mixed effects 
models with a Poisson distribution, an offset of follow-up time and a log link adjusting for baseline measures 
(additionally adjusting for buprenorphine eligibility and initiation of buprenorphine for Question 3 in Table 
10.1) will be used to compare event rates between PCST and Usual Care during the Phase 1 study period 
(Table 10.1; Questions 1 – 3). Repeated measures over time and clustering of recruitment sites will be taken 
into account via random effects. 
For time to event endpoints such as mortality, participants will be followed from baseline to 36 weeks, loss-to-
follow-up, or death, whichever comes first. Cox proportional hazards models will be used to compare risks of 


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all-cause mortality between PCST and Usual Care (Table 10.1; Questions 1 – 3), with the end of the 36-week 
study period and loss-to-follow-up treated as censoring events in the models. For time to event endpoints such 
as the first hospitalization (or fall), participants will be followed from baseline to 36 weeks, loss-to-follow-up, 
death or the first admission to hospital (or fall), whichever comes first. Cause-specific hazards models or sub-
distribution hazards models will be used to compare risks of the first hospitalization (or fall) between PCST and 
Usual Care (Table 10.1; Questions 1 – 3) where death is a semi-competing event, and the end of the 36-week 
study period and loss-to-follow-up are censoring events. All proportional hazards models will adjust for 
baseline measures, time-dependent buprenorphine eligibility, and time-dependent initiation of buprenorphine 
and take into account clustering of recruitment sites via random effects (i.e., proportional frailty models). The 
assumption of proportionality for all proportional hazards models will be examined using Schoenfeld residuals 
plots. If the assumption of proportionality is violated, models that incorporate stratification or time dependent 
covariate-effects will be considered. 
10.2.2.2. Subgroup Analyses 
Potential effect modification will be examined by including interaction terms between interventions and 
baseline factors such as gender, race, age, coping style, depression, and anxiety. For baseline factors with 
statistically significant interactions, intervention effects will be reported by subgroups. 
10.2.2.3. Missing Data  
If missing data are unavoidable, they will be addressed by 1) using models that are valid under the missing at 
random assumption, and 2) performing sensitivity analyses. The generalized linear mixed effects models are 
valid under the missing at random assumption. The extent and patterns of missing data will be examined, and 
logistic regression models will be used to identify factors associated with the missingness. Several approaches 
will be conducted to address the missingness. First, the generalized linear mixed effects models will further 
adjust for the identified factors associated with the missingness, compensating for potential violation of the 
missing at random assumption. Second, the propensity of the missingness, calculated from the above logistic 
regression, can be used to create inverse weighting in the generalized linear mixed effects models. Sensitivity 
analyses under missing not at random assumptions (e.g. pattern mixture models) will be conducted to examine 
the robustness of model-based results.63 For time to event analyses, competing risk models such as cause-
specific hazards models or sub-distribution hazards models will be used when there are competing events 
(e.g., death). 
10.2.3. Planned Interim Efficacy and Futility Analyses for the Phase 1 Randomization 
Prior to trial completion, only the DSMB and a designated study statistician from the SDRC will have access to 
data with unblinded randomization assignments. During each interim look, the DSMB could recommend early 
trial termination due to efficacy or futility of the primary objective or any operational inadequacy as follows. 
1. Efficacy: strong evidence is found for the primary hypothesis, indicating that a significant difference in 
changes in BPI Interference scores between PCST and Usual Care at Week 12 is likely to be concluded, 
resulting in a decision to stop the trial for superior efficacy. 


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2. Futility: weak evidence is found for the primary hypothesis, indicating a significant difference in 
changes in BPI Interference scores between PCST and Usual Care at Week 12 is unlikely to be 
concluded, resulting in a decision to stop for futility. 
3. Operational inadequacy: failure to obtain success in the implementation of the trial such as slow 
recruitment, poor retention, improper data handling, or inability to implement the protocol. 
For Phase 1 of the trial, one interim analysis is planned at 50% information time. However, the DSMB may 
request additional interim analyses and therefor a plan for an interim analysis with two looks at 50% and 75% 
information time is also provided. The 50% and 75% information times are defined as the times at which the 
randomized participants #320 and #480, respectively, have completed the Week 12 visit. 
Interim Analysis with One Look at 50% Information Time. To accommodate the additional interim look, a 
spending-function approach64 will be used to determine stopping bounds for efficacy and futility. For efficacy, 
an alpha-spending function is chosen to resemble the O’Brien-Fleming bounds.65 For futility, a beta-spending 
function is chosen to select a bound that approximates a conditional power of 20% or below. Stopping 
boundaries are depicted in Table 10.3 for a power of 90% and a two-sided type 1 error of 5% for an interim 
analysis with one look at 50% information time. At the 50% information time, if the test statistic for the 
primary objective, i.e., regression coefficient 𝛽4 divided by its standard error, is less than -2.89 (greater than -
0.97), the trial will stop for efficacy (futility). 
Table 10.3. Stopping Boundaries of Efficacy and Futility for a Power of 90% and at a Two-Sided Type 1  
Error of 5% for an Interim Analysis with One Look at 50% Information Time 
 
Interim Analysis Look 1 
Final Analysis 
Information Time 
50% 
100% 
Efficacy Boundary 
 
 
Test Statistic Critical Value 
-2.89 
-1.97 
Conditional Power at the Boundary 
99.9% 
 
Futility Boundary 
 
 
Test Statistic Critical Value 
-0.97 
-1.97 
Conditional Power at the Boundary 
20% 
 
gsDesign R package66 used to calculate stopping boundary and conditional power 
Interim Analysis with Two Looks at 50% and 75% Information Time. To accommodate a second interim look at 
75% information time, stopping boundaries are depicted in Table 10.4 for a power of 90% and a two-sided 
type 1 error of 5% for an interim analysis with two looks at 50% and 75% information time. At the 50% 
information time, if the test statistic for the primary objective, i.e., regression coefficient 𝛽4 divided by its 
standard error, is less than -2.89 (greater than -1.09), the trial will stop for efficacy (futility). At the 75% 
information time, if the test statistic is less than -2.50 (greater than -1.53), the trial will stop for efficacy 
(futility). 


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Table 10.4. Stopping Boundaries of Efficacy and Futility for a Power of 90% and at a Two-Sided Type 1 Error 
of 5% for an Interim Analysis with Two Looks at 50% and 75% Information Time 
 
Interim Analysis Look 1 
Interim Analysis Look 2 
Final Analysis 
Information Time 
50% 
75% 
100% 
Efficacy Boundary 
 
 
 
Test Statistic Critical Value 
-2.89 
-2.50 
-1.99 
Conditional Power at the Boundary 
99.9% 
96.3% 
 
Futility Boundary 
 
 
 
Test Statistic Critical Value 
-1.09 
-1.53 
-1.99 
Conditional Power at the Boundary 
20% 
32% 
 
If the interim analysis with two looks at 50% and 75% information time is conducted, the minimum detectable 
differences depicted in Table 10.2 will be updated by replacing the inflation factor of 1.173 for the interim 
analysis with one look at 50% information time with the inflation factor of 1.277 for the interim analysis with 
two looks at 50% and 75% information time. Table 10.5 depicts the minimum detectable difference between 
the PCST and Usual Care groups in change in BPI Interference from baseline to 12 weeks, for a power of 90%, 
at a type 1 error of 5%, an attrition rate of 20%, standard deviations of change of 2 and 3, a total number of 
participants ranging from 480 – 800 (participant numbers per Clinical Center ranging from 60 to 100), intra-
class correlation coefficients of 0 and 0.02, and an interim analysis of two looks at 50% and 75% information 
time. 
Table 10.5. Minimum Detectable Differences between the PCST and Usual Care Groups in the Change from 
Baseline to Week 12 in the BPI Interference 
10.3. Statistical Considerations for the Phase 2 Intervention 
This section describes statistical considerations for the exploratory objective of evaluating acceptability, 
tolerability, and efficacy of buprenorphine in Phase 2 of the trial. Participants who, at Week 24, meet the 
buprenorphine eligibility criteria are included in the following exploratory analyses. 
Due to the exploratory nature of Phase 2, potential numbers of participants initiating buprenorphine and 
declining buprenorphine are illustrated in Table 10.6 – Table 10.8 ranging from 20 per group to 80 per group. 
Row 
Total 
N 
Clinical 
Center 
n 
ICC 
Minimum Detectable Between-Group 
Difference in Change in BPI Score1 
If SD = 2 
If SD = 3 
1 
800 
100 
0 
0.58 
0.87 
2 
640 
80 
0 
0.65 
0.97 
3 
480 
60 
0 
0.75 
1.13 
4 
800 
100 
0.02 
0.76 
1.14 
5 
640 
80 
0.02 
0.82 
1.22 
6 
480 
60 
0.02 
0.90 
1.35 
1Effect sizes determined for power of 90%, type 1 error of 5%, attrition rate of 20%, standard deviations of change of 2 and 3, and 
interim analysis of two looks at 50% and 75% information time, using two-sample t tests. 


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Although we cannot predict how many participants among the 300 patients using opioids at trial enrollment 
will be eligible for the Phase 2 intervention at 24 weeks, under plausible assumptions we estimate that there 
will be at least 40 who are on sufficiently high doses of opioids at 24 weeks to meet the eligibility criteria for 
the buprenorphine intervention. 
10.3.1. Acceptability 
Participants who meet buprenorphine eligibility criteria at 24 weeks will be encouraged to switch from their 
full agonist opioid to buprenorphine. The acceptability objective explores the percentage of participants who 
initiate buprenorphine (acceptability), and also examines reasons for non-willingness to initiate buprenorphine 
(non-acceptability) (Table 10.1; Question 4). Table 10.6 depicts 95% confidence intervals for percentages of 
participants who initiate a switch from a full agonist opioid to buprenorphine for a range of numbers of 
participants eligible for and offered buprenorphine, and a range of percentages of participants who initiate a 
switch to buprenorphine. 
Table 10.6. 95% Confidence Intervals for % of Participants Willing to Switch from a Full Agonist Opioid 
 to Buprenorphine 
Offered 
Buprenorphine,  
N 
Initiated 
Buprenorphine, 
 N 
Initiated 
Buprenorphine, 
 % 
95% Confidence Interval for 
 Initiated Buprenorphine,  
% 
20 
5 
25 
(8.7, 49.1) 
40 
10 
25 
(12.7, 41.2) 
60 
15 
25 
(14.7, 37.9) 
80 
20 
25 
(16, 35.9) 
20 
10 
50 
(27.2, 72.8) 
40 
20 
50 
(33.8, 66.2) 
60 
30 
50 
(36.8, 63.2) 
80 
40 
50 
(38.6, 61.4) 
20 
15 
75 
(50.9, 91.3) 
40 
30 
75 
(58.8, 87.3) 
60 
45 
75 
(62.1, 85.3) 
80 
60 
75 
(64.1, 84) 
10.3.2. Tolerability 
Among the participants who are offered and agree to switch to buprenorphine, the tolerability outcome 
provides the number (percentage) of participants who do not discontinue buprenorphine due to adverse 
effects (Table 10.1; Question 5). For those who discontinue buprenorphine due to adverse effects, reasons for 
non-tolerability will be examined. Table 10.7 depicts 95% confidence intervals for percentages of participants 
who continue buprenorphine until the end of the study for a range of numbers of participants willing to switch 
from a full agonist opioid to buprenorphine and a percentage of participants who continue of 60%. 


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Table 10.7. 95% Confidence Intervals for % of Participants who Continue Buprenorphine Until the End of the 
Study (Week 36) 
Offered 
Buprenorphine,  
N 
Initiated 
Buprenorphine, 
 N 
Continued 
Buprenorphine until 
Week 36,  
N 
Continued 
Buprenorphine until 
Week 36, 
 % 
95% Confidence Interval  
for Continued Buprenorphine 
until Week 36,  
% 
20 
5 
3 
60 
(14.7, 94.7) 
40 
10 
6 
60 
(26.2, 87.8) 
60 
15 
9 
60 
(32.3, 83.7) 
80 
20 
12 
60 
(36.1, 80.9) 
20 
10 
6 
60 
(26.2, 87.8) 
40 
20 
12 
60 
(36.1, 80.9) 
60 
30 
18 
60 
(40.6, 77.3) 
80 
40 
24 
60 
(43.3, 75.1) 
20 
15 
9 
60 
(32.3, 83.7) 
40 
30 
18 
60 
(40.6, 77.3) 
60 
45 
27 
60 
(44.3, 74.3) 
80 
60 
36 
60 
(46.5, 72.4) 
10.3.3. Efficacy 
The exploratory efficacy endpoint is the primary efficacy endpoint used in Phase 1, the BPI Interference score, 
measured at 24 weeks and 36 weeks, where the baseline for Phase 2 is Week 24. The exploratory efficacy 
outcome (Table 10.1; Question 7) is the change in BPI Interference score between Week 24 and Week 36, and 
will be analyzed using a linear mixed effects model. The linear mixed effects model includes a fixed effect of 
time, taking into account the repeated measures over time via random effects. All repeated measures of the 
BPI Interference scores at Week 24 and Week 36 will be included in the model as the dependent variable. The 
linear mixed effects model is expressed as 𝑦𝑖𝑗= 𝛽0 + 𝛽1𝐼(𝑇𝑖𝑗= 36) + 𝜸𝑻𝑾𝑖𝑗+ 𝛼𝑖+ 𝜀𝑖𝑗, where 𝑦𝑖𝑗 is the BPI 
Interference score for participant i (i = 1, 2, …, I; I depends on the number of participants appropriate for 
buprenorphine and initiating buprenorphine at Week 24) at time point j (j = 1, 2), 𝑇𝑖𝑗 is the study weeks for 
participant i at time point j (𝑇𝑖1 = 24 and 𝑇𝑖2 = 36), 𝐼(∙) is an indicator function returning 1 (0) if the event is 
true (false), 𝑾𝑖𝑗 is a vector of measures for participant i at time point j, 𝛽1 and 𝜸 are regression parameters for 
the fixed effects, 𝛼𝑖 is the regression parameter for the random effect for participant i, and 𝜀𝑖𝑗 is the random 
error for participant i at time point j. Model diagnostics will be conducted to examine the assumption of 
normality. If there are potential violation of the assumptions, transformations of the data beginning with a log 
transformation will be explored. The exploratory efficacy estimand is the contrast between Week 24 and Week 
36 for the BPI Interference score; i.e., 𝛽1. The change in BPI Interference score and its 95% confidence interval 
will be presented. Signals of efficacy will be estimated from the participants who are eligible for and switch to 
buprenorphine. Table 10.8 depicts 95% confidence intervals for the change in BPI Interference scores for a 
range of numbers of participants switching to buprenorphine, an attrition rate of 20%, and a standard 
deviation of change of 2. 


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Table 10.8. 95% Confidence Intervals for the Change in BPI Interference Score between Weeks 24 and 36 
Offered Buprenorphine, 
N 
Initiated 
Buprenorphine, 
 N 
95% Confidence Interval for Change in BPI Interference 
Score1  
20 
5 
(-2.18, 4.18) 
40 
10 
(-0.67, 2.67) 
60 
15 
(-0.27, 2.27) 
80 
20 
(-0.07, 2.07) 
 
1Assumes a standard deviation of change of 2 and an attrition 
rate of 20%. 
10.4. Safety Analyses 
Proportions of participants with at least one adverse event and rates of adverse events will be determined. 
Differences between the PCST and Usual Care groups in the proportions and the rates will be compared using 
logistic regression models and Poisson regression models, respectively, adjusting for baseline measures. For 
participants who switch to buprenorphine, adverse events occurring during the buprenorphine phase (Weeks 
24-36) will also be summarized.  
10.5. Tabulation of Individual Participant Data 
Data will be tabulated in a de-identified fashion, without center or patient identifiers. 
10.6. Populations for Analyses 
For questions related to the Phase 1 intervention , analyses will use an intent-to-treat (ITT) approach, in which 
all available data on all randomized participants are included. Participants who discontinue an assigned 
intervention will be encouraged to remain in the trial to provide complete follow-up data and will be included 
in the ITT analysis. For participants with missing outcome ascertainment due to withdrawal or other reasons, 
data from earlier assessments will be used. For example, for the primary objective for Phase 1, if Week 12 
outcome data are not available, baseline data will be used. 
The characteristics at the time of randomization for those participants without complete follow-up will be 
examined; however, there will be limited statistical power to detect differences between participants with and 
without complete follow-up. To assess potential biases introduced by differential withdrawal among the 
intervention groups, comparisons of withdrawal rates and/or time to withdrawal will be performed as an 
ancillary analysis to the primary efficacy analysis. 
Other populations that may be used in secondary analyses are defined as follows:  
• 
As-treated population: Any participant randomized into the study regardless of whether they received 
study intervention. As-treated participants will be analyzed according to the study intervention 
actually received. 


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• 
All-treated population: Any participant randomized into the study that received at least some of the 
study intervention.  
• 
Per-protocol population: Any participant who was appropriately randomized and was exposed to the 
protocol-dictated study intervention for ≥ 75% of the planned duration and had the outcome 
assessments through Week 24. 
 


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11. 
REGULATORY, ETHICAL, AND OVERSIGHT CONSIDERATIONS  
11.1. Informed Consent Process and Participant Compensation 
Consent forms available in English and Spanish describing in detail the study interventions, study procedures, 
and risks will be provided to potential participants. Documentation of informed consent is required before any 
study procedures are conducted.  
Informed consent is a process that is initiated before an individual agrees to participate in the study and 
continues throughout the individual’s study participation. Consent forms will be Institutional Review Board 
(IRB)-approved and the potential participant will be asked to read and review the document. The investigator 
or a member of the research team designated by the investigator will explain the research study to the 
potential participant and answer any questions that may arise. A verbal explanation will be provided in terms 
suited to the individual’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants. Potential participants will have the opportunity to carefully review the 
consent form and ask questions prior to signing. The teach-back method will be used to assess the potential 
participant’s understanding of the research study. Potential participants will have the opportunity to discuss 
the study with family members or surrogates, and to fully consider the decision to participate or not. Potential 
participants will be informed that participation is voluntary and that they may withdraw from the study at any 
time, without prejudice. A copy of the signed informed consent document will be given to participants for their 
future reference. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
Participants will be compensated for the time and effort required to complete study activities. Compensation will 
be linked to the successful completion of Research Team Contacts and Follow-Up PRO questionnaires 
administered by CATI teams. Compensation amount will be standardized across Clinical Centers; however, 
compensation delivery methods will be determined by each Clinical Center individually.  
11.2. Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated by the Sponsor if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the Clinical Centers, SDRC, IRB, and the DSMB. If the study 
is prematurely terminated or suspended, the Clinical Center Principal Investigators will promptly inform study 
participants of the study status and of changes to their study visit schedule or procedures. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient recruitment that is not able to be improved adequately 
• 
Insufficient adherence to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 


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The study may resume once concerns about safety, protocol compliance, and data quality are addressed to the 
satisfaction of the sponsor, DSMB, IRB, and investigators are satisfied. 
In terminating the study, the Sponsor and the Principal Investigators will assure that adequate consideration is 
given to the protection of the interests of participants. 
11.3. Confidentiality and Privacy 
Information about study participants will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
participant authorization informing the participant of the following:  
• What protected health information (PHI) will be collected from participants in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research participant to revoke their authorization for use of their PHI 
If a participant revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to 
use all information collected prior to the revocation of participant authorization. For participants who have 
revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least 
vital status (i.e. that the participant is alive) at the end of their scheduled study period. 
Participants will be assigned a unique identifier at the time of enrollment that will be used for all data entered 
into the data management system. Clinical site personnel will de-identify all medical records before sending 
them to the SDRC by obliterating any Protected Health Information (PHI). Upon receipt, SDRC personnel will 
review the records to ensure that no PHI is visible. 
11.3.1. Certificate of Confidentiality  
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH). This certificate protects identifiable research information from forced 
disclosure. It allows the investigator and others who have access to research records to refuse to disclose 
identifying information on research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being 
compelled to disclose information that would identify research participants, Certificates of Confidentiality help 
achieve the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
11.4. Future Use of Data  
Data collected for this study will be stored and analyzed at the University of Pennsylvania Scientific and Data 
Research Center. After the study is completed, de-identified, archived data will be transmitted to and stored at 
the NIH HEAL Data Repository and/or the NIDDK Central Repository for use by other researchers including 
those outside of the study. Information about sending data to these repositories and future use will be 
included in the informed consent. 


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11.5. Safety Oversight 
11.5.1. Clinical Center Medical Monitoring 
Each Clinical Center Principal Investigator will be responsible for overseeing the safety of the study at his/her 
site. This safety monitoring will include careful assessment and appropriate reporting of adverse events as 
described in Section 9, as well as the construction and implementation of a site data and safety-monitoring 
plan. Medical monitoring will include a regular assessment of the number and type of serious adverse events. 
11.5.2. Internal Safety Committee 
A Safety Committee comprised of investigators from the Clinical Centers and the SDRC, research coordinators 
from the Clinical Centers, and Project Managers from the SDRC will review reports generated each month by 
the SDRC that include SAEs and AEs of Interest. Deaths will be reported by the SDRC to the Safety Committee 
when the SDRC becomes aware of their occurrence. The Safety Committee Chair will decide whether an ad hoc 
meeting of the Safety Committee is needed to review a death prior to the regularly scheduled monthly 
meeting. 
11.5.3. Independent Data and Safety Monitoring Board (DSMB) 
The information provided in this section of the protocol is a general description of the DSMB responsibilities 
and processes. A DSMB charter for the HOPE Consortium includes additional detail. The NIDDK DSMB charter is 
provided in Section 14.  
A DSMB has been established by the NIDDK to advise the Institute. The DSMB is comprised of individuals with 
expertise in clinical trials design and methodology, biostatistics, clinical nephrology, pain, opioids, behavioral 
interventions, and other relevant medical specialties. The DSMB members are appointed by the NIDDK and are 
not otherwise affiliated with the study. DSMB members will be free of conflicts of interest that could be 
affected by the outcomes of the study. During the study, DSMB members who develop real or perceived 
conflicts of interest that impact objectivity will disclose them to NIDDK project officers, who will arrange for 
replacement of the member, if indicated.  
The DSMB will review the protocol before initiation of the study. After initial approval, the primary 
responsibilities of the DSMB during the course of the study will be to: 
• Review safety data and provide input to protect the safety of the study participants; 
• Provide input on major changes to the research protocol and plans for data and safety monitoring;  
• Provide input on the progress of the study, including periodic assessments of data quality and timeliness, 
participant recruitment, accrual and retention, participant risk versus benefit, performance of the study 
sites, and other factors that may affect study outcomes;  
• Consider factors external to the study when relevant information becomes available, such as scientific or 
therapeutic developments that may have an impact on the need for continuation of the study, safety of 
the participants or the ethics of the study;  


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• Provide input on modification of the study protocol or possible early termination of the study because of 
attainment of study objectives, safety concerns, or inadequate performance (such as enrollment and 
retention problems). 
11.6. Quality Assurance and Quality Control 
The following processes or products will be used to maximize data quality, trial fidelity, and standardization 
across study sites. 
Manual of Procedures (MOP) – The MOP will provide detailed instructions for implementing the trial including, 
but not limited to, the performance of screening, baseline, enrollment, treatment allocation, intervention 
administration, data collection, and follow-up procedures. The MOP will provide instructions for case report 
form completion, use of the electronic data management system, and ordering buprenorphine from the 
central investigational pharmacy. The MOP will be available electronically to study personnel and will be 
updated online as necessary throughout the trial.  
Training and certification procedures – The SDRC will conduct required training sessions for investigators and 
research personnel before the study starts to train and certify research team members in the performance of 
study procedures. Separate training sessions led by consortium investigators with expertise in PCST and 
buprenorphine will be held for PCST coaches and buprenorphine prescribers, respectively.  
Quality Control (QC) Committee – The QC Committee will include investigators, research coordinators, and 
SDRC personnel. The Committee will meet regularly throughout the duration of the trial to review study-wide 
and site-specific reports generated by the SDRC using data from the data management system. The reports will 
include information about visit completion, study procedure completion, data completeness, timeliness of 
data entry, query/discrepancy resolution, PCST and buprenorphine intervention fidelity metrics (see Section 
6.4), and completeness of the centralized PRO ascertainment. The QC Committee will report to the Steering 
Committee and will work with research teams to improve processes as needed. 
Recruitment Committee – The Recruitment Committee will include investigators, research coordinators, SDRC 
personnel, and patient advisors. The committee will produce recruitment materials and dialysis facility 
informational materials that will be used by the Clinical Centers. The committee will monitor participant 
enrollment and retention throughout the duration of the trial using reports generated by the SDRC, and will 
work with research teams to identify approaches to improve performance as needed. Recruitment reports will 
be distributed study wide and reviewed on Steering Committee teleconferences. Clinical Centers will develop 
approaches to expanding to new enrollment sites if targets are not being met. The Steering Committee can 
consider modifications to the protocol to increase the duration of the enrollment period or facilitate 
enrollment in other ways if necessary. Such changes will need to be approved by the NIDDK and the DSMB, as 
well as the IRB, before being adopted.   
Standardized Instructions – Standardized, written instructions for use of the telehealth and IVR platforms will 
be provided to participants for the PCST intervention. Standardized safety information and instructions will be 
provided to participants receiving the buprenorphine intervention.  


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Site visits – Site visits with individual Clinical Center teams will be conducted either virtually or in-person while 
the trial is underway. 
Internal data quality control procedures – A data validation plan, rule set specifications, and programming logic 
to implement data validation rules will be implemented in the data management system.  
Reports – Reports created regularly by the SDRC will include 1) Recruitment, Retention, and Follow-Up, 2) 
Safety, and 3) Quality Control. These reports will be used by the relevant internal committees, as well as by the 
DSMB.  
11.7. Data Handling and Record Keeping  
The SDRC at the University of Pennsylvania is responsible for the overall management and monitoring of the 
trial data. Data collected at the Clinical Centers will be entered via a web-based Oracle relational data 
management system using electronic case report forms that incorporate range and logical edit checks, both 
within and cross forms. Data entry will be followed daily with manual and programmed checks and edits for 
errors and omissions.  
Access to the data management system will require individual user accounts with role-appropriate privileges. 
All data will be maintained in a secure electronic database located in the SDRC’s professionally managed data 
center employing FISMA compliant controls. The data management system will import data from electronic 
sources such as device outputs or files containing analysis results using processes that ensure secure 
transmission. 
The data management system is designed to prevent unauthorized access to trial data and to prevent data loss 
due to equipment failure or catastrophic events. The procedures to do so encompass user account 
management, user privilege assignment, data loss prevention (database backup), and data management 
system change management. User access will be controlled by assignment of confidential usernames and 
passwords. 
11.7.1. Study Records Retention  
Clinical Center investigators will retain study documents, including participant files and Regulatory Binders, for 
at least 5 years after the close of the study, or longer depending on site institutional requirements. The specific 
processes for destroying records will be in accordance with local institutional requirements. 
11.8. Protocol Deviations 
A protocol deviation is any change or alteration to the IRB-approved protocol without prospective IRB 
approval.  A protocol exception is a one-time, intentional change or alteration to the IRB-approved protocol 
that is approved by the IRB prior to implementation.  
Major Deviation: Any change/alteration that has or has the potential to: 1) adversely affect the rights, welfare 
or safety of the subjects, 2) adversely affect the integrity of the research data, or 3) affect the subject’s 
willingness to participate.  


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Examples of Major Deviations  
• Failure to obtain informed consent (i.e., no documentation of informed consent or informed consent 
was obtained after initiation of study procedures)  
• Informed consent obtained by someone not approved to obtain consent for the protocol  
• Use of invalid consent form (i.e., consent form without IRB approval stamp, or outdated/expired consent 
form)  
• Enrollment of a participant who is ineligible for the study  
• Performing a research procedure not in the approved protocol  
• Failure to report serious adverse event to sponsor/SDRC 
• Study medication dispensing or dosing error  
• Failure to follow the approved study protocol that affects participant safety or data integrity (e.g., failure 
to properly schedule study visits or failure to perform laboratory tests)  
• Continuing research activities after IRB approval has expired  
• Use of recruitment procedures that have not been approved by the IRB  
• Participant giving study medication to a third-party  
• Enrolling significantly more participants than approved in the IRB protocol  
Minor Deviation: Any change/alteration that has not or does not have the potential to:  
1) adversely affect the rights, welfare or safety of the subjects, 2) adversely affect the integrity of the research 
data, or 3) affect the subject’s willingness to participate. 
Examples of Minor Deviations 
• Delay in a study visit beyond the protocol-defined window  
• Failure to obtain a blood sample for laboratory measurements that are not related to safety monitoring 
Site investigators may not implement any major deviation from the protocol without prior review and 
agreement by the SDRC, and in accordance with IRB and local regulations, except when necessary to eliminate 
an immediate hazard to study subjects. When a deviation from the protocol is deemed necessary for an 
individual participant, the investigator must review the issue with the SDRC leadership. Such contact must be 
made as soon as possible to permit a review by the SDRC, and, if needed, the NIDDK, to determine the impact 
of the deviation on the participant and/or the study. Any significant protocol deviations affecting participant 
eligibility and/or safety must be reviewed and/or approved by the IRB and regulatory authorities, as applicable, 
prior to implementation. Minor protocol deviations (e.g., participant visit outside the study window) that do 
not impact participant eligibility or safety will be catalogued by each site and reported to the IRB at each 
continuing review. 


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11.9. Publications and Data Sharing  
Research results will be made available to the scientific community and public in a timely manner. The primary 
method by which data will be shared with the scientific community will be through peer-reviewed publications 
and presentations at scientific and professional society meetings. In addition, data and results will be shared 
with the DSMB and NIDDK in accordance with scheduled or ad hoc meetings. The study will be registered with 
clinicaltrials.gov prior to initiation, any changes to the protocol will be submitted to clinicaltrials.gov after they 
have been approved by the IRB, and trial results will be entered into clinictrials.gov in accordance with the 
clinicaltrials.gov reporting requirements. 
Results of the study carried out under this protocol, or any of the information provided by the HOPE 
Consortium for the purposes of performing the study, will not be published or passed on to any third party 
without the consent of the Steering Committee. Any investigator involved with this study is obligated to 
provide the SDRC with results of all study-related testing and all data derived from the study. Publications 
arising from the trial or other work of the HOPE Consortium will be subject to approval by the Publications 
Committee and Steering Committee as detailed in the HOPE Publication Policy. Trial data will be maintained by 
the SDRC, and data analyses for presentations and publications will be performed by the SDRC.  
Data from the study will be submitted to the NIH HEAL Data Repository and/or the NIDDK Central Repository in 
accordance with the NIH HEAL and the NIDDK data sharing policies, respectively.  
11.10. Conflict of Interest Policy 
All investigators are required to report all financial conflicts of interest on an annual basis. All conflicts of 
interest will be reported in manuscripts. If conflicts of interest arise during the conduct of the study, the 
Steering Committee will review and make determinations regarding any necessary management. 
 


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12. 
PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
V1.1 
12.2.2020 
Added language to Section 6.2.6 to 
clarify that VA recruitment sites will be 
using VA pharmacies to dispense 
buprenorphine 
VA CIRB required this language be added to 
the protocol 
V1.2 
5.7.2021 
The language used to discuss pregnancy 
related issues throughout the protocol 
has been updated to remove gender-
specific terminology.  
The new language does not exclude 
participants who are able to become 
pregnant but do not identify as women. 
The amount of time that the PRO 
ascertainment calls are expected to last 
has been updated to 45 minutes.  
This protocol initially included both shorter 
25-minute PRO ascertainment calls as well as 
45-minute calls. The shorter calls have been 
removed from the protocol.  
Language in section 5.4 Participant 
Recruitment and Eligibility Screening has 
been updated to include the following 
sentence: 
“Completion of the pre-screening survey 
is not required for study participation. 
Patients may be approached for consent 
and subsequent screening activities 
without having completed the pre-
screening survey.” 
This sentence has been added to make clear 
that the pre-screening is not a requirement 
for study participation. Participants can be 
consented without having completed the 
pre-screening survey.  
The following sentence has been added 
to Section 6.1.5.1: “After listening to 
their weekly coach feedback, 
participants may leave a message that 
their coach will access during regular 
business hours.” 
This sentence clarifies how IVR will facilitate 
communication between PCST coaches and 
participants after the first 12 weeks of PCST.  
Throughout the protocol the word 
“interventionist” has been replaced with 
“coach”.  
This is the terminology we use to describe 
the personnel that deliver the PCST 
intervention.  
In several sections throughout the 
protocol, the words “Clinical Center” 
have been replaced with “enrolling site”. 
In the sections where these changes have 
been made, the term “enrolling site” is a 
more accurate term since Clinical Centers 
can include multiple enrolling sites.  
 
 
 
 
 
 
 


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Version 
Date 
Description of Change  
Brief Rationale 
In Section 6.2.7.4 Initial Visit with 
Buprenorphine Prescriber the language 
has been updated to say:  
 “Following buprenorphine initiation, 
structured follow-up will occur at 
multiple time points within the first 3 
weeks after buprenorphine initiation. 
These follow-up visits will occur at 2-3 
days, 1 week, 2 weeks, and 3 weeks 
after initiation, but the timing can be 
modified based on the judgement of the 
buprenorphine prescriber.” 
The language in this section was internally 
inconsistent.  
Table 6.2 Buprenorphine Dosing has 
been updated in the following ways:  
- Column 4 now reads “Typical Dosing 
Regimens” instead of “Dosing 
Regimens” 
- In the “Typical Dosing Regimens” 
column for both the buccal and 
sublingual formulations, the option 
for once daily dosing has been 
removed 
Section 6.2.9 Buprenorphine 
Maintenance During and After the Trial 
has been modified to remove once daily 
dosing as a dosing frequency option 
Once daily dosing is not a commonly used 
dosing frequency for either of these 
formulations.  
Throughout the protocol the Pain 
Mapping Questionnaire has been added 
to the list of baseline PRO 
questionnaires. 
The pain mapping questionnaire was 
unintentionally excluded from the list of 
baseline PROs.  
Falls have been added to the list of 
Adverse Events of Interest in Section 9.2 
Adverse Events of Interest. 
Falls are one of the secondary outcomes as 
well as an Adverse Event of Interest. Falls 
were inadvertently left off the list of Adverse 
Events of Interest in section 9.2.  
V1.3 
7.16.2021 
Language in Section 6.2.8 was revised to 
clarify the procedures for switching a 
participant to buprenorphine.  
The new language provides additional 
guidance regarding the appropriate 
buprenorphine formulation (Belbuca or 
sublingual buprenorphine/naloxone) to use 
when switching to buprenorphine from a full 
agonist opioid.   


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Version 
Date 
Description of Change  
Brief Rationale 
“Dosages and dosing regimens for 
Belbuca and sublingual 
buprenorphine/naloxone are shown in 
Table 6.2. For participants using the 
crossover titration approach to 
transitioning to buprenorphine, Belbuca 
will be used to initiate the crossover 
titration. After the transition, Belbuca 
will be used for all participants who had 
been using a full agonist opioid at a dose 
of <30 MME/day. Belbuca will also be 
used for participants who had been 
using a full agonist opioid at a dose of 
30-35 MME/day, unless the maximal 
dose of Belbuca (450 mcg twice daily) is 
insufficient to manage their symptoms. 
As detailed in the Buprenorphine 
Manual of Procedures, the dose of 
buprenorphine will be adjusted 
(increased or decreased) based on 
adequacy of pain control, withdrawal 
symptoms, and tolerability.  
For participants using the traditional 
approach to transitioning to 
buprenorphine, either Belbuca or 
buprenorphine/naloxone can be used as 
the initial buprenorphine formulation 
depending on the full agonist opioid 
MME/day, in accordance with the 
guidelines in the Buprenorphine Manual 
of Procedures.” 
Table 6.2, Formulation-Specific 
Exclusions (buprenorphine/naloxone), 
has been updated in the following way: 
Old language:  
“1.  Use of full agonist opioid at dose 
<60 MME/day” 
 
New Language:  
“1.  Use of full agonist opioid at dose 
<30 MME/day” 
 
The following language has also been 
added to the footnote:  
“Note that these exclusions apply to the 
anticipated buprenorphine formulation 
that will be used immediately following 
This change made to correct an error in the 
prior wording. 


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Version 
Date 
Description of Change  
Brief Rationale 
the transition from the full agonist 
opioid. The exclusion does not apply to 
dose modifications required after a 
participant has been transitioned to 
buprenorphine.” 
The questionnaire “Internalized Stigma 
in Chronic Pain Scale” has been added to 
the list of Week 24 PROs. 
This questionnaire is part of an ancillary 
study.  
V1.4 
12.2.2021 
Removal of randomization for the 
assignment to the Phase 2 
buprenorphine intervention. 
The number of participants to initiate 
buprenorphine is significantly fewer than 
anticipated. By removing the requirement 
for randomization to buprenorphine vs no 
buprenorphine, and instead offering 
buprenorphine to all participants who meet 
the buprenorphine eligibility criteria, we will 
increase the sample and be better able to 
ascertain the exploratory outcomes of 
tolerability, acceptability, and efficacy of 
buprenorphine. 
V1.5 
3.8.2022 
Added language to clarify dental risks 
and to mitigate those risks.   
Added language to clarify responsibility 
for prescribing pain medication if 
buprenorphine is discontinued.  
List of adverse events of interest was 
updated. 
The FDA recently issued a report indicating 
that dental problems are a newly recognized 
adverse effect of buprenorphine delivered 
via buccal or sublingual administration.  
Additional detail about risks and ways to 
minimize those risks has been provided at 
the request of the IRB. 
This language has been changed to allow 
maximum flexibility when ensuring that a 
participant has continuity in pain 
management care, and will help to ensure 
that participants do not experience a gap in 
pain medication if they need to switch from 
buprenorphine back to their full agonist 
opioid medication. 
This language has been changed to reflect 
the events being monitored, and to include 
dental events in light of the FDA’s notice. 
V1.6 
2.20.2023 
Added language to Section 7.3:  
This change allowed recruitment sites to 
randomize participants beyond our target of 
640 if an individual had already consented to 
participate prior to the 640th randomization.   


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Version 
Date 
Description of Change  
Brief Rationale 
“Recruitment of new participants will 
conclude once 640 participants have 
been randomized. At the time of the 
640th randomization, participants who 
are “in the pipeline” (participants who 
provided consent and have been 
screened eligible but have not yet been 
randomized) will also be randomized 
and continue in the study.” 
V1.7 
7.7.2023 
Added one-time qualitative interviews 
for approximately 25 participants who 
were offered the Phase 2 buprenorphine 
intervention. 
The HOPE Trial DSMB requested this addition 
to the protocol. The purpose of the 
interviews is to understand why participants 
were willing or were not willing to switch 
from their full agonist opioids to 
buprenorphine when it was offered to them 
as part of the HOPE Trial. 


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29. Qaseem A, Wilt TJ, McLean RM, Forciea MA, Clinical Guidelines Committee of the American College of P. 
Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline 
From the American College of Physicians. Ann Intern Med 2017;166:514-30. 
30. Heapy AA, Higgins DM, Goulet JL, et al. Interactive Voice Response-Based Self-management for Chronic 
Back Pain: The COPES Noninferiority Randomized Trial. JAMA Intern Med 2017;177:765-73. 
31. Naylor MR, Naud S, Keefe FJ, Helzer JE. Therapeutic Interactive Voice Response (TIVR) to reduce analgesic 
medication use for chronic pain management. J Pain 2010;11:1410-9. 
32. Lacson E, Jr., Li NC, Guerra-Dean S, Lazarus M, Hakim R, Finkelstein FO. Depressive symptoms associate 
with high mortality risk and dialysis withdrawal in incident hemodialysis patients. Nephrol Dial Transplant 
2012;27:2921-8. 
33. Schouten RW, Harmse VJ, Dekker FW, van Ballegooijen W, Siegert CEH, Honig A. Dimensions of 
Depressive Symptoms and Their Association With Mortality, Hospitalization, and Quality of Life in Dialysis 
Patients: A Cohort Study. Psychosom Med 2019;81:649-58. 
34. Al Salmi I, Larkina M, Wang M, et al. Missed Hemodialysis Treatments: International Variation, Predictors, 
and Outcomes in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 
2018;72:634-43. 
35. Johansen KL, Chertow GM, Ng AV, et al. Physical activity levels in patients on hemodialysis and healthy 
sedentary controls. Kidney Int 2000;57:2564-70. 
36. Unruh ML, Buysse DJ, Dew MA, et al. Sleep quality and its correlates in the first year of dialysis. Clin J Am 
Soc Nephrol 2006;1:802-10. 
37. Abdel-Kader K, Unruh ML, Weisbord SD. Symptom burden, depression, and quality of life in chronic and 
end-stage kidney disease. Clin J Am Soc Nephrol 2009;4:1057-64. 
38. Cukor D, Ver Halen N, Asher DR, et al. Psychosocial intervention improves depression, quality of life, and 
fluid adherence in hemodialysis. J Am Soc Nephrol 2014;25:196-206. 
39. Malinoff HL, Barkin RL, Wilson G. Sublingual buprenorphine is effective in the treatment of chronic pain 
syndrome. Am J Ther 2005;12:379-84. 
40. Sorge J, Sittl R. Transdermal buprenorphine in the treatment of chronic pain: results of a phase III, 
multicenter, randomized, double-blind, placebo-controlled study. Clin Ther 2004;26:1808-20. 


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41. Daitch D, Daitch J, Novinson D, Frey M, Mitnick C, Pergolizzi J, Jr. Conversion from high-dose full-opioid 
agonists to sublingual buprenorphine reduces pain scores and improves quality of life for chronic pain 
patients. Pain Med 2014;15:2087-94. 
42. Daitch J, Frey ME, Silver D, Mitnick C, Daitch D, Pergolizzi J, Jr. Conversion of chronic pain patients from 
full-opioid agonists to sublingual buprenorphine. Pain Physician 2012;15:ES59-66. 
43. Oldfield BJ, Edens EL, Agnoli A, et al. Multimodal treatment options, including rotating to buprenorphine, 
within a multidisciplinary pain clinic for patients on risky opioid regimens: A quality improvement study. 
Pain Medicine 2018;19:S38-S45. 
44. Elkader A, Sproule B. Buprenorphine. Clinical pharmacokinetics 2005;44:661-80. 
45. Filitz J, Griessinger N, Sittl R, Likar R, Schuttler J, Koppert W. Effects of intermittent hemodialysis on 
buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with 
transdermal buprenorphine. Eur J Pain 2006;10:743-8. 
46. Mehrotra R, Cukor D, Unruh M, et al. Comparative Efficacy of Therapies for Treatment of Depression for 
Patients Undergoing Maintenance Hemodialysis: A Randomized Clinical Trial. Ann Intern Med 
2019;170:369-79. 
47. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 
1994;23:129-38. 
48. Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the brief pain inventory for use 
in documenting the outcomes of patients with noncancer pain. Clin J Pain 2004;20:309-18. 
49. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT 
recommendations. Pain 2005;113:9-19. 
50. Cleeland CS, Nakamura Y, Mendoza TR, Edwards KR, Douglas J, Serlin RC. Dimensions of the impact of 
cancer pain in a four country sample: new information from multidimensional scaling. Pain 1996;67:267-
73. 
51. Mendoza T, Mayne T, Rublee D, Cleeland C. Reliability and validity of a modified Brief Pain Inventory short 
form in patients with osteoarthritis. Eur J Pain 2006;10:353-61. 
52. Osborne TL, Raichle KA, Jensen MP, Ehde DM, Kraft G. The reliability and validity of pain interference 
measures in persons with multiple sclerosis. J Pain Symptom Manage 2006;32:217-29. 
53. Raichle KA, Osborne TL, Jensen MP, Cardenas D. The reliability and validity of pain interference measures 
in persons with spinal cord injury. J Pain 2006;7:179-86. 
54. Chen CX, Kroenke K, Stump T, et al. Comparative Responsiveness of the PROMIS Pain Interference Short 
Forms With Legacy Pain Measures: Results From Three Randomized Clinical Trials. J Pain 2019;20:664-75. 
55. Kean J, Monahan PO, Kroenke K, et al. Comparative Responsiveness of the PROMIS Pain Interference 
Short Forms, Brief Pain Inventory, PEG, and SF-36 Bodily Pain Subscale. Med Care 2016;54:414-21. 
56. Kroenke K, Theobald D, Wu J, Tu W, Krebs EE. Comparative responsiveness of pain measures in cancer 
patients. J Pain 2012;13:764-72. 
57. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in 
chronic pain clinical trials: IMMPACT recommendations. J Pain 2008;9:105-21. 
58. Krebs EE, Lorenz KA, Bair MJ, et al. Development and initial validation of the PEG, a three-item scale 
assessing pain intensity and interference. J Gen Intern Med 2009;24:733-8. 
59. McNeely J, Wu LT, Subramaniam G, et al. Performance of the Tobacco, Alcohol, Prescription Medication, 
and Other Substance Use (TAPS) Tool for Substance Use Screening in Primary Care Patients. Ann Intern 
Med 2016;165:690-9. 
60. Becker WC, Frank JW, Edens EL. Switching From High-Dose, Long-Term Opioids to Buprenorphine: A Case 
Series. Ann Intern Med 2020. 
61. Zwarenstein M, Treweek S, Gagnier JJ, et al. Improving the reporting of pragmatic trials: an extension of 
the CONSORT statement. BMJ 2008;337:a2390. 


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62. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics 1982;38:963-74. 
63. Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol deviation: a framework 
for relevant, accessible assumptions, and inference via multiple imputation. J Biopharm Stat 
2013;23:1352-71. 
64. Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error probability spending 
functions. Stat Med 1990;9:1439-45. 
65. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549-56. 
66. gsDesign: Group Sequential Design. R package version 3.0-1. 2016. at https://CRAN.R-
project.org/package=gsDesign.) 
67. Sullivan MJL BS, Pivik J. The Pain Catastrophizing Scale: Development and validation. Psychological 
Assessment 1995;7:524-32. 
68. Sobell LC, Brown J, Leo GI, Sobell MB. The reliability of the Alcohol Timeline Followback when 
administered by telephone and by computer. Drug Alcohol Depend 1996;42:49-54. 
69. Cleeland C. The Brief Pain Inventory: User Guide. Houston, TX: MD Anderson Cancer Center; 2009. 46. . 
70. MacFarlane GJ, Croft PR, Schollum J, Silman AJ. Widespread pain: is an improved classification possible? J 
Rheumatol 1996;23:1628-32. 
71. Cohen SR, Sawatzky R, Russell LB, Shahidi J, Heyland DK, Gadermann AM. Measuring the quality of life of 
people at the end of life: The McGill Quality of Life Questionnaire-Revised. Palliat Med 2017;31:120-9. 
72. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ 
primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA 
1999;282:1737-44. 
73. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the 
GAD-7. Arch Intern Med 2006;166:1092-7. 
74. Harland N, Georgieff, K,. Development of the Coping Strategies Questionnaire 24, a Clinically Utilitarian 
Version of the Coping Strategies Questionnaire. Rehabilitation Psychology 2003;48:4. 
75. Gruber-Baldini AL, Velozo C, Romero S, Shulman LM. Validation of the PROMIS((R)) measures of self-
efficacy for managing chronic conditions. Qual Life Res 2017;26:1915-24. 
76. Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes Measurement Information System 
(PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-
2008. J Clin Epidemiol 2010;63:1179-94. 
77. Buysse DJ, Yu L, Moul DE, et al. Development and validation of patient-reported outcome measures for 
sleep disturbance and sleep-related impairments. Sleep 2010;33:781-92. 
78. Schneider S, Choi SW, Junghaenel DU, Schwartz JE, Stone AA. Psychometric characteristics of daily diaries 
for the Patient-Reported Outcomes Measurement Information System (PROMIS(R)): a preliminary 
investigation. Qual Life Res 2013;22:1859-69. 
79. Rose M, Bjorner JB, Gandek B, Bruce B, Fries JF, Ware JE, Jr. The PROMIS Physical Function item bank was 
calibrated to a standardized metric and shown to improve measurement efficiency. J Clin Epidemiol 
2014;67:516-26. 
80. Zimet GD DN, Zimet SG, Farley GK. The Multidimensional Scale of Perceived Social Support. Journal of 
Personality Assessment 1988;52:30-41. 
81. Weisbord SD, Fried LF, Arnold RM, et al. Development of a symptom assessment instrument for chronic 
hemodialysis patients: the Dialysis Symptom Index. J Pain Symptom Manage 2004;27:226-40. 
82. Hahn EA, Devellis RF, Bode RK, et al. Measuring social health in the patient-reported outcomes 
measurement information system (PROMIS): item bank development and testing. Qual Life Res 
2010;19:1035-44. 
83. Williams DR, Yan Y, Jackson JS, Anderson NB. Racial Differences in Physical and Mental Health: Socio-
economic Status, Stress and Discrimination. J Health Psychol 1997;2:335-51. 


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84. (ed) GW. ECDEU Assessment Manual for Psychopharmacology. In: US Department of Health E, and 
Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, ed. Rockville, 
MD1976. 
85. Scott W, Yu L, Patel S, McCracken LM. Measuring Stigma in Chronic Pain: Preliminary Investigation of 
Instrument Psychometrics, Correlates, and Magnitude of Change in a Prospective Cohort Attending 
Interdisciplinary Treatment. J Pain 2019;20:1164-75. 


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14.  APPENDIX 
 


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14.1. Schedule of Procedures 
 
 
Pre-
Screening1 
Screening 
Visit1 
Phase 1 
(PCST or Usual Care) 
Phase 2 
Buprenorphine 
 
Procedure 
Point of Contact or 
Collection Method 
 
 
BSL1  
WK 0 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
SCREENING 
Preliminary eligibility 
assessment 
Pre-Screening 
Survey 
X 
 
 
 
 
 
 
 
 
 
 
 
Pain screening tool 
RC 
X 
 
 
 
 
 
 
 
 
 
 
 
Pain chronicity 
RC 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
RC 
 
X 
 
 
 
 
 
 
X2 
 
 
 
Demographics 
RC 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
RC 
 
X 
 
 
 
 
 
 
 
 
 
 
Dialysis history 
RC 
 
X 
 
 
 
 
 
 
 
 
 
 
Opioid history 
RC 
 
X 
 
 
 
 
 
 
 
 
 
 
Cognitive impairment 
RC 
 
X 
 
 
 
 
 
 
 
 
 
 
Review eligibility 
RC 
 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization (Phase 1) 
RC 
 
 
X 
 
 
 
 
 
 
 
 
 
Contact Opioid Prescriber 
RC 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Screen 
RC/dialysis unit 
staff 
 
 
 
 
 
 
 
 
X3 
 
 
 
PRO ASCERTAINMENT 
PROs 
CATI 
 
 
X 
 
 
X4 
 
 
X4 
 
 
X 
PAIN COPING SKILLS (PCST) 
Telehealth Skill Sessions 
PCST Coach 
 
 
Weekly 
 
 
 
 
 
 
IVR Booster Sessions 
Pre-recorded 
telephone sessions 
 
 
 
 
 
 
Daily 
 
 
 
BUPRENORPHINE 
Appropriateness/Eligibility for 
Buprenorphine 
Study investigator 
/designee 
 
 
 
 
 
 
 
 
X 
 
 
 
Buprenorphine consent/ 
administration/monitoring 
Study investigator 
/designee 
 
 
 
 
 
 
 
 
X 
RESEARCH TEAM CONTACTS 
Clinical outcome ascertainment  
RC 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event ascertainment 
RC 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication review 
RC 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CATI call scheduling 
RC 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BIOLOGICAL SAMPLES 
Blood collection 
RC/dialysis unit 
staff 
 
 
 
 
 
 
 
 
X3 
 
 
 
Saliva collection 
RC 
 
 
 
 
 
 
 
 
X5 
 
 
 
 
 
1 Pre-Screening, Screening and Baseline activities may be conducted over the course of several days or may be performed on a single day.  
2 Participants eligible for the buprenorphine intervention will provide written consent before initiating treatment with buprenorphine. 
3 Blood will be collected from participants of childbearing potential who meet the full agonist opioid dose criterion for buprenorphine eligibility criteria 
before being offered buprenorphine. 
4 At Weeks 12 and 24 the full set of PROs except for the Everyday Discrimination Scale will be ascertained. 
5Saliva collection for substance use screening will be performed for participants before the initial visit with the buprenorphine prescriber. 
Additional substance use testing during Phase 2 for those who switch to buprenorphine can be performed at the discretion of the buprenorphine 
prescriber. 
Abbreviations: RC, research coordinator; BSL, baseline; CATI, computer-assisted telephone interviewing; PCST, pain coping skills training; BUP, 
buprenorphine 


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14.2. PRO Questionnaire Schedule and Activities During Research Team Contacts 
Baseline PRO Questionnaires (Week 0) 
• 
Pain interference – Brief Pain Index (BPI) Interference47 
• 
Pain intensity – Brief Pain Index (BPI) Severity47 
• 
Pain catastrophizing – Pain Catastrophizing Scale (PCS) SF 667 
• 
Opioid use – Timeline Followback68 
• 
Pain Mapping Questionnaire69, 70 
• 
Quality of life –Single-Item QOL Scale [SIS] from McGill Quality of Life (MQOL) questionnaire71 
• 
Depression – Patient Health Questionnaire (PHQ-9)72 
• 
Anxiety – Generalized Anxiety Disorder (GAD-7)73 
• 
Coping – Coping Strategies Questionnaire 24 (CSQ-24)74  
• 
Self-efficacy - PROMIS Self-Efficacy for Managing Chronic Conditions – Managing Symptoms – Short Form 8A75 + 
Single item targeting self-efficacy for pain 
• 
Sleep quality – PROMIS Sleep Disturbance SF 6a + Sleep Duration Question76, 77 
• 
Fatigue – PROMIS Fatigue SF 6a76, 78 
• 
Physical functioning – PROMIS Physical Functioning SF 6b76, 79 
• 
Social support – Multidimensional Scale of Perceived Social Support (MSPSS)80 
• 
Dialysis symptom index81 
• 
Family Intrusion – PROMIS Satisfaction with Social Roles and Activities76, 82  
• 
Discrimination – Everyday Discrimination Scale83 
Follow-up PRO Questionnaires Weeks 12 & 24 
• 
Pain interference – Brief Pain Index (BPI) Interference47 
• 
Pain intensity – Brief Pain Index (BPI) Severity47 
• 
Pain catastrophizing – Pain Catastrophizing Scale (PCS) SF 667 
• 
Opioid use – Timeline Followback68 
• 
Quality of life – Single-Item QOL Scale [SIS] from McGill Quality of Life (MQOL) questionnaire71 
• 
Depression – Patient Health Questionnaire (PHQ-9)72 
• 
Anxiety – Generalized Anxiety Disorder (GAD-7)73 
• 
Coping – Coping Strategies Questionnaire: 1-item  
• 
Self-efficacy - PROMIS Self-Efficacy for Managing Chronic Conditions – Managing Symptoms – Short Form 8A75 + 
Single item targeting self-efficacy for pain 
• 
Sleep quality – PROMIS Sleep Disturbance SF 6a + Sleep Duration Question76, 77 
• 
Fatigue – PROMIS Fatigue SF 6a76, 78 
• 
Physical functioning – PROMIS Physical Functioning SF 6b76, 79 
• 
Social support – Multidimensional Scale of Perceived Social Support (MSPSS)80 
• 
Dialysis symptom index81 
• 
Satisfaction with treatment - Patient Global Impression of Change (PGIC)84 
• 
Family Intrusion – PROMIS Satisfaction with Social Roles and Activities76, 82  
• 
Internalized Stigma in Chronic Pain Scale (week 24 only)85 
 
Follow-up PRO Questionnaires Week 36 
• 
Pain interference – Brief Pain Index (BPI) Interference47 
• 
Pain intensity – Brief Pain Index (BPI) Severity47 
• 
Pain catastrophizing – Pain Catastrophizing Scale (PCS) SF 667 
• 
Opioid use – Timeline Followback68 
• 
Quality of life – Single-Item QOL Scale [SIS] from McGill Quality of Life (MQOL) questionnaire71 


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• 
Depression – Patient Health Questionnaire (PHQ-9)72 
• 
Anxiety – Generalized Anxiety Disorder (GAD-7)73 
• 
Coping – Coping Strategies Questionnaire: 1-item  
• 
Self-efficacy - PROMIS Self-Efficacy for Managing Chronic Conditions – Managing Symptoms – Short Form 8A75 + 
Single item targeting self-efficacy for pain 
• 
Sleep quality – PROMIS Sleep Disturbance SF 6a + Sleep Duration Question76, 77 
• 
Fatigue – PROMIS Fatigue SF 6a76, 78 
• 
Physical functioning – PROMIS Physical Functioning SF 6b76, 79 
• 
Social support – Multidimensional Scale of Perceived Social Support (MSPSS)80 
• 
Dialysis symptom index81 
• 
Satisfaction with treatment - Patient Global Impression of Change (PGIC)84 
• 
Family Intrusion – PROMIS Satisfaction with Social Roles and Activities76, 82  
• 
Discrimination – Everyday Discrimination Scale83 
Research Team Contacts (Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36) 
• 
Ascertainment of hospitalizations 
• 
Ascertainment of falls 
• 
Ascertainment of adverse events (SAEs and Adverse Events of Interest) 
• 
Documentation of changes to opioid prescriber(s) 
• 
Documentation of non-opioid analgesics, antidepressants, anxiolytic and sedatives/hypnotics 
• 
Documentation of non-study behavioral or other non-pharmacologic treatments for pain 
• 
Scheduling of Week 12, Week 24.and Week 36 CATI calls (as applicable) 
 
 


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14.3. Data Safety and Monitoring Board (DSMB) Charter  
This charter defines the roles and responsibilities of the Data and Safety Monitoring Board (DSMB) for The 
Hemodialysis Pain Reduction Effort (HOPE) study which is funded by the National Institute of Diabetes and 
Digestive and Kidney Diseases (NIDDK). 
The DSMB will serve in a consultative capacity to the NIDDK in accordance with the guidelines set forth in this 
charter. Typically, DSMB members review and agree to the charter at the initial meeting. If changes to the 
charter are necessary, the DSMB reviews and affirms their agreement with the changes.  Their concurrence 
will be noted in the DSMB meeting summary. 
DSMB Responsibilities 
Generally, the first responsibility of the DSMB will be to approve the final protocol of the clinical study named 
above, or the study/studies being undertaken by the research network named above so that the study/studies 
can begin enrolling patients. After initial approval, and at periodic intervals during the course of the study, the 
DSMB responsibilities are to:  
• 
Provide input to assist NIDDK in protecting the safety of the study participants;  
• 
Provide input to the NIDDK on major changes to the research protocol, informed consent documents 
and plans for data and safety monitoring; 
• 
Provide input to the NIDDK on the progress of the study, including periodic assessments of data quality 
and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, 
performance of the study sites, and other factors that may affect study outcomes; 
• 
Review areas of concern regarding the performance of individual sites and provide comment to the 
NIDDK on actions to be considered regarding sites that perform unsatisfactorily; 
• 
Consider factors external to the study when relevant information becomes available, such as scientific 
or therapeutic developments that may have an impact on the safety of the participants or the ethics of 
the study;  
• 
Provide input to the NIDDK on modification of the study protocol or possible early termination of the 
study because of attainment of study objectives, safety concerns, low likelihood of showing a benefit 
of the intervention, or inadequate performance (such as enrollment and retention problems); 
• 
If appropriate, review the interim analysis of efficacy in accordance with stopping rules which are 
clearly defined in the protocol and have the approval of the NIDDK with concurrence of the DSMB; 
• 
Provide input to the NIDDK on the desirability of proceeding to the full-scale study at the completion 
of a feasibility phase, if appropriate;  
• 
Provide input to the NIDDK on the potential impact of ancillary studies on the integrity of the parent 
study; and  
• 
Monitor clinical ancillary studies unless an independent DSMB is established or NIDDK determines that 
a DSMB is not required. 
 
 
 


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Membership 
The members have been appointed by the NIDDK in consultation with the study investigators.  Members of the 
DSMB shall have no financial, scientific, or other conflict of interest with the study. Collaborators or associates 
of the investigators in this study are not eligible to serve on the DSMB.  Written documentation attesting to 
absence of conflict of interest is required at least annually, and each time there is a change in site investigators 
and/or institutions involved in the study. 
The NIDDK will select a member of the DSMB to serve as the DSMB chairperson. S/He is responsible for 
overseeing the meetings and developing the agenda in consultation with the NIDDK.  The NIDDK will provide 
the DSMB Executive Secretary.  As appropriate, NIDDK personnel may serve as ex-officio (non-voting) 
members of the DSMB.  
DSMB Meetings 
The DSMB will typically meet twice a year, or as deemed necessary by the NIDDK Program Official with input 
from the DSMB.  An NIDDK representative will be present at every meeting of the DSMB. A quorum of more 
than half of the DSMB members is required in order to convene a meeting of the DSMB. 
Meetings shall be closed to the public because discussions may address confidential patient data. Meetings are 
attended, when appropriate, by the principal investigator and members of his/her staff as well as 
representatives of the Data Coordinating Center, including the study statistician.  Meetings may be convened 
as conference calls or webinars, as well as in person. In special circumstances, the meetings may also be 
conducted by email.  An emergency meeting of the DSMB may be called at any time by the DSMB chairperson 
or by the NIDDK Program Official should questions of patient safety arise. The DSMB chairperson must contact 
the NIDDK Program Official prior to convening any meeting. Meetings may not be held without an NIDDK 
representative present. 
Meeting Format 
An appropriate format for DSMB meetings consists of an open, closed (if the DSMB is monitoring a study in 
which the investigators are masked in any way), and executive session. This format may be modified as 
needed. 
Open Session: Members of the DSMB, the NIDDK, the principal investigator and members of the steering 
committee, including the study biostatistician may attend the open session.  Issues discussed will include the 
conduct and progress of the study, including patient recruitment, data quality, general adherence and toxicity 
issues, compliance with protocol, and any other logistical matters that may affect either the conduct or 
outcome of the study.  Proposed protocol amendments will also be presented in this session.  Patient-specific 
data and treatment group data may not be presented in the open session.  
Closed Session: The closed session will be attended only by DSMB members, unmasked members of the 
NIDDK, and the unmasked study biostatistician. The discussion at the closed session is completely confidential. 
All materials from the closed session will be destroyed at the end of the meeting. 
Baseline characteristics, adherence and dropouts, and adverse event data are reviewed by masked 
intervention groups, and potentially in specified subgroups as appropriate to the trial.  Primary and secondary 
outcomes may also be reviewed at DSMB request, on particular occasions, if information on these outcomes is 
deemed relevant to fulfilling the DSMB’s stated responsibilities. The DSMB may request unmasking of the data 
for either safety or efficacy concerns.  Procedures to accomplish unmasking of either individual or treatment 
group data are to be specified in the Data and Safety Monitoring Plan.1 
 
 


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Executive Session: The executive session will be attended by DSMB members and the NIDDK Program Official 
and the DSMB Executive Secretary. During the executive session, the DSMB will discuss the information 
presented during the closed and open sessions and provide input on the continuation or termination of the 
study, protocol modification or other changes to the conduct of the study.  The DSMB can be unmasked at any 
time if trends develop either for benefit or harm to the participants. 
The DSMB will make a recommendation for either continuation or termination of the study.  Termination may 
be suggested by the DSMB at any time.  Reasons for early termination include: 
• 
Serious adverse effects in entire intervention group or in a dominating subgroup; 
• 
Greater than expected beneficial effects; 
• 
A statistically significant difference by the end of the study is improbable; 
• 
Logistical or data quality problems so severe that correction is not feasible. 
 
Sound rationale for either decision (continuation or termination of the study) should be presented to the 
NIDDK; this information will not be shared with the investigators until/unless the study is terminated. The 
NIDDK will make the final decision regarding termination and is responsible for notifying the PI of their 
(NIDDK’s) decision to terminate the study.  
 
Reports to the DSMB  
Reports will be prepared by the Data Coordinating Center on a quarterly or semi-annual basis as decided by 
the NIDDK Program Official and the DSMB. The reports will be distributed to the DSMB, the NIDDK Program 
Official and the DSMB Executive Secretary at least 10 days prior to a scheduled meeting. These reports shall be 
provided in sealed envelopes within an express mailing package, by secure email, or by access to a secure 
website, as the DSMB prefers. The contents of the report are determined by the NIDDK with recommendations 
from the DSMB. Over time, additions and other modifications to these reports may be directed by the NIDDK 
and the DSMB on a one-time or continuing basis.  
Data reports for randomized clinical studies or any study in which the investigators are masked in generally 
consist of two parts: an Open Report and a Closed Report.  
Open Session Report: This portion of the report provides information on study aspects such as accrual, 
baseline characteristics, and other general information on study status.  This report is generally shared with all 
investigators involved with the clinical study.  The reports contained in this section generally include: 
• 
Comparison of Target Enrollment to Actual Enrollment by Month; 
• 
Comparison of Target Enrollment to Actual Enrollment by Site; 
• 
Overall Subject Status by Site, including: Subjects Screened, Enrolled, Active, Completed and 
Terminated; 
• 
Demographic and Key Baseline Characteristics by Group; 
• 
Treatment Duration for Subjects who Discontinue Therapy; 
• 
Adverse Events/Serious Adverse Events by Site and Subject. 
Closed Session Report: This report may contain data on study outcomes, including safety data. Data will be 
presented by masked treatment groups; however, the DSMB may request that the treatment groups be 
unmasked to ensure that there are no untoward treatment effects. The Closed Session Report is considered 
confidential and should be destroyed at the conclusion of the meeting. Data files to be used for interim 
analyses should have undergone established editing procedures to the extent possible. This report should not 
be viewed by any members of the clinical study except the designated unmasked study statistician. 
 


Protocol #843471 
HOPE Trial  
Version V1.7; July 7, 2023 
 
Page 92 of 92
 
THIS IS A CONFIDENTIAL DOCUMENT AND SHOULD NOT BE DISTRIBUTED 
 
 
Documentation of DSMB Meetings  
Meeting Summary: A formal summary containing the DSMB’s input on the conduct of the study and their 
recommendation regarding continuation of the study will be prepared by the DSMB Executive Secretary.  Each 
DSMB summary will include the DSMB’s recommendation regarding continuation or termination of the study. 
The DSMB meeting summary will not include unmasked data, discussion of the unmasked data, or any other 
confidential data. Once completed, the summary is sent to the DSMB members for their review and 
concurrence.  When the summary is satisfactory to the DSMB members and concurrence with the summary is 
received, the summary will be sent to the PI. It is the responsibility of the PI to distribute the summary to all 
co-investigators. 
Substantiation of the DSMB Recommendation Regarding Study Continuation: When requested by the NIDDK, 
the DSMB will prepare a statement explaining the rationale for their recommendation to continue or 
terminate the study. This statement will be provided directly to the NIDDK Program Official and will not be 
shared with the investigators or masked NIDDK personnel. 
Letter from the NIDDK Program Official to the Investigators: A letter to the investigators from the NIDDK 
Program Official will accompany the DSMB summary following each DSMB meeting. This letter will contain any 
guidance from the NIDDK Program Official in reference to the DSMB summary. 
It is the responsibility of the study investigators to assure that the letter from the Program Official is submitted 
to all the Institutional Review Boards (IRBs) associated with the study.  If the meeting summary is to be 
submitted to the IRBs in addition to the Program Official’s letter, the letter will so state. 
 
Confidentiality and Objectivity  
All materials, discussions, and proceedings of the DSMB are completely confidential. Members and other 
participants in DSMB meetings are expected to maintain confidentiality.   Closed session meeting materials 
should be destroyed in a secure manner (shredding) following each meeting. 
In order to maintain their objectivity, DSMB members are expected not to discuss the study/studies with the 
investigators except during DSMB meetings.  Questions or concerns that arise between DSMB meetings that 
might lead to discussion between DSMB members and the investigators should be brought to the attention of 
the NIDDK Program Official.  
 
 
 
 

ICF_002.pdf: 
HOPE TRIAL – VERSION 8: SEPTEMBER 20, 2022 
 
 
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[INSERT SPECIFIC RECRUITMENT SITE] 
RESEARCH PARTICIPANT INFORMED CONSENT FORM 
Protocol Title:   
HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis 
A National Institutes of Health HEAL Initiative Trial  
Principal Investigator: 
Insert site-specific PI information 
Study Sponsor 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
Emergency Contact: 
Insert Emergency Contact  
Insert Phone Number/Pager, etc. 
RESEARCH STUDY SUMMARY FOR POTENTIAL PARTICIPANTS 
You are being invited to participate in a research study. Your participation is voluntary, which means 
you can choose whether or not you want to participate. Before deciding to enroll you will need to 
understand what the study requires and its risks. You should ask the study team any questions you 
have about participating before agreeing to join the study. If you have any questions about your rights 
as a research participant at any time before, during or after participation, please contact the 
Institutional Review Board (IRB) at (215) 898-2614 for assistance.  
The focus of this research study is chronic pain experienced by people receiving hemodialysis. The 
study is testing two interventions to reduce the negative effects of pain on how people feel and 
participate in life activities. Although reducing the use of pain medication is not the main purpose of 
the study, it is possible that if you receive the study interventions you may need less medication to 
treat your pain.  
There are two phases in this trial: Phase 1 and Phase 2. During Phase 1, some participants will get 
Pain Coping Skills Training which teaches people skills for coping with pain, and some participants will 
continue their usual care. In Phase 2, those participants who are using an opioid pain medication may 
be offered the opportunity to switch to a pain medication called buprenorphine. Throughout the study, 
participants will be asked to complete phone surveys about pain and symptoms. Study participation 
will last for 8 – 10 months. Most study activities can happen during dialysis treatments or at home. 
There are no guaranteed benefits of being in the research study. Discussions during the study could 
be about sensitive topics that may be upsetting. Some people in the study will be treated with 
buprenorphine but this is not required for study participation. Side effects of buprenorphine include 
withdrawal symptoms, constipation, dizziness, drowsiness, headache, nausea and dental problems.  
Please note that there are other factors to consider before agreeing to participate, such as additional 
procedures and use of your personal information. If you think you might be interested in participating 
and want to learn more about the study, a member of the study team will review the full information 
with you. You are free to decline or stop participation at any time during or after the explanation 
process. 
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WHY AM I BEING ASKED TO VOLUNTEER? 
You are being invited to participate in this research study because you are receiving hemodialysis for 
kidney failure and you have ongoing pain. The research team is going to talk to you about the 
research study and they will give you this consent form to read. You may also want to discuss the 
study with your family, friends, or doctors. Please ask the study doctor or other members of the 
research team if you have any questions. If you decide to participate, you will be asked to sign this 
form and will be given a copy to keep. If you decide not to participate there will be no penalty or loss 
of benefits to which you are otherwise entitled.  
WHAT IS THE PURPOSE OF THIS RESEARCH STUDY?  
The goal of this study is to improve pain and reduce the negative impact it has on the lives of people 
being treated with dialysis. To do this we will test an approach called Pain Coping Skills Training to 
see how effective this method is at treating pain. This training is done by video or telephone either 
during dialysis or at home. A second goal is to determine whether a drug called buprenorphine 
improves pain.  
It is important to note that the purpose of this study is not to take away your pain medication. The goal 
of the study is to see if the interventions reduce the negative impact of pain, which may help people 
need less pain medication.  
HOW LONG WILL I BE IN THE STUDY? HOW MANY OTHER PEOPLE WILL BE IN THE STUDY? 
Your participation in the study will last 8 to 10 months. The study will enroll 640 participants 
throughout the United States. The study is expected to be completed within four years.  
WHAT AM I BEING ASKED TO DO?  
The first step is to make sure that you are eligible for the study meaning that it is safe and appropriate 
for you to participate. If you are eligible, you will be asked to complete two study phases. For Phase 1 
you will be assigned to one of 2 groups: Pain Coping Skills Training or Usual Care. These Phase 1 
groups are described in detail below. After 24 weeks (about 6 months), you will be evaluated for 
eligibility for Phase 2 of the study. You will be eligible for Phase 2 if you are using opioid medication 
for your pain. If you are able to become pregnant you will be asked to complete a blood pregnancy 
test and will be required to have a negative result before participating in Phase 2. You might also 
need to have a blood test to check your liver function if this is not already available in your medical 
records. If you are eligible for Phase 2, you will meet with a study doctor and be encouraged (but not 
required) to change from your current pain medication to buprenorphine which you will take for 12 
weeks. Before switching to buprenorphine, you will be asked to complete a saliva drug test. This test 
is to monitor for drugs or medications that should be avoided while taking buprenorphine. Specific 
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information about buprenorphine is provided below. All participants, regardless of Phase 2 eligibility, 
will be followed in the study for 36 weeks (about 9 months). 
Figure 1. Study Design 
 
Screening Visit (today):  
The purpose of today’s visit is to explain the study procedures and to see if you are eligible to join. As 
part of your screening you will be asked to:  
• Complete the informed consent process with a member of the research team. This will include 
going through the informed consent form and having your questions answered. If you choose 
not to participate in the study and do not sign this form, no further research procedures will 
take place; 
• Answer questions about your medical history including information about your kidney disease, 
pain experience, and mental health; 
If you are eligible for the study you will be asked to schedule your baseline activities and complete a 
W-9 tax form for your compensation. 
 
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Baseline Survey (within 4 weeks of screening): 
At the baseline visit, which may take place in person or by telephone, a member of the research team 
will ask you additional questions about your medical history and the medicines you are taking. You 
will also complete a set of surveys by telephone. The phone surveys are described further later in this 
form. 
Group Assignment (Randomization): 
You will be randomly assigned by a computer to one of two groups: Pain Coping Skills Training or 
Usual Care. You will have an equal chance of being assigned to either of these groups like flipping a 
coin. Neither you nor your study doctor gets to choose which group you are assigned to. Before you 
decide to participate, you should think about whether you would be okay being assigned to either 
group. 
Phase 1 Intervention Groups (Weeks 0 – 24):  
Pain Coping Skills Training Group: If you are assigned to this group, you will work with a trained 
personal coach to help you learn skills to manage pain, the impact pain has on your life, and the 
emotional distress pain can cause. The Pain Coping Skills Training includes the following:    
Weeks 1-12: Weekly, 45-50-minute telehealth sessions focused on developing coping skills. 
Telehealth means real-time video similar to Facetime or Skype. The skills taught in these 
sessions are designed to reduce the negative effects pain has on how you feel and function 
and also might help you to reduce use of pain medications.  
 
Telehealth sessions will require the use of a smartphone, tablet, or computer. If you do not 
have access to one of these, a device will be given to you at your dialysis clinic for use during 
the study. The devices (either your own or one provided by the study) will use a secure system 
that reduces risks to your privacy. The telehealth sessions with your coach can take place 
during your dialysis sessions if that is your preference. If so, you will be given a headset and 
audio device so other people in the dialysis unit cannot hear what your coach is saying and 
cannot easily hear what you are saying. 
Weeks 13-24:  Daily, 5-minute telephone booster sessions delivered through a system called 
Interactive Voice Response (IVR). Each day you will receive a scheduled, automated, pre-
recorded phone call (without a live person on the phone) during which you will be asked to 
answer brief questions about your pain. Based on your responses to these questions, once 
each week you will be provided with personalized feedback from your coach in the form of a 
message that you can access through the IVR system. You will also be able to listen to pre-
recorded, short messages that review different coping skills that you learned during the first 12 
weeks of the study.  
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Interactive Voice Response (IVR) calls will require the use of a smartphone, cell phone, or 
landline so that you may use the keypad to enter data and listen to pre-recorded messages. 
The IVR platform is compliant with the Health Insurance Portability and Accountability Act 
(HIPAA) to protect your privacy. Your coach will show you how to use the IVR system and will 
be able to answer any questions you may have.  
Usual Care Group: If you are assigned to this group, you will be provided with information about pain, 
pain medications, and ways to manage pain. You will continue to work with your usual doctors to 
manage your pain.  
For both the Pain Coping Skills Training and Usual Care groups, information describing the trial and 
your assigned study group will be provided to the doctor(s) who normally help you manage your pain.  
Phase 2 Intervention: Buprenorphine (Weeks 24 – 36):  
Phase 2 of the study will begin at Week 24 of your participation and will last for 12 weeks. 
Participants from both groups who, at the end of Phase 1, are taking opioid pain medications above a 
specific dose will be encouraged (but not required) to change from their current pain medication to 
buprenorphine. Buprenorphine is a unique type of opioid medication that has similar effects on pain 
as other opioid medications but has a lower risk of slowing or stopping your breathing. If you are not 
taking opioid medications at all or above the specific dose, you will not be offered buprenorphine and 
you will continue to be followed in the trial until Week 36.  
To determine if you can switch to buprenorphine, we will review your most recent liver function tests. 
If you have had these tests performed as part of your usual care within the 12 weeks before Phase 2, 
we will be able to use those results. If you have not had liver function tests performed within the 12 
weeks before Phase 2 these tests will need to be done in order to determine eligibility. If you are able 
to become pregnant you will be asked to complete a blood pregnancy test and will be required to 
have a negative result before being offered buprenorphine. Because the blood for both the liver 
function and pregnancy test can be obtained at dialysis through the dialysis tubing, these 
measurements will not require a needle stick. Each of these tests requires 5 - 10 ml (1 - 2 teaspoons 
of blood), which means that if you require both tests, the amount of blood required will be 10 - 20 ml 
(2 - 4 teaspoons).  
If you are eligible for buprenorphine you will be asked to switch from your current opioid medication to 
buprenorphine. You will meet with the study doctor and will be provided with individualized dosage 
recommendations and instructions. You will be asked to sign a new informed consent form before 
starting buprenorphine and will have time to get your questions answered before you sign the form. 
Before your visit with the study doctor you will be asked to complete a saliva drug test to monitor for 
drugs or medications that should be avoided while taking buprenorphine. You will not be required to 
start buprenorphine or change your medication if that is your preference. Regardless of whether or 
not you start buprenorphine, you will continue to be followed in the trial until Week 36. 
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HOW WILL INFORMATION BE COLLECTED? 
Check-Ins with the Research Team (Every 4 weeks):  
You will be contacted by research coordinators either in-person or by telephone every 4 weeks 
throughout your study participation regardless of your assigned group. During these check-ins you 
will be asked questions about recent hospitalizations, falls, medical events, changes to your 
medications, and any new or different ways you are treating or managing your pain. During these 
check-ins you will also schedule your upcoming telephone surveys. 
Telephone Surveys (Weeks 0, 12, 24 & 36):  
Your name and phone number will be provided to interviewers working with the study at the 
University of New Mexico and the University of Pittsburgh. Your research team will schedule a time, 
based on your availability, for the interviewers to contact you to complete survey calls. During these 
calls, you will be asked a variety of questions about how you are feeling physically, emotionally, and 
mentally, as well as your opioid pain medication use. These telephone calls are expected to take up 
to 45 minutes. 
Communication with your Doctor(s) (Weeks 0 & 24 - 36) 
If you take opioid pain medication, the research team will contact your nephrologist and the doctor 
who prescribes the medicine to inform them of your participation in this research study. If you switch 
your usual opioid pain medication to buprenorphine as part of the study, the study team will let your 
doctor(s) know this and will work with them to plan for use of buprenorphine or your current opioid 
pain medication after the study ends.   
WHAT ARE THE POSSIBLE RISKS? 
There are risks associated with this study that you should be aware of:   
Emotional Distress: During the study you will be asked to answer questions about sensitive topics 
that may be upsetting. The research team will help you get additional care, if needed.  
Buprenorphine: Buprenorphine is an FDA-approved medication for the treatment of Opioid Use 
Disorder (OUD) and for the treatment of pain. Common side effects of buprenorphine are opioid 
withdrawal, constipation, dizziness, drowsiness, headache, dry mouth, mouth numbness, insomnia, 
abdominal pain, nausea, numbness and tingling. Dental problems such as tooth decay, cavities, oral 
infections, and loss of teeth have recently been reported as possible side effects of buprenorphine.  
These may happen even if you have no history of dental issues.  The FDA has said that the benefits 
of buprenorphine still outweigh the risks.  
You can do the following to decrease the risk of dental problems: 
- 
After the medication film has dissolved, you should take a large sip of water and rinse your 
mouth.  
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- 
Wait at least one hour after taking buprenorphine before brushing your teeth.  
- 
Visit your dentist soon after switching to buprenorphine and attend regular dental check-ups 
while taking buprenorphine so that your dentist can monitor your dental health.  
Opioid Withdrawal: If you are currently using opioid pain medications, and you reduce your opioid 
pain medicine or switch to buprenorphine, you may experience withdrawal symptoms such as 
nausea, vomiting, diarrhea, new or increased pain, severe itching, depression, agitation, sweating, 
headache and/or shaking due to reducing opioid doses, switching from one opioid medication to 
another, or transitioning to non-opioid medications. Study staff will talk to you about withdrawal 
symptoms, take precautions to prevent withdrawal, and manage symptoms if they occur. You may 
have some of these symptoms or you may have none at all. 
Reproductive risks: You will not be offered buprenorphine if you are pregnant, breastfeeding, or 
planning to become pregnant. If you are able to become pregnant, you will have a pregnancy test to 
determine your eligibility for the buprenorphine portion of this study. If you become pregnant while 
you’re in this study, tell us right away.   
If you are able to become pregnant and you are taking buprenorphine, you will need to take steps to 
prevent pregnancy by using a medically accepted method of birth control or abstaining from sexual 
intercourse with persons of the opposite sex. Accepted methods include intrauterine devices (IUD), 
hormonal implants or injections, birth control pills, patches, or ring, a diaphragm with spermicide, or 
latex condoms.  
Unforeseeable Risks: This research study may involve risks that are currently unforeseeable.  
WHAT IF NEW INFORMATION BECOMES AVAILABLE ABOUT THE STUDY? 
During this study, we may find more information that could be important to you. This includes 
information that, once learned, might cause you to change your mind about being in the study. We 
will notify you as soon as possible if such information becomes available. A Data and Safety 
Monitoring Committee, which is an independent group of experts, will review the safety of this study 
while the study is being carried out. 
WHAT ARE THE POSSIBLE BENEFITS OF THE STUDY?  
There are no guaranteed benefits for being in the research study.  
Your participation in this research study may contribute to the development of treatments for chronic 
pain management in patients receiving maintenance hemodialysis and may benefit the future health 
of the community at large. 
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WHAT OTHER CHOICES DO I HAVE IF I DO NOT PARTICIPATE?  
If you decide not to participate in this study, your care will not be impacted. You will continue to get 
care from your usual dialysis team and other medical providers.  
WILL I BE PAID FOR BEING IN THIS STUDY? 
As compensation for the time required for this research, you will receive up to $550 for successfully 
completing all study activities. A breakdown of the compensation plan is detailed in the table that 
follows. Please note: In order to be compensated for your participation in this study, you must provide 
your Social Security Number. It is important to know that if you earn more than $600 in one year from 
being in research studies, including this one, at INSERT SPECIFIC SITE NAME that money will be 
reported to the IRS for tax purposes. Researchers will use your data to make discoveries. If this study 
leads to new tests, medicines or products, they could make a profit. You will not get any of these 
profits. As the sponsor of this study, NIDDK will not financially benefit from any discoveries that may 
result from this study. 
Table 1. Study Compensation 
 
WILL I HAVE TO PAY FOR ANYTHING? 
There will be no cost to you for being in this research study. You and/or your health insurance may be 
billed for the costs of medical care during this study for expenses that would have occurred if you 
were not in the study. 
Study Time Point  
Study Week 
Compensation 
Check-in 1/Baseline 
0 
$25 
Telephone Survey 1 
0 
$50 
Check-in 2 
4 
$25 
Check-in 3 
8 
$25 
Check-in 4 
12 
$25 
Telephone Survey 2 
12 
$50 
Check-in 5 
16 
$25 
Check-in 6 
20 
$25 
Check-in 7 
24 
$25 
Telephone Survey 3 
24 
$100 
Check-in 8 
28 
$25 
Check-in 9 
32 
$25 
Check-in 10 
36 
$25 
Telephone Survey 4 
36 
$100 
TOTAL 
$550 
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WHAT HAPPENS IF I AM INJURED FROM BEING IN THE STUDY?  
Medical care will be provided if needed to treat injuries directly resulting from taking part in this 
research. This care will be billed to your insurance company or other third parties, if appropriate, for 
the costs of the care you get for the injury, but you may also be responsible for costs if they are not 
covered by your insurance. 
There are no plans for the [insert specific clinical center] to pay you or give you other compensation 
for the injury. If you feel this injury was caused by medical error on the part of the study doctors or 
others involved in the study, you have the legal right to seek payment, even though you are in a 
study. You do not give up your legal rights by signing this form.   
For participants who take buprenorphine as part of the trial, $500.00 will be provided to cover costs of 
the recommended dental evaluation.  The study will not cover the costs for any additional dental work 
that is required. 
If you think you have been injured as a result of taking part in this research study, tell the person in 
charge of the research study as soon as possible. The researcher’s name and phone number are 
listed on the first page of this form. 
CAN I LEAVE THE STUDY BEFORE IT ENDS? 
If you decide to participate, you are free to leave the study at any time. Leaving the study will not 
change your future care. If you are taking buprenorphine as part of the study and decide to leave the 
study before it ends, the research team will work with you and your doctors to set up a plan for either 
continuing or stopping the buprenorphine. 
Your participation in the study may be stopped early by your research team or the Study sponsor 
(NIDDK) because:  
• The Principal Investigator (research doctor) feels it is needed for your health or safety. Such an 
action would not require your consent, but you will be informed if such a decision is made and 
the reason for this decision. 
• The Sponsor, the study Principal Investigator, or the Food and Drug Administration (FDA) has 
decided to stop the study before it has been completed. 
WHAT PERSONAL HEALTH INFORMATION ABOUT ME MAY BE COLLECTED, USED OR 
SHARED WITH OTHERS? 
The following information may be collected from you, your medical records, or your dialysis unit 
records: 
• Name, address, telephone number, date of birth 
• Email address 
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• Social Security number (to pay you) 
• Medical history  
• Prescription information gathered from your doctor, medical records, and/or pharmacy records  
• Current medications or therapies  
• Information from visits, questionnaires, and blood or saliva tests  
• Recordings of Pain Coping Skills Training sessions, IVR voice messages, and answers to the 
daily IVR system call questions (if you are assigned to the PCST group) 
• Safety information such as adverse events 
WHY IS MY PERSONAL HEALTH INFORMATION BEING USED? 
Your information is used by the research team to contact you during the study. Your information and 
results of tests and procedures are used to: 
• Do the research 
• Oversee the research 
• To see if the research was done right.   
WHO CAN SEE OR USE MY PERSONAL HEALTH INFORMATION?   
The following individuals may use or share your information for this research study: 
• The study doctor and the study team at ____________ 
• The University of Pennsylvania Institutional Review Boards (the committees that oversee 
research on human research participants)  
• The Scientific and Data Research Center (SDRC) at the University of Pennsylvania 
• The researchers at the University of New Mexico and the University of Pittsburgh who are 
conducting the telephone interviews 
• The Pain Coping Skills Training (PCST) coaches and quality monitors, if you are assigned to 
the PCST Group 
• The contractor, Tech4Research, that maintains the IVR system used to deliver the brief 
telephone PCST booster sessions, if you are assigned to the PCST group 
• The centralized pharmacy if you change from your current pain medication to buprenorphine 
• The clinical laboratory at Hennepin Healthcare if you change from your current pain medication 
to buprenorphine 
• The Data and Safety Monitoring Board (DSMB) for this study 
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• Representatives of government agencies, including the National Institutes of Health (NIH), the 
National Institute of Digestive, Diabetes and Kidney Diseases (NIDDK) which is the 
government agency sponsoring this study), the Office of Human Research Protections, and 
others who watch over the safety, effectiveness, and conduct of the research.  
• Other approved personnel at [insert specific recruitment site], at your dialysis unit, or the 
HOPE Trial research team who may need to access your information to do their duties (for 
example: to provide treatment, to make sure the research was done correctly, for accounting 
or billing matters, etc.).  
If anyone new is added to this list, they will need to follow [insert specific recruitment site]’s rules 
developed to protect your privacy. 
ELECTRONIC MEDICAL RECORDS AND RESEARCH RESULTS 
An Electronic Medical Record (EMR) is an electronic version of the record of your care within a health 
system. An EMR is simply a computerized version of a paper medical record and is different from the 
Data Management System that the research team uses to track information collected about you for 
the research study. 
If you have ever received care within the [INSERT LOCAL HEALTH SYSTEM HERE] (outpatient or 
inpatient) and are participating in a [INSERT HEALTH SYSTEM OR SITE] research study, 
information related to your participation in the research (i.e. laboratory tests or clinical procedures) 
may be placed in your existing EMR maintained by [INSERT LOCAL HEALTH SYSTEM HERE]  in 
addition to the Data Management System used by the research team.  
If you have never received care within [INSERT LOCAL HEALTH SYSTEM HERE] and decide to 
enroll in this research study, an EMR may be created for you for the purpose of maintaining any 
information produced from your study participation. The creation of this EMR is required for your 
participation in this study. In order to create your EMR, the study team will need to obtain basic 
information about you that would be similar to the information you would provide the first time you visit 
a hospital or medical facility (i.e. your name, the name of your primary doctor, the type of insurance 
you have). Information related to your participation in the study (i.e. laboratory tests or clinical 
procedures) may be placed in this EMR.  
Once placed in your EMR, your information may be accessible to appropriate [INSERT LOCAL 
HEALTH SYSTEM HERE] workforce members that are not part of the research team.  Information 
within your EMR may also be shared with others who are determined by [INSERT LOCAL HEALTH 
SYSTEM HERE] to be appropriate to have access to your EMR (e.g., health insurance company, 
disability provider, etc.). 
 
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HOW WILL MY PERSONAL HEALTH INFORMATION BE PROTECTED?   
When your information is released outside of insert site name you are not identified by name, social 
security number, address, or any other direct personal identifier. You are identified by a unique ID 
number that is assigned to you for this study. The link between your name and code number is kept in 
a secure file and is not shared with anyone outside insert site name. The exception to this is that your 
contact information will be provided to the University of New Mexico, the University of Pittsburgh, and 
the University of Pennsylvania. If you are in the Pain Coping Skills Training group, your contact 
information and responses to daily IVR questions will be held in the IVR system and accessible to the 
coaches and IVR system vendor, Tech4Research, for the purpose of carrying out the study. 
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Your personal information may be given out if 
required by law. If information from this study is published or presented at scientific meetings, your 
name and other personal information will not be used.  
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. This 
means that the researchers cannot release or use information, documents, or samples that may 
identify you in any action or suit unless you say it is okay. They also cannot provide them as evidence 
unless you have agreed. This protection includes federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. An example would be a court subpoena. 
There are some important things that you need to know. The Certificate of Confidentiality DOES NOT 
stop reporting that federal, state or local laws require. Some examples are laws that require reporting 
of child or elder abuse, some communicable diseases, and threats to harm yourself or others.  The 
Certificate CANNOT BE USED to stop a sponsoring United States federal or state government 
agency from checking records or evaluating programs. The Certificate DOES NOT stop disclosures 
required by the federal Food and Drug Administration (FDA).  The Certificate also DOES NOT 
prevent your information from being used for other research if allowed by federal regulations. 
Researchers may release information about you when you say it is okay. For example, you may give 
them permission to release information to insurers, medical providers or any other persons not 
connected with the research. The Certificate of Confidentiality does not stop you from willingly 
releasing information about your involvement in this research. It also does not prevent you from 
having access to your own information. 
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you have 
consented to in this informed consent document. Your individual research test results will not be 
included in your medical records. 
The HOPE Trial Scientific and Data Research Center (SDRC) at the University of Pennsylvania 
stores study information from all participating research centers. All information will be sent to the 
SDRC by a secure internet connection. The study information is stored in secure electronic files at the 
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University of Pennsylvania. Only authorized members of the research study have permission to see 
these data. 
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 may include a 
summary of the results of the study. You can search this website at any time.   
HOW LONG MAY THE [INSERT INSTITUTION] USE OR DISCLOSE MY PERSONAL HEALTH 
INFORMATION?   
Your permission for use of your personal health information for this specific study does not expire.  
Your information may be held in a research database. However, personal health information collected 
in this study may not be re-used or re-disclosed for a purpose other than this study unless: 
• You have given written permission 
• The University of Pennsylvania’s Institutional Review Board grants permission 
• As permitted by law  
COLLECTION OF IDENTIFIABLE BIOSAMPLES 
As a part of your participation in this study, you may be asked to provide saliva or blood samples. 
These samples will be used to make sure that it is safe for you to participate in Phase 2 of the 
research study. If you are asked to provide blood or saliva samples as part of this study, those 
samples will not be stored for future use and will not be used for any other reason. Whole genome 
sequencing, which involves analyzing your entire genetic code, will not be conducted on your 
samples. Your samples will not be used for commercial profit.  
WILL I RECEIVE THE RESULTS OF RESEARCH TESTING? 
Yes, you will receive results from tests performed as a part of the research study. If you are required 
to have a blood pregnancy test the results will be placed in your medical record and will be provided 
to you. If you are required to complete a saliva drug test the results might be entered into your 
medical record and will be communicated to you by a member of the research team.  
FUTURE USE OF DATA AND BIOSAMPLES  
Data without personal identifiers may be shared with investigators that are part of HOPE during and 
after the study. 
At the end of the study, all data (without any personal identifiers) will be sent from the SDRC to the 
NIDDK Central Repository and the NIH HEAL Repository where it will stay. The purpose of sending 
data to these repositories is to make data available for use in research on pain, hemodialysis, and 
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other health-related research, after the current study is completed. Sending data to the repositories 
may give scientists valuable research material that can help them to develop new diagnostic tests, 
new treatments, and new ways to prevent diseases. Researchers who plan to use your data for future 
scientific study will be required to request and receive all the necessary approvals or waivers from the 
NIDDK and from the NIH HEAL program before using your data. Data will only be released to 
scientists who are qualified and prepared to conduct a research study.   
If you are asked to provide a blood sample or saliva sample as a part of this research study, your 
sample(s) will not be stored or shared for future research purposes. 
CAN I CHANGE MY MIND ABOUT GIVING PERMISSION FOR USE OF MY INFORMATION? 
You can change your mind and withdraw consent to continue participation in this study up until the 
end of the study. When study researchers receive instructions from you to withdraw consent to 
continue participation in the study, they will not collect any more data on you for the purpose of the 
study. Data collected up until the time that you withdraw may be retained and used in order for the 
study to be scientifically valid. Data sent to the NIDDK Repository or the NIH HEAL Repository will be 
given a unique code number and identifiable information will be removed. Data that have been 
stripped of personal identifiers cannot be retrieved. After the HOPE Trial ends, you will not be able to 
withdraw your data because the Repository will not know which data comes from you. The data will 
stay in the Repository indefinitely. 
WHAT IF I DECIDE NOT TO GIVE PERMISSION TO USE AND GIVE OUT MY HEALTH 
INFORMATION? 
If you do not give permission to use and give out your health information you will not be able to be in 
this research study. You will be given a copy of this Research Subject HIPAA Authorization 
describing your confidentiality and privacy rights for this study. By signing this document, you are 
permitting the INSERT SPECIFIC SITE to use and disclose personal health information collected 
about you for research purposes as listed above. 
WHO CAN I CALL WITH QUESTIONS, COMPLAINTS OR IF I AM CONCERNED ABOUT MY 
RIGHTS AS A RESEARCH PARTICIPANT? 
If you have questions, concerns or complaints regarding your participation in this research study or if 
you have any questions about your rights as a research participant, you should speak with the 
Principal Investigator listed on page one of this form. If a member of the research team cannot be 
reached or you want to talk to someone other than those working on the study, you may contact the 
Office of Regulatory Affairs at the University of Pennsylvania with any question, concerns or 
complaints by calling (215) 898-2614. 
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SIGNING THE CONSENT FORM 
When you sign this form, you are agreeing to take part in this research study. This means that you 
have reviewed the consent form, your questions have been answered, and you have decided to 
volunteer. Your signature also means that you are permitting the [INSERT INSTITUTION HERE] to 
use your personal health information collected about you for research purposes within our institution. 
You are also allowing the [INSERT INSTITUTION HERE] to disclose that personal health information 
to outside organizations or people involved with the operations of this study. 
A copy of this consent form will be given to you. 
 
 
 
_____________________________        __________________________________     ___________ 
Name of Participant  
 
 
Signature of Participant 
 
 
 
Date 
(Please Print)  
 
 
_____________________________ 
__________________________________     ____________ 
Name of Person Obtaining 
 
Signature of Person Obtaining                  
Date 
   Consent (Please Print)   
 
Consent 
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