Optimization and Multi-Site Feasibility of Yoga for Chronic Pain in People in YOGAMAT-II - Phase II
Phase: NA
Conditions: Opioid Use, Chronic Pain
Sponsor: Butler Hospital

 
 
 
Optimization and Multi-Site Feasibility of Yoga for Chronic 
Pain in People in Treatment for Opioid Use Disorder 
NCT04641221 
Protocol date: 1/18/2024 
 
 
 
 
Clinical Intervention Study 
Protocol

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Optimization and Multi-Site Feasibility of Yoga for Chronic 
Pain in People in Treatment for Opioid Use Disorder 
 
Principal Investigators:   
Lisa Uebelacker, Ph.D., MPI 
Professor, Brown University 
Co-Director of Behavioral Medicine and Addictions Research, Butler Hospital 
 
Michael Stein, M.D., MPI 
Chair of the Department of Health Law, Policy and Management at the Boston University 
School of Public Health 
Associate Director of Behavioral Medicine and Addictions Research, Butler Hospital 
 
Supported by:  
The National Center for Complementary and Integrative Health, 
R01AT010863 
 

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TOOL REVISION HISTORY 
Version Number: 1.0 
Version Date: 12/17/19 
Summary of Revisions Made: N/A 
 
Version Number 1.1 
Version Date: 5/27/2020 
Summary of Revisions Made: Added personnel; updated planned enrollment numbers; clarified 
inclusion/ exclusion criteria; made other minor clarifications; added assessments of depression, 
anxiety, and prescribed medications; added a qualitative exit interview in Phase 1; clarified which 
staff will be blind to randomized assignment; defined unanticipated problems; updated plans for 
determination of final intervention components.  
 
Version Number 1.2 
Version Date: 6/25/20 
Summary of Revisions Made:  Modification to inclusion criteria regarding text messaging 
 
Version Number 1.3 
Version Date: 9/17/2020 
Summary of Revisions Made: Provided an option for remote recruitment, classes, and assessments. 
Specified that we will give all participants a study cell phone. Modified inclusion criteria slightly 
because of remote recruitment, classes, and assessments.  Changed the term “home practice” to 
“personal practice” to reflect terminology we have chosen to use in the study. Clarified several data 
analysis decisions. 
 
Version Number 1.4 
Version Date: 10/27/2020 
Changed amount for returned phone from $40 to $35.  
 
Version Number 1.5 
Version Date: 2/2/2021 
Corrected a typo: removed mention of urine toxicology in Table 4. 
 
Version Number 2.0  
Version Date: 10/8/2021 
Summary of revisions:  
1. Dropped exclusion criterion: “planning to move out of the area in the next 6 months.”  
2. Specified that, if BL is conducted within two weeks of the initial screen, the only inclusion 
criterion that needs to be verified at the BL is the BPI-score and the worst pain in previous 
week score.   
3. Clarified options for outreach to participants.  
4. Planned to make all available yoga classes open to participants from either site.  
5. Planned to invite participants to continue to attend classes after the first 12 weeks while 
they are still completing follow-up assessments for the study.   
6. Clarified that sometimes the first 1:1 yoga meeting will occur within the first month of the 
intervention period, and that the second 1:1 meeting may occur anytime in the 2nd month 
of the intervention period.   
7. Reduced % of classes requiring adherence ratings from 20% to 10%.  
8. Decreased total allowable class size to 8.   

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9. Clarified options for receiving intervention-component text messages.  
10. Removed the BREQ from the Baseline assessment.  
11. Added a brief measure of other treatments for pain besides medications at BL and M3.   
12. Added a self-report survey option for weekly yoga journal.  
13. Added $5 payments for completion of the weekly yoga journal.  
14. Clarified that the Weekly Yoga Journal has been designed using TimeLine Follow-Back 
methodology so previous (missed) data can still be collected.  
15. Replaced the Penn Craving Scale with the McHugh Opioid Craving Scale.   
16. Removed specification for when chart review should occur from protocol.  
17. For participants from sites external to CODAC and BMC, we need a way of verifying 
medication status and dosage during initial screening (because we don’t have access to their 
charts). We planned to give participants a menu of acceptable options, such as the 
participant showing the researcher their most recent pill bottle (for buprenorphine) over 
Zoom.  Other information will be collected via interview if necessary as well.  
18. Added an additional endpoint interview (and compensation) on intersectional stigma and 
how yoga may or may not increase resilience. Added a set of procedures for contacting 
people who already completed the study to see if they would like to participate in this 
interview.  
19. Removed the “Type of assessment” column from the Assessment table.  
20. Added a brief assessment at Month 9.  
21. Updated personnel list.  
22. Added the option for recruiting from sites external to CODAC/ BMC.   
23. Clarified when return of the study cell phone will occur.  
24. Removed table including study staff and blinding status; replaced staff names with roles 
throughout the protocol.  
25. Added participant stakeholders as advisors.  
 
Version Number 2.1  
Version Date: 03/08/22 
Summary of revisions:  
1. Clarified that informed consent may take place at the end of the initial screening or at the 
start of the BL assessment. We made some clarifications to how the consent process occurs, 
including how participants may receive a written copy of the consent form, and the fact that 
participants engage in a teach-back process with study staff to ensure they understand the 
study 
2. Added $10 compensation for informed consent meeting. 
3. Revised exclusion criteria on homelessness to more specifically require that individuals 
have access to a reasonably safe, reliable place to engage in personal yoga practice and a 
private space to participate in online yoga classes.  
4. Made modifications to procedures re: recontacting Phase 1 participants. We specified that 
research staff with whom the participant had prior contact will recontact them (i.e., may not 
be a research assistant), and removed the 2-contact limit. 
 
Version Number 2.2  
Version Date: 09/06/22 
Summary of revisions:  
1. Made modifications to the inclusion criteria for Phase 2 intersectional stigma interviews. 
We specified that up to 24 Black/African American or related race/ethnicities (e.g., Black 
and any other race/ethnicity) and/or Hispanic/Latino/a/x, and up to eight White/Non-
Hispanic participants – with efforts made to counterbalance by Black/African American and 

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Hispanic/Latino/a/x, as well as gender within each ethno-racial group where possible – 
would be approached to participate in the interview at the three-month visit. We specified 
there will no longer be the inclusion criteria requiring that participants endorse some 
experience of stigma in their lifetime; all eligible and interested participants will be 
enrolled. 
2. Added an additional recruitment method, allowing us to recruit potentially eligible 
participants from Butler Hospital.  
 
Version Number 2.3  
Version Date: 11/29/22 
Summary of revisions:  
1. Updated the Study Team Roster: 
a. Added Dr. Lily Pike as a Co-I, removed Sophie Sprecht, and updated Dr. Lynn 
Taylor’s role, to reflect changes in study team personnel at CODAC Behavioral 
Healthcare.  
b. Added Dr. Robert Bales as a Co-I of new recruitment site, Cleveland Clinic. Also 
added Linda Libertini as Research Coordinator for that site. 
2. Modified our study cellphone procedures: Instead of requiring participants to return their 
phone to study personnel at the end of their first twelve weeks, the data plan for that phone 
will be canceled and participants will be allowed to keep the phone. We therefore removed 
the $35 compensation for returning the study cell phone. 
3. Removed Logistic Barriers measure from BL assessment. This measure asks about current 
barriers to yoga practice, and since participants will not have started the yoga intervention 
and are excluded if they have a yoga practice at BL screening, it does not make sense to ask 
about barriers at this time point. 
4. Added $20 compensation for participants who complete the M9 assessment 
5. Added a brief qualitative exit interview for participants who withdraw from the study, along 
with $20 compensation for those who complete the interview. 
 
Version Number 2.4 
Version Date: 5/5/23 
Summary of revisions:  
1. Updated the Study Team Roster: 
a. Changed Dr. Marielle Baldwin from Site PI to Co-I, and added Dr. Eric Roseen as the 
new Site PI for Boston Medical Center  
2. Updated who can be approached for the Phase 2 intersectional stigma interviews 
3. Added a newsletter option  
4. Specified that we may recruit more than one participant advisor per site per year 
5. Included a raffle as an extra incentive for completing follow-up assessments.  
 
Version Number 2.5   
Version Date: 7/18/23 
Summary of revisions:  
1. Updated the Study Team Roster: 
a. Added Dr. Emily Hurstak as the new Site PI for Boston Medical Center 
b. Specified under Informed Consent Procedures that for verbal consents and paper 
consents signed in-person, an audio recording or scanned copy of the consent 
(respectively) is stored in Box as documentation.  
 

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Version Number 2.6 
Version date: 10/20/2023 
Summary or revisions:  
1. Clarified options by which participant may verify their buprenorphine or 
methadone prescription.  
2. Removed Dr. Tremont as a co-Investigator.  
 
Version Number 2.7      
Version Date: 12/13/23 
Summary of Revisions: 
1. Clarified the 3 main study sites (i.e., where research staff are located) as Butler 
Hospital, Boston Medical Center, and the Cleveland Clinic. 
2. Clarified Cleveland Clinic as being responsible for screening and consenting, only. 
3. Removed Donnell Van Noppen as Coordinator and replaced with Julie Desaulniers. 
4. Clarified that self-report versions of follow-up surveys may be sent via email OR text. 
 
Version Number 2.8 
Version Date: 1/18/24 
Summary of Revisions: 
1. Included the option to extend study cell phone service longer than 12 weeks for 
participants meeting certain criteria. 
2. Re-instated a short version of the Qualitative Exit Interview at M3 and M12 for Phase 2.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
STUDY TEAM ROSTER 
8 
PARTICIPATING STUDY SITES 
10 
PRÉCIS 
11 
1. STUDY OBJECTIVES 
13 
1.1 
Primary Objective 
13 
2. BACKGROUND AND RATIONALE 
13 
2.1 
Chronic pain in people receiving OAT 
13 
2.2 
Study Rationale 
14 
3. STUDY DESIGN 
15 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS 
15 
4.1 
Inclusion Criteria 
15 
4.2 
Exclusion Criteria 
15 
4.3 
Study Enrollment Procedures 
16 
5. STUDY INTERVENTIONS 
18 
5.1 
Interventions, Administration, and Duration 
18 
5.2 
Handling of Study Interventions 
18 
5.3 
Concomitant Interventions 
20 
5.3.1 
Allowed Interventions 
20 
5.3.2 
Required Interventions 
20 
5.3.3 
Prohibited Interventions 
20 
6. STUDY PROCEDURES 
20 
6.1 
Schedule of Evaluations 
21 
6.2 
Description of Evaluations 
24 
6.2.1 
Screening Evaluation 
24 
6.2.2 
Baseline – Phase 1 and Phase 2 
24 
3.2.3 
Blinding 
25 
6.2.4 
Follow-up Visits 
25 
6.2.5 
Completion/Final Evaluation 
28 
6.2.6.  Procedures for re-contacting Phase 1 participants to participate in the Qualitative 
Interview—Intersectional Stigma.  
28 
6.2.7.  Procedures for re-contacting Phase 2 participants to participate in the Qualitative 
Interview—Intersectional Stigma. 
29 
6.2.8. Newsletter.  
29 
6.2.9. Raffle for completing follow-up assessments.  
29 
7. SAFETY ASSESSMENTS 
29 
7.1 
Specification of Safety Parameters 
32 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
32 
7.3 
Adverse Events and Serious Adverse Events 
32 
7.4 
Reporting Procedures 
33 

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7.5 
Follow-up for Adverse Events 
34 
7.6 
Safety Monitoring 
35 
8. INTERVENTION DISCONTINUATION 
35 
9. STATISTICAL CONSIDERATIONS 
35 
9.1 
General Design Issues 
35 
9.2 
Sample Size and Randomization 
35 
9.2.1 Treatment Assignment Procedures 
36 
9.3  
Definition of Populations 
36 
9.4 
Interim Analyses and Stopping Rules 
37 
9.4.1 Interim Analysis 
37 
9.4.2 Stopping Rules 
37 
9.5 
Outcomes 
37 
9.5.1 Primary/Proximal Outcome 
37 
9.5.2 Secondary/Distal Outcomes 
37 
9.6 
Data Analyses 
38 
10. DATA COLLECTION AND QUALITY ASSURANCE 
40 
10.1 
Data Collection Forms 
40 
10.2 
Data Management 
40 
10.3 
Quality Assurance 
40 
10.3.1 Training 
40 
10.3.2 
Quality Control Committee 
40 
10.3.3 
Metrics 
40 
10.3.5 
Monitoring 
41 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY 
41 
11.1 
Institutional Review Board (IRB) Review 
41 
11.2 
Informed Consent Forms 
41 
11.3 
Participant Confidentiality 
41 
11.4 
Study Discontinuation 
41 
12. COMMITTEES 
41 
13. PUBLICATION OF RESEARCH FINDINGS 
42 
14. PARTICIPANT STAKEHOLDERS AS ADVISORS 
42 
15. REFERENCES 
43 
16. SUPPLEMENTS/APPENDICES 
44 
 
 
 
 

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STUDY TEAM ROSTER  
MPIs:  
Lisa Uebelacker, Ph.D., MPI 
Professor, Brown University 
Co-Director of Behavioral Medicine and Addiction Research, Butler Hospital 
Address: Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906 
Tel: (401) 455-6381; Fax: 401-455-6235; Email: luebelacker@butler.org 
 
Michael Stein, M.D., MPI 
Chair of the Department of Health Law, Policy and Management at the Boston University 
School of Public Health 
Associate Director of Behavioral Medicine and Addictions Research, Butler Hospital 
Address: 715 Albany St., Talbot Bldg. 
Tel: (617) 358-1956; Email: mdstein@bu.edu 
 
Butler:  
Ana Abrantes, Ph.D., Co-I 
Professor, Brown University 
Co-Director of Behavioral Medicine and Addictions Research 
Address: Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906 
Tel: (401) 455-6440; Fax: 401-455-6685; Email: ana_abrantes@brown.edu 
 
Bradley Anderson, Ph.D., Co-I 
Research Data Analyst, Butler Hospital 
Address: Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906 
Tel: (401) 486-0703; Email: bjanderson@butler.org 
 
Tosca Braun, Ph.D., Co-I 
Assistant Professor, Brown University 
Research Psychologist, Butler Hospital 
Address: Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906 
Tel: (401) 455-6219 Email: tosca_braun@brown.edu 
 
Julie Desaulniers, M.S.      
Research Coordinator 
Address: Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906 
Tel: (401) 793-0914     ; Email: jdesaulniers@butler.org        
 
CODAC: 
Lily Pike, M.D., Co-I 
Medical Director, Pawtucket and East Bay sites, Opioid Treatment Program, CODAC 
Behavioral Healthcare, Inc. 
Address: CODAC Behavioral Healthcare, Inc., 600 Pawtucket Ave, Providence, RI 02904 
Tel: (401) 808-6278; Email: lpike@codacinc.org  
                                           
Boston Medical Center:  
Marielle Baldwin, M.D., M.P.H., Co-I 
Medical Director for the Stimulant Treatment & Recovery Team (START) Clinic at BMC 
Address: 11 Melnea Cass Blvd., Boston, MA 02119 

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Tel: (404) 290-5172; Email: marielle.baldwin@bmc.org 
 
Emily Hurstak, M.D., M.P.H., Co-I 
Medical Director, Grayken Center for Addiction’s SUD Care Continuum ECHO® 
Primary Care Physician, Boston Medical Center's General Internal Medicine and OBAT 
Address: 801 Massachusetts Ave., Boston, MA 02119 
Tel: (617) 414-5951; Email: emily.hurstak@bmc.org   
 
Eric Roseen, D.C., PhD, Site PI BMC 
Director of Program for Integrative Medicine & Health Disparities, Boston Medical Center 
Assistant Professor, Boston University School of Medicine 
Address: Crosstown Center, 801 Massachusetts Ave., Second Floor, Boston, MA 02119 
Tel: (701) 739-2621; Email: eric.roseen@bmc.org       
 
 
Lucy Lorin 
Research Coordinator 
Address: 771 Albany St., Boston, MA 02118 
Tel: (617) 851-1326; Email: lucy.lorin@bmc.org  
 
Cleveland Clinic 
Robert Bales, M.D., M.P.H., Co-I 
Family Medicine Physician, South Pointe Hospital 
Address: South Pointe Hospital Medical Office Bldg., Mail Code Suite 207, 20050 Harvard 
Rd., Warrensville Heights, OH 44122 
Tel: (216) 491-1010; Email: balesr@ccf.org  
 
Linda Libertini 
Research Coordinator 
Address: Cleveland Clinic Community Care, 9500 Euclid Ave., Cleveland, OH 44195 
Tel: (216) 448-8339; Email: libertl@ccf.org  
 
Robert Saper, M.D., M.P.H., Co-I 
Chair, Department of Wellness and Preventive Medicine at Cleveland Clinic 
Address: Cleveland Clinic Community Care, 1950 Richmond Rd., Lyndhurst, OH 44124   
Tel: (216) 448-3042; Email: saperr@ccf.org   
 
      
University of Rhode Island: 
Lynn Taylor, M. D., Co-I 
Research Professor, University of Rhode Island 
Address: The University of Rhode Island, 80 Washington St., Rm. 525, Providence, RI 02903 
Tel: (401) 277-5001; Email: letaylor@uri.edu 

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PARTICIPATING STUDY SITES 
 
Prime:  
Butler Hospital: 
Lisa Uebelacker, Ph.D., MPI 
Professor, Brown University 
Assistant Director of Psychosocial Research, Butler Hospital 
Address: Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906 
Tel: 401-455-6381; Fax: 401-455-6235; Email: luebelacker@butler.org  
 
Recruitment:  
Boston Medical Center:  
Marielle Baldwin, M.D., M.P.H., Co-I 
Medical Director for the Stimulant Treatment & Recovery Team (START) Clinic at BMC 
Director of the Family Medicine Addiction Pathway 
Assistant Professor, Department of Family Medicine 
Address: 11 Melnea Cass Blvd., Boston, MA 02119 
Tel: 404-290-5172; Email: marielle.baldwin@bmc.org  
 
CODAC Behavioral Healthcare, Inc: 
Lily Pike, M.D., Co-I 
Medical Director, Pawtucket and East Bay sites, Opioid Treatment Program, CODAC 
Behavioral Healthcare, Inc. 
Address: CODAC Behavioral Healthcare, Inc., 600 Pawtucket Ave, Providence, RI 02904 
Tel: (401) 808-6278; Email: lpike@codacinc.org                            
 
Cleveland Clinic: 
Robert Saper, M.D., M.P.H., Co-I 
Chair, Department of Wellness and Preventive Medicine at Cleveland Clinic 
Address: Cleveland Clinic Community Care, 1950 Richmond Road, Lyndhurst, OH 44124   
Tel: (216) 448-3042; Email: saperr@ccf.org  
 
Other Investigator Institutions:  
Boston University: 
Michael Stein, M.D., MPI 
Chair of the Department of Health Law, Policy and Management at the Boston University 
School of Public Health 
Director of Behavioral Medicine and Addictions Research, Butler Hospital 
Address: 715 Albany St., Talbot Bldg. 
Tel: 617-358-1956; Email: mdstein@bu.edu 
 
                               
 
 

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PRÉCIS  
Study Title  
Optimization and Multi-Site Feasibility of Yoga for Chronic Pain in People in Treatment for 
Opioid Use Disorder 
 
Objectives  
Our project will have two phases. Specific aims for each phase are: 
Phase 1 – MOST Preparation Phase:  
1. To conduct a pilot trial at two new OAT clinic sites, enrolling n=10 at both sites, 
for a total n=20.  
2. Establish clinical trial procedures and document feasibility at both sites prior to 
conducting a fully powered optimization trial.  
3. Demonstrate our ability to a) recruit participants; b) train yoga teachers to fidelity; 
c) randomize participants to intervention components and correctly administer 
components; d) run classes; and e) collect follow-up assessments.  
 
Phase 2 – MOST Optimization Phase:  
1. To conduct a 2x2x2x2 factorial experiment that will allow us to evaluate the 
impact of each of the 4 intervention components on yoga dosage received. We 
plan to enroll a total n=192. All participants will receive the core yoga 
intervention, with random assignment to the additional four intervention 
components.  
2. Use results from Phase 2 to choose an efficient combination of intervention 
components that, together with standard yoga classes, maximizes yoga dosage. 
3. Examine mechanisms by which components are hypothesized to work. 
 
The primary objective for this project is to develop an efficient combination of intervention 
components that, together with standard yoga classes, maximizes yoga dosage. We will also be 
able to examine mechanisms by which components are hypothesized to work. 
 
Design and Outcomes   
In Phase 1, we will conduct a pilot trial of our standard yoga intervention and four 
intervention components to demonstrate feasibility. Participants will be patients engaged in 
opioid agonist therapy (OAT) with chronic pain.  
 
In Phase 2, we will conduct a factorial RCT to evaluate the impact of each of the 4 
intervention components on yoga dosage received. Participants will be patients engaged in 
opioid agonist therapy (OAT) with chronic pain.  

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Interventions and Duration  
Yoga classes. Participants will be asked to attend one class (approximately 45-60 mins 
long) per week for 12 weeks. Classes will be either in person or over a secure video-based 
platform, such as Zoom. Participants in Phase 1 will participate for 3 months (12 weeks of 
intervention, 3-month follow up interview at end of treatment). Participants in Phase 2 will 
participate for 12 months (12 weeks of intervention, 9 months of follow up). 
 
Component 1: Participants will be randomized to receive or not receive personal practice 
videos featuring study yoga teachers.  
 
Component 2: Participants will be randomized to receive or not receive two 1:1 sessions 
with a yoga teacher, one at the start of the study and one in the second month of the intervention 
period. Sessions will either be in person or over a secure video-based platform.  
 
Component 3: Participants will be randomized to receive or not receive text messages 
cuing personal practice.  
 
Component 4: Participants will be randomized to receive or not receive monetary 
incentives for class attendance.  
 
Sample Size and Population  
The proposed project will include up to 20 participants in a pilot trial (Phase 1), and 192 
participants in a factorial randomized controlled trial (Phase 2). Participants will be individuals 
engaged in OAT with chronic pain aged 18 or over, regardless of gender. 
 
 

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1. STUDY OBJECTIVES 
1.1 
Primary Objective 
Our project will have two phases. Specific aims for each phase are: 
Phase 1 – MOST Preparation Phase:  
1. To conduct a pilot trial at two new OAT clinic sites, enrolling n=10 at both sites, 
for a total n=20.  
2. Establish clinical trial procedures and document feasibility at both sites prior to 
conducting a fully powered optimization trial.  
3. Demonstrate our ability to a) recruit participants; b) train yoga teachers to fidelity; 
c) randomize participants to intervention components and correctly administer 
components; d) run classes; and e) collect follow-up assessments.  
 
Phase 2 – MOST Optimization Phase:  
1. To conduct a factorial experiment that will allow us to evaluate the impact of each 
of the 4 intervention components on yoga dosage received. We will enroll a total 
n=192. All participants will receive the core yoga intervention, with random 
assignment to the four intervention components outlined above.  
2. Use results from Phase 2 to choose an efficient combination of intervention 
components that, together with standard yoga classes, maximizes yoga dosage. 
3. Examine mechanisms by which components are hypothesized to work. 
 
2. BACKGROUND AND RATIONALE 
2.1 
Chronic pain in people receiving OAT 
Chronic pain is a significant problem for at least half of all persons receiving opioid agonist 
therapy (OAT) for opioid use disorder – i.e., buprenorphine/ naloxone (BUP) or methadone 
maintenance treatment (MMT). In OAT patients, chronic pain is associated with disability, 
psychiatric disorders, physical problems, and increased misuse of opioids or other illicit drugs. 
Behavioral interventions, such as CBT, mindfulness-based interventions, or yoga may be useful 
adjunctive interventions for decreasing pain-related disability. Hatha yoga may be a useful 
adjunctive approach for decreasing pain-related disability and pain severity, and preventing 
opioid misuse during OAT. There is evidence supporting its efficacy in other chronic pain 
populations, and yoga may target cravings and other risk factors for opioid relapse. It is essential 
that a future efficacy trial employ an intervention that is efficient, economical and scalable, but 
that allows (and encourages) participants to receive a “dosage” of yoga sufficient to adequately 
test the hypothesis that yoga is effective, i.e., reduces pain interference, and improves other pain 
and substance use outcomes. 
 

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2.2 
Study Rationale 
Yoga is an ancient Indian system of philosophy and practice 1. Most U.S. practitioners 
practice hatha yoga, which includes physical postures (āsanas), breath control (prāṇāyāma), and 
meditative practices. (In this proposal, when we refer to yoga, we are referring to hatha yoga). A 
meta-analysis of yoga across chronic pain conditions (including back pain, headache, rheumatoid 
arthritis, n = 16 studies) reported that yoga had a moderate-large effect on pain2. Yoga also had a 
moderate-large impact on pain-related disability and a moderate impact on depressed mood 
(SMD = -0.65) 2.  
There are various plausible mechanisms by which yoga may have an impact on individuals 
with chronic pain. First, yoga may promote mindfulness in everyday life. Mindfulness practices 
may help people with chronic pain experience the sensory component of pain with less negative 
affect, leading to better quality of life and less pain-related interference. Second, yoga may 
decrease pain catastrophizing 3, 4, in which patients develop a disproportionate interpretation of 
chronic pain as calamitous and threatening, leading to avoidance of physical and other activities 
5. Amongst OAT patients, pain catastrophizing is associated with increased risk for opioid 
misuse 6, 7, increased craving 8, and more pain-related disability 9. Engaging in yoga may help 
people who have feared exercise to start engaging in gentle physical activity again. Third, yoga 
may have a direct impact on mood symptoms that often co-occur with pain such as depression or 
anxiety 10-12 which are common in people with opioid use disorder 13, 14 and are associated with 
increased risk for opioid or other substance misuse 15-17. Finally, hatha yoga may serve to 
increase overall physical activity. Yoga may improve core and other muscle strength as well as 
endurance 18.  
Yoga is increasingly popular and available, with the percent of US adults practicing yoga 
increasing from 8.9% in 2012 19 to 14.3% in 2017 20. Yoga is increasingly being offered at 
addiction treatment centers 21, 22. Yoga can also be adjunctive to other pain and substance use 
treatment. Yoga classes may also be structured in such a way to allow for rolling rather than 
cohort enrollment, thus increasing access.  
Although yoga has been recommended as a complementary treatment 23, there are few 
studies of yoga for people with substance use disorders 24, including a few feasibility studies 25, 
26. The only study of which we are aware that hatha yoga for OAT patients with chronic pain is 
our pilot project. In brief, we assessed feasibility and acceptability of a 12-week manualized 
yoga program (vs. a 12-week health education program) in OAT patients with chronic pain. Our 
pilot study was largely successful, showing excellent feasibility for recruitment, instructor 
fidelity, and participant retention in follow-up assessments. Our primary challenge was in class 
attendance, a common problem with behavioral interventions for OAT patients 27-29. 
3. STUDY DESIGN 
In Phase 1, we will enroll 10 participants at each recruitment site (n=20).  The purpose of 
Phase 1 (MOST Preparation Phase)  is to allow us to establish and refine procedures at these new 
sites and document aspects of feasibility, including our ability to a) recruit participants; b) train 
yoga teachers to fidelity; c) randomize participants to intervention components and correctly 
administer these components; d) run classes; and e) collect follow-up assessments. Enrollment 
period for this phase will last approximately 4 months. 

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In Phase 2, we will conduct a fully powered optimization trial. We will enroll 192 
participants, planning to role approximately equal numbers of participants in both sites. In both 
phases, all participants will receive the core yoga intervention (12 weeks of weekly manualized 
yoga classes), with random assignment to the 4 key intervention components. Participants will be 
patients enrolled in methadone or buprenorphine/naloxone treatment with chronic pain. 
Enrollment period for this phase will last approximately 2 years. 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 
Inclusion Criteria 
Participants must meet all of the relevant inclusion criteria at initial screening and 
baseline to participate in the study. Details for assessment timing are described below.  
Inclusion Criteria – Phase 1 and 2 
1) Enrolled in MMT or BUP treatment for > 3 months  
2) Plan to continue treatment for next 6 months  
3)  Chronic pain, defined as: 
a) pain for at least half the days over the previous three months,  
b) a mean score of 4 or higher on the BPI Pain Interference Scale (with reference to 
chronic pain),  
c) and pain severity of 4 or higher on a Visual Analog Scale (0-10) indicating “worst pain 
in the last week.” Pain severity score will also refer to the areas of their body in which 
they have chronic pain.   
4) Aged > 18  
5)  Proficiency in English sufficient to engage in informed consent in English, understand 
classes taught in English, and read short sentences  
6) Available at least one of the times study classes are offered. 
4.2 
Exclusion Criteria 
All participants meeting any of the exclusion criteria at initial screening or baseline 
will be excluded from study participation.  Details for assessment timing are 
described below.  
Exclusion Criteria – Phase 1 and 2 
1) Currently taking yoga classes or practicing yoga at home once per week or more often. 
2) Medical conditions that would make participation in yoga unsafe or not possible, 
including active malignancy treatment, fracture, recent joint surgery, use of assistive 
ambulatory devices other than a cane. (In cases where this is unclear, site PI will make 
final determination based on available evidence.)  
3) Severe or progressive neurologic deficits. (In cases where this is unclear, site PI will 
make final determination based on available evidence.) 

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4) Other severe disabling chronic medical and/or psychiatric comorbidities deemed by the 
site PI on a case-by-case basis to prevent safe or adequate participation in the study (e.g., 
cognitive impairment that prevents a participant from understanding assessments; history 
of disruptive behavior in medical settings; severe disabling heart failure or lung disease) 
5) Surgery requiring overnight hospitalization planned in the next 3 months 
6) Pregnancy 
7) No access to a reasonably safe, reliable place to engage in personal yoga practice and a 
private space to participate in online yoga classes. 
 
4.3 
Study Enrollment Procedures  
Recruitment and Screening 
 
Recruitment will be in collaboration with opioid agonist therapy (OAT) clinics. The 
investigators will educate OAT providers about the study at regular clinic meetings.  With 
assistance from providers and clinic staff and using electronic health records, research staff will 
identify potentially eligible individuals. Research staff will call these participants, send them a 
letter (via mail or via secure MyChart message, following local site guidelines), respond to a text 
or email from the participant, and/ or approach them at an appointment to tell them about the 
study if they are interested. Research staff may also do presentations to potential participants at 
sites. We will also use passive recruitment methods, e.g., posting fliers in clinic spaces, 
newsletters, newspapers, and advertising via social media. 
 
Participants may be recruited from Butler Hospital’s inpatient, partial hospital, or 
outpatient services. Butler Hospital patients’ medical records will be reviewed in order to assess 
potential eligibility (e.g., must be taking methadone or buprenorphine). Using standard Butler 
Hospital procedures, study staff will approach participants appearing to meet study criteria and 
tell them about the study. Participants will be told about the opportunity to participate in a yoga-
based intervention for chronic pain as an adjunct to their current substance use treatment. If 
participants agree, we will ask them to complete a “Permission to Contact” form, and then study 
staff will contact participants in the next few days (or following their discharge if inpatient). 
 
We may recruit participants from community sites that are not affiliated with BMC,      
Butler Hospital, or the Cleveland Clinic. 
 
Interested participants will undergo a brief (10-20 minutes) telephone or in-person screen 
to confirm inclusion/exclusion criteria. For those appearing to meet study criteria, the RA will 
explain the research study, and if the patient is interested, schedule a time to conduct informed 
consent, verify inclusion criteria, and administer baseline assessments. The research team will 
review recruitment (and retention) rates weekly. 
 
Study staff from Butler Hospital, BMC, or Cleveland Clinic may be engaged in 
recruitment. 
Informed Consent Procedures 
 
 Participants appearing to meet study criteria will either complete informed consent at 
that time or will be scheduled to complete an informed consent and comprehensive baseline 
assessment at a later time. This assessment may be over the telephone, via videoconferencing, or 

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in person. During the informed consent process, research staff will carefully explain all aspects 
of the study, the potential risks and benefits, and the expected duration and time commitment of 
their participation. The participant will be given the opportunity to read through the consent form 
(which may be provided via email, via a shared screen, or via a paper copy) and ask questions.  
Participants also participate in a teach-back process regarding key aspects of the study to ensure 
they have understood what the study involves. Documentation of informed consent may occur 
via one of several methods: a) a written informed consent document, scanned and saved in a 
HIPAA-compliant, CNE instance of Box Drive; b) a REDCap document with an electronic 
signature; c) audio recording of informed consent, saved in a HIPAA-compliant, CNE instance 
of Box Drive. The final option is necessary because a) participants may not be able to attend an 
in-person visit at the clinic due to COVID restrictions; and b) some participants may not have the 
technology needed to access REDCap.  
 
A member of the research staff will also sign the consent form or another form indicating 
that they conducted the consent process (either on paper or electronically). Consent forms will be 
stored in a secure location at Butler Hospital or Boston Medical Center, or be located in 
REDCap. With their permission, participants will be sent (via mail or email) or given a copy of 
the consent form for their records.   
Study staff from Butler Hospital, BMC, or Cleveland Clinic may conduct informed consent.  
After informed consent is obtained, participants will then be evaluated using the baseline 
diagnostic and assessment measures to confirm eligibility.  
               Participants recruited from the Cleveland Clinic will be transferred to staff at Butler 
Hospital for the baseline assessment and remainder of their study appointments. Cleveland Clinic 
will only be responsible for screening and consenting participants. 
Enrollment and Randomization 
 
Enrollment procedures are identical for Phase 1 and Phase 2. 
 
Randomization will occur after participants are deemed eligible. To be eligible after 
consent participants must: 1) have completed the baseline assessments and passed inclusion 
criteria, and 2) confirmed their interest.  
 
All participants receive the standard yoga intervention, and are randomized to receive or 
not receive four intervention components. Each participant will be randomized to one of 16 study 
groups. Participants are considered “enrolled” after randomization. 
 
Once enrolled, a participant will receive a) a study cell phone with a data plan; b) a yoga 
mat; c) small tripod, and d) a booklet describing basic yoga practices and ways to more safely 
engage in yoga. The study cell phone may be used for assessment phone calls, study classes via a 
secure video-based platform, and to administer some study intervention components. Once a 
participant receives the phone, a study staff member will call them to give the participant any 
guidance that they need regarding how to use the phone for study-related activities. During the 
course of the study, participants will not be restricted from using the phone for other activities.   

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For most participants, the data plan for the phone will end after 3 months  and they may 
keep the study cell phone. However, we may allow some participants to continue with their study 
phone plan beyond the 3 months. At the Month 3 assessment, research staff will ascertain 
whether the participant meets any of these criteria: 1.) does not have their own phone; 2.) has a 
phone but it frequently goes in and out of service; or 3.) has concerns about continued access to 
their phone for some other reason. If the participant meets these criteria, research staff will 
inform them that we will continue to keep their study cell phone on for another 3 months so that 
we can remain in contact for scheduling and completing study assessments. We will also inform 
the participant that if we cannot reach them via the study cell phone, we will terminate service. 
We will repeat these procedures, as needed, for the Months 6, 9, and 12 time points.    
        
 Documentation of Reasons for Ineligibility 
 
All participants who express interest in the study will be tracked in a separate database 
along with the status of their participation. Any participant who is screened for any aspect of the 
study including Phase 1 or Phase 2 (even if only one inclusion criterion is assessed before the 
participant is determined not eligible) will have a study record documenting which inclusion 
criteria were assessed and the outcome of that assessment (i.e., as part of a study log).  
 
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
Standard Yoga classes are administered to a group of participants. All participants will 
receive the standard yoga class intervention. Participants will be invited to attend one yoga class  
per week. Classes may be offered at multiple time slots. Classes will take place via a secure 
video-based platform such as Zoom; they are planned to be 60 minutes long. Registered yoga 
teachers will deliver the intervention.  Participants from either recruitment site may attend any 
available class. Potential risks include loss of privacy or breach of confidentiality, increased 
distress or physical pain due to procedures, ineffective intervention (i.e., lack of improvement in 
physical pain symptoms), and mild physical injury. 
Components of Yoga Intervention are delivered to the participants individually based 
on randomization assignment. Components include: 1) Personal practice videos featuring study 
yoga teachers, 2) two 1:1 sessions with a yoga teacher (via a secure video-based platform), 3) 
Text messages cuing personal practice for the first 3 months, 4) Monetary incentives for class 
attendance for the first 3 months. Potential risks include loss of privacy or breach of 
confidentiality, increased distress or physical pain due to procedures, ineffective intervention 
(i.e., lack of improvement in physical pain symptoms), and mild physical injury. 
COVID-related adjustments.  We will offer classes and intervention-related meetings 
via a secure video-based platform on study-provided cell phones in Phase 1 and in Phase 2.  
 

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5.2 
Handling of Study Interventions  
Yoga Intervention 
Yoga classes. All participants will receive the manualized hatha yoga program. 
Participants will be asked to attend one 60-minute class per week for 12 weeks via a secure 
video-based platform. Each class will consist of: greeting and discussion of personal practice; 
centering and breath awareness; pranayama (breathing practices); warm up movements; an asana 
sequence; a seated meditation; and final discussion of personal practice. Classes will 
acknowledge the validity of participants’ pain and gently challenge them to try a new way of 
coping with it; emphasize breathing in every part of the class; and run the class at a slow pace. 
Class size will range between 1 and 8 participants.  
 
Yoga Personal practice. Personal practice will be essential for increasing yoga “dosage.” 
When participants first start class, we will give them a yoga mat to take home, a curated list of 
YouTube videos, and written instructions for personal practices that can be used to manage pain 
and cope with urges to misuse opioids and other substances. In each class, the yoga instructor 
will review specific practices and recommend that participants try those practices at home. The 
practices will always be ones that carry with it minimal risk of injury, and instructors will go 
over safe practice in class. Participants may continue in the study regardless of whether they 
practice at home.  
 
Intervention Component 1: Personal practice Videos Featuring Study Yoga Teachers. 
As part of the standardized yoga intervention, all participants will receive a curated list of 
YouTube videos for yoga personal practice. However, participants randomized to receive 
component 1 will also receive study-specific videos of varying lengths featuring study teachers 
and only yoga practices taught in class. Participants will be randomized to either receive or not 
receive study-specific videos. 
 
Intervention Component 2: Initial and 1-Month 1:1 Session with Yoga Teacher. 
Participants randomized to receive this component will receive two 1:1 sessions with the yoga 
teacher, with one session occurring in the first month of the intervention (ideally right around the 
time of the first class), and one in the 2nd month of the intervention. (Some flexibility is allowed 
due to scheduling challenges). Sessions will be via a secure video-based platform. The yoga 
teacher will address the individual’s specific physical concerns and provide individualized 
advice about a) listening to one’s own body; and b) what to do if one is unsure about the physical 
sensations associated with a specific practice. Participants will be randomized to either receive or 
not receive 1:1 sessions. 
 
Intervention Component 3: Text messages cuing personal practice. Text messages may 
be useful to cue participants to engage in yoga personal practice. Immediately post-
randomization, for applicable participants, we will ask participants to choose the time of day they 
would like to receive these messages and whether they prefer to receive them to their study 
phone, personal phone, or both. Participants will be randomized to either receive or not receive 
regular text messages cuing personal practice. 
 
Intervention Component 4: Monetary incentives for class attendance. Financial 

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incentives can increase session attendance for physical activity interventions. Participants 
randomized to this component will receive $15 for each yoga class attended. Participants will be 
randomized to either receive or not receive monetary incentives for class attendance. 
 
Yoga Instructors. The Yoga Alliance is a professional organization which sets standards 
for yoga teacher training. Teachers will have met criteria to be Registered Yoga Teachers 
(RYTs) at the Yoga Alliance. Teachers will have study-specific training on research methods, 
OAT, chronic pain, adverse events, and the yoga manual. They will meet approximately monthly 
for supervision.  Yoga supervisors will also review audio recordings or video recordings of 
classes to assess instructor adherence.  
 
Yoga instructor Manual Fidelity. All classes will be audio recorded or video recorded. 
We have developed a fidelity measure that assesses: a) practices used; and b) style, in order to 
evaluate whether yoga teachers can reliably deliver the manualized program. We will conduct 
adherence ratings of      each teacher’s first class, plus an additional random 10% of all other 
classes on an ongoing basis, and review results with teachers. 1:1 sessions may be recorded as 
well and reviewed on an as-needed basis.  
 
Yoga Intervention After Initial 12 weeks.  
 
Participants who are in the study follow-up period (i.e., have completed their initial 12 
weeks of yoga classes) will be invited to continue to participate in classes if they wish, provided 
their participation does not increase a given class size over 8. They will not receive any of the 
other 4 intervention components.  
5.3 
Concomitant Interventions  
 
5.3.1 Allowed Interventions 
Once a participant is enrolled in the study, participants will not be excluded for any 
concomitant intervention. For example, if a participant begins outside yoga classes or starts a 
pain management regimen while they are in the study, we will record that information, but not 
require that they discontinue study interventions. If a participant changes their dose of OAT, type 
of OAT, or stops taking OAT, we will record that information, but not require that they 
discontinue study participation.  
 
5.3.2 Required Interventions 
None 
5.3.3 Prohibited Interventions 
None 
6. STUDY PROCEDURES 

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6.1 
Schedule of Evaluations 
Table 1: Assessment schedule for Phase 1 and Phase 2 
Assessment 
Screening 
 
Informed 
Consent 
Form 
 
Baseline  
Visit 1 
 
Baseline 
Visit 2 
After 
initial 
class 
Weekly 
during  
M1, M2, 
M3 
M1 
visit 
M2 
visit 
M3 visit 
M6 visit 
(Phase 
2 only) 
Month 9 
call 
(Phase 2 
only) 
M12 visit 
(Phase 2 
only) 
Withd
rawal 
Inclusion/Exclusion   
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent Form  
 
X6 
 
 
 
 
 
 
 
 
 
 
 
Enrollment and Randomization  
 
 
 
X 
 
 
 
 
 
 
 
 
 
Credibility Expectancy Questionnaire 
(CEQ) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
     Weekly Yoga Journal  
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Injuries due to yoga  
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Systematic Assessment for Treatment 
Emergent Events (SAFTEE) 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Chart Review1 
 
 
X2 
 
 
      
 
 
X2 
 
 
X2 
 
Other Adverse Events 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
SUD, psychiatric, sleep, and pain 
medications (modified TRAQ) 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
Tampa Scale of Kinesiophobia (TSK) 
 
 
X 
 
 
 
X 
X 
X 
 
 
 
 
Self-efficacy for exercise 
 
 
X 
 
 
 
X 
X 
X 
 
 
 
 
Logistic Factors 
 
 
      
 
 
 
X 
X 
X 
 
 
 
 

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Assessment 
Screening 
 
Informed 
Consent 
Form 
 
Baseline  
Visit 1 
 
Baseline 
Visit 2 
After 
initial 
class 
Weekly 
during  
M1, M2, 
M3 
M1 
visit 
M2 
visit 
M3 visit 
M6 visit 
(Phase 
2 only) 
Month 9 
call 
(Phase 2 
only) 
M12 visit 
(Phase 2 
only) 
Withd
rawal 
Behavioral Regulation in Exercise 
Questionnaire (BREQ-2), modified for 
yoga 
 
 
      
 
 
 
X 
X 
X 
 
 
 
 
Brief Pain Inventory (BPI)3 
 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
Numerical Rating Scale (NRS), Pain 
Severity 
 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
WHO Quality of Life, Brief Version 
(WHOQOL-BREF) 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
PROMIS Depression Scale 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
PROMIS Anxiety Scale 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
Addiction Severity Index (ASI) 
 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
McHugh Opioid Craving Scale 
 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
Demographics  
 
 
X 
 
 
 
 
 
 
 
 
 
 
Review of Medical Comorbidities 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pain Treatment Use 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Qualitative Exit Interview – Study 
Procedures (Phase 1: long version;  
Phase 2: short version) 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Qualitative Exit Interview-- 
Intersectional Stigma (Phase 2 only) 
 
 
 
 
 
 
 
 
X4 
 
 
 
 
Qualitative Exit Interview-- Study 
Feedback & Reasons for Withdrawal 
(Phase 2 only) 7 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Assessment 
Screening 
 
Informed 
Consent 
Form 
 
Baseline  
Visit 1 
 
Baseline 
Visit 2 
After 
initial 
class 
Weekly 
during  
M1, M2, 
M3 
M1 
visit 
M2 
visit 
M3 visit 
M6 visit 
(Phase 
2 only) 
Month 9 
call 
(Phase 2 
only) 
M12 visit 
(Phase 2 
only) 
Withd
rawal 
Payment  
 
 
 
 
 
$10 
$10 
 
 
$5 for 
each 
weekly 
assmt5 
 
$20 
$20 
$30 (overall 
assessment) 
 
$20 (Phase 2 
qualitative exit 
interview, if 
conducted) 
$30 
$20 
$40 
$20 
 
1For participants who are not part of the BMC or CODAC system, data typically collected via chart review may be collected by one of the following 
methods:  self-report, pharmacy (with permission of participant), or treatment provider medical records or provider (with permission of participant). For 
collecting information about medication and dosage, we will have a menu of options for how participants can verify their dose, including methods determined 
to be secure (e.g., HIPAA-compliant Zoom or Box upload of image). If participants choose to share information through a method that is not secure (e.g., text 
or email), they will first be consented to the risks of doing so. How data are collected will be clearly marked in the database. 
 2Chart reviews cover a designated time period (e.g., 3 months before study starts and the time a participant is in the study.) However, staff will typically 
conduct the chart reviews in batches once a participant completes the study. Therefore, the chart review may not occur immediately at the designated time 
point, but will cover the designated time period. Note: data collected from chart reviews is limited to treatment with methadone or buprenorphine/naloxone 
(including dosage, appointments attended, etc.) and does not include any adverse event ascertainment.  
3When calculating the BPI- Pain Interference Scale, we will not include the “work” item, as we anticipate that this item does not apply to a large proportion of 
our sample.  
4Intersectional stigma interviews will be completed in a subset of participants, including all participants from Phase 1 who agree to complete it, and up to 32 
participants in Phase 2. Phase 2 will enroll up to 24 participants who self-report being Black, African American, a related race/ethnicity (e.g., Afrikaner; Black 
and any other race/ethnicity), and/or Hispanic/Latino/a/x, and up to eight White/Non-Hispanic participants. Efforts will be made to counterbalance 
Black/African American and Hispanic/Latino/x participants as well as gender within each ethno-racial group where possible. There are no additional inclusion 
criteria. Using standard study procedures at the 3-month visit, eligible participants will be reminded about the opportunity to participate in an additional exit 
interview related to their experience of the yoga program and their strengths and resiliency navigating difficult experiences. If participants agree, they will be 
scheduled for the interview. 
5This will be paid at the end of each month. Only assessments that are completed within the assessment window (i.e., due date + 6 days) will be compensated.  
6In order to maximize flexibility for the participant, informed consent may take place at the end of the initial screening, as its own appointment between 
screening and BL, or at the start of the BL assessment.  
7The column furthest to the right (“Withdrawal”) may occur at any point between the Baseline Visit 2 and M12, following a participant’s withdrawal from the 
study intervention, assessments, and/or other study procedures.

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6.2 
Description of Evaluations  
Assessments will be administered by research assistants (RAs) trained in procedures to ensure 
confidentiality and proper management of research data. 
 
Assessments will be administered via interview (on the phone, via secure video-based platform, 
or in-person). We will provide participants with a document with response options to look at while 
they are responding to assessment questions. In cases where, after repeated attempts, we are unable to 
reach a participant for an assessment via interview, we may email or text (based on participant 
preference)       an online survey version via REDCap. 
 
We will track the type of interview (on the phone, via secure video-based platform, or in-
person) for each assessment. 
 
6.2.1 Screening Evaluation 
Consenting Procedure 
All phases will have a) agreement from the individual to conduct brief eligibility screening and 
b) informed consent from the individual at the first visit.  
For information about agreement to screening, please see section 4.3 Study Enrollment 
Procedures.  
Screening 
For Phases 1 and 2, the screen may be conducted up to 30 days prior to BL.  
6.2.2 Baseline – Phase 1 and Phase 2 
Consenting Procedure  
Informed consent will be obtained prior to or at the baseline appointment.  
Please see section 4.3 for more information about the consent procedures. 
Documents will be stored in a locked file cabinet, or will be located in REDCap or Box.  
Staff at BMC, Butler Hospital, or Cleveland Clinic may conduct informed consent.  
Baseline Screening  
After informed consent/assent is complete, RAs will confirm eligibility.  
If the screening visit occurred > 14 days prior to the baseline visit, they will confirm all 
eligibility criteria.  
If the screening visit occurred < 14 days prior to the baseline visit, they will only need to re-
confirm the following screening criteria: pain chronicity, pain interference, and pain severity. 
To do this, staff will administer the following:  
 
● BPI –Pain Interference  

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● NRS– Average and worst pain in the past week 
      
If participants meet all eligibility criteria, we will then conduct the remainder of the BL 
assessments. 
  
 
For participants who do not meet eligibility criteria, we will inform the individual without 
stating a specific reason for exclusion. We will provide referrals to the community upon 
request. 
 
Baseline Assessments – Phases 2 
Remaining Baseline      assessments include:  
● TRAQ 
● TSK 
● Self-Efficacy for exercise 
● WHOQOL-BREF 
● PROMIS® Depression Scale 
● PROMIS® Anxiety Scale 
● ASI 
● McHugh Opioid Craving Scale 
● Demographics 
● Pain Treatment Use 
 
Randomization  
Allowable window between BL and randomization is 14 days. Participants are considered 
enrolled after randomization. The participant is invited to begin the study intervention within 1 week of 
randomization.  
Payment 
 
Payment to participants for completion of the informed consent is $10, and for completion of 
the baseline assessment is $10. The two procedures may be combined in one visit or in separate visits. 
Participants who attend a visit or phone meeting to complete informed consent will be compensated 
even if they decline participation in the rest of the study.  
 
3.2.3 Blinding 
Follow-up assessments will be conducted by research staff who are blind to which arm 
participants were randomized.            
      
6.2.4 Follow-up Visits 
For the purposes of targeting dates for monthly follow-up assessments, we will consider each 
month = 28 days (4 weeks exactly). For all follow-up assessments, research staff will make every 
effort to conduct the assessment within one week before or one week after the exact due date of the 
assessment. However, because all data can be analyzed with modern statistical methods regardless of 
whether it was collected inside that window, RAs will still collect data if possible even if it is later than 
that window. We will record the optimum date for the assessment (e.g., Enrollment + 84 days for M3 

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assessment) as well as the actual date of the assessment. Follow-up visits will typically be conducted 
via a secure video-based platform, telephone and a REDCap link, or via telephone only (if participant 
does not have access to a computer/ smartphone, e.g., pre-randomization, or at M6 or M12 follow-up).  
If allowed by site policies, we may conduct follow-up visits in person with COVID precautions.  
Similarly, for assessment of personal yoga practice (Weekly Yoga Journal), research staff will 
make every effort to conduct the assessment on a weekly basis (starting seven days from the date of 
randomization). However, because the Weekly Yoga Journal uses a time-line follow-up method, data 
from any missed weeks will still be collected during the next weekly or monthly assessment that is 
completed with the participant.  
Staff at Butler Hospital or BMC may conduct follow-up visits.  
 
 Phase 1 and Phase 2 Visits:  
● 
Weekly for 12 weeks 
o Study classes/groups 
o Weekly Yoga Journal 
o Injuries due to yoga 
o CEQ (after initial class only) 
o Any other AEs reported to RAs 
o Payment: $5 – for completion of the Weekly Yoga Journal (if completed within 
window (due date + 6 days).  Payment is provided in a lump sum at the end of 
the month.  
 
● 
Month 1 
o Any other AEs reported to RAs 
o TSK 
o Self-efficacy for exercise 
o Logistic Factors 
o BREQ-2 
o BPI 
o NRS 
o ASI 
o McHugh Opioid Craving Scale 
o Payment: $20 
 
● 
Month 2 
o Any other AEs reported to RAs 
o TSK 
o Self-efficacy for exercise 
o Logistic Factors 
o BREQ-2 
o BPI 
o NRS 
o ASI 
o McHugh Opioid Scale 
o Payment: $20 

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● 
Month 3 (Final evaluation for Phase 1) 
o Any other AEs reported to RAs 
o TRAQ 
o TSK 
o Self-efficacy for exercise 
o Logistic Factors 
o BREQ-2 
o BPI 
o NRS 
o WHOQOL-BREF 
o PROMIS® Depression Scale 
o PROMIS® Anxiety Scale 
o ASI 
o McHugh Opioid Scale 
o Pain Treatment Use 
o SAFTEE 
o Chart Review 
o Qualitative Exit Interview-- Study Procedures (Phase 1—long version;  Phase 2 
– short version) 
o Qualitative Exit Interview – Intersectional Stigma (All participants Phase 1; 
select participants Phase 2) 
o Payment: $30 for the overall assessment. Participants who complete the entire 
assessment will be entered into a lottery to receive a $100 bonus incentive (paid 
via giftcards or Clincard, depending on site). Participants may receive an 
additional $20 if they complete the Qualitative Exit Interview—Intersectional 
Stigma.  
 
Phase 2 Visits Only: 
● 
Month 6 
o Weekly Yoga Journal 
o Injuries due to yoga 
o Any other AEs reported to RAs 
o TRAQ 
o BPI 
o NRS 
o WHOQOL-BREF 
o PROMIS® Depression Scale 
o PROMIS® Anxiety Scale 
o ASI 
o McHugh Opioid Craving Scale 
o Payment: $30. Participants who complete the entire assessment will be entered 
into a lottery to receive a $100 bonus incentive (paid via giftcards or Clincard, 
depending on site). 
 
● 
Month 9 
o Weekly Yoga Journal 
o Injuries due to yoga 

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o Any other AEs reported to RAs 
o Payment: $20 
 
● 
Month 12 (Final evaluation for Phase 2) 
o Weekly Yoga Journal 
o Injuries due to yoga 
o Any other AEs reported to RAs 
o TRAQ 
o BPI 
o NRS 
o WHOQOL-BREF 
o PROMIS® Depression Scale 
o PROMIS® Anxiety Scale 
o ASI 
o McHugh Opioid Craving Scale 
o Chart Review 
o Qualitative Exit Interview-- Study Procedures (Phase 2 – short version) 
o Payment: $40. Participants who complete the entire assessment will be entered 
into a lottery to receive a $100 bonus incentive (paid via giftcards or Clincard, 
depending on site). 
 
6.2.5 Completion/Final Evaluation 
Even if participants drop out of study treatment, we will attempt to collect data at all 
assessment points if participants agree to it. 
6.2.6. Procedures for re-contacting Phase 1 participants to participate in the 
Qualitative Interview—Intersectional Stigma.  
First, study staff will review a participant’s Phase 1 materials, and contact participants only by 
methods that they originally agreed to be acceptable to them. Participants who did not complete the 
post-program (M3) assessment will not be recontacted. Next, research staff with whom participants 
had regular contact during the parent trial will contact participants via their preferred contact method(s) 
to briefly share information about the sub-project, as follows: 
“Hi, this is [RA]. We are writing/ calling to see if you are interested in doing an additional 
interview for the yoga research program you were in.  We want to ask you more about topics 
related to the research. We would pay you for the interview.  Please respond if you would like 
to hear more about this.”   
Participants will be contacted by research staff. Those responding attesting their interest will be 
provided more information about the study purpose and incentive details. The study RA will conduct 
an audio recorded oral consent process for this additional interview, and document oral consent. The 
audio-recorded consent will then be saved in a secure location, consistent with the parent study 
procedures. The research staff member will then coordinate scheduling with the interviewer.  
We have completed a request for a Waiver of Authorization for use of PHI (attached) in order 
to be able to recontact participants.   
Nature of the interview: This qualitative interview will include questions about participants’ 
pain, experiences of the yoga program, substance use, health behaviors (like eating and exercise), 
adverse interpersonal experiences experienced (like discrimination, teasing, bullying, unfair treatment, 

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or other experiences of victimization), and how participants cope with, manage, and/or find resiliency 
through such experiences. The interviewer will query participant perceptions of how yoga or related 
practices may have helped people cope with experiences of stigma, and perceptions of how yoga may 
be tailored to help people cope with such experiences. 
6.2.7. Procedures for re-contacting Phase 2 participants to participate in the 
Qualitative Interview—Intersectional Stigma. 
 
In order to give all participants the same opportunity to take part in this additional interview, 
we will re approach active Phase 2 participants who a) were ineligible based on previous criteria 
(protocol v.2.2) when they endorsed “no” to the initial stigma screening question that is no longer 
used, b) missed their 3-month interview and were not invited to complete a stigma interview, as this 
was the only visit that was initially approved for scheduling the interview. This interview will be 
initially offered at the 3-Month time point, but participants may complete it at any point after that until 
they are no longer in the study. 
6.2.8. Newsletter.  
In order to give participants a voice and enhance retention, we may create a newsletter 2-3 
times per year. The newsletter will include contributions from yoga teachers and study investigators, 
and anonymous contributions from study participants. Staff will review participant contributions to 
ensure that they do not include personal identifiers or other information that could clearly identify the 
participant.  Contributions may be short essays, poems, news updates, or pictures. Newsletters will be 
reviewed by project coordinators, Co-Is, and MPIs before being finalized. When we produce a 
newsletter, we will have it available for all sites from which we recruit participants. If we have 
permission to contact participants electronically, we will send them an electronic link to the newsletter 
via text or email.  
6.2.9. Raffle for completing follow-up assessments.  
The study statistician will create 3 lists of random numbers such that when a person qualifies 
for entry into the “raffle,” their ID number will be entered onto the list to determine if they are 
randomly selected to receive the bonus payment. Approximately 1 in 10 people will receive the bonus 
payment.  
7. SAFETY ASSESSMENTS  
For yoga, the only expected adverse event is:  
● Physical injury (mild). This includes mild aches or pain during or shortly after yoga classes. 
Risks of study participation include:  
● Perception of coercion 
● Loss of privacy or breach of confidentiality 
● Increased distress due to intervention or assessment procedures 
● Physical injury  
 
Risks and measures to reduce those risks are detailed below. 
 
Perception of coercion to participate in the study.  The risk of potential coercion will be 
minimized by following standard procedures for obtaining informed consent.  All patients will be 
instructed that their decision as to whether to participate in the study will not influence their current or 

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future standing with Butler Hospital, CODAC, BMC, Cleveland Clinic or sites external to any of these 
facilities. They will also be informed of their right to withdraw from the study at any time. 
 
Confidentiality and loss of privacy. Breach of confidentiality is highly unlikely because all data are 
identified only by numeric code and are stored in locked file cabinets or secure databases. A master list 
of names and numbers is kept in a separate database and is used to facilitate the collection of follow-up 
data. Only research staff at the relevant sites will have access to the master list linking names and code 
numbers. All staff are or will be fully trained in relevant ethical principles and procedures, particularly 
around confidentiality and protection of human subjects. All assessment and treatment procedures will 
be closely supervised by the project’s professional staff. All recordings will be erased upon completion 
of data analysis. The investigative team will strictly adhere to the guidelines for research outlined by 
the Butler Hospital’s Institutional Review Board (IRB), Rhode Island State law, and the DHHS Federal 
Policy for the Protections of Human Subjects (45 CFR, Part 46). 
 
 
 
 
All data collected will be entered into an electronic database which is stored on a secure server 
(REDCap) that is backed up on a daily basis. Patient identifying information will be password 
protected and stored on a secure server. All paper files will be kept in a locked filing cabinet. Audio 
recordings will be stored on a secure server or kept in a locked filing cabinet. No subject will be 
identified in any report of the project.  
REDCap is a secure, web-based application developed by Vanderbilt University for building 
and managing surveys and databases. It is primarily designed to support online or offline data capture 
for research studies, quality improvement, and operations. REDCap provides easy data manipulation 
(with audit trails for reporting, monitoring and querying patient records), real-time data entry 
validation, and an automated export mechanism to common statistical packages. 
Care New England’s instance of REDCap is hosted within the Care New England data center in 
Warwick, RI. This REDCap instance is role-based and is fully integrated with CNE’s Active Directory 
structure. It enjoys 24/7/365 enterprise-level support and security inherent to CNE’s HIPAA-compliant 
data center. Network transmissions (data entry, survey submission, and web browsing) to and from 
REDCap are protected via TLS 1.2 encryption.  REDCap’s data is stored on encrypted servers within 
CNE’s data center. 
The REDCap Consortium is composed of thousands of active institutional partners in over one 
hundred countries who utilize and support REDCap. REDCap was developed specifically around 
HIPAA-Security guidelines, and more information about the consortium and system security can be 
found at http://www.projectredcap.org/.  
Due to the nature of text messaging technology and email, there is a small, but potential, 
privacy risk when communicating through text messages or email messages. Text or email message 
communications are not encrypted and therefore this information can be read if intercepted while in 
transit. Although we have a strict patient confidentiality policy there is a possibility for the text 
messaging or email communications to be intercepted or accessed without the participant's 
authorization. This will be made clear in the informed consent process, and we will remind participants 
of the risks of sending sensitive information by text or email.  It is important to note that study staff 
will only be conveying general information by text messaging or email. Study staff will not send 
confidential or sensitive personal t by text message at any time. Email messages may include links to 
REDCap. Text messages will be sent from a dedicated password-protected study cell phone; email will 
be sent from a carene.org account or an account at the site (e.g., BMC.org). The loss of privacy is a 

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serious risk, but we believe that it is highly unlikely as we have extensive experience taking measures 
appropriate to safeguarding confidential information.  
     
For streaming video classes, we will choose a secure, HIPAA compliant video service such as 
Zoom. Classes will be monitored to ensure that people who should not be a part of the class do not 
enter electronically. We will ask participants to find as private a space as possible for their real-time 
yoga classes, and we will make sure all participants are aware of the possibility of a breach of privacy 
if another participant discloses their identity outside of the context of class. (This breach of privacy is 
possible in in-person classes as well). All participants will be asked to keep the names of other 
participants in their class confidential. 
 
Protections against increased distress due to assessment or intervention procedures. The risks of 
possible distress due to the assessment and treatment procedures will be minimized by:  a) using 
assessments and procedures which have been widely used in previous clinical and research studies; b) 
training yoga instructors in how to minimize and manage distress that may occur in class; and c) 
having study investigators with medical or psychology degrees available to counsel participants should 
they report experiencing distress.  
In the Endpoint Qualitative Interview –Intersectional Stigma, participants will be reminded that 
they do not have to answer any question that they do not want to answer.  In addition, the interview 
template will be designed with an emphasis on strengths and resiliency in navigating difficult 
experiences. The interviewer will be a clinical psychologist trained in conducting qualitative 
interviews of a sensitive nature, and will be able to address any distress or concerns that may emerge 
during the interview, including follow-up referrals for behavioral health in the unlikely event this 
should be necessary.  
 
Protections against risk of physical injury. The risk of physical injury will be minimized by: a) 
excluding participants with contraindicated medical conditions; and b) requiring all instructors to be 
certified yoga teachers with experience in directing people in how to achieve yoga postures without 
physical injury; and c) giving all participants a guidebook that explains safer ways to engage in yoga 
practices. Class content will be designed to accommodate the needs of yoga-naïve students who are not 
currently physically active. By presenting modifications of all postures, and by using props (e.g., 
chairs), the risk for injury will be minimal. We will not use postures in this study that are most 
commonly associated with adverse events, such as headstands, shoulder stands, or handstands.  
 
Potential Benefits 
The direct benefits to participants include the possibility of enjoyment of yoga classes and 
decreased pain. By participating in the clinical research project, participants may benefit from the 
additional contact with research staff that they will receive. The participant will be contributing to 
scientific research on optimizing dosage of yoga to the greatest degree possible in an OAT population. 
Given this level of risk(s) to the patients and the likelihood that some will benefit and the even greater 
possibility of benefits to the larger population of individuals in OAT through scientific gain, the 
risk/benefits ratio seems favorable. 
 
Risk-Benefit Ratio. 
 
We believe that most serious risks (e.g., loss of confidentiality, major psychological distress 
due to study participation, or serious physical injury due to yoga participation) to subjects are very 
unlikely. We have attempted to minimize these risks (described above). While some risks may be more 

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likely to occur (e.g., minor, transient psychological distress), these risks are much less serious. 
Therefore, the potential benefits of the proposed study seem to outweigh the potential risks of this 
study for the individual participants. 
7.1 
Specification of Safety Parameters 
 
 
Table 2 Assessment and Management of Safety Issues 
Safety Issue 
How assessed 
When Assessed in 
Phase 2/Phase 3 
Relevant Research Staff 
Actions 
Injuries due 
to yoga 
Structured self-report 
Weekly during first 3 
months 
Follow until resolution; may result 
in changes to yoga instructor 
manual 
Other AEs 
SAFTEE 
Participant report to 
research staff 
 
M3 
BL, M3, M6*, M12* 
Any point 
If related to study participation, 
follow resolution; potential 
changes to procedures 
particularly if AE is also 
unexpected 
*Phase 2 only 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
See Table 2 
7.3 
Adverse Events and Serious Adverse Events  
Adverse Event (AE) definition: An adverse event (AE) is any unfavorable and unintended 
diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which 
either occurs during the study, having been absent at baseline, or if present at baseline, appears to 
worsen. Adverse events are to be recorded regardless of their relationship to the study intervention.   
Serious Adverse Event (SAE) definition: A serious adverse event (SAE) is one that meets one or 
more of the following criteria: 
 
● Results in death 
● Is life-threatening (places the subject at immediate risk of death from the event as it occurred; 
includes a suicide attempt or drug overdose) 
● Results in inpatient hospitalization or prolongation of existing hospitalization 
● Results in a persistent or significant disability or incapacity 
● Results in a congenital anomaly or birth defect   
 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the event 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Study staff will record all reportable events with start dates occurring any time after informed 

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consent is obtained at least until the final day of study participation. Each time participants attend a 
yoga class, we will inquire about injuries due to yoga. For all participants in either the Phase 1 or 2, at 
Month 3 (end of intervention), study staff will administer the SAFTEE in order to inquire about the 
occurrence of AE/SAEs during the previous 3 months. This allows us to systematically assess the 
number      of adverse events, severity, and resulting impairment.  Finally, any time a participant 
reports an adverse event to any staff member, a research assistant will contact the participant to 
ascertain information for recording of the adverse event. For adverse events ascertained by any of these 
three possible methods, the research assistant gets information on what happened, start and stop dates, 
severity, functional impact, interactions with healthcare professionals, perceived cause, and possible 
relation to study participation. With this information, site PIs or Co-Is, with input from MPIs if needed, 
will code severity, causal relationship, and whether the event was expected. If necessary, staff will 
seek further information from the participant or other sources before coding. AEs will be coded on a 
weekly basis. Any potential SAE will be immediately reviewed by one of the MPIs or site PIs (or a 
qualified designee in their absence) and coded; this coding will subsequently be reviewed by the Safety 
Monitoring Committee (SMC).   
 
7.4 
Reporting Procedures 
Reporting for Multi-Center Trials 
The site PI must immediately report to the coordinating center MPIs any serious adverse event 
that is possibly study related within 48 hours of PI awareness of the event. Unrelated SAEs must be 
reported within 7 days.  
 
The site PI must also report any unanticipated problems (see below) within 48 hours of PI 
awareness of the event. The Site PI must also report any protocol violations to the coordinating center 
PI within 7 days of PI awareness.  Participating centers must also submit all reports to their local IRB 
in accordance with their institutional policies. 
 
AE/SAE Reporting 
SAEs that are unanticipated, serious, and possibly related to the study intervention will be 
reported to the Safety Monitoring Committee (SMC), IRB, and NCCIH in accordance with 
requirements.  We will use the Butler Hospital IRB-approved AE report form. 
 
● Unexpected fatal or life-threatening SAEs related to the intervention will be reported to the 
IRB, NCCIH Program Officer, and SMC within 3 days of the investigator becoming aware of 
the event. Other serious and unexpected SAEs related to the intervention will be reported 
within 7 days. These timeframes follow guidance from NCCIH and are consistent to local IRB 
policies.  
 
Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to 
the SMC, IRB, and other oversight organizations in accordance with their requirements, and will be 
reported to NCCIH on an annual basis.  
 
● Unrelated SAEs that are fatal or life threatening must be reported to the Butler Hospital IRB 
within 7 days of the investigator becoming aware of the event.  
● Unrelated SAEs that are not fatal or life-threatening must be reported to the Butler Hospital 
IRB annually.  

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All other AEs documented during the course of the trial will be reported to NCCIH on an 
annual basis by way of inclusion in the annual report and in the annual AE summary which will be 
provided to NCCIH and to the SMC. The SMC Report will state that all AEs have been reviewed.  
 
Unanticipated Problem Reporting 
 
OHRP considers unanticipated problems, in general, to include any incident, experience, or outcome 
that meets all of the following criteria: 
1. 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied; 
2. 
Related or possibly related to participation in the research (in this guidance document, possibly 
related means there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
3. 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
Incidents or events that meet the OHRP criteria for unanticipated problems require the creation and 
completion of an unanticipated problem report form. OHRP recommends that investigators include the 
following information when reporting an adverse event, or any other incident, experience, or outcome 
as an unanticipated problem to the IRB: 
 
● Appropriate identifying information for the research protocol, such as the title, investigator’s 
name, and the IRB project number; 
● A detailed description of the adverse event, incident, experience, or outcome;  
● An explanation of the basis for determining that the adverse event, incident, experience, or 
outcome represents an unanticipated problem;  
● A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the unanticipated problem. 
 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported using the 
following timeline:   
 
● Unanticipated problems that are not SAEs will be reported to the IRB, SMC, and NCCIH 
within 14 days of the MPIs becoming aware of the problem.  
● See above for SAE reporting.  
 
All unanticipated problems should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and OHRP within 
one month of the IRB’s receipt of the report of the problem from the MPIs. 
 

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7.5 
Follow-up for Adverse Events 
Any SAEs related study participation will be followed for outcome information until resolution 
or stabilization. Follow-up reports will be submitted to the IRB, SMC, or NCCIH as required in each 
specific instance.  
7.6 
Safety Monitoring  
NCCIH requires that all Human Subjects research studies undergo independent monitoring, and 
NCCIH Program Officials will provide specific guidelines to the PI for the study.   
8. INTERVENTION DISCONTINUATION  
Participants will be discontinued from an intervention in the following circumstances:  
 
● If a participant, their primary care provider, or their OAT provider does not believe it is 
in the best interest of the participant to continue. As soon as an MPI or site PI is 
informed of this, they will speak with the participant about discontinuation. There may 
be circumstances (e.g., worsening pain, an injury in yoga class) when the MPI reaches 
out to a primary care provider, OAT provider to actively inquire if they have concerns 
about the participant continuing to participate. 
● If a participant chooses to discontinue attendance.  
● If one of the MPIs or site PIs, in consultation with the relevant instructor, finds the 
participant to be so disruptive to the rest of the class that they have a repeated and 
substantive negative impact on the other participants. 
● If a participant knowingly compromises the confidentiality of another class participant.  
 
Participants will continue with subsequent assessments with their permission.  Assessment 
schedule and assessments used will not change.  
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
The overall goal of this balanced factorial optimization trial is to develop a yoga intervention 
package that is optimized for achieving maximal “dosage” of yoga received.  
We will document feasibility and acceptability of a yoga program for chronic pain at two new 
recruitment sites and develop a yoga intervention optimized for maximizing the dose of yoga received. 
We will also examine mechanisms by which components may serve to increase yoga dosage received.  
9.2 
Sample Size and Randomization 
In RCTs a conclusion is made regarding the effect of intervention based on rejecting the null 
hypothesis with Type I error < some predefined α. In contrast, in an optimization trial, a decision is 
made to include or exclude specific components in an intervention that will be tested in a future RCT. 
In this scenario, Type II error may be as pernicious as Type I error. Therefore, based on 
recommendations of Collins 30 this study will be powered with α/2 = .10. Because intervention effects 
are uncorrelated (or nearly uncorrelated if the design is not perfectly balanced), the alpha will not be 
corrected for multiple comparisons and all effects have equal statistical power. Assuming 
approximately 17% attrition for our primary outcome of dosage, we estimated power for n= 158 (192-
34). To estimate the minimum detectable effect size we assumed a small correlation (r = .15) between 

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recruitment site and yoga attendance and used the FactorialPowerPlan 31 macro in R. The proposed 
design has sufficient power (1 – β > .80) to detect a standardized difference in means of .40 or larger. 
Power to detect a medium standardized effect (d = .50) is > .90. 
 
9.2.1 Treatment Assignment Procedures 
Eligible individuals who consent to participate will be randomly assigned to one of 16 study 
conditions (Table 3). Our study statistician who has no contact with study participants and will have no 
access to outcome data until database lock, will create randomization tables using Microsoft Excel and 
upload to our data collection system (REDCap) prior to the start of recruitment for Phase 1. Because 
this is a 16-cell design, we will not stratify by any variables at baseline. Block size is effectively 12 
(i.e., number of participants per cell.) 
Study staff will not have access to randomization tables. When a person is deemed eligible, 
study staff will verify the stratification variables in REDCap and then click the “RANDOMIZE” 
button.  
For Phase 1, given there are few participants, we want to ensure that each site has an 
opportunity to pilot each intervention component and certain key combinations. 
 
Table 3. Balanced Factorial Design Assessing Four 
Candidate Intervention Components  
 
COMPONENT 
Phase 1 Phase 2 
Cell 
1 
2  
3 
4 
n 
n 
1 
No 
No 
No 
No 
1 
12 
2 
No 
No 
No 
Yes 
1 
12 
3 
No 
No 
Yes 
No 
1 
12 
4 
No 
No 
Yes 
Yes 
1 
12 
5 
No 
Yes 
No 
No 
1 
12 
6 
No 
Yes 
No 
Yes 
1 
12 
7 
No 
Yes 
Yes 
No 
1 
12 
8 
No 
Yes 
Yes 
Yes 
2 
12 
9 
Yes 
No 
No 
No 
1 
12 
10 
Yes 
No 
No 
Yes 
1 
12 
11 
Yes 
No 
Yes 
No 
1 
12 
12 
Yes 
No 
Yes 
Yes 
2 
12 
13 
Yes 
Yes 
No 
No 
1 
12 
14 
Yes 
Yes 
No 
Yes 
1 
12 
15 
Yes 
Yes 
Yes 
No 
2 
12 
16 
Yes 
Yes 
Yes 
Yes 
2 
12 
 

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9.3  
Definition of Populations 
All data analysis will use the intent to treat population and use all available data. There is no 
per protocol analysis planned.  
 
9.4 
Interim Analyses and Stopping Rules 
9.4.1 Interim Analysis   
There are no interim or futility analyses planned.   
Data analysis of Phase 1 data will occur during and immediately after data collection in Phase 1. 
Data analysis of Phase 2 data will occur after data collection in Phase 2.  
9.4.2 Stopping Rules   
This study will be stopped prior to its completion if: (1) the intervention is associated with 
adverse effects that call into question the safety of the intervention; (2) difficulty in study recruitment 
or retention will significantly impact the ability to evaluate the study endpoints; (3) any new 
information becomes available during the trial that necessitates stopping the trial; or (4) other 
situations occur that might warrant stopping the trial.  
 
9.5 
Outcomes  
9.5.1 Primary/Proximal Outcome   
Phase 1 is a pilot study to assess feasibility. The primary aims and outcome assessments are 
shown in Table 4 below. 
Table 4. Targets for Phase 1 Pilot Study.  
Feasibility Area 
Method of assessment 
Target at each site 
Recruit participants 
Number recruited per 
month 
Recruit 10 participants in 4 months.  
Train yoga teachers to fidelity 
Teacher fidelity scale 
Each teacher demonstrates >80% fidelity on 
final 3 classes rated. 
Randomize participants to 
intervention components and 
correctly administer these 
components 
Randomization errors; 
receipt of incorrect 
intervention 
components 
No errors/ incorrect components received in 
2nd half of participants randomized.  
Collect follow-up assessments 
Percent of follow-up 
assessments collected 
(for M1, M2, and M3) 
> 70% with sufficient data collected on 
dosage; 
>  70% of other follow-up assessments 
collected, including chart reviews  
 
The proximal outcome of Phase 2 is yoga dosage received. This will be calculated by adding 
the total      number of minutes per week in the study yoga class and total number of minutes per week 
in personal practice (or outside yoga classes). Research staff will take attendance at study yoga classes, 
and, in the event someone does not attend the entire yoga class, will record the number of minutes 
present in class. We will measure personal practice using the Weekly Yoga Journal. 

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9.5.2 Secondary/Distal Outcomes   
Consistent with the U01 mechanism, our focus in this study is NOT on the distal outcomes; rather, 
it is on yoga dosage received. However, we will collect distal outcome data to demonstrate feasibility 
of data collection for future research. Distal outcomes include: Pain interference, Pain Severity, 
Quality of Life, Depression, Anxiety, Substance Use, Retention in OAT, and Opioid Craving. The 
primary outcome for a future efficacy study will be pain interference.  
 
9.6 
Data Analyses  
Phase 1 Data Analysis: See Section 9.5.1 
Phase 2 Data Analysis: We plan to assess 4 candidate intervention components for possible 
inclusion in an optimized intervention that will be evaluated in a future RCT. To do so, we will use a 
balanced factorial ANOVA illustrated in Table 2. Each component will have two conditions producing 
a 24 = 16 cell design with 4 main effects, 6 possible 2-way interactions, 3 possible 3-way interactions, 
and 1 possible 4-way interaction. In a fully balanced design using effect coding (not dummy coding), 
all effects in the model are uncorrelated and the n for each condition for all effects is N/2 (i.e., 96 
without attrition; 79 estimated with 17% attrition for this primary outcome). Note that specific cells are 
not compared against other specific cells.  
We will use a general linear model with each candidate component coded using effect (1 vs -1) 
coding. Recruitment site, sex, age, and OAT type will be covariates. The pragmatic exigencies of field 
research will likely result in imperfect balance (e.g., individual cells may have slightly varying n). 
However, we anticipate only very small variations in cell sizes and thus estimated model coefficients 
will be nearly, but not perfectly, uncorrelated.  
To augment traditional frequentist statistics and facilitate interpretation we will calculate the 
Bayes factor. Based on the observed data, a Bayes factor estimates the strength of evidence supporting 
one hypothesis (model) in favor of a competing hypothesis (model).32 
We will track which classes each participant attends, and who teaches each class. As a 
sensitivity analysis, we will include not only site as a fixed effect, but also teacher. We will include a 
dummy variable for each teacher to represent whether or not the participant had exposure to that 
particular teacher (i.e., took at least one class with that teacher).  
 
 
 
Determination of Final Intervention Components:  
Goal: To determine which components will be included in the final, optimized intervention package. 
 
Components: 
All participants: attendance at 1 class (with 2 time choices) per week; materials for personal practice 
1. Personal practice videos featuring study yoga teachers 
2. Initial and 1-month 1:1 session with a yoga teacher 
3. Text messages cuing personal practice 
4. Monetary incentives for class attendance 
Once data collection is complete, we will convene a meeting (or conference call) to make decisions 
about which intervention components should be included in the final intervention package. Participants 
in this meeting will include:   
1. MPIs and co-Is and consultant Dr. Guastaferro;   

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2. Selected NCCIH staff (e.g., PO); and  
3. Selected yoga instructors  
At this meeting we will review all data collected.  
 
Step 1: For each intervention component, we will first review the main and 2nd order interaction effects 
from the factorial experiment on the primary outcome of number of yoga minutes per week. We 
assume data will be missing at random. Missing data will be addressed using multiple imputation by 
chained equations.33 Because the goal is intervention optimization, retention of components will not be 
based on a single criterion. We will initially choose to include all components for which there is a main 
or sympathetic interaction effect with a) an effect size (SMD) of 0.40 (estimated, based on preliminary 
data, to be 31 mins of yoga per week) or greater favoring the component; OR b) p < .10 favoring the 
component OR c) if the estimated Bayes factor provides substantial or stronger evidence preferring the 
intervention hypothesis to the hypothesis of no treatment effect. (See below for more information on 
Bayes factor).  
 
Special cases:  
1. Of monetary incentives for class attendance, we will look specifically at class attendance. If 
monetary incentives increase class attendance, and do not decrease overall minutes of practice, 
we will choose to include.  
2. 3rd and 4th order interactions may be tricky to interpret. We will look at them, but place priority 
on main effects and 2nd order interactions in making decisions.  
3. It is possible that 2nd order interactions may be antagonistic where the combination of two or 
more components is less effective than would be expected based on the main effects alone. At 
the same time, there may be significant positive main effects for both components. In this case, 
we will examine graphical depictions of results in order to determine whether to include both of 
the two components in question. 
Step 2: All components that pass Step 1 will then be examined in light of their feasibility and 
acceptability. Data that bear on feasibility and acceptability include:  
1. Participants’ responses to qualitative interviews 
2. Yoga instructors’ experiences (field notes) 
3. Feedback from administrators/ clinicians at sites [from field notes (clinicians) and structured 
interviews (key administrators)] 
4. Adverse events determined to be related to a given component 
5. Number of 1:1 sessions attended (relevant for the 1:1 session intervention component only); 
use of personal practice videos (relevant for the personal practice video component only). We 
note that even one 1:1 session, or a small amount of use of personal practice videos, could have 
an impact on pain interference or other relevant outcomes. 
6. % of follow-up assessments completed (not expected to be different between groups; we would 
consider a difference of 15% in proportion of participants observed at M3 to be of concern, and 
would likely be a statistically significant difference) 
In determining feasibility, each component that passed Step 1 will be determined to be:  
1. Acceptable and feasible without any changes. 
2. There are minor changes that we judge do not affect the core nature of the intervention that we 
can make to increase acceptability and feasibility to a higher level (e.g., 1:1 meetings were 
scheduled for 45 minutes but everyone agrees that 30 minutes was adequate and even 
preferable).  

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3. Not acceptable/ feasible.  
Step 3. All components that passed Step 1 and Step 2 will be included in the final optimized 
intervention. We will make minor changes to components if indicated in Step 2.  
 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
Most data will be collected and entered directly into REDCap. Data collected on paper CRF 
will be double-entered into REDCap. There will also be a database that we will use for tracking 
participants.  
Any data, forms, reports, audio recordings, and other records that leave either recruitment site 
will be identified only by a participant identification number (Study ID, SID) to maintain 
confidentiality. All paper records will be kept in a locked file cabinet. All data collected will be entered 
into an electronic database which is stored on a secure server (REDCap) that is backed up on a daily 
basis. Participant identifying information will be stored in a separate REDCap database. Care New 
England’s instance of REDCap has been deemed HIPAA compliant by CNE Information Technology. 
10.2 Data Management  
All data will be collected via REDCap.  Paper CRFs, when collected, will be double-entered 
into REDCap. The Data Manager will oversee the REDCap database. Any discrepancies will be 
resolved by the Project Manager in consultation with the MPIs as needed.  
 
Please see also “Data Handling and Record Keeping” in the DSMP.  
 
10.3 Quality Assurance  
10.3.1 Training 
All research personnel, including yoga instructors will have formal training in research with 
human subjects (e.g., CITI training, NIH Human Subjects training). Study PIs, co-Is, and research 
managers and coordinators will provide training to and supervise research assistants. Research 
assistants will also have training in Good Clinical Practice. Drs. Uebelacker and Tremont will provide 
training and supervision to yoga instructors.  
 
10.3.2 Quality Control Committee  
Study MPIs and co-Is will be responsible for quality control of this study. They review 
recruitment and retention reports, and AE reports, on a weekly      basis.  
 
10.3.3 Metrics 
 
Protocol Deviations 
During weekly study meetings, protocol deviations will be discussed with the MPIs, including 
plans for corrective action. Site PIs, co-Is, and study coordinators will also be alerted to deviations as 
they occur and will alert the MPIs for any deviation requiring immediate action. Protocol deviations 
will be logged on the protocol deviation tracking sheet and filed in the regulatory binder. 
 

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All assessment time points have a window of time for completion. However, typically due to 
circumstances outside of the control of the research staff, assessments occasionally occur outside of 
that window. Assessments that occur outside of the recommended window for completion will be 
considered to be protocol deviations, and will be logged as such.  
 
Protocol deviations will be reported to NCCIH once per year, in the annual review. The SMC 
will also receive a list of protocol deviations in their interim or annual reports.  Per Butler Hospital 
IRB policy, “major protocol deviations/violations, defined as those which increase risk to participants” 
will be reported promptly to the IRB and no more than 10 working days after the investigator is aware 
of the event. Minor protocol deviations do not need to be reported.  
 
10.3.5 Monitoring 
A study co-I or research manager or research coordinator  will conduct protocol and data 
quality monitoring twice a year at each study site using the Quality Management review checklists. 
During Phase 1, all participant and other study records will be reviewed. During Phase 2, a random 
sample of 10-20% of participant and study records will be reviewed at each monitoring time point.  
 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed consent documents and any subsequent modifications will be 
reviewed and approved by the IRB or ethics committee responsible for oversight of the study. The 
consent form should be separate from the protocol document.  
11.2 Informed Consent Forms 
Informed consent will be obtained from each participant. The consent form will describe the 
purpose of the study, the procedures to be followed, and the risks and benefits of participation. A copy 
will be given to each participant and this fact will be documented in the participant’s record.  
11.3 Participant Confidentiality  
Any data, forms, reports, audio recordings, and other records that leave the site will be 
identified only by a participant identification number (Study ID, SID) to maintain confidentiality. All 
paper records will be kept in a locked file cabinet. All data collected will be entered into an electronic 
database which is stored on a secure server (REDCap) that is backed up on a daily basis. Participant 
identifying information will be password protected and stored on a secure server. Care New England’s 
instance of REDCap has been deemed HIPAA compliant by CNE Information Technology. 
 
Information will not be released without written permission of the participant, except as 
necessary for monitoring by IRB, the FDA, the NCCIH, and the OHRP. 
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the NCCIH, the OHRP, or other 
government agencies as part of their duties to ensure that research participants are protected.  

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12. COMMITTEES 
There will be a Safety Monitoring Committee.  
13. PUBLICATION OF RESEARCH FINDINGS  
Drs. Stein and Uebelacker will be responsible for oversight and approval of any publications or 
presentations that arise from this research.  
 
14. PARTICIPANT STAKEHOLDERS AS ADVISORS  
 
We would like to include one participant per site per year as a participant advisor in this study.  
 
Selection and enrollment: Each study site will nominate one or more person(s) whom they think will 
be able to serve in this role. A participant advisor will be a person with lived experience in MMT or 
BUP treatment, and may be a person who has previously participated in the parent study. They will be 
aged 18 or older.  
Recruitment: A study investigator, research coordinator, or research assistant who already knows the 
participant will approach the participant and ask them if they are interested in serving in this role. If 
they are, study staff will conduct informed consent with the participant, using procedures described in 
the parent study document. Once this is complete, the participant will be considered enrolled as a 
participant advisor.  
 
Procedures: Participant advisors will be asked to attend 2-4 meetings per year with study staff, to 
discuss study rationale, procedures, and any challenges that study staff are experiencing. Meetings may 
occur by telephone, videoconference, or in person. The participant advisor will not have access to any 
PHI of other participants, except that they may, if they all agree, attend a meeting that includes      
other participant advisors. 
 
Study staff will maintain field notes reflecting (non-identifiable) feedback from participant advisors. 
Field notes may be used in publications describing this study.  
 
Participants will be paid $50/ hour for their participation, up to $200/ year.  
 
Loss of confidentiality is the primary risk. Participants will not be asked to disclose any information 
about themselves, but may choose to do so. Confidentiality will be protected as described above in this 
proposal.  Potential benefits include the opportunity to be a part of the research project and influence 
the research direction. Overall, we believe risks are minor and the risk-benefit ratio is favorable.  

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16. SUPPLEMENTS/APPENDICES 
None