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

 
 
 
 
 
 
 
 
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 
Assistant Director of Psychosocial 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 
Director of Behavioral Medicine and Addictions Research, Butler Hospital 
 
Supported by:  
The National Center for Complementary and Integrative Health, 
U01AT010863 
 

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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. 
 
 

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TABLE OF CONTENTS 
STUDY TEAM ROSTER .......................................................................................................................................... 6 
PARTICIPATING STUDY SITES ........................................................................................................................... 8 
PRÉCIS ........................................................................................................................................................................ 9 
1. STUDY OBJECTIVES ....................................................................................................................................... 11 
1.1 
Primary Objective ............................................................................................................................................. 11 
2. BACKGROUND AND RATIONALE ............................................................................................................... 11 
2.1 
Chronic pain in people receiving OAT ..................................................................................................... 11 
2.2 
Study Rationale ................................................................................................................................................. 12 
3. STUDY DESIGN ................................................................................................................................................. 12 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ........................................................................... 13 
4.1 
Inclusion Criteria .............................................................................................................................................. 13 
4.2 
Exclusion Criteria ............................................................................................................................................. 13 
4.3 
Study Enrollment Procedures ..................................................................................................................... 14 
5. STUDY INTERVENTIONS .............................................................................................................................. 15 
5.1 
Interventions, Administration, and Duration ....................................................................................... 15 
5.2 
Handling of Study Interventions ................................................................................................................ 16 
5.3 
Concomitant Interventions .......................................................................................................................... 17 
5.3.1 
Allowed Interventions ............................................................................................................................... 17 
5.3.2 
Required Interventions............................................................................................................................. 17 
5.3.3 
Prohibited Interventions .......................................................................................................................... 17 
6. STUDY PROCEDURES .................................................................................................................................... 17 
6.1 
Schedule of Evaluations ................................................................................................................................. 18 
6.2 
Description of Evaluations ............................................................................................................................ 20 
6.2.1 
Screening Evaluation ................................................................................................................................. 20 
6.2.2 
Baseline – Phase 1 and Phase 2 ............................................................................................................. 20 
6.2.3 
Blinding ........................................................................................................................................................... 21 
6.2.4 
Follow-up Visits ........................................................................................................................................... 23 
6.2.5 
Completion/Final Evaluation ................................................................................................................. 25 
7. SAFETY ASSESSMENTS ................................................................................................................................. 25 
7.1 
Specification of Safety Parameters ............................................................................................................ 27 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .............. 27 

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7.3 
Adverse Events and Serious Adverse Events ........................................................................................ 27 
7.4 
Reporting Procedures ..................................................................................................................................... 28 
7.5 
Follow-up for Adverse Events ..................................................................................................................... 30 
7.6 
Safety Monitoring ............................................................................................................................................. 30 
8. INTERVENTION DISCONTINUATION ....................................................................................................... 30 
9. STATISTICAL CONSIDERATIONS ............................................................................................................... 31 
9.1 
General Design Issues ..................................................................................................................................... 31 
9.2 
Sample Size and Randomization ................................................................................................................ 31 
9.2.1 Treatment Assignment Procedures .......................................................................................................... 31 
9.3  
Definition of Populations............................................................................................................................... 32 
9.4 
Interim Analyses and Stopping Rules ...................................................................................................... 32 
9.4.1 Interim Analysis ............................................................................................................................................... 32 
9.4.2 Stopping Rules ................................................................................................................................................... 32 
9.5 
Outcomes ............................................................................................................................................................. 32 
9.5.1 Primary/Proximal Outcome ........................................................................................................................ 32 
9.5.2 Secondary/Distal Outcomes ........................................................................................................................ 33 
9.6 
Data Analyses ..................................................................................................................................................... 33 
10. DATA COLLECTION AND QUALITY ASSURANCE ................................................................................ 35 
10.1 
Data Collection Forms .................................................................................................................................... 35 
10.2 
Data Management............................................................................................................................................. 35 
10.3 
Quality Assurance ............................................................................................................................................. 36 
10.3.1 Training ............................................................................................................................................................. 36 
10.3.2 
Quality Control Committee ................................................................................................................ 36 
10.3.3 
Metrics ........................................................................................................................................................ 36 
10.3.5 
Monitoring ................................................................................................................................................ 36 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ............................................................................... 37 
11.1 
Institutional Review Board (IRB) Review .............................................................................................. 37 
11.2 
Informed Consent Forms .............................................................................................................................. 37 
11.3 
Participant Confidentiality ........................................................................................................................... 37 
11.4 
Study Discontinuation .................................................................................................................................... 37 
12. COMMITTEES ................................................................................................................................................ 37 
13. PUBLICATION OF RESEARCH FINDINGS .............................................................................................. 37 
14. REFERENCES .................................................................................................................................................. 38 
15. SUPPLEMENTS/APPENDICES .................................................................................................................. 39 

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STUDY TEAM ROSTER  
MPIs:  
 
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 
 
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 Street, Talbot Building 
Tel: 617-358-1956; Email: mdstein@bu.edu 
 
Butler:  
 
Ana Abrantes, Ph.D., Co-I 
Professor, Brown University 
Associate 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 
 
Celeste Caviness Ph.D.  
Project Manager, Butler Hospital 
Address: Butler Hospital, 345 Blackstone Blvd, Providence, RI 02906 
Tel: 401-455-6648, Fax: 401-455-6685; E-mail: ccaviness@butler.org 
 
CODAC: 
 
Lynn Taylor, M. D., Co-I 
Research Professor, University of Rhode Island 
Director of HIV and Viral Hepatitis Services and Chair of the Research Committee at CODAC 
Behavioral Healthcare 
Address: CODAC Behavioral Healthcare, Inc., 349 Huntington Ave., Providence, RI, 02909 
Tel: 401-942-1450; Fax: 401-946-1550; Email: ltaylor@codacinc.org 
 
Sophie Sprecht-Walsh, L.P.N. 
Nursing Coordinator at CODAC Behavioral Healthcare 
Address: CODAC Behavioral Healthcare, Inc., 349 Huntington Ave., Providence, RI, 02909 

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Tel: 401-942-1450; Cell: 401-952-1045; Email: sophiesprecht@gmail.com  
 
Boston Medical Center:  
 
Robert Saper, M.D., M.P.H., Co-I 
Professor, BUSM 
Director of Integrative Medicine, Department of Family Medicine 
Address: 771 Albany Street, Boston, MA, 02118 
Tel: 617-414-6276; Email: Robert.saper@bmc.org  
 
Joanna D’Afflitti, M.D., Co-I 
Medical Director for the Office-Based Addiction Treatment program at BMC 
Address: 801 Massachusetts Ave, 6th Floor, Boston, MA, 02119 
Tel: 617-414-5951; Email: jld74@bu.edu  
 
Jessica Howard 
Title: Project Manager  
Address: 771 Albany Street, Boston, MA, 02118 
Tel: 617-285-8746. 
Email: Jessica.howard@bmc.org 
 
Lucy Lorin 
Title: Research Coordinator 
Address: 771 Albany Street, Boston, MA, 02118 
Email: Lucy.lorin@BMC.org 
 
Rhode Island Hospital:  
 
Geoffrey Tremont, Ph.D., Co-I 
Associate Professor, Brown University 
Director of the Neuropsychology Program, Rhode Island Hospital 
Address: 593 Eddy Street, POB 430, Providence, RI, 02903 
Tel: 401-444-4500; Fax: 401-444-6643; Email: gtremont@lifespan.org  

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PARTICIPATING STUDY SITES 
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  
 
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 Street, Talbot Building 
Tel: 617-358-1956; Email: mdstein@bu.edu 
 
Boston Medical Center:  
Robert Saper, M.D., Co-I 
Associate Professor, BUSM 
Director of Integrative Medicine, Department of Family Medicine 
Address: 771 Albany Street, Boston, MA, 02118 
Tel: 617-414-6276; Email: Robert.saper@bmc.org  
 
Rhode Island Hospital: 
Geoffrey Tremont, Ph.D., Co-I 
Associate Professor, Brown University 
Director of the Neuropsychology Program, Rhode Island Hospital 
Address: 593 Eddy Street, POB 430, Providence, RI, 02903 
Tel: 401-444-4500; Fax: 401-444-6643; Email: gtremont@lifespan.org  
 
CODAC Behavioral Healthcare, Inc: 
Lynn Taylor, M. D., Co-I 
Research Professor, University of Rhode Island 
Director of HIV and Viral Hepatitis Services and Chair of the Research Committee at CODAC 
Behavioral Healthcare 
Address: CODAC Behavioral Healthcare, Inc., 349 Huntington Ave., Providence, RI, 02909 
Tel: 401-942-1450; Fax: 401-946-1550; Email: ltaylor@codacinc.org  
 
 
 
 
 

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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.  
 
Interventions and Duration  

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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 initial and 1-
month 1:1 sessions with a yoga teacher. 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:  
4. 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.  
5. Use results from Phase 2 to choose an efficient combination of intervention 
components that, together with standard yoga classes, maximizes yoga dosage. 
6. 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 to participate in the study.  
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 pain for at least half the days over the previous three 
months, a mean score of 4 or higher on the BPI Pain Interference Scale (with 
reference to chronic pain), 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 baseline will be excluded 
from study participation. 
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.) 
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) Plan to move out of the area within 6 months.  

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8) Homeless, defined as any time in the past month sleeping in a shelter or on the street.  
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 clinic staff and using electronic health records, research staff will identify 
potentially eligible individuals. Research staff will call these participants, send them a letter, and/ 
or approach them at an appointment to tell them about the study if they are interested. We will 
also use passive recruitment methods, e.g., posting fliers in clinic spaces. Interested participants 
will undergo a brief (5-10 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. 
 
Informed Consent Procedures 
 
Research assistants will perform this process. Participants appearing to meet study 
criteria will be scheduled for a more comprehensive baseline assessment. This assessment may 
be either over the telephone or in person. If it is over the telephone, we will send a written 
version of the informed consent document to the participant ahead of time. With the participant’s 
permission, this may be sent via email or US mail.  During the baseline assessment, research 
staff will carefully explain all aspects of the study, then potential risks and benefits, and the 
expected duration and time commitment of their participation. If the patient verbally consents, 
the patient will be presented with a written explanation, will be given the opportunity to ask 
questions. Documentation of informed consent may occur via one of several methods: a) a 
written informed consent document; b) a REDCap document with an electronic signature; c) 
audiorecording of informed consent. 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 (either on paper or electronically). 
After informed consent is obtained, participants will then be evaluated using the baseline 
diagnostic and assessment measures to confirm eligibility. Consent forms will be stored in a 
secure location at Butler Hospital (for patients recruited at CODAC) or Boston Medical Center, 
or be located in REDCap. Participants will be given a copy of the consent form to keep.  
 
Enrollment and Randomization 
 
Enrollment procedures are identical for Phase 1 and Phase 2. 
 

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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 and two blocks; and c) a booklet describing basic yoga practices and ways to more safely 
engage in yoga. The study cell phone will 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.  
Participants will be asked to return the phone at the end of study participation.   
  
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 timeslots. Classes will take place at the 
clinic/facility where they receive OAT or via a secure video-based platform such as Zoom; they 
are planned to be 60 minutes long. Registered yoga teachers will deliver the intervention. 
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 participant individually based on 
randomization assignment. Components include: 1) Personal practice videos featuring study 
yoga teachers, 2) 1:1 session with yoga teacher at baseline and 1 month (in-person or via a secure 
video-based platform), 3) Text messages cuing personal practice, 4) Monetary incentives for 
class attendance. 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. Due to COVID restrictions, we may not be able to offer 

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classes or 1:1 sessions with yoga teachers in-person. Thus, we will offer classes and meetings via 
a secure video-based platform on study-provided cell phones. Whether interventions are via a 
secure video-based platform or in person may fluctuate during Phase 1 of the study. Prior to the 
start of Phase 2, we will decide on the best modality to provide interventions for Phase 2, and 
then stay with that modality throughout the duration of Phase 2, barring unforeseen 
circumstances.  
 
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 in person or 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 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 12 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 prior to the first group class, and one after 1 month. Sessions 
will be in person or 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-

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randomization, for applicable participants, we will ask participants to choose from a list of text 
messages the ones they expect would be most helpful to receive during the study. Participants 
may also choose to receive messages via email instead of text, and time of day they would like to 
receive them. We will send messages every day or every other day, per participant choice. They 
may choose to change their choices once per month. Participants will be randomized to either 
receive or not receive regular text messages cuing personal practice. 
 
Intervention Component 4: Monetary incentives for class attendance. Transportation 
and other costs such as childcare associated with attendance may be a significant barrier for 
some participants. Financial 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 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.  
There will be at least 2 trained yoga teachers at each site. 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 20% of classes on an ongoing basis, and review results with teachers. 
 
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 
Type of Assessment 
Screening: 
(Up to 30 
days before 
BL1) 
Baseline  
Visit 1 
 
After 
initial 
class 
Weekly 
M1, M2, 
M3 
M1 visit M2 visit 
M3 visit 
M6 visit 
(Phase 2 
only) 
M12 visit 
(Phase 2 
only) 
Inclusion/Exclusion   
Interview, pre-
randomize. 
X 
X 
 
 
 
 
 
 
 
Informed Consent Form  
Pre-randomize. 
 
X 
 
 
 
 
 
 
 
Enrollment and Randomization  
Interview  
 
 
X 
 
 
 
 
 
 
 
Credibility Expectancy Questionnaire (CEQ) 
Self-report 
 
 
X 
 
 
 
 
 
 
Homework Questionnaire  
Self-report 
 
 
 
X 
 
 
 
X 
X 
Injuries due to yoga  
Self-report 
 
 
 
X 
 
 
 
 
 
Systematic Assessment for Treatment Emergent 
Events (SAFTEE) 
Interview 
 
 
 
 
 
 
X 
 
 
Chart Review 
Chart Review 
 
X 
 
X 
 
 
 
X 
X 
Other Adverse Events 
Interview 
 
X 
 
X 
X 
X 
X 
X 
X 
SUD, psychiatric, sleep, and pain medications 
(modified TRAQ) 
Interview 
 
X 
 
 
 
 
X 
X 
X 
Tampa Scale of Kinesiophobia (TSK) 
Self-report 
 
X 
 
 
X 
X 
X 
 
 
Self-efficacy for exercise 
Self-report 
 
X 
 
 
X 
X 
X 
 
 
Logistic Factors 
Self-report 
 
X 
 
 
X 
X 
X 
 
 
Behavioral Regulation in Exercise Questionnaire 
(BREQ-2), modified for yoga 
Self-report 
 
X 
 
 
X 
X 
X 
 
 

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Assessment 
Type of Assessment 
Screening: 
(Up to 30 
days before 
BL1) 
Baseline  
Visit 1 
 
After 
initial 
class 
Weekly 
M1, M2, 
M3 
M1 visit M2 visit 
M3 visit 
M6 visit 
(Phase 2 
only) 
M12 visit 
(Phase 2 
only) 
Brief Pain Inventory (BPI)* 
Self-report 
 
X 
 
 
X 
X 
X 
X 
X 
Numerical Rating Scale (NRS), Pain Severity 
Self-report 
 
X 
 
 
X 
X 
X 
X 
X 
WHO Quality of Life, Brief Version (WHOQOL-
BREF) 
Self-report 
 
X 
 
 
 
 
X 
X 
X 
PROMIS Depression Scale 
Self-report 
 
X 
 
 
 
 
X 
X 
X 
PROMIS Anxiety Scale 
Self-report 
 
X 
 
 
 
 
X 
X 
X 
Addiction Severity Index (ASI) 
Interview 
 
X 
 
 
X 
X 
X 
X 
X 
Penn Craving Scale 
Self-report 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
Self-report, blind DB 
 
X 
 
 
 
 
 
 
 
Review of Medical Comorbidities 
Self-Report 
 
X 
 
 
 
 
 
 
 
Qualitative Exit Interview (Phase 1 only) 
Interview 
 
 
 
 
 
 
X 
 
 
Payment  
 
 
$10 
 
 
$20 
$20 
$30 
(assmt) 
+ $35 
(return 
of study 
cell 
phone) 
$30 
$40 
* When 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.  

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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 or in-person). We will provide 
participants with a document with response options to look at while they are responding to 
assessment questions.  
 
We will track type of interview (on the phone or in-person) for each assessment. 
 
6.2.1 Screening Evaluation 
Consenting Procedure 
All phases will have a) agreement from individual to conduct brief eligibility screening 
and b) informed consent 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, because all inclusion criteria are verified or re-verified at BL the 
screen may be conducted as many as 30 days prior to BL. 
 
6.2.2 Baseline – Phase 1 and Phase 2 
Consenting Procedure  
Informed consent will be obtained 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.  
In-Person Screening  
After informed consent/assent is complete, RAs will administer the following to ascertain 
inclusion criteria during BL1:  
 
● BPI –Pain Interference  
● NRS– Average and worst pain in the past week 
● Review of Medical Comorbidities 
 
 
  
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 

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stating specific reason for exclusion. We will provide referrals to the community upon 
request. 
Baseline Assessments – Phases 2 and 3 
Remaining Baseline1 assessments include:  
● TRAQ 
● TSK 
● Self-Efficacy for exercise 
● Logistic Factors (from Cardiac Rehabilitation Barriers Scale) 
● BREQ-2 
● WHOQOL-BREF 
● PROMIS® Depression Scale 
● PROMIS® Anxiety Scale 
● ASI 
● Penn Craving Scale 
● Demographics 
 
Randomization  
Allowable window between BL1 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 this visit is $10.  
 
6.2.3 Blinding 
Follow-up assessments will be conducted by research staff who are blind to which arm 
participants were randomized.  See table on next page.  
 
 

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Personnel 
Role 
Site 
Blind?  Description of activities/ reason for status 
Uebelacker, Lisa 
MPI 
Butler 
Yes 
 
Abrantes, Ana 
Co-I 
Butler 
No 
Will serve as an Investigator who is not 
blind, and available to consult with 
project manager or other staff about a) 
SAE reports that may relate to 
randomization; b) other randomization-
related activities or problems 
Caviness, Celeste 
Project manager 
Butler 
No 
Will supervise randomization, conduct 
unblinded data audits at both sites, and 
prepare unblinded reports 
Herman, Debra 
Project manager 
Butler 
No 
Will supervise randomization, conduct 
unblinded data audits at both sites, and 
prepare unblinded reports 
Anderson, Bradley 
Study statistician 
Butler 
Yes 
 
Audet, Daniel 
Data manager 
Butler 
Yes  
Will work with Dr. Anderson to provide 
blinded reports; will serve as back-up to 
blind RA at CODAC 
TBN  
Research assistant 
Butler 
Yes 
Will assist with recruitment (pre-
randomization) and conduct follow-up 
assessments at CODAC 
TBN 
Research assistant 
Butler 
No 
Will recruit participants and facilitate 
randomized intervention components at 
CODAC 
TBN 
Consultant --Lead 
yoga instructor 
Butler 
No  
Will provide supervision to yoga 
instructors re: 1:1 visits  
Guastaferro, Kate 
Consultant – 
MOST expert 
Butler 
Yes 
 
TBN 
Yoga instructors 
(n=3) 
Butler 
No 
Providing 1:1 visits 
Stein, Michael 
MPI 
BU 
Yes 
 
Taylor, Lynn 
Site PI 
CODAC 
Yes 
 
Sprecht-Walsh, 
Sophie 
Site coordinator 
CODAC 
No 
Will serve as back-up to non-blind RA at 
CODAC 
Bordeau, Alisha 
CFO/ research 
administration  
CODAC 
Yes 
 
Tremont, Geoffrey 
Co-I 
RIH 
No 
Will provide supervision to yoga 
instructors re: 1:1 visits 
Saper, Robert 
Site PI 
BMC 
Yes 
Oversee all recruitment, eligibility, 
consent, intervention, and data collection 
activities at BMC 
D’Afflitti, Joanna 
Co-I 
BMC 
Yes 
Primary role in recruitment and 
consultation regarding any issues related 
to OAT treatment and eligibility 
Lorin, LucyHoward, 
Jessica 
Project manager 
BMC 
Yes 
Subcontracts, invoices, oversee research 
staff 
TBN  
Research assistant 
BMC 
Yes 
Will assist with recruitment (pre-
randomization) and conduct follow-up 
assessments 

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TBN 
Research assistant 
BMC 
No 
Will recruit participants and facilitate 
randomized intervention components 
Garcia Drago, 
Victoria 
Yoga instructor 
BMC 
No 
Providing 1:1 visits 
 
 
6.2.4 Follow-up Visits 
For the purposes of targeting dates for an assessment, 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 two-week window. We will record optimum date for the assessment 
(e.g., Enrollment + 84 days for M3 assessment) as well as the actual date of the assessment. Note 
that we will attempt to conduct follow-up visits in person, but if that is not possible, we will 
collect data via 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).  
 
 Phase 1 and Phase 2 Visits:  
● 
Weekly for 12 weeks 
o Study classes/groups 
o Homework Questionnaire 
o Injuries due to yoga 
o CEQ (after initial class only) 
o Any other AEs reported to RAs 
 
● 
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 Penn 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 

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o Penn Craving Scale 
o Payment: $20 
 
● 
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 Penn Craving Scale 
o SAFTEE 
o Chart Review 
o Qualitative Exit Interview (Phase 1 only) 
o Payment: $30 
 
Phase 2 Visits Only: 
● 
Month 6 
o Homework questionnaire 
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 Penn Craving Scale 
o Chart Review 
o Payment: $30 
o  
● 
Month 12 (Final evaluation for Phase 2) 
o Homework questionnaire 
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 Penn Craving Scale 

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o Chart Review 
o Payment: $40 
 
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. 
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 future standing with Butler Hospital, CODAC, or BMC. 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 stored 
in a separate database and 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), 

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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 inherit 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 not to send sensitive information by text or email.  It is important to note 
that we will only be conveying general information by text messaging or email. No confidential 
or sensitive personal information will be sent 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 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 disclosestheir 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.  
 
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, blocks), the risk for injury will be minimal.  We will 

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not use postures in this study that are most commonly associated with adverse events, such as 
headstands, shoulderstands, 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 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 

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baseline, appears to worsen. Adverse events are to be recording 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 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 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, Dr. Taylor or Dr. Saper, with input from Drs. Stein or Uebelacker, 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. 
 

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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.  
 
 
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; 

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● 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. 
 
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.  

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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 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. 
 

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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 
 
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.  

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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 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 
Personal practice Questionnaire. 
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).  

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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;   
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. 

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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).  
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, Mr. Audet will oversee the REDCap database. Any 
discrepancies will be resolved by the Project Manager in consultation with the MPIs as needed.  

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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). Drs. Stein, Uebelacker, 
Saper, Taylor, Caviness, and Herman, and Ms. Howard 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  
Drs. Uebelacker, Stein, Saper, Taylor, Herman, and Caviness will be responsible for 
quality control of this study. They review recruitment and retention reports, and AE reports, on 
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. Drs. Caviness or Herman (at CODAC) or Ms. Howard (at 
BMC) 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. 
 
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 
Dr. Caviness or Herman 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.  
 

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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 stored in a separate database and 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.  
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. 

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15. SUPPLEMENTS/APPENDICES 
None