Effect of Mindfulness on Opioid Use and Anxiety During Primary Care Buprenorphine Treatment (R33 Phase)
Phase: NA
Conditions: Opioid-use Disorder, Stress Related Disorder, Anxiety, Pain Interference
Sponsor: Cambridge Health Alliance

Effect of Mindfulness Training on Opioid Use
and Anxiety During Primary Care
Buprenorphine Treatment
(MINDFUL-OBOT)
NCT04278586
Study Protocol
Version Date: 1/06/2023
Phase 1: Primary Care RCT
Phase 2: Live-Online RCT
PRINCIPAL INVESTIGATOR
Zev Schuman-Olivier, MD
1
Mindful-OBOT Clinical Trial Protocol V2.20.

1.
TOOL REVISION HISTORY
Version Number: 1
Version Date: 06/19/19
Summary of Revisions Made:
Version 1: Initial Submission
Version Number: 1.1
Version Date (Resubmitted at 3 points): 10/7/19, 10/31/19, 11/8/19
Summary of Revisions Made:
Upon the request of the IRB the following stipulations have been made to the protocol:
1. Protocol version and version date updated
2. Pagination corrected to 99 total pages
3. Added Nancie Rouleau and Roger Weiss to the protocol
4. Update Roger Weiss as a non-CHA affiliated team member
5. MTPC-OUD enrollment corrected and justified based on Mindful-OBOT R-21 pilot
6. Time of treatment discontinuation revised and updated with correct information
7. Length of LDM and MCS sessions clarified in Figure 3
8. Inclusion criteria in regards to the definition of 90 days of abstinence refined
9. Clarified when participants enter MCS, and when they stay in LDM
10. Rationalized option for M-ROCC participants to switch back into GBOT
11. Weekly/Biweekly Group timing clarified
12. Alternatives to participation clarified
13. Information on social media privacy and security added
14. Consenting procedure section updated to include CHA and non-CHA sites
15. Procedure for assigning study numbers and acrostics clarified
16. Timing of randomization updated
17. Included company information of prepaid cards, and what data will be shared with
CT Payer
18. Risks of participants disclosing private information added
19. Included timeframe for reporting unanticipated problems that are not adverse
20. Revised protocol for Heart Rate Detection task to indicate no intervention in the event
of abnormal heartrate detection
21. Description of exported file of site-specific medical record information updated
22. Removed reference to paper and pen surveys
23. Reference to disguising information updated to reflect procedure for creating study
numbers and acrostics
24. Clarified study payments.
25. Removed all references to qualitative interviews
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Mindful-OBOT Clinical Trial Protocol V2.20.

26. Removed reference to obtaining a waiver of consent
27. Removed grammatical error in section 7.2.1
28. Clarified statement on group acceptability survey matching
29. Clarified Sarah Moore’s institution
Version Number: 1.2 (Initial Submission to NCCIH for Approval)
Version Date:10/22/19
Summary of Revisions Made:
Version 1.2:
1. Removed Dharma Cortes from the study team roster
2. Removed Genie Bailey from the study team roster
3. Removed Yanyi Jiang from study team roster
4. Removed Cassandra Harding from the study team roster
5. Added Farah Samawi to the study team roster
6. Added Timothy Creedon to the study team roster
7. Removed Jen Brownstein from the study team roster
8. Reduced study enrollment from 280 to 180
9. Reduced study length from 52 weeks to 24 weeks and changed 6 month references to
24 weeks for consistency
10. Changed study title from “Effects of Mindfulness Training on Primary Care
Buprenorphine Treatment Retention” to “Effect of Mindfulness Training on Opioid
Use and Anxiety During Primary Care Buprenorphine Treatment”
11. Edited font size to be consistent throughout document
12. Corrected spelling of Alexandra Comeau’s name
13. Removed reference to R01 grant
14. Removed SSTAR as a site
15. Removed North Shore Peabody site
16. Replaced references to 8 sites across 5 institutions with five primary care sites and
clarified figures to reflect this change.
17. Added 16-week version of MTPC-OUD intensive
18. Added Senior Research Coordinator to Data Quality monitoring table
19. Changed primary outcomes to R33 outcomes instead of R01 outcomes, focusing on
change in PROMIS anxiety.
20. Clarified Richa Gawande’s role
21. Clarified that manual will be sent to NCCIH prior to the start of R33 study enrollment
22. Clarified Serious Adverse Event as ”life-threatening” overdose requiring naloxone
reversal, rather than just “overdose”.
23. Clarified Data Quality Monitoring table reviewer roles
24. Corrected grammatical error in section 7.2.1
25. Added Beck Anxiety Inventory (BAI) as a secondary outcome
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Mindful-OBOT Clinical Trial Protocol V2.20.

26. Added PROMIS Anxiety T score less than 50 (raw < 13) as an exclusion criteria and
modified screening procedure to reflect this.
Version Number: 1.3 (Re-Submission to NCCIH and CHA IRB for Approval)
Version Date1/6/2020: Modification 1
Summary of Revisions Made:
1. PROMIS Anxiety T score less than 55 (raw < 16) will be excluded from the
secondary analysis of PROMIS Anxiety and BAI outcomes, because 55 is the cutoff.
for mild anxiety. This analysis will be conducted in subset with anxiety disorders.
2. Changed primary and secondary outcomes to the outcomes from original R33 grant
with opioid negative time periods as a primary outcome.
3. Changed sample size from 180 enrolled to 210 enrolled, and included updated power
analysis for this sample.
4. Removed PROMIS Anxiety T score less than 50 (Raw<13) as an inclusion criterion.
5. Clarified procedures for obtaining waivers of consent.
6. Defined MOCA as Montreal Cognitive Assessment.
7. Changed payment method from CT payer to PNC bank, and specified which data will
be collected by PNC bank.
8. Clarified Richa Gawande’s role in study meetings.
9. Added Kayley Okst as a research coordinator.
10. Added language about matching acceptability of GBOT and LDM study group times
when there are multiple GBOT groups to consider at a site.
11. Increased transportation reimbursement amount from $25 total to $10 for each study
session.
12. Clarified process for data transfer from EHR to REDCap.
13. Changed 6 month references to 24 weeks for consistency.
14. Included section on measuring and reporting of participant adherence to treatment
protocol.
15. Removed reference to Myspace in sending private messages.
16. Clarified worsening of underlying illness section.
17. Clarified when data analyst and study methodologists will become unblinded.
18. Corrected fishbowl ratios to be in line with evidence-based protocol by Petry, et al.
19. Added the Nonattachment to Self Scale and adjusted survey length accordingly.
20. Clarified use of False Discovery Rate procedures for addressing multiple comparisons
among secondary and exploratory outcomes.
21. Clarified use of PROMIS-ASF 8a T score greater than 55 to determine presence of an
anxiety disorder in participants during screening and for inclusion in secondary
analysis for effects on anxiety.
Version Number: 1.4 (Second Re-Submission to NCCIH for Approval)
4
Mindful-OBOT Clinical Trial Protocol V2.20.

Version Date:1/29/2020 (Modification 1 second resubmission to CHA IRB)
Summary of Revisions Made:
1. Included statement that clinical support staff and other patients in clinical groups that
participants are randomized into will not need to be added to the study protocol in a
comparative effectiveness trial.
2. Clarified that the study team will obtain waivers of consent at sites.
3. Clarified word missing in statement on group acceptability survey matching.
4. Formatted GBOT framework figure and made it landscape for readability.
5. Included that life-threatening suicide attempts and life-threatening opioid overdoses
requiring naloxone administration will be considered Serious Adverse Events, and
non-life-threatening suicide attempts are only unexpected if person has no history of
suicidality or risk factors.
6. Clarified the SAE definition to be aligned with CHA policy on AE reporting.
Clarified the requirement for life threatening overdose (defined by requiring
naloxone) and life-threatening suicide attempts (defined by requiring ED visit or
inpatient hospitalization) to be SAEs. Clarified that inpatient admission strictly due to
substance use disorder alone is not SAE. Added additional categories for CHA policy
(e.g. birth defects, etc.).
7. Clarified reporting time frame for SAE and UAs to be consistent with CHA policy on
AE reporting.
8. Clarified power statement.
9. Fixed missing reviewer in monitoring table for major protocol violations and
corrected capitalization error.
Version Number: 1.5
Version Date: 3/17/2020 (Modification 1 third resubmission to CHA IRB)
Summary of Revisions Made:
1.
Moved information regarding non-study participant involvement in study groups to
section 5.1.
2. Corrected grammatical errors in interventions and duration section.
3. Corrected range of standard of care for opioid treatment from 24 weeks to 3-12 months.
4. Corrected planned number of enrollments at each study site.
5. Removed reference to 6-month study in secondary objective section.
6. Stated that the document used to collect PHI and enter this information into the PNC
bank secure server will be shredded after it the information is entered.
7. Provided gift card alternative to participants who are unwilling to provide PHI to PNC
bank.
8. Made references to PROMIS Anxiety (PROMIS-ASF) scale consistent and clear
throughout protocol.
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Mindful-OBOT Clinical Trial Protocol V2.20.

9. Made references to PROMIS Pain (PROMIS-PISF) scale consistent and clear throughout
protocol.
10. Clarified references to 52-week follow up throughout protocol.
11. Clarified that weekly surveys will be sent via email with secure REDCap link, and that
these surveys will be completed using a CHA IT approved iPad if this is not possible.
12. Included the Substance Craving Scale (SUBCS)
13. Included the Pain Catastrophizing Scale (PCS)
Version Number: 1.6
Version Date: 4/14/20 (Modification 1 fourth resubmission to CHA IRB)
Summary of Revisions Made:
1. Corrected wording error in “standard clinical staff in comparative effectiveness study”
section.
2. Clarified at which sites GBOT is the standard of care, and which sites are running
standard of care GBOT groups.
3. Expanded inclusion criteria to allow enrollment of participants with a diagnosis of OUD
and an anxiety or stress disorder who do not meet the less than 90 days of abstinence
criterion.
4. Specified that initial EHR screening will occur after participant is referred to the study.
Version Number: 2.0
Version Date: 9/3/20 (Modification 2 submitted to NIH)
Summary of Revisions Made:
1. Removed all references to in person groups and replaced with references to live-online
groups.
2. Specified that while participants will be recruited virtually from multiple different sites,
the study will now be conducted centrally at the CHA Center for Mindfulness and
Compassion.
3. Changed primary outcome to focus on focus on abstinence from illicit opioids.
4. Changed main secondary outcomes to focus on change in co-morbid anxiety, pain,
cocaine use, and benzodiazepine use.
5. Removed GBOT arm and replaced it with a standard control group arm.
6. Added qualitative interview as an exploratory outcome.
7. Clarified that groups will not be billable to insurance and will instead be run as research
groups.
8. Indicated that group leadership manuals will be adapted to a suit a live-online setting.
9. Replaced all references to urine screens with live-online supervised oral fluid screens.
10. Added Computerized Adaptive Testing for Mental Health (CAT-MH) for psychiatric
comorbidity as an exploratory outcome and replaced the MINI with baseline CAT-MH
for screening.
6
Mindful-OBOT Clinical Trial Protocol V2.20.

11. Removed SART, HDT, and HBDT from survey battery.
12. Changed survey battery timepoints to occur at baseline, 8 weeks, 16 weeks, and 24 weeks
and updated survey references to reflect this change.
13. Indicated that participants will undergo a pre-enrollment phone screen to determine
eligibility if they consent to do so.
14. Removed requirement that participant referral take place over EHR.
15. Changed randomization ratio to 1:1 (M-ROCC:Control)
16. Removed language about comparative effectiveness and inclusion of standard clinical
staff in groups since study will change to clinical trial examining efficacy of live-online
M-ROCC versus a control group.
17. Added the Self-Critical Rumination Scale and the Experiences Questionnaire subscale for
Decentering
18. Removed all references to 52 week follow-up from protocol.
19. Removed PROMIS Depression and substituted it with CAT-DI
20. Removed references to mediation analyses
21. Removed cannabis use as an inclusion criteria
Version Number: 2.1
Version Date: 9/1/20
Summary of Revisions Made:
1. Corrected grammar and spelling errors throughout document.
2. Specified use of practice dose ladder in M-ROCC intervention.
3. Provided further details regarding live-online control intervention.
4. Edited figure 1 to reflect updated recruitment approach.
5. Clarified group session frequency during first 4 weeks of intervention.
6. Inserted information on handling of missing assessment data.
7. Replaced PNC bank as the preferred gift card vendor with Tango and removed references
to SSN collection.
8. Changed anticipated loss during screening and baseline assessments.
9. Specified that oral-fluid swab chamber will be placed in clear view of the research.
coordinator during the testing period.
10. Replaced DERS-36 with DERS-16 to reduce participant burden.
11. Removed reference to obtaining waiver of consent
12. Revised primary outcomes to encompass biochemically confirmed opioid abstinent
periods using both oral fluid tests and self-report
Version Number: 2.2
Version Date: 9/24/20
Summary of Revisions Made:
1. Removed references to SMART IRB, reliance agreements, and site PIs throughout
protocol.
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Mindful-OBOT Clinical Trial Protocol V2.20.

2. Defined MBI in precis section before using acronym.
3. Reinserted relevant descriptions of intervention, duration, sample size and population
which were previously deleted in error.
4. Corrected number of interventions in study rationale section.
5. Defined relationship between RNCMs and BMC.
6. Standardized recruitment process across protocol, by which referring clinicians and nurse
care managers will obtain verbal consent to share information with the study team, and
not engage in any study related activities.
7. Clarified use of scheduling acceptability form.
8. Specified process for destroying phone screen data for participants who do not enroll in
the study.
9. Clarified that participants with transient symptoms related to recent substance use will be
able to wait for a re-review of eligibility after 30 days.
10. Moved M-ROCC group outline figure to interventions section.
11. Standardized MCS group administration, whereby MCS groups will be held online via
zoom as live online community groups for addiction recovery and mindfulness
maintenance, and not at individual sites.
12. Moved description of M-ROCC development to background section.
13. Defined where ascending practice dose ladder is implemented.
14. Defined difference between LDM and MTPC-OUD groups.
15. Clarified that participants will be able to advance from the LDM group to either an MCS
or MTPC-OUD group.
16. Moved qualitative interview description to study procedures section.
17. Indicated that an electronic consent module will be used to document consent in
REDCap.
18. Described qualitative interview download and transcription method.
19. Clarified modules used in CAT-MH screening tool and that CAT-MH will be integrated
into REDCap.
20. Specified under which circumstances oral fluid screen results will be shared with a
patient’s referring provider.
21. Specified number of referring primary care sites across MA and use of Facebook for
recruitment as well from primary care site referrals.
22. Included information on what data that will be shared with referring providers and
specified that groups will not replace standard of care at each site.
23. Specified that participants will receive gift cards via email when using tango.
24. Required study staff to use secure technology to communicate with participants.
25. Updated lottery draw contingency management procedure and specified when
participants will make lottery draws.
26. Clarified that participant EHR will not be accessed.
27. Removed reference to use of lockboxes to transport paper data.
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Mindful-OBOT Clinical Trial Protocol V2.20.

28. Specified payment amount for qualitative interview completion.
29. Indicated that the study flyer will be posted on the CHA addictions website.
30. Removed statement that suicide risk detected by CAT-MH will automatically trigger an
email to the study team.
31. Specified information that will be collected on study inquiry contact form (phone screen)
Version Number: 2.3
Version Date: 10/27/20
Summary of Revisions Made:
1. Expanded abbreviation of Training and Technical Assistance (TTA).
2. Removed references to Facebook advertisement.
3. Included structure of live-online CMC MCS groups.
4. Removed remaining references to site research coordinators.
5. Removed references to CAT-MH data being stored outside of REDCap.
6. Renamed “double-locked lockboxes and filing cabinets” section as “online database
storage”.
7. Specified that participants will receive iPhone SEs via mail after they have been
randomized to join the study.
8. Clarified that live-online control group will run for 80-90 minutes including a 30-minute
group check-in.
9. Rephrased study design to make clear that participants from different primary care sites
will come together for study groups.
10. Fixed grammatical errors throughout protocol.
11. Made references to 3 non-CHA affiliated and 2 CHA affiliated OBOT sites consistent
throughout protocol.
12. Corrected team study roster to list individual’s institution, rather than their institution of
primary employment.
13. Removed non-CHA affiliated staff who will be added in future SMART IRB amendment.
14. Clarified that the three affiliated non-CHA sites (BMC, North Shore, Lynn) will not
engage in study activities until their corresponding reliance agreement has been executed.
15. Made references to primary and secondary outcomes consistent across protocol.
16. Corrected conditions for participant completion bonus to be consistent across protocol
and ICF.
Version Number 2.4
Version Date: 11/20/20
Summary of Revisions Made:
1. Corrected grammatical errors throughout document.
2. Specified that R21 pilot data indicated reduction in positive Benzodiazepine and Cocaine
urine screen tests.
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Mindful-OBOT Clinical Trial Protocol V2.20.

3. Restated that if the participant fails a second informed consent quiz, they will be
ineligible to participate in the study.
Version Number 2.5
Version Date: 12/20/20
Summary of Revisions Made:
1. Added Gabriella Conversano to the protocol as a research assistant.
2. Added Bari-Sue Brodsky to the protocol as an M-ROCC group leader.
3. Added Ashley Mallon to the protocol as an M-ROCC group leader.
4. Added Emily Tavanese to the protocol as an M-ROCC group leader.
5. Added Joseph Rosansky to the protocol as a research assistant.
6. Added Megan Edge to the protocol as a research assistant.
7. Added Caitlyn Wilson to the protocol as a research assistant.
8. Added Audrey Cabral to the protocol as a research assistant.
9. Added Connor Stuart to the protocol as a control group leader.
10. Added Esteban da Cruz to the protocol as a research assistant.
11. Removed Brian Mullin from the protocol.
12. Changed study email from stressreductionstudy@challiance.org to
stressreduction@challiance.org.
Version Number 2.6
Version Date: 3/4/21
Summary of Revisions Made:
1. Specified use of Facebook advertisement for recruitment.
2. Modified weekly survey to include Buprenorphine dosage and concomitant medication
prescriptions.
3. Added credibility/expectancy surveys to assess for treatment expectations.
4. Specified that participants who received a study smartphone must return the phone to the
study team to be eligible to receive the study completion bonus.
5. Clarified in schedule of evaluations that oral-fluid toxicology will be assessed monthly
for the first 12-weeks of the study.
6. Added “Droplr” as a HIPAA compliant screenshotting tool which will be used to
document oral fluid toxicology screen results.
7. Specified use of password-protected REDCap survey links.
8. Added 48 hour completion bonus for large survey batteries.
9. Updated ATLAS.ti version from 7.0 to 8.4.4.
10. Corrected grammatical errors throughout protocol.
11. Clarified that qualitative interviews will be conducted for 30-60 minutes.
12. Replaced self-compassion scale short form with full self-compassion scale.
13. Removed FFMQ, ISMI, MAIA subscales 2 and 3.
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Mindful-OBOT Clinical Trial Protocol V2.20.

14. Moved CAT-MH scheduling to occur at baseline, 12 weeks, and 24 weeks.
15. Corrected oral fluid toxicology screen frequency on informed consent assessment.
16. Replaced full MOCA with MOCA-BLIND.
17. Expanded study referral form to include clinician contact information, and patient
scheduling information.
18. Removed Farah Samawi from study team roster.
19. Corrected payment information on ICF assessment.
20. Moved demographics survey from baseline battery to screening battery.
21. Specified that participants can request that attendance and oral fluid toxicology results be
mailed to them on a monthly basis.
Version Number 2.7
Version Date: 5/18/21
Summary of Revisions Made:
1. Added additional information about Facebook advertisements
2. Clarified contact with buprenorphine prescriber
3. Clarified contact with referring provider
4. Clarified portions of adverse event protocols
Version Number 2.8
Version Date: 6/14/21
Summary of Revisions Made:
1. Removed Ian Concannon from study team roster
2. Added Leah Howard to the study team roster as a research coordinator
3. Added Paula Gardiner to the study team roster as a M-ROCC group leader and a
Co-Investigator
4. Added Colleen LaBelle to the study team roster as the Boston Medical Center Site PI
5. Added Boston Medical Center as a relying site
6. Modified study-related injury section of the informed consent form as per request by
Boston Medical Center
Version Number 2.9
Version Date: 7/22/21
Summary of Revisions Made:
1. Clarified that BMC staff will not engage in any recruitment, screening or consenting
tasks, but will instead provide study team contact information to their patients.
Version Number 2.10
Version Date: 8/24/21
Summary of Revisions Made:
1. Removed Audrey Cabral from the study team roster
2. Removed Emily Tavanese from the study team roster
3. Added Joshua Phillips to the study team roster as a research assistant
4. Added Sarah King-McKeon to the study team roster as a M-ROCC group leader
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Mindful-OBOT Clinical Trial Protocol V2.20.

Version Number 2.11
Version Date: 9/9/21
Summary of Revisions Made:
1. Removed Mark Albanese from the study team roster.
Version Number 2.12
Version Date: 9/13/21
Summary of Revisions Made
1. Expanded recruitment to Connecticut, Florida, Maine, New Hampshire, New York,
Rhode Island, Texas, and Vermont.
2. Removed contingency management lottery draw from protocol.
3. Added $5 study gift cards for each group attended.
4. Added $5 study gift cards for each bi-weekly period in which all weekly surveys and oral
fluid tests have been completed.
5. Added Instagram advertisement capacity and expanded advertisement variations.
6. Added FFMQ to survey battery.
7. Removed state specific language from provider email.
8. Included a letter template version of the provider email.
9. Clarified that the study groups are interventions/programs rather than a treatment that
must be provided by a licensed clinician.
10. Specified that control group leaders will require 1 year of prior experience leading
recovery support groups for patients with OUD.
11. Updated ICF title to more accurately reflect presence of treatment in the study.
12. Updated suicidality management plan.
Version Number 2.13
Version Date: 10/8/21
Summary of Revisions Made:
1. Added subtitle specifying change in study design from primary care phase to live-online
focus.
2. Specified that oral fluid toxicology screen results will not be shared with a participant’s
Buprenorphine prescriber.
3. Specified how Instagram advertisements will be managed.
4. Removed duplicate reference to Massachusetts as a recruitment state.
5. Changed inclusion criteria to focus on participant state of residence rather than the
location of their Buprenorphine prescriber.
6. Edited Figure 1 to reflect additional recruitment sources.
7. Specified that all advertisements will need approval by the IRB prior to their use.
8. Specified from which account Facebook and Instagram advertisements will originate.
Version Number 2.14
Version Date: 11/18/21
Summary of Revisions Made:
1. Added four new participant flyer versions
2. Enabled control participants to undergo a qualitative interview.
3. Shortened phone pre-screening survey.
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Mindful-OBOT Clinical Trial Protocol V2.20.

4. Updated ICF assessment to reflect accurate payment information.
5. Added the “HEARD” contact information database as a recruitment source.
6. Added shortened versions of Facebook advertisements.
Version Number 2.15
Version Date: 2/28/22
Summary of Revisions Made:
1. Removed dollar sign graphic from study flyers.
2. Clarified purpose and data storage procedures of the “HEARD” database.
3. Clarified that Facebook interests will not be used in advertisements.
4. Changed order of phone pre-screening form.
5. Added Stiven Topalli to the study team roster.
6. Added Omnia Eldoghry to the study team roster.
7. Specified qualitative interview themes for the control arm.
Version Number 2.16
Version Date: 7/11/22
Summary of Revisions Made:
1. Removed Sasha Oxnard from the study team roster.
2. Removed Dave Roll from the study team roster.
3. Removed Caitlyn Wilson from the study team roster.
4. Removed Alex Brunel from the study team roster.
5. Added Gareth Parry to the study team roster.
6. Added Ashley Rector to the study team roster.
7. Added Hannah Goodman to the study team roster.
8. Added Elizabeth Gracey to the study team roster.
Version Number 2.17
Version Date: 8/2/22
Summary of Revisions Made:
1. Added Teresa Yeh to the study team roster.
2. Removed Kayley Okst from the study team roster.
3. Removed Leah Howard from the study team roster.
4. Removed Timothy Creedon from the study team roster.
Version Number 2.18
Version Date: 8/25/22
Summary of Revisions Made:
1. Added Javier Barria to the study team roster.
2. Removed Ashley Mallon from the study team roster.
3. Extended the study to new states including California, North Carolina, Alabama, Arizona,
Virginia, Illinois, and Michigan.
4. Adding an apartment/mailbox number and zip code to the demographics form since they need
this information to send packages to participants.
5. Changing the phone number on the flyer.
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Version Number 2.19
Version Date: 12/06/22
Summary of Revisions Made:
1. Added Tori Blot to the study team roster.
2. Added Lolita Roland to the study team roster.
3. Removed Megan Edge from the study team roster.
4. Removed Gabriella Conversano from the study team roster.
5. Removed Esteban da Cruz from the study team roster.
6. Removed Stiven Topalli from the study team roster.
Version Number 2.20
Version Date: 01/06/23
Summary of Revisions Made:
1. Added Danielle La Camera to the study team roster.
2. Added Acelya Aslan to the study team roster.
3. Increased the number of the maximum enrolled participants
4. Added the study measure PhenX_A to the 24-week large survey battery
Table of Contents
TEAM STUDY ROSTER
9
PRÉCIS
14
1. STUDY OBJECTIVES
15
1.1 PRIMARY OBJECTIVE
15
1.2 SECONDARY OBJECTIVES
15
1.3 EXPLORATORY AIMS:
15
2. BACKGROUND AND RATIONALE
16
2.1 BACKGROUND ON CONDITION, DISEASE, OR OTHER PRIMARY STUDY FOCUS
16
2.2 STUDY RATIONALE
21
3. STUDY DESIGN
22
4. SELECTION AND ENROLLMENT OF PARTICIPANTS
24
4.1 INCLUSION CRITERIA
24
4.2 EXCLUSION CRITERIA
25
4.3 STUDY ENROLLMENT PROCEDURES
25
5. STUDY INTERVENTIONS
28
5.1 INTERVENTIONS, ADMINISTRATION, AND DURATION
28
5.2 HANDLING OF STUDY INTERVENTIONS
33
5.3 CONCOMITANT INTERVENTIONS
34
5.3.1 ALLOWED INTERVENTIONS
34
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Mindful-OBOT Clinical Trial Protocol V2.20.

5.3.2 REQUIRED INTERVENTIONS
35
5.3.3 PROHIBITED INTERVENTIONS
35
5.4 ADHERENCE ASSESSMENT
35
6. STUDY PROCEDURES
37
6.1
SCHEDULE OF EVALUATIONS:
37
6.2
DESCRIPTION OF EVALUATIONS
39
6.2.1
SCREENING EVALUATION
40
6.2.2 ENROLLMENT, BASELINE, AND/OR RANDOMIZATION
41
6.2.3 BLINDING
44
6.2.4 FOLLOW-UP VISITS
45
6.2.5 COMPLETION/FINAL EVALUATION
46
7. SAFETY ASSESSMENTS
48
7.1 SPECIFICATION OF SAFETY PARAMETERS
49
7.2 METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY PARAMETERS
49
7.2.1
EXPECTED RISKS
49
7.2.2
EXPECTED BENEFITS
52
7.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
52
7.4
REPORTING PROCEDURES
53
7.5
FOLLOW-UP FOR ADVERSE EVENTS
56
7.6
SAFETY MONITORING
56
8. INTERVENTION DISCONTINUATION
57
9. STATISTICAL CONSIDERATIONS
59
9.1
GENERAL DESIGN ISSUES
59
9.2
SAMPLE SIZE AND RANDOMIZATION
60
9.3
DEFINITION OF POPULATIONS
61
9.4
INTERIM ANALYSES AND STOPPING RULES
61
9.5
OUTCOMES
61
9.5.1
PRIMARY OUTCOME
62
9.5.2
SECONDARY OUTCOMES
62
9.6
DATA ANALYSES
63
10. DATA COLLECTION AND QUALITY ASSURANCE
67
10.1
DATA COLLECTION FORMS
67
10.2
DATA MANAGEMENT
75
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Mindful-OBOT Clinical Trial Protocol V2.20.

10.3 QUALITY ASSURANCE
79
10.3.1
TRAINING
79
10.3.2
QUALITY CONTROL COMMITTEE
81
10.3.3
METRICS
81
10.3.4
PROTOCOL DEVIATIONS
81
10.3.5
MONITORING
81
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY
83
12. COMMITTEES
85
13. PUBLICATION OF RESEARCH FINDINGS
85
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Mindful-OBOT Clinical Trial Protocol V2.20.

2. TEAM STUDY ROSTER
Role
(e.g., PI, Co-I,
coordinator)
Name
(include
degree)
Institution
Phone #
Pager #
Status
PI
Zev
Schuman-Olivi
er, MD
Cambridge Health
Alliance
617-591-6056
617-546-1
609
Active
Co-I, Quantitative
Methodologist
Benjamin
Cook, PhD,
MPH
Cambridge Health
Alliance
617-806-8741
Active
Co-I, Research
Scientist / MTPC
Supervisor
Richa
Gawande, PhD
Cambridge Health
Alliance
617-591-6055
Active
Co-I, M-ROCC
Clinical Director
Alaine (Kiera)
Fredericksen
LICSW
Cambridge Health
Alliance
617-591-6439
Active
Co-I, CMC Medical
Director/MTPC
Supervisor
Todd Griswold
Cambridge Health
Alliance
617-591-6187
978-761-7
380
Active
Co-I, GBOT
Specialist
Randi Sokol,
MD
Cambridge Health
Alliance
781-338-0500
215-873-7
771
Active
Co-I, Primary Care
Addictions Specialist
Ellie Grossman,
MD
Cambridge Health
Alliance
617-591-6300
617-546-0
500
Active
Data Analyst
Lydia Smith
Cambridge Health
Alliance
781-850-6592
Active
Research Coordinator
Alexandra
Comeau
Cambridge Health
Alliance
617-591-6055
Active
Co-I, Qualitative
Investigator
Sarah Moore,
PhD, LCSW
Cambridge Health
Alliance
603-646-7000
Active
Site PI -- Lynn
Dr. Annalee
Wells, MD
Lynn Community
Health Center
781-581-3900
Active
Site PI -- North Shore
Dr. Laura
Holland, MD
North Shore
Community Health
978-825-1131
Active
Co-I, Neurocognitive
Consultant
Nancie
Rouleau, PhD
Cambridge Health
Alliance
(418) 663-5741
Active
Co-I, Clinical Trials
Consultant
Roger Weiss,
MD
Cambridge Health
Alliance
617-855-2242
Active
M-ROCC Group
Leader
Dr. Bari-Sue
Brodsky, MD
Cambridge Health
Alliance
978-532-4903
Active
Research Assistant
Joseph
Rosansky
Cambridge Health
Alliance
617-575-5802
Active
Control Group
Leader
Connor Stuart
Cambridge Health
Alliance
617-591-8567
Active
Site PI – Boston
Medical Center
Colleen LaBelle
Boston Medical
Center
617-797-6712
Active
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Mindful-OBOT Clinical Trial Protocol V2.20.

Co-I, M-ROCC
Group Leader
Dr. Paula
Gardiner, MD
Cambridge Health
Alliance
781-929-6460
Active
M-ROCC Group
Leader
Sarah
King-McKeon
Boston Medical
Center
(617) 983-3680
Active
Research Assistant
Joshua Phillips
Cambridge Health
Alliance
617-851-8625
Active
Research Assistant
Omnia Eldoghry
Cambridge Health
Alliance
(781) 475-3985
Active
Data Analyst
Gareth Parry
Cambridge Health
Alliance
617-851-8625
Active
Research
Coordinator
Elizabeth
Gracey
Cambridge Health
Alliance
617-851-8625
Active
Research Coordinator
Hannah
Goodman
Cambridge Health
Alliance
617-851-8625
Active
Research Assistant
Ashley Rector
Cambridge Health
Alliance
617-851-8625
Active
M-ROCC Group
Leader
Teresa Yeh
Cambridge Health
Alliance
617-575-5985
Active
Data Analyst
Javier Barria
Cambridge Health
Alliance
617-851-8625
Active
Research Coordinator
Tori Blot
Cambridge Health
Alliance
617-851-8625
Active
M-ROCC Group
Leader
Lolita Roland
Cambridge Health
Alliance
617-851-8625
Active
Research Assistant
Danielle La
Camera
Cambridge Health
Alliance
617-851-8625
Active
Research Assistant
Acelya Aslan
Cambridge Health
Alliance
617-851-8625
Active
Personnel virtually present during study procedure:
At least one of the following personnel will be virtually present during study and
group procedures:
Zev Schuman-Olivier, MD, Principal Investigator; Richa Gawande, PhD, Alaine
Fredericksen, LICSW, Site-PI, or research coordinators (Hannah Goodman, Elizabeth
Gracey) or research assistants (Joseph Rosansky, Joshua Phillips, Omnia Eldoghry,
Ashley Rector, Tori Blot, Acelya Aslan, Danielle La Camera).
Study team members responsible for the following activities:
At least one of the following personnel will be responsible for obtaining and
documenting informed consent: Zev Schuman-Olivier, MD, Principal Investigator,
Alaine Fredericksen, LICSW, Richa Gawande, PhD, research coordinators (Hannah
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Mindful-OBOT Clinical Trial Protocol V2.20.

Goodman, Elizabeth Gracey), or research assistants (Joseph Rosansky, Joshua
Phillips, Acelya Aslan).
The following personnel will be responsible for providing on-going information to
the study sponsor and the IRB: Zev Schuman-Olivier, MD, Principal Investigator.
At least one of the following personnel will be responsible for maintaining
participants’ research records: Zev Schuman-Olivier, MD, Principal Investigator,
Research Coordinators (Hannah Goodman, Elizabeth Gracey).
Inclusion of study personnel:
The research team would consist of the following: Zev Schuman-Olivier, MD (PI);
Benjamin Cook, PhD who is a quantitative methodologist and Director of the
Health Equity Research Lab, Cambridge Health Alliance/Harvard Medical
School; Richa Gawande, PhD (Research Scientist and MTPC supervisor); Randi
Sokol, MD who is a primary care physician with expertise in Group-Based Opioid
Treatment (GBOT); Alaine Fredericksen, an experienced addictions social worker
who has been leading MTPC groups and is clinical director for M-ROCC, and site
PIs who also provide clinical administrative leadership from Lynn Community
Health (Dr. Annalee Wells), and North Shore Community Health (Dr. Laura
Holland). Qualitative experts include Sarah Moore, PhD who has expertise in
conducting qualitative research studies involving mindfulness with people with
substance use disorder. Nancie Rouleau, PhD is a neuropsychologist with
expertise conducting research with neurocognitive tasks. Additional staff include
Todd Griswold, MD (CMC Medical Director/MTPC Supervisor); Ellie Grossman,
MD (Primary Care Addictions Specialist); Alexandra Comeau, MA (Research
Coordinator); Roger Weiss, MD (Clinical Trials Consultant), Bari-Sue Brodsky,
MD (M-ROCC Group Leader), Paula Gardiner, MD (M-ROCC Group Leader and
Co-Investigator), Colleen LaBelle (Site – PI BMC) Joseph Rosansky (Research
Assistant), Connor Stuart (Control Group Leader), Joshua Phillips (Research
Assistant), Sarah King-Mckeon (M-ROCC Group Leader), Omnia Eldoghry
(Research Assistant), Hannah Goodman (Research Coordinator), Elizabeth
Gracey (Research Coordinator), Ashley Rector (Research Assistant), Gareth Parry
(Data Analyst), Teresa Yeh (M-ROCC Group Leader), Tori Blot (Research
Coordinator), Lolita Roland (M-ROCC Group Leader), Acelya Aslan (Research
Assistant), Danielle La Camera (Research Assistant).
PARTICIPATING STUDY SITES
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Mindful-OBOT Clinical Trial Protocol V2.20.

The study will be conducted at the CHA Center for Mindfulness and Compassion
with online recruitment (DUNS number: 805262995).
The following affiliated sites from collaborating institutions that offer primary care
office-based opioid treatment will contribute to online recruitment efforts and provide
trained intervention group co-leaders. We will also recruit from other interested
Office-Based Addiction Treatment (OBAT) sites in Massachusetts, Connecticut,
Florida, Maine, New Hampshire, New York, Rhode Island, Texas, Vermont,
California, North Carolina, Virginia, Alabama, Arizona, Illinois, and Michigan, but
referring providers from these other sites will not be part of the study team. The 3
non-CHA affiliated study sites will be added through SMART IRB reliance
agreements, and no site will be involved in study tasks until its corresponding reliance
agreement has been executed.
Cambridge Health Alliance (DUNS number: 805262995)
CHA Central Street Care Center (26 Central St, Somerville MA 02143)
CHA Revere Care Center (454 Broadway, Revere, MA 02151)
Lynn Community Health Center (DUNS number: 030834915), 269 Union St;
Lynn, MA 01901
Boston Medical Center (DUNS Number: 00-549-2160), 801 Massachusetts Avenue,
Boston MA 02118
North Shore Community Health Salem (DUNS number: 144117538), 47 Congress
Street Salem, MA 01970
To maximize efficiency and consistency across participating sites, we will utilize a
single IRB (sIRB) to streamline the IRB review and approval of the research. The
Cambridge Health Alliance Institutional Review Board (CHA IRB) will act as the
sIRB for all sites. The PI has worked closely to obtain approval for several clinical
trials in the past with CHA IRB, both for primary care and OUD populations.
CHA will utilize SMART IRB (www.smartirb.org) to document reliance and all
participating sites will cede to CHA IRB. SMART IRB is a national IRB Reliance
Agreement that contains many features to aid in the acceptance, coordination, and
implementation of a single IRB review model in a highly cost-effective manner. Each
institution and site investigator retain responsibility for the conduct of research at
their site. As such, investigators at relying sites must provide relevant information to
20
Mindful-OBOT Clinical Trial Protocol V2.20.

their local IRB, if there is one, for institutional review. Institutional review of each
site’s local requirements (e.g., human subject training requirements, conflict of
interest, and consent forms to ensure locally required language is included for
compensation for injury, conflict of interest, etc.) and “non-IRB” institutional reviews
by ancillary committees (e.g., institutional biosafety, radiation safety) must be
performed by each institution, as applicable.
The BMC team will not obtain verbal consent from participants to share their contact
information with the study team. Instead, the BMC team will distribute IRB approved
flyers throughout the center, and participants will be given the option to self-refer.
BMC will also provide study team members who will act as group leaders for the
M-ROCC arm of the study. Context surrounding adverse events will be shared with
the relevant BMC team members, as is outlined in protocol section 7.5.
3. PRÉCIS
Study Title
Effect of Mindfulness Training on Opioid Use and Anxiety During Primary Care
Buprenorphine Treatment
Objectives
We will conduct a randomized controlled trial comparing a live-online Mindful
Recovery Opioid Care Continuum (M-ROCC) group (a motivationally-responsive,
trauma-informed extended 24-week Mindfulness-Based Intervention (MBI) with an
ascending practice dose ladder approach that offers mindfulness training instruction
optimized to enhance self-regulation and catalyze recovery) with a live-online control
group, to examine the efficacy of M-ROCC on abstinence from illicit opioids while
also targeting co-morbid anxiety, pain, and substance use (cocaine, benzodiazepines
(BZD)).
Design and Outcomes
This will be a RCT designed to compare live-online M-ROCC groups with a
live-online control group on the primary outcome of
the number of biochemically confirmed illicit opioid negative abstinent periods
(defined by a negative oral fluid test [negative for opiate, oxycodone, fentanyl,
methadone] AND no self-reported illicit opioid use) during weeks 13-24 of study (six
two-week periods of opioid abstinence during the final 12 weeks of the study).
.
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Mindful-OBOT Clinical Trial Protocol V2.20.

Clinical secondary outcomes include level of anxiety measured by the Patient
Reported Outcomes Measurement Information System – Anxiety Short Form 8a
(PROMIS-ASF), level of pain interference measured by the PROMIS Pain
Interference Scale (PROMIS-PISF), and the number of positive oral fluid tests for
BZD or cocaine during the final 12 weeks of the study. Other exploratory outcomes
will be level of anxiety measured by the Beck anxiety inventory (BAI), 24-week
intervention retention, as well as mechanisms of self-regulation assessed by
self-report and behavioral measures (emotion regulation, decentering/metacognitive
monitoring, interoception, experiential avoidance, self-critical rumination, and
self-compassion) and their mediating effects on anxiety and opioid abstinence.
Qualitative interviews will be conducted with a minimum of 12 and a maximum of 30
M-ROCC or control group completers until thematic saturation to examine themes
regarding live-online mindfulness delivery and to compare responses with our R21
qualitative outcomes from our in-person M-ROCC group model. Computerized
Adaptive Testing for Mental Health (CAT-MH) will be used to assess changes in
psychiatric co-morbidity. Finally, exploratory outcomes of stigma, mindfulness,
perceived stress, pain catastrophizing, interpersonal conflict, and shared identity
within group will be measured.
Interventions and Duration
Live-Online M-ROCC:
The live-online M-ROCC program is directly adapted from Mindfulness Training for
Primary Care (MTPC), which was developed and tested in the MINDFUL-PC
research study and piloted for OUD in the R21 study. M-ROCC is based on a model
of human experience which identifies experiential avoidance and disconnection from
our bodies and from others as fundamental causes of human distress, and addictive
behavior in particular. M-ROCC is a 6-month long Mindful Recovery OUD Care
Continuum designed with the clinical needs of OUD participants to be delivered in
primary care clinics. Due to COVID-19, this study will test the curriculum delivered
in a virtual setting online as a research intervention separate from clinical care.
Below we describe the adjustment of the program with logistical constraints of the
COVID-19 pandemic in mind. The M-ROCC curriculum focuses on integration of
mindfulness practice for living well through stress, anxiety, depression, pain and
addiction recovery. The M-ROCC curriculum has three primary components.
1) LDM (Low-Dose Mindfulness): A four-week introductory mindfulness program
for OUD with monthly rolling admission, which includes 50 minutes of
mindfulness introduction and explicit training in the use of mobile mindfulness
22
Mindful-OBOT Clinical Trial Protocol V2.20.

apps. LDM introduces participants to the ascending practice dose ladder. The live
online session will be 80-90 minutes with 30 minutes of group check-in and
online toxicology testing with staff followed by 60 minutes of the mindfulness
program.
2) MTPC-OUD (Mindfulness Training for Primary Care – OUD): A sixteen-hour
curriculum delivered in either (a) eight-week intensive mindfulness group with an
ascending practice dose ladder and skill integration over the course of the eight
weeks, 120 minutes per session, or (b) sixteen-week intensive mindfulness group
with an ascending practice dose ladder and skill integration over the course of
sixteen weeks with 60 minutes per session. While the LDM group format will be
delivered in the same manner in all study cohorts, the MTPC-OUD curriculum
format will be interchangeable in different cohorts depending on the
implementation needs of group leaders. The live online session will be 80-90
minutes with 30 minutes of group check-in and online toxicology testing with
staff followed by 60 minutes of the mindfulness program.
3) MCS (Mindfulness Maintenance Check-in Support): Various ongoing weekly
mindfulness continuation groups with check-in and reminders, leveraging mobile
mindfulness application and motivational-oriented counseling for graduates of
LDM for 50 minutes of mindfulness practice. MCS will be available for the
duration of the study. After LDM completion, 20 weeks is the longest expected
duration of MCS for a participant who goes directly from LDM to MCS and does
not choose to enroll in MTPC-OUD. Free MCS groups will be available through
the CMC Free Live Online Community Program.
Within the M-ROCC curriculum there is flexibility, so that each participant who
enrolls will begin in LDM for four weeks. If the participant is able to develop a home
practice and begins ascending the practice ladder, then they will be given the option
to move to the intensive MTPC-OUD or the ongoing MCS depending on readiness.
Participants can repeat LDM, transfer to the MCS group or transition from the LDM
or MCS into intensive MTPC, forming a continuous practice and check-in support
continuum that encourages increased practice with the spirit of autonomy,
collaboration, and naturalistic selection based on participant motivation and capacity.
Live-Online Control Group:
The live-online control group will be attention- and time-matched to the M-ROCC
LDM and MCS groups. This weekly control group will run for 80-90 minutes, with
30 minutes of group check-in and online toxicology testing with staff followed by
50-60 minutes of group time. As an active group comparator, this group will isolate
23
Mindful-OBOT Clinical Trial Protocol V2.20.

mindfulness components by controlling for the therapeutic aspects of a group. Group
content is derived from commonly used methods in community substance use
disorder treatment and recovery groups, including elements of Motivational
Interviewing, CBT, Community Reinforcement, and Twelve Step Facilitation, as well
as educational and didactic components. These live-online control groups will
function as research groups only and will not replace standard of care at sites, but
they may provide a therapeutic benefit to participants lacking a recovery group due to
the constraints of COVID-19.
Sample Size and Population
We anticipate an approximate enrollment of N=236 with a maximum of N=280
participants prescribed buprenorphine from Connecticut, Florida, Maine,
Massachusetts, New Hampshire, New York, Rhode Island, Texas, Vermont,
California, North Carolina, Virginia, Alabama, Arizona, Illinois, or Michigan over
eight months. We anticipate enrolling approximately 30 participants per month. We
anticipate 192 (81%) participants to be randomized (1:1 ratio, block size of 4, 6, 8 to
M-ROCC or live-online control, respectively) in online groups (n=96 M-ROCC,
n=96 Control), and of these we anticipate 45 (47% of those who began LDM) will
begin the 16 session MTPC-OUD intensive group. This estimate is based on our
experience in the R21 Mindful-OBOT pilot, in which 47% of participants enrolled in
our initial pilot site began an MTPC-OUD group.
Participants will be patients living in U.S. states approved by the IRB for recruitment
who are prescribed Buprenorphine. We will recruit from one of the three non-CHA
affiliated sites from collaborating institutions that offer primary care office-based
opioid treatment, from two sites affiliated with CHA, and from OBAT sites in U.S.
states approved by the IRB for recruitment, and also via Facebook and Instagram.
Participants must be 18-70 years old and must be able to use an electronic device with
a video camera to attend study groups and complete questionnaires. This study will
enroll individuals of any gender, and any demographic group, including pregnant
women.
Participants must have a diagnosis of opioid use disorder, be prescribed
buprenorphine, have sufficient English fluency to understand procedures and
questionnaires, and be without acute severe mental illness (mania, psychosis,
suicidality with intent/plan) and ability to provide informed consent. This trial is
limited to English-speaking participants at this time since the intervention curricula
have not been adapted to other languages.
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Mindful-OBOT Clinical Trial Protocol V2.20.

1. STUDY OBJECTIVES
1.1 Primary Objective
1.1.a. Opioid Abstinence: Compare effects of live-online M-ROCC vs. a live-online control
group on the number of biochemically confirmed illicit opioid negative abstinent periods
(defined by negative oral fluid tests [negative for opiate, oxycodone, fentanyl, methadone]
AND no self-reported illicit opioid use) during weeks 13-24 of study.
H1a: M-ROCC will have more abstinent time periods than the control group during
weeks 13-24.
1.2 Secondary Objectives
1.2.a. Clinical Co-morbidity: Compare effects of M-ROCC vs. the control arm on anxiety
and pain.
H2a: Among those with anxiety disorders, M-ROCC will have greater reduction in
anxiety than control group at 24 weeks.
H2b: M-ROCC will have greater reduction in pain interference than control group at 24
weeks.
1.2.b. Cocaine and Benzodiazepine Use: Compare effects of live-online M-ROCC vs. the
control arm on cocaine and benzodiazepine use.
H3a: M-ROCC will have fewer positive oral fluid tests for cocaine than a control group
during weeks 13-24.
H3b: M-ROCC will have fewer positive oral fluid tests for BZDs than a control group
during weeks 13-24.
1.3 Exploratory Aims:
We will examine the impact of M-ROCC randomization status and mindfulness practice dose
on intervention retention at 24 weeks, substance craving, opioid craving, psychiatric
co-morbidity (Computerized Adaptive Testing for Mental Health; CAT-MH), and
self-regulation targets including experiential avoidance, self-compassion, emotion regulation,
interoceptive regulation, self-critical rumination, perceived stress, and interpersonal conflict,
assessed at baseline and weeks 8, 16, and 24.
25
Mindful-OBOT Clinical Trial Protocol V2.20.

2. BACKGROUND AND RATIONALE
2.1 Background on Condition, Disease, or Other Primary Study Focus
Opioid use disorder (OUD) and overdose due to opioid-induced respiratory depression is
a serious public health issue with 42,249 opioid overdose deaths in 2016, which was a
5-fold increase from 19991. Driven initially by two decades of increasing prescription
opioid use2 and followed by a population transition from heroin, starting in 20113, the
“opioid overdose epidemic” has intensified4.
Office-based opioid treatment (OBOT) with buprenorphine/naloxone (B/N) has emerged
as a popular evidence-based treatment for OUD5. Buprenorphine (BUP) is a partial opioid
mu-receptor agonist that prevents opioid withdrawal, blocks opioid euphoria6 and
prevents opioid overdose7.
About 1/3 of BUP-waivered prescribers nationally are primary care providers (PCP)8.
Most US counties do not have a waivered provider to prescribe B/N, and in many
counties, PCPs are the only access point. Therefore, the development of disseminable
interventions that help PCPs address patient psychosocial stress and psychiatric
symptoms during OBOT may improve access to care and prevent overdose deaths.
Retention in B/N treatment is important because dropout from opioid substitution
treatment is associated with relapse9 and an increased risk of overdose and death10. Only
about 46-50% of patients are retained in B/N treatment at 24 weeks11. One major
predictor of poor retention is psychosocial stress and psychiatric co-morbidity related to
mental illness, e.g., anxiety12, Post-Traumatic Stress Disorder (PTSD)13. Additionally,
co-morbid cocaine use is a predictor of opioid use and attrition from treatment14,15. Also,
increased pain and pain volatility among those with chronic pain syndromes are
associated with increased opioid use during BUP treatment16.
The COVID-19 pandemic also threatens Office-Based Opioid Treatment (OBOT) by
restricting access to in-person treatment for co-morbidity that can impact BUP treatment
outcomes. The pandemic has led to nationwide changes in OUD treatment. Many primary
care facilities are presently unable to hold in-person Group Based Opioid Treatment
(GBOT) groups. Therefore, it is crucial that these services be delivered in a feasible
online format such that OUD patients can still receive the quality care they need.
More than 30% of patients with OUD get benzodiazepine (BZD) prescriptions during the
first year of opioid treatment17. Early in treatment, patients receiving B/N treatment
frequently request a benzodiazepine prescription to mitigate anxiety and insomnia
symptoms, to deal with psychosocial stress, and to regulate emotions18. Among those in
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Mindful-OBOT Clinical Trial Protocol V2.20.

OBOT who do not receive a BZD prescription, 67% still report a history of BZD
misuse19. Mixing BZDs and opioids can lead to synergistic overdose20, cognitive
impairment21, and accidental injuries19. Heavy BZD use reduced HCV antiviral treatment
uptake22. Much concern and debate exists about BZD diversion within B/N programs22.
Therefore, non-pharmacologic approaches to anxiety, stress, and emotional dysregulation
are needed.
Unfortunately, many B/N studies for OUD have reported limited benefit from behavioral
interventions23. For instance, in a RCT (n=166), Feillin et al found no significant
differences between medication management and a behaviorally-enhanced approach on
percentage of opioid negative urine tests and only 45% of randomized patients completed
the 24-week trial. In a second study, Fiellin et al examined the effect of adding 12
sessions of CBT to medication management in a 24-week study of opioid users in
primary care (n=141) and again found no difference between groups on opioid use and
41% of subjects completed the trial. Ling et al tested Cognitive Behavioral Therapy
(CBT), contingency management, and their combination against medication management
alone, finding no specific differences between group and 50% completed the 32-week
trial. Finally, Weiss et al conducted the Prescription Opioid Addiction Treatment Study
(POATS) trial at 10 NIDA Clinical Trials Network sites (n=360), comparing medical
management with individual drug counseling plus medication management after 12
weeks of B/N stabilization, finding no group differences. Considering the failure of these
established behavioral therapy approaches to impact key opioid use disorder outcomes,
there is a need to develop and evaluate the impact of innovative, evidence-based,
behavioral therapies with a different theoretical approach, such as Mindfulness-Based
Interventions (MBI)23–25.
Since stress, pain, anxiety, and depression are frequently co-morbid with OUD,
alternative behavioral interventions that successfully target those symptoms could be
promising. Mindfulness-based interventions (MBI) have been developing for the past 30
years with an initial focus on chronic pain26,27, stress reduction28, and anxiety disorders29.
MBIs start with present-moment awareness without judgment and focus on mindfulness
practice as a mechanism for change30. The methodology and treatment fidelity of MBIs
are becoming increasingly refined and mindfulness has emerged as a commonplace
intervention in US medical schools31. Interventions that involve mindfulness meditation
are attractive because of reported impact from MBIs on co-morbid symptoms of
anxiety32, depression33, and pain34–36, based on findings from meta-analyses. Mindfulness
also has been shown through meta-analysis to decrease physiologic markers of stress37,
which is important because stress can be a trigger for craving38, relapse39, addiction
persistence40, and stress system dysregulation is a problem among OUD users41,42. Stress
is also linked with anxiety and depression, as well as exacerbations of mental illness,
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Mindful-OBOT Clinical Trial Protocol V2.20.

such as bipolar disorder43 and schizophrenia44. Mindfulness has also been shown to have
a mild effect on insomnia and can serve as an auxiliary treatment for sleep complaints45.
Even as mindfulness emerged as a mental health treatment, the role for mindfulness in
medication-assisted treatment (MAT) for OUD remained unclear. When we started
researching mindfulness and OUD in 2004, the initial aim was to assess whether
mindfulness meditation was acceptable and feasible during MAT, and whether it could
impact behavior. The first mindfulness-oriented randomized controlled trial (RCT) during
MAT for OUD was a NIDA-funded trial of Spiritual Self Schema therapy by Margolin et
al and delivered by Dr. Schuman-Olivier who is PI, for reducing HIV risk among
methadone-maintained cocaine users. This intervention focused on integrating CBT
schema therapy with mindfulness meditation. The initial pilot RCT (n=72) found
reductions in HIV-risk behaviors (OR: = 8.89; CI: 95% = 1.62-48.93) after 8 weeks of
mindfulness compared with controls46. A feasibility pilot among HIV+ cocaine users
maintained on methadone (n=38) demonstrated reduced impulsivity after 12 weeks and
increased motivation for drug abstinence, HIV risk prevention, and medication
adherence47. Using an ascending practice dose ladder approach, this study found that 64%
reported greater than 30 min/day of practice by 12 weeks. While some recent feasibility
studies have been published48, since this initial MAT RCT in 2004, no federally-funded
RCTs have been published from a MBI within buprenorphine or methadone treatment.
Even though there is limited evidence among OUD MAT, Mindfulness Based Relapse
Prevention (MBRP) has been well-studied for substance use disorders (SUD) in general.
Among a sample of primarily alcohol and stimulant users, MBRP demonstrated relative
efficacy at 12 months with fewer substance use days and decreased heavy drinking
compared to relapse prevention and treatment as usual49. Higher levels of home
mindfulness practice were associated with lower alcohol and other drug use and craving,
but the benefits faded during months 2-4, suggesting a longer trial or additional support
could be helpful50. In addition, this RCT population was recruited during after-care
post-detox and only had 9% of the sample with OUD.
Through multiple pilot studies of MBRP, several mechanisms of action of mindfulness
have been elucidated, which could be applicable to addiction treatment outcomes51,52.
Mindfulness training reduces negative affect and psychiatric impairment, which was
effective in reducing substance use53, through decoupling the association between
negative affect and substance use craving54. In summary, MBRP has established the
relative efficacy of mindfulness for SUD but has yet to be extended to patients with OUD
prescribed BUP, and the effects of home practice seem to wear off quickly after the
8-week program ended. In addition, meta-analysis of 9 MBRP studies suggested that
while MBRP reduced craving symptoms, it did not impact substance use outcomes55.
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Mindful-OBOT Clinical Trial Protocol V2.20.

Therefore, the standard MBRP 8-week program does not appear to have sustained impact
on substance use, suggesting longer mindfulness interventions or enhanced programs are
needed to get the full benefit from the intervention.
Other MBIs have also been shown to engage mechanisms potentially relevant to
addiction treatment outcomes56,57. For instance, a RCT of Mindfulness Training for
Smokers reported reduction in tobacco use after 4 weeks of intensive mindfulness
training, and demonstrated decoupling of the relationship between craving and smoking58.
This program integrated mindfulness theory with a model of operant conditioning to
intensify the application of mindfulness to behavior change59. Mindfulness Oriented
Recovery Enhancement (MORE) was designed for reducing opioid misuse among people
on opioid therapy for chronic pain, adding innovative exercises like mindful savoring.
Patients in MORE had less momentary pain and reported more positive affect60. Opioid
misusers had decreased attentional bias, which was also associated with greater perceived
control over the pain and attenuated emotional reactivity61. Finally, self-compassion has
emerged as a protective factor for substance use62 and is a mechanism for reducing
anxiety and depressive symptoms63. The Mindful Self-Compassion program has emerged
as the 4th most common MBI nationally31, and can be particularly helpful with the impact
of toxic shame64, which can drive substance use and relapse65,66. As Wilson et al point
out, an intervention that could incorporate new innovative developments in the
mindfulness field, while letting go of the requirement for the standard time format,
leveraging mobile technology, and delivering guidance in a motivationally appropriate
way during different points in the change process, could offer a more impactful
intervention for substance use disorders57.
As part of the Mindfulness Research Collaborative, a network of researchers funded
by the NIH Science of Behavior Change (SOBC) Initiative67, we have been involved in
an ongoing process of systematic review and meta-analysis, examining the relationship
between mindfulness practice, self-regulation targets and health behavior change. This
process has developed on our original model68, identifying evidence for three broad
self-regulation domains targeted by mindfulness meditation, including cognitive control
processes, emotion regulation, and self-related processes.
(A)
Cognitive
Control
processes
(COG) include attention (i.e. orienting,
alerting69,70, vigilance71, attentional lapses72); executive function, conflict monitoring73,74,
impulsivity and inhibitory control75,76, and metacognitive awareness77–79/decentering80,81..
Studies indicate that meditation training, such as MBIs, engage these cognitive
processes82,83,92–95,84–91.
(B) Emotion regulation (EMO), which is the capacity to alter the magnitude or
duration of an emotional response96. Poor emotion regulation impairs the capacity for
self-regulation behaviors that support addiction recovery97. MBIs favorably engage
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measures of emotion regulation such as amygdala activation87,98–101, sympathetic
hyperarousal88,102–106, and emotional responses to stressful situations106–114.
(C) Self-related processes (SRP), including: (i) self-efficacy – the belief in one’s
capabilities to execute the courses of action required to manage prospective situations
(such as coping with a trigger)115,116, which is a central aspect of self-regulation and
behavior change117,118; (ii) self-compassion – the capacity to extend compassion to oneself
in instances of perceived inadequacy or failure, rather than engaging in self-destructive
behaviors (self-judgment, isolation, rumination) or in permissive, risky behaviors119–121:
self-compassion has been found to promote health behaviors such as adhering to diets122,
smoking cessation123, physical activity124, and seeking medical treatment when needed125;
(iii) self-related rumination or mind-wandering – which may be beneficial in some
cases126–128, but can be detrimental when negatively-valenced or disrupting goal directed
activity79,98,128–133; and (iv) interoceptive awareness – awareness of internal manifestations
of emotions and feelings and inner body sensations134–136, which is considered
fundamental to the ‘experiencing self’137–142, seems to be involved drug craving143, urges
and emotional decision-making144, engages insula cortex activation145,146, and is of major
interest in MBI research68,87,153–162,133,163,146–152.
Considering this self-regulation model and the innovative MBI trainings developed over
two decades, we set out to develop an empirically supported MBI that would specifically
engage these mechanistic self-regulation targets and enhance them to specifically support
the initiation and maintenance of behavior change. As part of the SOBC Initiative, our
laboratory has aimed to build on the first-generation Mindfulness-Based Program
framework30 and the fundamental teaching processes developed in Mindfulness-Based
Stress Reduction and Mindfulness-Based Cognitive Therapy164, while also learning from
the multitude of specific MBI adaptations for SUD56 with the goal to develop a MBI
focused on harnessing mindfulness practice to catalyze behavior change among a broad
primary care population. Using skills and exercises developed in empirically-supported
evidence-based mindfulness-oriented addiction treatments, i.e., Mindfulness-Based
Relapse Prevention, Mindfulness Training for Smokers, and Mindfulness-Oriented
Recovery Enhancement as well as Mindfulness-Based Cognitive Therapy, Mindful
Self-Compassion, and Motivational Interviewing165, we have created a seamless and
potentially more potent MBI: Mindfulness Training for Primary Care (MTPC). In
addition, unlike other stagnant MBIs whose manual is fixed, MTPC, developed through
the iterative SOBC process for the past 3 years, has been adapted to incorporate and
enhance the strategies supported by empirical evidence about mechanistic self-regulation
targets involved in behavior change. In two clinical trials, MTPC has reliably resulted in
increased rates of health behavior change initiation166. Because of this capacity to focus
on empirically-supported behavior change mechanisms and its integration of core
exercises and concepts from earlier, addiction-focused MBIs, MTPC is ideally suited for
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a trial with OUD. In addition, because it is already designed for implementation in
primary care, it can be tested in a real-world treatment setting where there is greater
external validity than in closed research settings.
The M-ROCC program is directly adapted from Mindfulness Training for Primary Care
(MTPC), based on a model of human experience which identifies experiential avoidance
and disconnection from our bodies and from others as fundamental causes of human
distress, and addictive behavior in particular. MTPC-OUD has 4 threads in addition to the
core focus on present moment awareness that emerge in every session, including 1)
autopilot and mindful behavior change, 2) interpersonal mindfulness practice to
reduce interpersonal reactivity and self-regulation failures in social contexts167 (e.g.,
corrosive couple conflict168) that can lead to substance use169, 3) common humanity and
stigma reduction through kindness and self-compassion, and 4) autonomy and choice
through a group leader who plays a collaborative, co-participatory role, which is
trauma-informed170,171 and motivationally-sensitive. Because trauma is common among
patients with OUD172, a trauma-informed mindfulness program that supports choice is
important to prevent retraumatization173. MTPC emphasizes choice and trains group
leaders to adapt sessions with the expectation that people in the group have trauma.
MTPC has been shown to support behavior change among people with PTSD166. In
MTPC-OUD, we adapted the standard daily practice dose for MTPC to start with 20-25
minutes a day instead of 40 minutes a day, with the goal of continuing the ascending
practice dose ladder to attain 30-45 minutes of daily practice by the end of the 8-week
intensive program. Based on 3 decades of science and practice of MBI development30,
MTPC was designed in an iterative process integrating strategies from other MBIs to
empirically engage self-regulation target mechanisms to enhance the impact of
mindfulness on behavior change outcomes: e.g., savoring practice helps address hedonic
dysregulation among opioid-dependent patients174; urge surfing helps tolerate craving175
and negative affective experiences176. MTPC also applies a mindfulness approach to
values exploration177,178 in a way that helps people develop discrepancy while supporting
autonomy and confidence, consistent with processes from both Self-Determination
Theory and Motivational Interviewing179. Finally, MTPC explicitly recognizes the
ubiquity of medication in primary care and has modules designed to help people be
mindful of experiences arising around medication180,181. This is particularly important in
BUP treatment where people have a strong affective relationship with their medication
and substantial internalized stigma about being on BUP182,183. Within MTPC,
self-compassion is more explicitly cultivated to help reduce substance use risk62, address
the toxicity of shame and regret that can drive addiction relapse cycles184, and weaken the
impact of internalized stigma185 related to BUP and seeking addiction treatment186.
In addition to MTPC, we have also developed a low-dose mindfulness (LDM)
intervention for primary care. The LDM approach provides brief didactic and experiential
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exposure to mindfulness and then leverages online resources and provides encouragement
with ongoing practice reminders. In two primary care samples, we demonstrated LDM
paired with smartphone mindfulness app links and reminders reliably resulted in stress
reduction (d= -0.52; -0.58)166,187. In our R21 pilot study, the M-ROCC program including
LDM and 16 hours of intensive MTPC curriculum demonstrated reductions in
experiential avoidance, anxiety and pain interferences and increased mindfulness,
self-compassion and interoceptive awareness (p<0.05). In addition, cocaine and
benzodiazepine positive urine tests became less frequent over time in the program
(p<0.05).
In conclusion, mindfulness shows promise as a behavioral intervention for OUD, because
of its impact on self-regulation and co-morbid symptoms such as anxiety. Yet, standard
approaches may lack the potency and may be either too long or too short for OUD
patients based on the heterogeneity of their motivation upon entrance to B/N treatment. A
RCT comparing the efficacy of 24-weeks of a live-online Mindful Recovery Opioid Care
Continuum (M-ROCC) group with 24-weeks of a live-online control group could have a
major impact on clinical OUD treatment, and if successful, could also revolutionize MBI
addiction research by demonstrating a stage-oriented, motivationally-informed program.
A successful live-online group model of a behavioral intervention for OUD for patients
prescribed buprenorphine through primary care office-based opioid practices in our
region that reduced anxiety, enhanced treatment retention, and reduced illicit opioid use
during buprenorphine treatment would be in high demand. Importantly, this model would
likely be rapidly disseminated as a national model in primary care addiction treatment
and could help reduce relapse and put a stop to the ever-increasing rate of overdose
deaths.
2.2 Study Rationale
This study offers five innovations that will shift current research and clinical paradigms:
1.
Motivationally-Responsive MBI: This is the first study to design and evaluate the
impacts of a stage-oriented, motivationally-responsive, mindfulness continuum.
M-ROCC starts with a focus on engagement and enhancing confidence, providing
flexibility in training session type depending on participant motivation.
2.
Ascending Practice Dose Ladder: The ascending practice dose ladder provides
steady encouragement throughout and builds practice confidence and prevents early
dropout from negative self-attributions.
3.
Live-Online Delivery: No published RCT of online MBIs during BUP treatment
exists. This format allows for MBIs to be delivered to patients prescribed BUP, even
under the constraints of the COVID-19 pandemic.
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4.
Primary Care Focus: This is the first MBI program designed for primary care
BUP treatment for OUD. Prior MBI studies focus on other substance use disorders or on
methadone treatment even though primary care BUP in office-based opioid treatment is
becoming the most common way that people get OUD treatment.
5.
Optimized for Self-Regulation and Behavior: MTPC is optimized using a
mechanistic self-regulation framework from the NIH Science of Behavior Change
(SOBC) Initiative168 to catalyze behavior change166.
Developed through stakeholder collaboration, the continuum has been designed for
participants to move through the three component phases at their own pace, allowing for
flexible implementation and dissemination.
3. STUDY DESIGN
This will be a RCT comparing the efficacy of 24-weeks of a live-online Mindful Recovery
Opioid Care Continuum (M-ROCC) group with 24-weeks of a live-online control group.
Participants will be recruited from 3 affiliated sites from collaborating institutions that offer
primary care office-based opioid treatment, in addition to 2 affiliated with CHA (see figure 1), as
well as from OBAT sites in US states approved by the IRB for recruitment, and through
Facebook and Instagram advertisements. The 3 non-CHA sites will execute SMART IRB
reliance agreements with CHA and will not engage in study activities until their corresponding
reliance agreements have been executed. We will enroll patients prescribed buprenorphine into a
study that will be run remotely with assessments that can be completed fully online. Each study
group will include patients prescribed buprenorphine. We will primarily recruit from various
different primary care buprenorphine practices. Participants from various recruitment sites will
come together for the live-online study groups. M-ROCC and live-online control groups will not
replace standard of care at any sites and will instead be conducted as research groups.
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Mindful-OBOT Clinical Trial Protocol V2.20.

Figure 1. Five affiliated primary care sites and non-affiliated recruitment sources in the
MINDFUL-OBOT study
Figure 2. Study Schema
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Mindful-OBOT Clinical Trial Protocol V2.20.

4. SELECTION AND ENROLLMENT OF PARTICIPANTS
4.1 Inclusion Criteria
All of the following are required criterion for inclusion in the study:
1. 18-70 years old
2. Participant lives in Massachusetts, Connecticut, Florida, Maine, New
Hampshire, New York, Rhode Island, Texas, Vermont, California, North
Carolina, Virginia, Alabama, Arizona, Illinois, or Michigan.
3. Participant is currently prescribed Buprenorphine.
4. Diagnosis of opioid use disorder prescribed a stable dose of buprenorphine (at
least 4 weeks)
5. Less than 90 days of abstinence (from non-prescribed opioids or
benzodiazepines, cocaine, or alcohol) OR OUD with a co-morbid anxiety or
stress disorder (as evaluated by Computerized Adaptive Testing for Mental
Health [CAT-MH] or PROMIS-ASF > 55).
6. Able to use an electronic device with a videocamera to attend study groups
and complete questionnaires.
7. Sufficient English fluency to understand procedures and questionnaires
8. Ability to provide informed consent.
4.2 Exclusion Criteria
Any of the following is regarded as a criterion for exclusion from the study:
1. Active psychosis
2. Bipolar I disorder history or severe level of mania on CAT-MH (>71)169
3. Acute suicidality or self-injurious behavior or severe level of suicidality on
CAT-SS (>71)170
4. Cognitive inability as demonstrated by both the inability to complete an
informed consent assessment AND complete the Montreal Cognitive
Assessment (MOCA-BLIND) <16171,172 when given chances on two different
days
5. Current participation in another experimental research study
6. Previous participation in an 8-week intensive Mindfulness-Based Intervention
in past 3 years or participation in the MINDFUL-OBOT pilot study
7. Expected medical hospitalization in next 6 months
8. Expected incarceration in next 6 months
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9. Substance use severity requiring likely inpatient treatment in opinion of
principal investigator (e.g., severe alcohol withdrawal symptoms, severe
benzodiazepine withdrawal symptoms, etc.).
10. Inability to participate in group intervention without disrupting group in
opinion of principal investigator.
4.
4.3 Study Enrollment Procedures
Participant Recruitment
We will primarily recruit from 3 non-CHA affiliated sites who have established
experience providing OBOT (Boston Medical Center (BMC), Lynn Community
Health Center (LCHC), and North Shore Community Health (NSCH)), as well as 2
CHA affiliated sites with an existing partnership with CHA (CHA Revere, CHA
Union Square), in addition to up to 50 different primary care sites in Massachusetts
associated with the MA OBAT Training and Technical Assistance (TTA) network,
OBAT sites in U.S. states approved by the IRB for recruitment, and via Facebook and
Instagram advertisements. To ensure a rigorous design, we will refer to the study
during recruitment as a “study comparing two group programs designed to help
reduce stress, anxiety, and craving during recovery,” which would avoid the impact of
expectation bias towards or against mindfulness.
Referral process is described below. Participants will be recruited through:
1. A color flyer describing the details of the study, given to site staff at primary
care sites throughout U.S. states approved by the IRB for recruitment to
distribute to patients.
2. Information about the study will be posted on the CHA Addictions and CHA
CMC website after IRB approval of the patient flyer.
3. The MA OBAT Training and Technical Assistance program will send a
provider flyer to all nurse care managers working in OBAT across the state of
Massachusetts to distribute to prescribers. Providers will receive a provider
version of this flyer which will help them identify patients who may be
interested and eligible.
4. Patients will be given the study flyer by their providers and nurse care
managers. Providers and nurse care managers will not recruit or consent
patients to the study, but rather will have the flyer available for any patients
prescribed BUP who may be interested. Providers will refer interested patients
to the study staff via email (stressreduction@challiance.org) and/or by
completing a google form on the CHA CMC website. Providers will receive
verbal consent from their patients to pass along their names, phone number,
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and email address to study staff so that they may be contacted regarding their
interest in the study. Clinicians will be asked to include their email, as well as
the optimal method and time to reach the patient they are referring. The
referring clinician will only be contacted by the study team regarding
enrollment status (i.e., enrolled or not enrolled) once a patient has signed the
ICF and consented to this contact. Patients will also be encouraged to contact
study staff via email if they are interested in the study.
5. Advertisements will be distributed to potential participants via Facebook and
Instagram advertising. All advertising management will be conducted through
Facebook, which controls advertisement on both social media platforms. The
text and images used in the advertisements will be the same across platforms
unless otherwise specified. The research team will not specifically choose
individuals or groups to see these advertisements. The ad dissemination
process will be completely automated, and Facebook will use a proprietary
algorithm to identify users to whom the advertisements will be displayed.
Specifically, these advertisements will be targeted to Facebook and Instagram
users between the ages of 18-65+ who live in U.S. states approved for
recruitment. Facebook does not allow advertisers to specify target ages above
65 and the research team will instead screen out referred participants who are
over the age of 70 during the initial phone pre-screening call. Facebook will
not share any user information with the research team, and the research team
will not be able to identify the specific Facebook and Instagram users to
whom the advertisements are displayed. Individual users will have the ability
to like and comment on the advertisements and to post the advertisements to
their personal pages; however, this would be done at a user’s own personal
discretion and no incentives will be provided for liking or sharing the
Facebook or Instagram ads for this study. Furthermore, to protect
confidentiality, our research team will not track or record any information
about specific Facebook or Instagram users who may like, comment on, or
repost the study advertisements. All Facebook and Instagram advertisements
will advertised by Cambridge Health Alliance’s official Instagram account,
“cambhealthalliance”.
6. The recruitment team will not communicate with group moderators, groups, or
individuals on Facebook or Instagram. The advertisements will be run through
Facebook and the recruitment team will not specifically choose individuals or
groups to see the advertisement. The criteria specified during the
advertisement creation will be used by Facebook’s algorithm to determine
who is able to view the ads.
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7. The principal investigator will not recruit his own patients into the study,
though recruitment coordinators and Co-Is will support patient recruitment at
each site.
8. Google advertisements and bulk-mail advertisements to local catchment area
will be used if recruitment is slower than expected. All advertisements will
require IRB approval prior to use.
9. The study team will utilize contact information in the Helping to Enhance
Addiction Recovery Database (HEARD). Only participants from the
“Exploring the attitudes and experiences of patients engaged in buprenorphine
treatment during the COVID-19 pandemic” study who indicated their interest
in future research opportunities will be contacted. The HEARD database
contains contact information for individuals with OUD prescribed
Buprenorphine who have indicated a willingness to be contacted about future
research opportunities. Participants who elect to provide contact information
and indicate that they would like to be contacted about future research
opportunities will have their contact information (email address and phone
number) added to a confidential, password-protected database by a team
member who is listed on both study rosters. This database will only contain
email addresses and phone numbers, and it will not be connected in any way
to other data collected as part of this investigation. Participants from the
present Mindful-OBOT R33 study who have indicated a willingness to be
contacted about future research opportunities in the phone pre-screening form
or the ICF will also have their names, phone numbers and email addresses
added to this database. The PI will seek IRB approval for use of this database
in any future research. Contact information will be stored for a period of five
years or until we receive a request to remove someone’s contact information
from the database.
Procedures for documentation of reasons for ineligibility and for non-participation
of eligible candidates (e.g. Screening Log)
Interested patients will be referred to the study by their medical provider or nurse care
manager via email or phone. Referring providers or nurse care managers will be able to
describe the study to patients and obtain verbal consent to share patient names and
contact information directly with the study team for study coordinators to reach out.
Patients may also hear about the study through Facebook, Instagram, google ads or bulk
mail ads and will have the option to express interest to the study team through a google
form created to collect contact information. Since we will be recruiting patients from
different primary care sites across the region, a trained Research Coordinator (RC) will
conduct 15-30 minute phone screens with each interested patient to assess their
eligibility. Patients will verbally consent to the phone screen and will be read a statement
of confidentiality (see phone screen script included in the application). This will protect
patients from unnecessarily consenting to and enrolling in the study and completing
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screening measures if there is an obvious reason for their ineligibility that emerges
through the phone screen. Decisions on inclusion/exclusion will be made by the RC with
support from the PI, CMC medical director, and MINDFUL-OBOT clinical director. The
participant will also be asked to provide emergency contact information (name and phone
number) for their buprenorphine prescriber (in the demographics survey), who the study
team will reach out to provide more context surrounding emergencies or potentially
life-threatening AEs involving the participant. If the participant meets inclusion and
exclusion criteria, then the RC will contact the patient and suggest scheduling an online
study screening and consent visit via zoom videoconferencing. If the participant is
deemed ineligible to participate during this screen, their reason for ineligibility will be
documented and all pre-screening data will be removed from the pre-screening database.
During this visit, the patient will be given a verbal overview of the key information
related to the study by the research coordinator, and an opportunity to consent to
enrollment via the electronic consent module in REDCap. Once a patient completes the
consent process by scoring at least 90% on the online consent assessment and signs the
electronic consent form through REDCap, he/she will be referred to as a “participant” in
the study. However, if the patient is unable to score 90% or higher on the consent
assessment, then the research coordinator will administer the Montreal Cognitive
Assessment-Blind (MOCA-BLIND) online through zoom to assess for eligibility (a study
comparing the MOCA administered via videoconference vs. in person did not generate
significant differences in outcome between the two groups193). If they pass the
MOCA-BLIND, then they will be allowed to review the consent document again with the
research coordinator and complete a new consent assessment. If the participant does NOT
pass the consent assessment on the second attempt, then they will no longer be eligible to
join the study. If they do not pass the MOCA-BLIND, then the screening visit is over, and
they will be able to be assessed once more on another day (since substance use can
temporarily increase psychiatric symptoms and impact cognitive performance). On
another day the coordinator will meet with the patient via zoom videoconferencing to
review the protocol highlights again with the interested patient and offer a second chance
to complete the consent assessment and MOCA-BLIND. If the participant has a
MOCA-BLIND score below 16 on two separate occasions or scores less than 90% on the
consent assessment again, they will not be eligible. If both failures are considered to be
potentially due to ongoing substance use, then they may be screened again after 30 days
if there has been a clinically significant change in their substance use status based on the
judgement of the Principal Investigator (for example, they stopped alcohol use or tapered
off the illicit benzodiazepine use, etc.). Once they sign the consent, they will receive a
baseline diagnostic assessment using CAT-MH to identify psychiatric diagnoses and risk
factors, and a review with a clinician will be required if there is possible psychiatric
exclusion. Participants will also complete the PROMIS-ASF and the PhenX Substance
Abuse and Addiction Core toolkit.
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During this screening process, all eligible participants will need to rate the level of
scheduling accessibility of the study groups days and times for both M-ROCC and the
control group times being offered. Scheduling acceptability for assigned group will also
be used as a covariate in statistical analyses.
If the participant is not excluded based on diagnosis, then they will be scheduled to
complete the baseline survey and behavioral measures. If the participant has exclusion
criteria on diagnostic assessments or cannot complete baseline measures, then the
participant will not be eligible for randomization. Since participants with opioid use
disorder often have transient mental health symptoms or intoxication related to recent
substance use, participants with transient symptoms related to recent substance use will
be able to wait for a re-review of eligibility after 30 days.
5. STUDY INTERVENTIONS
Figure 3. M-ROCC Group Outlines
5.1 Interventions, Administration, and Duration
Interventions: Live-Online M-ROCC, the Mindful Recovery OUD Care Continuum
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Mindful-OBOT Clinical Trial Protocol V2.20.

While the 8-week MBI standard has been helpful for research reproducibility, it often can
lead participants with OUD to feel overwhelmed by practice expectations, unintentionally
causing self-judgment and shame, leading to relapse. For others, just as mindfulness
begins to click for them at 8 weeks, the program ends. For this reason, M-ROCC is
stage-oriented and motivationally-responsive. M-ROCC (Fig.3) meets participants where
they are. The introductory low-dose mindfulness group (LDM) is the first stage and it is
designed to foster engagement, reduce stress, introduce skills for autonomic regulation,
and provide a non-judgmental group environment, exposing participants to mindfulness
and self-compassion with a 4-week minimum commitment194,195. The LDM group uses
rotating short modules in 50-minute sessions for 4-8 weeks with short mindfulness
practices, experiential exercises, recordings, and introduction to free online mindfulness
resources, with demonstrated feasibility to integrate into addiction treatment110. M-ROCC
allows people to repeat the 4-week LDM group as needed as they work with the
ascending practice dose ladder and become ready for the intensive group, working to
build confidence, safety, self-efficacy, and enhance motivation for mindfulness and
recovery. After completion of LDM, participants are encouraged to start an intensive
group (MTPC-OUD) of 6-15 people. If at least 8 people are ready to transition to an
intensive group after 4 weeks then the group will be able to do so. Those who are not
ready to transition when the majority of the group transition at either 4 or 8 weeks, can
transition to another LDM group at another time if they would like to do so. Participants
will join an MTPC-OUD group for 16-weekly 90 minute sessions, which are designed to
enhance self-regulation, integrate mindfulness for living well through stress, anxiety,
depression, pain and addiction recovery, create an experience of common humanity, and
learn from each other’s experiences196. The 16-week MTPC-OUD group is designed to
minimize scheduling difficulties on behalf of both patients and providers, and to increase
feasibility in primary care settings where scheduling a longer group may be challenging.
Whereas the LDM group is designed to introduce participants to mindfulness practice in
an accessible and motivational manner, the MTPC-OUD group is more similar in content
to an intensive 8-week MBIs in terms of practice and content. Participants are asked to
engage in longer practices (~30 minutes) designed to address more complex topics such
as self-compassion, self-management for chronic illnesses, and skills for addressing
cognitive patterns of worry and rumination that could otherwise overwhelm novice
meditators. After completion of MTPC-OUD, participants can go to a mindfulness
maintenance (MCS) group, available in the form of CMC’s weekly free live online
mindful recovery addiction maintenance community group. This group will run for 60
minutes, and will begin with a longer mindfulness practice followed by a brief inquiry, a
brief recovery check-in, and concluding with a shorter mindfulness practice. MCS groups
may also be available in the wider community. These groups are flexible in terms of
delivery, provided they meet the requirements to be considered an MCS group
(mindfulness practice, inquiry and discussion, group check-in). Participants will be given
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the option to participate in one of these groups in order to strengthen their practice,
however community groups will not be considered to be part of the study or the
M-ROCC curriculum. M-ROCC’s key focus on autonomy, collaboration and naturalistic
selection to different levels based on readiness reduces unnecessary attrition and
decreases the likelihood of participants feeling shame or failure if they fail to attain
higher levels of practice.
Importantly, due to the impact of COVID-19 all M-ROCC groups will take place online
via HIPAA compliant Zoom software. Each M-ROCC group will start with a 15-30
minute live-online check-in period. During this time, participants will be able to meet
together in groups of three to discuss their week and experience with mindfulness
practices. This brief group is designed to foster interpersonal connection in an online
setting where it may otherwise be difficult for participants to interact. Each week we will
randomly select 3-6 individuals who will conduct supervised oral fluid toxicology tests
during this check-in period with study staff in a private Zoom breakout room. The study
team will aim to supervise oral fluid testing among participants once every 2 weeks. If
participants do not show up for group but they were randomly selected, then they will be
expected to meet within 24 hours with study staff by video to conduct the online
screening test.
The Mindful Recovery Opioid Care Continuum (M-ROCC) integrates an ascending
practice dose ladder across the 3 group stages. This slow and focused approach to
developing home practice differs from standard MBIs which expect static high levels of
practice throughout. In a previous pilot of an 8-week MBI group for OUD, participants
reported feeling discouraged, overwhelmed, guilty, and that it moved too fast to learn and
remember the multiplicity of skills taught each week. More time was needed to develop
mindfulness practice confidence, which is important because mindfulness practice dose is
associated with the amount of neurophysiologic change people experience during MBIs
(e.g., attention/inhibitory control)197.
The ascending practice dose ladder, which is introduced in the LDM group, provides
steady encouragement to increase mindfulness of breathing by an average of 5 minutes of
practice per week, building up to 20 minutes a day, providing validation for any practice
they are doing, building confidence and self-efficacy. Once the participant begins the
MTPC-OUD group they will therefore have an existing mindfulness practice, which will
allow them to engage in longer 30-minute practices without being overwhelmed. If the
program moves too fast with unrealistic expectations at the outset, then self-stigma,
self-criticism, regret, and avoidance can lead to dropout, which has more substantial
clinical implications in OUD treatment (relapse, overdose) than in standard MBIs for
other diagnoses, where completion rates are often around 50%49. In the M-ROCC R21
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Mindful-OBOT Clinical Trial Protocol V2.20.

pilot, one participant stated the most important part of the LDM group was “going from 5
minutes to 15 minutes a day of practice”. In this way, a stage-oriented continuum of
care holds promise to impact OUD outcomes.
Comparator (Live-Online Control) Design:
This randomized controlled trial will employ an attention- and time-matched live online
control group as a standalone comparator intervention. In a similar manner to the
M-ROCC check-in group, this weekly control group will offer participants the ability to
connect in groups and discuss the challenges that they are facing online with each other.
This approach allows for participants to connect in a manner that they would not
otherwise be able to, considering that the majority of B/N prescription sites are not
offering in-person groups as a result of the COVID-19 pandemic. After completion of the
testing and check-in groups, the full group will come together for a 45-60-minute
check-in as a group. As an active group comparator, this method will help to isolate
mindfulness aspects by controlling for the therapeutic aspects of group and will match the
toxicology screening methods across groups as well. Group content will derive from
commonly used methods in community substance use disorder programs and recovery
groups, including an eclectic curriculum designed to emulate common curricular
elements, with representation from commonly implemented evidence-based approaches
(Motivational Interviewing, CBT, Community Reinforcement and Twelve Step
Facilitation198), using engagement and group building processes commonly used in
addiction community groups199. The manualized group will be standardized across each
control group to ensure low variability across cohorts, starting with group check-in and
then presentation of a skill and/or discussion of a topic.
Administration
Participants will be enrolled on a rolling basis in preparation for their randomization to
either the live-online M-ROCC or live-online control arm. Initially, randomization will
only occur once 24 patients are ready for randomization. Following this initial group,
every 4 weeks if at least 24 participants have completed baseline measures and are ready
to start a group, they will be randomized using randomly selected block sizes of 4, 6 and
8200 with a 1:1 ratio (24 weeks of live online M-ROCC : 24 weeks of live online control
group). Next, after randomization, the participant will be informed about their assignment
and given a start week for group sessions (either live online control or live online
M-ROCC LDM) and will be given information about the group and its structure with a
start date scheduled. We will aim to recruit constantly, with a new M-ROCC and control
group beginning every 4-5 weeks.
We will aim for participants to begin attending control or LDM groups as soon as
possible after randomization, but at least within 4 weeks. The study timeline will start
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Mindful-OBOT Clinical Trial Protocol V2.20.

with week 1 being the first week the participant is assigned to start the study assigned
group. Participants will continue to participate in standard care at each site while awaiting
randomization and group placement, as well as throughout their enrollment in the study.
For both study arms, participants will verify their presence with the group leader or
research coordinator who will take attendance each week, which will be transferred to
REDCap by the research coordinator after group.
After completion of the rigorous RCT consisting of 4-8 weeks of low dose mindfulness
(LDM), LDM participants will be encouraged to proceed after LDM into the remainder
of the M-ROCC program with a naturalistic design to evaluate the choices and outcomes
that OUD participants make when engaging in additional mindfulness training
(MTPC-OUD) and MCS sessions. After completion of LDM, participants may repeat
with multiple cycles of LDM or may enter the next MTPC-OUD group. The availability
of MTPC-OUD groups will depend on the number of group participants interested.
Intensive mindfulness group-based intervention will be scheduled after 8 participants are
willing to transition to intensive, but can only start when there is a critical mass greater
than 6 participants to maintain the synergistic container effects important to the
mindfulness group approach176, such as common humanity and learning from each other’s
experiences.
MTPC-OUD intensive groups will run every 1-2 months and MCS groups will be run
continuously in the form of free live online addiction mindful recovery groups. The CMC
Free Live Online addiction recovery group led by the M-ROCC clinical director is a
live-online group (https://www.chacmc.org/connect) following the MCS curriculum,
which can be accessible by Zoom for anyone, and would be available for any study
participant who has completed an MTPC-OUD group, or who is not comfortable moving
from their LDM group to an MTPC-OUD group.
We anticipate about half of the M-ROCC sample will choose to initiate MTPC-OUD
within the first 8 weeks. This is based on our having 9 out of 18 people who enrolled in
the LDM in our initial pilot site choose to participate in MTPC-OUD.
M-ROCC participants may join the MCS or the intensive MTPC for the remainder of the
study according to their choice. In the pilot study, 2 out of 18 people who started
M-ROCC chose to return to a standard group-based opioid treatment (GBOT) level of
care and 2 transitioned to individual therapy. Given the risk of overdose in this
population, after 4 weeks of LDM, if a participant in M-ROCC chooses to leave the
M-ROCC group and return to another level of care (perhaps because of schedule or
change in risk level), then we believe it is imperative that we allow them to do that to
avoid risk of harm. This is part of the naturalistic design and data on switching will be
collected.
The LDM and MTPC group sessions will not be billed to insurance as group
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Mindful-OBOT Clinical Trial Protocol V2.20.

psychotherapy or shared medical visits and no-co-pays will be collected. These will be
run as research groups – this will be outlined in the consent form. Participants will be
required to remain in their existing BUP treatment program in addition to being
randomized to either study arm. MCS groups will be 50 minute groups that participants
will be able to join after the study, if the study group ends at 20 weeks for them, or if they
decide not to do the live-online intensive MTPC-OUD program. Free MCS groups will
be available through the CMC Free Live Online Community Program.
Duration
Participants will complete study procedures for a total of 24 weeks. Participants will be
asked to make a live-online group commitment for at least 4 weeks (attending groups
once a week), after which they will be encouraged to attend weekly groups for 16
additional weeks. Since group participants will be referred from multiple different sites,
the importance is that the requirement is the same across both study arms.
If a participant is in the MTPC-OUD group at week 24, then they will still complete the
week 24 assessments within the 2-week completion window even though they have not
completed the MTPC-OUD group.
Any assessment battery (specifically online surveys not including oral fluid screens)
completed more than 2 weeks after it is expected to be completed by the study timeline
would be marked as outside the acceptable assessment window and excluded from
primary analyses. Sensitivity analyses for late survey data collected outside this time
window will be conducted and if it does not differ than it may be considered for inclusion
in analyses.
Alternatives to Participation
Patients receiving buprenorphine at their primary care site can stay in the regular clinical
OBOT program at their individual site and opt to not participate in this research study.
5.2 Handling of Study Interventions
The MTPC manual and the Low-Dose Mindfulness (LDM) manual have been tailored
specifically for participants with OUD in primary care buprenorphine treatment. Prior to
the start of the R33 M-ROCC groups, the manuals will be finalized based on the
remaining participant feedback from the R21 phase, and merged into a single adapted,
stage-based Mindful Recovery OUD Care Continuum document with an ascending
practice dose ladder, which was demonstrated to result in high levels of daily mindfulness
practice among participants with MAT in previous trials. These manuals will be further
refined for adaptation to a live-online setting. This manual will be sent to NCCIH prior to
start of R33 study enrollment.
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Mindful-OBOT Clinical Trial Protocol V2.20.

5.3 Concomitant Interventions
5.3.1 Allowed Interventions
All other non-experimental interventions are allowed as long as they do not conflict with
inclusion/exclusion criteria. Many participants are also receiving standard care for their
chronic illness and mental health, which may include trials of psychopharmacologic
agents or psychotherapy.
5.3.2 Required Interventions
Participants will be required to remain in their regular OBOT program according to
standard of care at their referring site. All BUP prescriptions will be tracked and managed
by the participant’s clinical team. There are no additional required interventions except
the mindfulness practice, which will be encouraged in M-ROCC.
5.3.3 Prohibited Interventions
Psychopharmacologic treatments AND diagnoses related to active psychosis, thought
disorder, schizophrenia, or schizoaffective disorder as these would indicate that the
participant meets one of the exclusion criteria. Psychopharmacologic treatments with
atypical antipsychotics and mood stabilizers for the adjunctive treatment of mood
disorders or bipolar 2 disorders are NOT prohibited unless there is active psychosis.
5.4 Adherence Assessment
Measurement and Reporting of Participant Accrual, Compliance with
Inclusion/Exclusion Criteria:
Review of the rate of participant accrual and compliance with inclusion/exclusion criteria
will occur monthly by the data analyst with reports to PI monthly to ensure that a
sufficient number of participants are being enrolled. Accrual will be reported twice yearly
to the DSMB.
Measurement and Reporting of Participant Adherence to Intervention Protocol:
Participants will be considered adherent to the intervention protocol if they attend at least
3 LDM or control groups. Participants will be considered adherent to the overall
M-ROCC intervention if they attend at least 12 MTPC-OUD or MCS groups and were
adherent to the LDM group with at least 3 LDM sessions attended. Participants will be
considered adherent to the control intervention if they complete 15/24 control groups.
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Mindful-OBOT Clinical Trial Protocol V2.20.

They will be adherent to weekly surveys and eligible for a completion bonus if they
complete 75% of these survey sessions and all 2-week time periods have an oral fluid
screen. If assigned a study phone, participants must also return this phone to be eligible to
receive this bonus.
Measurement and Reporting of Group Leader Adherence to Intervention Manual:
Data on adherence to the intervention protocol will be collected weekly by research staff
and reviewed monthly by the PI, and twice yearly by the study statistician and DSMB.
Adherence of participants will be evaluated by attendance at weekly sessions (Control,
LDM, MCS or MTPC-OUD). Adherence for each intervention session will be rated on
the following scale: 0 = absence; 1 = completed; 2 = incomplete (with comments). An
explanation of study staff efforts to monitor and address participant adherence deficits
will be documented and reviewed twice weekly by the senior RC. All sessions will be
audio recorded, and 10% of recordings will be reviewed by a trained reviewer rating for
adherence, competence, and fidelity, using the MBI:TAC201.
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Mindful-OBOT Clinical Trial Protocol V2.20.

6. STUDY PROCEDURES
6.1
Schedule of Evaluations: Table 1a: Schedule of Evaluation from Screen to Wk 8
Consent &
Screening
Baseline
Study Week
1
2
3
4
5
6
7
8
Informed Consent and
Screening Session
 
 
 
 
 
 
 
 
 
 
Informed Consent Form
X
 
 
 
Consent Quiz
X
PROMIS-ASF
X
 
 
X 
MOCA-BLIND – if required
X
CAT-MH
X
PhenX Addiction Core T1
X
Demographics Survey
X
Baseline Battery
 
 
 
 
 
 
 
 
 
 
Meditation and Mindfulness
Experience (SMME)
X
 
 
Adverse Childhood
Experiences (ACE)
X
 
 
Clinical Assessments
 
 
 
 
 
 
 
 
 
 
PROMIS-PISF
X
X 
Beck Anxiety Inventory (BAI)
X
X
Oral Fluid Toxicology Results
X
X
X
Weekly Survey
X
X
X
X
X
X
X
X
Pain Catastrophizing Scale
(PCS)
X
X
Substance Craving Scale
(SUBCS)
X
X
X
X
X
X
X
X
X
Self-Regulation Battery
 
 
 
 
 
 
 
 
 
 
Experiential Avoidance
(BEAQ)
X
X
Difficulty in Emotion
Regulation (DERS-16)
X
X 
Perceived Stress Scale (PSS)
X
X 
Self-Compassion Scale (SCS)
X
X 
Interoceptive Awareness
(MAIA-2)
X
X 
Nonattachment to Self Scale
(NTS)
X
X 
Self-Critical Rumination Scale
(SCRS)
X
X
Experiences Questionnaire
Decentering Subscale (EQD)
X
X
Mechanisms Battery
 
 
 
 
 
 
 
 
 
 
Interpersonal Mindfulness
Scale
X
X
Credibility/Expectancy Survey
-Stress
X
Credibility/Expectancy Survey
- OUD
X
Five Facet Mindfulness
Questionnaire (FFMQ)
X
X
Group Attitudes Survey
 
X
Monitoring surveys
 
 
 
 
 
 
 
 
 
 
Weekly Mindfulness Practice
Diary
 
X
X
X
X
X
X
X
X
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Mindful-OBOT Clinical Trial Protocol V2.20.

Weekly Recovery Skills Diary
X
X
X
X
X
X
X
X
Adverse Events Reporting
Form
 
X
X
X
X
X
X
X
X
Qualitative Interview
Duration (min)
69
77
7
13
7
17
7
7
7
76
Payments for Study Visits ($)
20
40
7
12
7
12
7
12
7
52
Table 1b: Schedule of evaluations weeks 9-24
Study Week
Duration (min)
9
1
0
11
12
1
3
14
15
16
1
7
18
19
20
2
1
22
2
3
24
Informed Consent and Screening
Session
 
Informed Consent Form
20
Consent Quiz
10
PROMIS-ASF
X
X
3
MOCA-BLIND – if required
10
CAT-MH
X
X
12
PhenX Addiction Core T1
10
Demographics Survey
4
Baseline Battery
SMME
3
Adverse Childhood Experiences
(ACE)
4
Clinical Assessments
PROMIS-PISF
X
X
3
Beck Anxiety Inventory (BAI)
X
X
5
Oral Fluid Toxicology Results
X
X
X
X
X
X
X
10
Weekly Survey
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1
Pain Catastrophizing Scale (PCS)
X
X
3
Substance Craving Scale (SUBCS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2
Self-Regulation Battery
Experiential Avoid (BEAQ)
X
X
3
Emotion Regulation (DERS-16)
X
X
5
Perceived Stress (PSS)
X
X
3
Self-Compassion (SCS)
X
X
5
Interoceptive Awareness (MAIA-2)
X
X
5
Nonattachment to Self Scale (NTS)
X
X
2
Self-Critical Rumination Scale
(SCRS)
X
X
3
Experiences Questionnaire
Decentering Subscale (EQD)
X
X
5
Mechanisms Battery
Interpersonal Mindfulness Scale
X
X
4
Credibility/Expectancy Survey
-Stress
3
Credibility/Expectancy Survey -
OUD
3
Five Facet Mindfulness
Questionnaire (FFMQ)
X
X
6
Group attitudes
X
X
2
Monitoring surveys
Weekly Mindfulness Practice Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2
Weekly Recovery Skills Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2
Adverse Events Form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2
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Mindful-OBOT Clinical Trial Protocol V2.20.

Qualitative Interview
X
60
Visit Duration (min)
7
7
7
31
7
17
7
76
7
17
7
17
7
17
7
98
Payments for Visits ($)
7
12
7
12
7
12
7
52
7
1
2
7
12
7
12
7
102
6.2
Description of Evaluations
6.2.1
Screening Evaluation
Pre-Screening Process
In order to be eligible to participate in the study, all patients must have an active
buprenorphine prescription from a provider and must reside in a state approved by the
IRB for recruitment. Study participants will be referred by their provider, by the
OBOT nurse care manager, or they will be self-referred. Referring clinicians will be
able to collect verbal consent to share patients’ name, email and phone number with
study RCs who can reach out to the patient to describe the study in more detail.
Referring clinicians will also be able to provide study team contact information to the
participant so that they will be able to contact the Research Coordinator (RC) directly.
The providers will not be members of the study staff, they are members of the clinical
staff who will work with study staff to help make the study available to their patients
should their patients find it a good fit.
Following the participant’s referral to the study, the RC will conduct a brief phone
screen, with the outcomes recorded in a REDCap survey, to determine the participants
eligibility. If the participant meets inclusion and exclusion criteria based on the phone
screen, then the RC will contact the patient and suggest enrollment in the study
followed by study screening. If the participant is deemed ineligible to participate
during this screen, their reason for ineligibility will be documented and all
pre-screening data will be removed from the pre-screening database.
For patients for whom there are clinical eligibility questions, eligibility will be
reviewed by MINDFUL-OBOT Clinical Director, MINDFUL-OBOT PI, or CMC
Medical Director prior to the screening visit. The research coordinator will review
information provided by the participant during their phone screen to confirm evidence
of inclusion criteria. If the patient appears eligible from the brief review, then the
Research Coordinator will call all patients with a referral to schedule a screening
visit. Eligibility and phone screen information will be stored in a secure REDCap
database.
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Mindful-OBOT Clinical Trial Protocol V2.20.

6.2.2 Enrollment, Baseline, and/or Randomization
Study enrollment is defined as the date when the informed consent is completed.
Once the participant is determined eligible from screening, they will complete their
baseline measures. Once baseline measures are completed if they are still eligible,
then the participant is ready for randomization, which is described below.
Consenting Procedure
Electronic informed consent will be obtained from each participant at entry into the
study via a secure REDCap server hosted at CHA. Informed consent is obtained by
the following process:
Consent for Participants for study:
Low-Risk: The informed consent document will include a full description of the study
procedures and associated risks. Because these interventions are well-established with
more than 1000 studies demonstrating the safety and efficacy of Mindfulness-based
interventions203, the groups represent a low-risk experience.
Consent procedure: Strict confidentiality during the consenting procedure will be
maintained through the use of REDCap for document consent, and the study staff will
be trained on maintaining confidentiality during the consent process. The study staff
will call or video chat with the participant to guide them through the consenting
process. The research coordinator will first describe the measures taken to keep the
consent session confidential and safe for the participant, and then will describe the
key information of the study verbally, using a study schema diagram designed for
easy patient comprehension, and will then give the patient time to review the consent
form on their own. The patient will be given a chance to ask questions and express
any concerns about the study.
Prior to study enrollment, during the consent process, the participant will be asked to
provide their personal information (name, date of birth, address, phone number). No
study-specific procedures or investigations will be performed before the patient has
signed and dated the Informed Consent Form. The electronically signed and dated
informed consent forms will be stored in a secure REDCap server hosted by CHA.
The RC will also sign the consent form, indicating that they were present during the
consent process. The participant will be emailed a copy of their signed and dated
consent form for their own records. Once participant consent has been obtained, the
RC will ship a package to the participant containing Oral Fluid Toxicology testing
kits.
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Mindful-OBOT Clinical Trial Protocol V2.20.

Consent assessment: The participant will also be asked to complete an Informed
Consent Assessment via REDCap to ensure comprehension of the study procedures,
rights of participants, as well as understanding of the risks and benefits of the study.
The participant will not be able to sign the document without having at least 90%
correct answers on the consent assessment.
Participants will be given the opportunity to review the study procedures with a
trained study staff member if they fail the consent assessment. Participants will
also be given an opportunity to correct their answers on the consent assessment. If
they can’t pass the assessment with at least 90% completely correct answers after
reviewing it and the protocol with the coordinator, then they will meet
individually with the Research Coordinator or other approved study personnel to
be evaluated for the presence of cognitive deficits disrupting their ability to
complete study tasks, including completing the MOCA-BLIND204 to evaluate for
cognitive deficits that may prevent them from comprehending the study
intervention and study assessments. If participants do not obtain a score of 16 or
higher on the MOCA-BLIND, the session will end and they will be permitted to
reschedule to take the MOCA-BLIND once more on a different day. If they do
not obtain a score of 16 or higher on the second day, they will not be permitted to
join the study. Since participants with opioid use disorder often have transient
mental health symptoms or intoxication related to recent substance use,
participants with transient symptoms related to recent substance use may be able
to wait for a re-review of eligibility after 30 days based on the judgement of the
Principal Investigator.
Participants with at least one score of 90% or higher on the Informed Consent
assessment AND a score of 16 or higher on the MOCA-BLIND within up to two
screening visits will be eligible for participation in the study. Once the participant
demonstrates understanding of the study and agrees to participate in the study, the
consent will be signed in the presence of the research coordinator or another trained
member of the study team staff. After completion, participants will be given an
additional copy of the signed informed consent form for their own records.
Consented patients will be assigned a numeric study number based on their order of
enrollment and study acrostic which is based on letters (to allow for cross-referencing
and prevent mistaken confusion among participants if a digit is incorrect), and will
complete the screening and baseline assessment battery, which will take place after
informed consent.
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Mindful-OBOT Clinical Trial Protocol V2.20.

Screening Assessments (Consent and Screening Visit)
After participant consent has been obtained, the research coordinator will provide the
participant with a secure REDCap link to the PROMIS-ASF, and PhenX toolkit
surveys, as well as a secure link to a screening CAT-MH survey, to evaluate for
eligibility prior to proceeding with baseline assessments. The RC will also supervise
an oral fluid test with the participant to assess for substance use. If the screening
process suggests that the participant meets exclusion criteria or brings up other
questions about eligibility, then the RC will contact the PI or clinical director to
review the information and decide prior to proceeding to baseline assessments. If a
participant’s PROMIS-ASF T score is greater than 55 (Raw > 16), then the
participant will be determined to have an anxiety disorder even if it was not
previously diagnosed clinically.
Since participants with opioid use disorder often have transient mental health
symptoms or intoxication related to recent substance use, participants with transient
symptoms related to recent substance use may be able to wait for a re-review of
eligibility after 30 days.
During this screening visit, all eligible participants will be asked to fill out a
Scheduling Acceptability form to rate the level of acceptability of the available study
group day and time for both M-ROCC and control group times at the site, asking on a
0-10 scale how much they will be able to attend the group times.
Baseline Assessments (Baseline Visit)
Baseline Survey Session and Computer Tasks Visit:
Eligible participants will complete baseline surveys through a link to the secure
REDCap database. They will receive a password protected survey link through an
email from the study team.
All participants will be shipped a package containing sponge-based testing kits for
Oral Fluid Toxicology testing. Oral fluid toxicology tests will be conducted via
videochat with a research coordinator to ensure proper collection. The participant will
hold the results panel of the test up to their camera for the research coordinator to
screenshot using the HIPAA compliant screenshotting tool “Droplr”. These
screenshots will be stored in Droplr’s secure cloud server before being transferred to
the secure CHA Google Drive. Participant faces and other PHI will not be included in
the screenshot.
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Mindful-OBOT Clinical Trial Protocol V2.20.

The Baseline Survey Session is expected to take approximately 1.5 hours. Please refer
to schedule of evaluations (Section 6.1) for an exact list of assessments used in this
session.
 
Randomization
We will randomize participants in a 1:1 ratio of M-ROCC arm to control arm. We will
randomize participants in randomly selected blocks of 4, 6, or 8 in a 1:1 ratio.
Randomization will be conducted as follows:
1) Participants who complete baseline measures and have a scheduling
acceptability form will be entered into the randomization database.
2) Upon final review of eligibility, eligible participants will be marked as ready
for randomization in the study database, which will alert the data analyst by
automated email generated by REDCap.
3) The data analyst will randomize participants who are ready using a randomly
selected block size (4, 6 or 8) (1:M-ROCC; 1:Control) and will enter the
randomization status into the Study Status spreadsheet which the research
coordinators will have access to and is kept secure within the CHA G Suite
system.
4) The research coordinator will call the participant by phone to let them know
the date/time that they can start LDM/Control.
Participant De-identification, Randomization, Allotment, and Blinding:
Upon consenting to the study, each participant will be assigned a study number by the
research coordinator. Randomization will occur using the assigned study number,
which the Data Analyst will use to enter each participant into the randomization
spreadsheet. The Data Analyst will be blinded to participant identity prior to and
during randomization. The research coordinator will not have access to the
randomization spreadsheet.
6.2.3 Blinding
See Table 2 for blinding status for study staff. Participants will not be blinded to their
assigned study arm (M-ROCC vs. control), nor will the research coordinators, data
analyst, or methodologists. The PI will be blinded to assigned study arm when
reviewing data quality, adverse events, protocol violations, etc.
Table 2. Blinding Status of Study Staff
Study Role
Blinding Status
Time of unblinding
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Mindful-OBOT Clinical Trial Protocol V2.20.

PI
Blinded
When all primary outcome data
have been collected and when
database is locked
Data Analyst (Lydia Smith, Gareth
Parry, Javier Barria)
Not Blinded
Will prepare reports for DSMB with
unblinded data, but will not
have contact with participants.
Methodologists (Creedon/Cook)
Not Blinded
Will review reports for DSMB with
unblinded data, but will not
have contact with participants.
RCs
Not blinded
Clinical/Medical Directors
Not blinded
Participants
Not blinded
6.2.4 Follow-up Visits
Overview of Study Visits:
All study visits will be conducted via Zoom video and password protected REDCap
surveys rather than in person. Study visits are outlined below:
●
Consent and Screening Session (1 hours)
●
Baseline Assessment Session (1.5 hours)
●
8-week visit assessment (1 hour)
●
16-week visit assessment (1 hour)
●
24-week visit assessment (1 hour)
●
Oral fluid toxicology screens will be conducted at least once every two weeks
during the study and will be entered into REDCap by study staff
●
Weekly monitoring surveys will be collected monitoring substance use and
Weekly Mindfulness Practice Diary
Participant Communication
Study staff will conduct outreach phone calls every two weeks during the 6-month
study. If a participant does not respond to the phone call and has not been responsive
within the past two weeks, study staff will reach out using e-mail, text message, or
private message via Facebook or Instagram. Phone number, e-mail address, social
media handle, and the names and contact for three close contacts will be recorded in
the demographics survey outlined in the participant consent form. We will also collect
the name and phone number of the patient’s buprenorphine prescriber in the
demographics survey. The prescriber would only be contacted in case of emergency
or potentially life-threatening adverse event relating to the patient.
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Mindful-OBOT Clinical Trial Protocol V2.20.

According to Mitchell et al, sending private messages via text or Facebook was a
more effective way of communication with SUD participants than leaving
voicemails204. Only private, direct messages will be sent to participants through
private social media messaging. The voicemail, text, email, and social media
outreach attempts will be limited to scheduling and general content and will not
include any mention of the research study or the nature of the study. Study
participants will be contacted through the “Stress Reduction Study” Facebook and
Instagram accounts.
Only secure WiFi will be used to communicate with participants. If a study staff
member’s home WiFi is not password protected, they will be required to use a study
phone. Only a CHA IT approved secure study cell phone and computer, both
password-secured, will be used to communicate with participants. All communication
will be logged in a G-suite secure study call log, and messages will be deleted from
the study cell phone or social media site once logged in the call log.
6.2.5 Completion/Final Evaluation
Final primary outcome/endpoint is number of biochemically confirmed oral fluid
toxicology opioid negative abstinent periods (two-week periods of opioid abstinence
during weeks 13-24 of the study defined as the number of biochemically confirmed
illicit opioid negative abstinent periods (defined by negative oral fluid tests (negative
for opiate, oxycodone, fentanyl, methadone) AND no self-reported illicit opioid use)
during weeks 13-24 of study.
Final study session is week 24 and all the evaluation measures and assessment
batteries that happen within two weeks of that day. Please refer to schedule of
evaluations for an exact list of assessments used in this session.
Participant Reimbursement:
Participants will be paid using either anonymous, retail, online reward cards, OR
anonymous, HITECH safe reloadable prepaid cards. Specifically, these online reward
cards would be provided through a company like Tango
(https://www.tangocard.com), a HIPAA compliant rewards service, or Comdata, a
CHA approved reloadable gift card vendor. Use of Tango will require the input of
participant email. Use of anonymous, retail, non-reloadable prepaid cards will not
require any participant information to be recorded.
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Participants will also be rewarded with a completion bonus for an oral fluid screen
completion rate of at least 90%, completion of baseline, 8-week, 16-week, and
24-week assessments, and completion of more than 75% of weekly surveys. If
assigned a study phone, the participant must also return this phone to be eligible to
receive this bonus. Participants will receive an email notification for each weekly gift
card they receive.
For completing baseline, 8-, 16-, and 24-week survey batteries within 48 hours of
their assignment, participants will be rewarded with $5.
Payment will be given as follows:
●
$20 at the Screening/Consent visit for completion of screening
●
Up to $45 at Baseline Visit for completion of baseline visit
●
$5 per group attended ($120 total)
●
$5 per bi-weekly period in which all assigned weekly surveys and
oral-fluid toxicology screens are complete ($60 total)
●
Up to $45 at 8 Week Assessment
●
Up to $45 at 16 Week Assessment
●
Up to $45 at 24 Week Assessment
●
Up to $48 for 24-week completion bonus if participants complete at least
90% of their randomly assigned oral fluid screens weeks AND complete
75% of weekly surveys between weeks 1 and 24. If assigned a study
phone, the participant must also return this phone to be eligible to receive
this bonus. This bonus could range from $36 to $48 depending on how
many weekly surveys are completed ($2 for each weekly survey
completed).
●
$50 for completing an optional M-ROCC or control completer qualitative
interview (available for first 30 completers).
●
Up to $478 total
Study Payments will be given the following times:
Payment 1: $20 for Screening/Consent visit
Payment 2: Up to $45 at Baseline survey/computer visit
Payment 3: Up to $45 at 8 Week Assessment
Payment 4: Up to $45 at 16 Week Assessment
Payment 5: Up to $143 at 24 Week Assessment
Weekly Payments: Up to $180 spread out across 24-weeks. Participants will be able
to choose whether they receive these payments each time they are earned, or at the
end of each large survey battery.
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6.2.6 Qualitative Interviews
We will conduct a minimum of 12 and a maximum of 30 qualitative interviews of
M-ROCC or control group completers, defined as having attended at least 3 LDM
sessions and 12 MTPC-OUD/MCS sessions or 15 control sessions of a possible total of
24 sessions. Interviews will be conducted with a minimum of 6 and a maximum of 15
participants from each study arm. Interviews will last between 30 and 60 minutes. All
completers will be invited to interview until thematic saturation is reached. Interviews
will be conducted on the HIPAA-compliant videoconferencing technology platform
Zoom. Research staff with qualitative interviewing experience will be trained to conduct
productive post-study interviews, oversee preparation of transcripts and ensure
compatibility for it to be entered into the software program ATLAS.ti version 8.4.4 to
enable comparison across qualitative data sources.
The M-ROCC qualitative interviews will be structured to identify:
1) Themes regarding online mindfulness delivery.
2) Challenges of online group delivery
3) Strengths of online group
4) Subjective experience of the online supervised oral fluid testing process
5) Benefits of group-based approach to treatment, hypothesizing that reasons for
mindfulness group retention will also include mindfulness practice benefits, body
awareness, emotion regulation, acceptance of medication, and values clarification.
The control group qualitative interviews will be structured to identify:
1) Themes regarding online GBOT delivery, such as shared identity, accountability, and
supportive community.
2) Challenges of online group delivery
3) Strengths of online group
4) Subjective experience of the online supervised oral fluid testing process.
5) Benefits of group-based approach to treatment, hypothesizing that group-based treatment
creates an atmosphere of mutual identification and acceptance in which participants gain
support and inspiration through positive role modeling.
Analysis of the qualitative data obtained through these interviews will begin with
transcription. The text output from the qualitative interviews will be generated using
Transcription Star transcription services (https://www.transcriptionstar.com/), an online
service provider that specializes in HIPAA compliant audio transcription. To protect
human subjects’ privacy, only the audio (mp3) files from qualitative interviews will be
sent to Transcription Star. The study staff will only record and download interview data
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using a desktop computer at the CMC office in order to ensure that the interview files are
securely maintained. Files will be downloaded to the secure CHA server before being
de-identified and uploaded to the secure G-Drive. Study staff will anonymize the mp3
files (using Audacity) by removing any identifiers mentioned during the interview.
Audacity has been previously approved by the CHA IT department, and only saves files
locally. The qualitative interviews will be converted from video mp4 format to audio mp3
format using Zoom HIPAA compliant conversion software. Audio recordings in mp3
format will be uploaded to transcriptionstar.com and will be securely stored and
transmitted using HTTPS and Transport Layer Security (TLS) 1.2 encryption, which is
the highest level of security available. Once the transcriptions are complete, the text of
the transcripts will be checked against the digital recordings and errors will be corrected.
The transcripts will then be prepared as rich text format files for compatibility with the
computer software, ATLAS.ti, version 8.4.4207. In addition, other data sources will also be
entered by research staff into ATLAS.ti to enable comparison across qualitative data
sources.
The transcriptions of the interviews will be coded using two approaches simultaneously:
1) coding using revised a priori codes based on the themes described above; and 2) open
coding to identify new concepts found in the data178. Trustworthiness of the data will be
determined through investigator meetings180, the application of analytic reflexivity in the
interpretive process180, and constant comparison of emerging themes181. To refine themes,
the team will further analyze all excerpts within a theme into sub-categories as well as
define and name themes. Finally, qualitative themes and results in the primary care
implementation pilot will be compared.
7. SAFETY ASSESSMENTS
AEs will be systematically assessed at each assessment visit (weekly surveys,
baseline, 8, 16, 24). In addition, group leaders and research coordinators will be
trained to identify and report any adverse events that may occur or are reported during
weekly live-online group visits. All AEs will be reviewed weekly by the Senior RC
and the MINDFUL-OBOT Clinical Director, and monthly by the PI, and SAEs will
be reviewed by PI within 24 hours. Please see adverse events section (7.3) below.
7.1 Specification of Safety Parameters
Participants are assessed regularly for AEs, hospitalization, and changes in
medication.
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7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
a.
7.2.1 Expected Risks
1. Worsening of underlying illness
People with OUD are at high risk of worsening of the underlying disorder, which
can lead to opioid overdose, intoxication, life-threatening accidents, inpatient
hospitalization for detoxification or stabilization, and death. Given the high rate of
relapse and overdose death both in this population of patients with OUD, inpatient
hospitalization for opioid use disorder and overdose death are both risks that are
expected to occur to the study but will be unlikely to be related to the protocol.
Co-morbid psychiatric disorders are common, especially PTSD, MDD, Bipolar
Disorder, Anxiety disorders, and OCD. Worsening of underlying mental illness
may also occur, which would be an expected adverse event. Suicidality is a
common symptom in this population and suicidal ideation is an expected symptom
as a sign of worsening of underlying mental illness or opioid use disorder. Non-life
threatening suicide attempts associated with an overdose, or any non-life
threatening, self-harm among patients with prior suicidality, self-harm, past suicide
attempts, or other risk factors would be an expected risk of the study. However, if a
participant without previous suicidality, previous self-harm, or other risk factors
were to attempt to commit suicide or physically harm themselves, then this would
be unexpected. Life threatening suicide attempts are an unexpected events.
Medical events related to injection, inhalation or other methods of administration
of opioids and other drugs of abuse can also happen and would be expected risks
in this population.
2. Time spent learning mindfulness techniques
Participants will be invited to practice mindfulness skills and techniques at home,
which may involve negotiating with those at home to create time and space for
practice. This will not be required of them.
For #3 and #4 below, research coordinators, group leaders, and the PI will be
trained to respond to escalating anxiety, psychosis, or any other worsening
psychiatric symptoms. They will be trained to alert the buprenorphine prescriber or
their delegate (e.g. nurse care manager) by phone/page or electronic medical
record (within participating healthcare systems) within 24 hours of becoming
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aware of the escalating symptoms, and to contact the CMC Medical Director or
Principal Investigator by phone or page as soon as possible and at most within 24
hours of alerting the existing care provider (s) to review the case. The care team
and study staff will work together to determine the appropriate referral, including
referral to outpatient mental health and/or local Emergency Department if
necessary.
3. Increased anxiety due to difficulties in mental training program
Mindfulness practices can sometimes cause anxiety for those who practice.
Support from the Group Leader and the group can help participants recognize that
this anxiety is part of the process and can help people learn to manage these
feelings. If meditation and mental exercises are causing a worsening of anxiety for
participants, they will be encouraged within groups to change their approach to the
practice. Research coordinators will assess for worsening symptoms every two
weeks during the engagement call adverse events report, and also during each
live-online group session. If the participant(s) are unable to find a way to practice
without eliciting an increase in symptoms, then they may be asked to stop
practicing and to meet with either the M-ROCC Clinical Director, the CMC
Medical Director, or the Principal Investigator for an evaluation. The participant
may ultimately be terminated from the study if they are experiencing an adverse
reaction. These participants may continue to receive other treatments at their
primary care site as part of their ongoing treatment plan.
4. In some very rare cases, meditation practice can lead to a dissociative state or
to psychosis208. This is more likely in participants with current conditions of or a
predisposition to psychosis. Participants experiencing active psychosis are
excluded from participating in this study. If a participant begins to experience
these feelings during his or her time in the study, then the study staff and care team
will work together to alert the appropriate care team providers and study
investigators immediately. The participant may be asked to stop practicing and to
meet with either the CMC Medical Director or the Principal Investigator for an
evaluation in person or via videoconference while a member of the study staff is
onsite with the person. Videoconferencing will occur through the HIPAA
compliant and encrypted communications platform zoom. The participant may
ultimately be terminated from the study if he or she is experiencing an adverse
reaction. These participants may continue to receive other treatments at their
primary care site as part of their ongoing treatment plan. If the participant
experiences a dissociative state or psychosis during a group session, the research
coordinator and/or group leader will ask the participant to meet with them
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individually in an online breakout room, while the other/group leader continues on
with the session and will contact the appropriate care provider(s).
5. Physical discomfort due to gentle movement aspect of training. The training
will involve gentle movements and stretching. Some participants could experience
physical discomfort during this aspect of training. If a participant feels discomfort,
he or she will be encouraged to engage in a less straining manner. If discomfort
continues, then the participant will be asked to sit out of this brief element of
training and discuss the areas of discomfort with their PCP before return to
practice of physical postures. Severe discomfort is not expected, but could
possibly occur. In this case, the participant will be treated for this pain, and
encouraged to return to practice stationary forms of mindfulness. If a participant
gets hurt or get sick as a direct result of being in this study, emergency treatment
will be given to them. All needed emergency care is available to participants, just
as it is to the general public. Cambridge Health Alliance has not set aside any
money to pay for a research-related injury or illness.
6. Feelings of embarrassment or anxiety when asked personal survey question.
Some survey questions are of a sensitive or personal nature and may cause the
participant to become upset. In some rare cases, participants may require mental
health support upon feeling upset by the survey questions. A participant’s
referring clinician will be contacted if the participant needs additional mental
health support. The PI, M-ROCC Clinical Director, and CMC medical director
will remain available to field questions from participants about their experience
with mindfulness and any adverse experiences. The clinical director will help to
monitor participants and work with the referring clinician to coordinate behavioral
health care for participants.
7. Monitoring may lead to anxiety and difficulty with completion of interviews may
lead to feelings of guilt or shame. Staff will specifically be trained not to shame
anyone about missed sessions, but instead focus on what they can do to complete
the next ones.
8. Despite efforts to prevent data breaches, any use of electronic devices and internet
data transmission can result in a breach of confidentiality.
9. Group members will be asked to keep what others share confidential, but they may
not. As a result, some private information may be disclosed by other group
members.
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7.2.2 Expected Benefits
1. Participants may learn about others who have similar problems as they do, helping
them feel less alone
2. Participants may feel increased accountability in their recovery by being in group
3. Participants may have less of a need for symptom-relieving medication like
benzodiazepines and opioids.
4. Participants may find that they smoke fewer cigarettes and drink less alcohol.
5. Participants can learn skills for controlling behavior and improved well-being.
6. Participants may feel less depression, anxiety, stress, and pain.
7. Participants may benefit from the support of group-based intervention.
8. Participants may feel more joy and gratitude.
7.3
Adverse Events and Serious Adverse Events
Following NCCIH request, a detailed Data and Safety Monitoring Plan (DSMP) was
designed and a DSMB assigned. Please see appendix at the end of this document.
Adverse event reporting guidelines are detailed in the DSMP and copied below.
Definition:
In this study we will use the FDA definition of adverse events (AEs): “any untoward
medical occurrence that may present itself during treatment or administration with a
pharmaceutical product [or group-based treatment intervention], and which may or
may not have a causal relationship with the treatment.” Serious adverse events for this
trial will be defined as any AE temporally associated with the participants’
involvement in research that meets any of the following criteria:
●
Results in death;
●
Is life-threatening (i.e., any suicide attempt requiring emergency department
or inpatient care will be a SAE, but parasuicidal gestures or self-harm that is
not life-threatening or requiring immediate medical care will be an AE, but
NOT a SAE; any opioid overdose requiring Naloxone reversal will be a SAE);
●
Inpatient hospitalization or prolongation of existing hospitalization (other than
admissions for substance use disorder, which will be classified as an AE, but
this alone is not sufficient to classify as an SAE since this may be for
detoxification or as a beneficial step towards recovery);
●
Results in congenital anomaly/birth defect;
●
Results in a persistent or significant disability/incapacity or permanent
incapacity or substantial disruption to conduct of normal life functions;
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●
Based upon appropriate medical judgement may jeopardize the participant’s
health and may require medical or surgical intervention to prevent one of the
outcomes listed in this definition.
Classification of AE Severity:
AEs will be labeled according to severity, which is based on their impact on the
participants. An AE will be termed “mild” if it does not have a major impact on the
participant, “moderate” if it causes the participant some minor inconvenience, and
“severe” if it causes a substantial disruption to the participant’s well-being. Of note, a
severe AE and a serious adverse event (SAE) are distinct terms. A participant could
experience a severe AE that does not meet the above-listed definition of an SAE;
alternatively, a participant could experience a moderate AE that meets the SAE
definition.
AE Attribution Scale:
AEs will be categorized according to the likelihood that they are related to the study
intervention. Specifically, they will be labeled unrelated, possibly related, or
definitely related to the study intervention.
7.4
Reporting Procedures
This study will comply with the reporting requirements from the Cambridge Health
Alliance IRB. The PI will report to the CHA IRB, DSMB, and NCCIH any of the
following unanticipated problems and adverse events that occur 1) during the conduct
of the study, 2) after study completion, or 3) after participant withdrawal or
completion:
1. Internal adverse events that are unexpected, and related or possibly related to
the research and that indicate there are new or increased risks to participants;
2. External adverse events that are serious, unexpected, and related or possibly
related to the research and that indicate there are new or increased risks to
participants that require some action (e.g., modification of the protocol,
consent process, or informing participants);
3. Deviation from the approved research protocol or plan without IRB approval
in order to eliminate apparent immediate hazard to participants or harm to
others;
4. Deviation from the approved research protocol or plan that placed participants
or others at an increased risk of harm regardless of whether there was actual
harm to participants or others;
5. Any event that requires prompt reporting according to the research protocol or
investigational plan or the sponsor;
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6. Breach of confidentiality or violation of HIPAA
7. Procedural error regardless of whether participants experienced any harm;
8. Interim analysis, safety monitoring report, publication in a peer-reviewed
journal, or other finding that indicates that there are new or increased risks to
participants or others or that participants are less likely to receive any direct
benefits from the research;
9. Complaint by/on behalf of a research participant that indicates that the rights,
welfare, or safety of the participant have been adversely affected or that
cannot be resolved by the investigator;
10. Incarceration of a research participant during participation in this study (which
is not currently approved for involvement of prisoners as participants);
11. Noncompliance with applicable regulations or requirements or determinations
of the IRB identified by the research team or others that indicates that the
rights, welfare, or safety of participants have been adversely affected;
12. Suspension or termination of the research, in whole or in part, based on
information that indicates that the research places participants at an increased
risk of harm than previously known or recognized;
13. Suspension or disqualification of an investigator by the sponsor, or others;
14. Scientific misconduct; or
15. Any other problem that indicates that the research places participants or others
at an increased risk of harm or otherwise adversely affect the rights, welfare or
safety of participants or others.
Procedures for collecting and reporting unanticipated problems:
All unanticipated problems (including AEs) will be collected by the PI or other study
staff on an AE Tracking Log form, at the following time points: at study assessment
time points at baseline and weeks 8, 16, 24, in each weekly survey, and additionally
on an ad-hoc basis.
Reports of unanticipated problems involving risks to participants or others will be
submitted to the IRB, DSMB and NCCIH within 5 working days of the date the
investigator first becomes aware of the problem.
Reporting Unanticipated Problems that are Adverse Events:
Any unanticipated untoward or unfavorable medical occurrence, including abnormal
sign, symptom, or disease, that indicates that the research places participants at
increased risk of physical or psychological harm than previously known or
recognized will be submitted as an AE to the IRB, DSMB, and NCCIH. The PI will
provide the following information in the report:
1. a detailed description of the adverse event;
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2. the basis for determining that the event is unexpected in nature, severity, or
frequency;
3. the basis for determining that the event is related or possibly related to the
research procedures;
4. the basis for determining that the research places participants at an increased
risk of harm (i.e., a serious adverse event); and
5. whether any changes to the research or other corrective actions are warranted.
Reporting Unanticipated Problems that are not Adverse Events:
All other unanticipated problems incidents, experiences, information, outcomes, or
other problems that indicate that the research places participants at an increased risk
of physical, psychological, economic, legal, or social harm than was previously
known or recognized will be submitted as an “Other Event” to the IRB, DSMB, and
NCCIH within 5 business days. The investigator will provide the following
information in the report:
1. a detailed description of the unanticipated problem;
2. the basis for determining that the problem is unexpected;
3. the basis for determining that the problem indicates that the research places
participants at an increased risk of harm; and
4. whether any changes to the research or other corrective action are warranted.
SAE Reporting:
SAEs that are unexpected, serious, and possibly related to the study intervention will
be reported to the IRB, DSMB, and NCCIH in accordance with requirements.
Any SAE, whether related to study intervention or not, will be reported to the IRB
and the DSMB within 5 business days. The initial SAE report will be followed by
submission of a completed SAE report. SAEs that are unanticipated, serious, and
possibly related to the study intervention will be reported to the NCCIH within 5
business days. Anticipated or unrelated SAEs will be handled in a less urgent
manner but will be reported to the IRB in accordance with their requirements. A
summary of the SAEs that occurred during the previous year will be included in the
annual progress report to NCCIH. In the annual AE summary, the DSMB Report will
state that they have reviewed all AE and SAE reports.
7.5
Follow-up for Adverse Events
Communication of Adverse Events:
The PI and the study Clinical Director will be notified of all adverse events that occur
within 48 hours of it being reported to the study team. The PI will then decide what
appropriate actions to take in order to ensure participant safety. These include
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encouraging the participant to contact their PCP or mental health provider; contacting
the participant’s prescriber; or contacting the participant by phone or email to obtain
updates on the adverse event. If the PI determines that a member of the participants
clinical team should be contacted to provide context surrounding the potentially
life-threatening AE, the study team will use the emergency contact information
provided in the demographics form by the participant. In some cases, the participant
may have already contacted their relevant providers, and/or the participant has
already improved in which case no action is necessary.
Once the necessary steps to ensure participant safety have been enacted, the CMC
medical director and/or PI will discuss what actions need to be taken with regard to
the study: discontinuing the participant from the intervention temporarily until
conditions have improved; discontinuing from the intervention permanently but
keeping them in the study; or having them drop out of the study entirely.
7.6
Safety Monitoring
The PI and data analyst will review with the research coordinators data collection,
data completeness and accuracy, as well as protocol compliance on a monthly basis.
Study progress and safety will be reviewed monthly (and more frequently if needed).
Progress reports, including participant recruitment, retention/attrition, and AEs, will
be provided to the DSMB every 6 months (see DSMP for details).
Possible Risk of Suicide:
During screening, study applicants will undergo a battery of psychological tests,
including the CAT-MH, to determine their eligibility and safety of their participation
in this study. Special attention will be placed on history of homicide or suicide
attempts and the presence of any current imminent plan. Applicants who are actively
suicidal will not receive the study interventions and will be evaluated by the PI to
determine whether study participation is appropriate.
If imminent risk of suicide or danger to self or others is evidenced during a screening
evaluation, then the participant will be excluded from participation and will be
referred to the appropriate level of care as soon as possible. While maintaining
contact with the participant, the study team member will contact the National Suicide
Prevention Lifeline (800-273-8255) via the CHA HIPAA compliant Google meet
application. The PI will be responsible for overseeing risk assessment during
screening and study visits. Study PI, Zev Schuman-Olivier, MD, will be contacted by
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page as soon as possible to help with clinical management. If the PI is unavailable,
Todd Griswold (CMC Medical Director) can be consulted to cover.
If a participant describes feelings of suicidality while participating in a group, the
study staff or group leader present during the group will help to manage this event
with the current standard of care and will make immediate contact with the PI, Zev
Schuman-Olivier, or clinical coverage listed above. The participant will be referred to
the emergency room or the appropriate level of care, and the study staff member will
contact the National Suicide Prevention Lifeline via the Google meet application. The
PI will be notified within 24 hours of any suicidality.
8. INTERVENTION DISCONTINUATION
Participant Withdrawal/Termination Criteria:
Withdrawal/Termination criteria for Participants:
Participants may be discontinued from just the study intervention (“Group
Discontinuation”) OR both the study intervention and study assessments (“Study
Withdrawal”) at any time.
Specific reasons for discontinuing a participant (“Group Discontinuation”) from the
group are:
1. Voluntary discontinuation by the participant who is at any time free to
discontinue his or her participation in the group, without prejudice to further
treatment.
2. Safety reasons as judged by the investigator.
3. Substance use disorder or psychiatric symptoms worsen to a level that
requires a higher level of care.
4. Revealing private information about other participants in the groups.
Specific reasons for withdrawing a participant (“Study Withdrawal”) from the entire
study are:
1. Voluntary discontinuation by the participant who is at any time free to
discontinue his or her participation in the study, without prejudice to further
treatment.
2. Safety reasons as judged by the investigator.
3. Incorrect enrollment (i.e., the participant does not meet the required
inclusion/exclusion criteria) of the participant.
4. Active severe substance use disorder or level of intoxication during study
procedures that precludes ability to conduct assessments.
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5. Participants unable to complete baseline assessments.
Participants who discontinue will be asked about the reason(s) for their
discontinuation and the presence of any adverse events. If possible, they will be seen
and assessed by the Principal Investigator. Serious and Unexpected Adverse events
will be followed up.
If participants are terminated from group intervention for any reason (except
incorrect enrollment or safety concerns that endanger the study team), then they will
still be expected to complete their outcome assessments, unless the participant
revokes informed consent and withdraws from study.
Safety precautions for discontinuing a participant will be followed. Participants will
be informed about discontinuation from group by the clinician leading the group and
alternative treatment options will be discussed with the participant. If the participant
is not available to receive this communication, then a letter will be sent informing
the participant about the group discontinuation and providing alternative treatment
options. Decisions about group intervention discontinuation will be made by the PI
and group leaders but will be discussed with the CMC Medical Director for
consultation prior to providing a group discontinuation letter.
If a participant is withdrawn from the study, they will be contacted by the Principal
Investigator and informed the reason they are being withdrawn. A Withdrawal Letter
will be sent informing the participant about the study withdrawal. If the participant
was still in a study group, then the group discontinuation process will also be
completed as described above with attention to providing alternative treatment
options.
Participation in this research study is voluntary. Participants can choose not to
participate, and their decision will in no way affect the quality of care they receive at
their site or their working relationship with their site. Participants may elect at any
point to discontinue their participation in this study.
Participants who become pregnant during the study will not be discontinued. The
current standard of care for women with opioid use disorder is to be maintained on
medication-assisted treatment with methadone or buprenorphine during the
pregnancy. In fact, buprenorphine treatment leads to shorter duration of neonatal
abstinence syndrome than methadone209, leading buprenorphine to be the gold
standard for treatment during pregnancy. To reduce risk of fetal exposure to
naloxone, the current standard is for pregnant participants to be maintained on
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buprenorphine alone (Subutex) instead of buprenorphine/naloxone (Suboxone)
combination210; however, the American College of Obstetricians and Gynecologists
reported in their clinical guidelines that it is possible that the combination
medication (Buprenorphine/Naloxone) will increasingly be prescribed as multiple
recent studies have supported its safety211–214. Importantly, in this study, we will not
be prescribing buprenorphine to study participants, but rather enrolling pregnant
participants taking buprenorphine prescribed by their health care provider as study
participants into groups. If a participant becomes pregnant during the study, then the
study team will alert the prescriber about the pregnancy and encourage the provider
to follow their standard of care. Mindfulness groups during pregnancy have been
shown in meta-analysis to reliably reduce anxiety, depression, and stress215.
Preliminary studies suggest mindfulness groups are safe and acceptable for pregnant
women with opioid use disorder216.
New Information
Any pertinent new information will be communicated to study participants via
e-mail if they have an e-mail address, otherwise via phone, by the research
coordinator. In light of new information, participants may elect to discontinue their
participation in the study.
9. STATISTICAL CONSIDERATIONS
b.
9.1
General Design Issues
Retention can be a problem in OUD behavioral therapies studies. To support the
attractiveness of the study and ensure outcome measure completion, we will provide
$5 gift cards for each week that a participant attends a group session and $5 for each
bi-weekly period in which all assigned surveys and toxicology screens have been
completed. We will obtain phone number and email of 3 close contacts in the
demographics form so that we can more easily reach participants who may not be
attending study sessions. We will call participants every other week for brief
engagement calls, which has worked to increase retention by 20% in previous studies
and will call all participants who missed a session within 48 hours.
9.2
Sample Size and Randomization
Justification of Sample Size and Power Calculations:
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This study will enroll an approximate of n = 236 and maximum of n = 280
participants who will sign informed consent and our power analyses have identified
that we will have the sample to identify meaningful effects with an effective sample
size of n=156 with 78 individuals in the M-ROCC arm and 78 individuals in the
control group. We expect to randomize at least 192 participants (96 M-ROCC: 96
Control) over 8 months in order to have an effective sample size of n=156. We will
aim to recruit participants with an active buprenorphine prescription from providers
in U.S. states approved for recruitment by the IRB to enroll patients at a rate of
approximately 30 participants per month, anticipating 19% loss during screening and
baseline assessments, so we can randomize approximately 24 participants each month
for 8 months.
Based on R21 urine toxicology data, we will focus our primary outcome analysis on
the impact of M-ROCC on opioid use starting 12 weeks after intervention
assignment. We estimate a mean of 4.67 negative tests for all illicit opioids (opiates,
oxycodone, fentanyl, methadone) out of 6 random oral fluid toxicology tests
conducted during the last 12 weeks in M-ROCC (SD 1.23) (n=78) and 4.11 negative
tests for all illicit opioids in the control check-in group (SD 1.27) (n=78). We
anticipate an effect size of Cohen's d = 0.45 for between-group difference in
percentage of monthly positive toxicology screens. Participation of N=192
individuals randomized (with an effective sample size of 156 with 78 individuals in
the M-ROCC arm and 78 individuals in the control group) allows for > 80% power to
detect an effect size of 0.45 for negative toxicology for all illicit opioids between
M-ROCC and control arms. This power calculation was generated assuming a t-test
of the difference between two means, a 1:1 intervention to control recruitment ratio, a
type I error of 0.05, a two-sided comparison, and a design effect of 1.23 derived from
an ICC of 0.01 with 8 group clusters with average cluster size of 24, which represents
the average number of people randomized in each monthly cohort to either live-online
M-ROCC or the live-online control group. This level of cluster was selected because
it will encompass cohort effects. As the primary outcome will be analyzed in an
intent-to-treat analysis, it is not sensitive to the number of individuals who drop out of
the study after randomization. For secondary outcomes, based on pilot data and other
relevant studies, we anticipate dropout from intervention in M-ROCC between
17-28% at 24-weeks and dropout in the control groups of 21-44% at 24-weeks14,217–220.
In previous primary care studies, we have reported the impact of MTPC
over 24 weeks on reductions in anxiety as measured by the PROMIS-ASF as d =
-0.72 (n=81), p<0.001166 and d = -0.80, p<0.001 (n=136)187. In our recent R21 pilot
study, we reported significant Anxiety reductions over 24 weeks among patients with
co-morbid anxiety at baseline (>55 at baseline) (p < .05, ES = -0.556). Given the
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likelihood of a small effect of control on Anxiety after 4 weeks of buprenorphine
treatment221, we anticipate an effect size of d = -0.56 for between-group change in
PROMIS-ASF.
9.3
Definition of Populations
Intent-To-Treat analyses will be performed according to the following definition of
the intent to treat population: All individuals who are randomized in the study, which
is defined as those individuals who complete informed consent, meet inclusion
criteria and do not meet exclusion criteria, complete all baseline assessments, are
randomized and receive information about their randomization status.
9.4
Interim Analyses and 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) any new
information becomes available during the trial that necessitates stopping the trial; or
(3) other situations occur that might warrant stopping the trial. If the DSMB feels that
a safety review to consider stopping the trial is required, then a safety review will be
scheduled with the PI, and the IRB and sponsor will be informed. While no formal
interim analyses are planned, we do plan to provide regular data monitoring for
consistency and to decrease missing values. During these checks, we will monitor the
data for unusual patterns that might suggest issues related to safety or adverse effects.
9.5 Outcomes
9.5.1 Primary Outcome
Biochemically-confirmed opioid abstinence, which is defined as the number of
two-week periods with a negative oral fluid test [negative for opiate,
oxycodone, fentanyl, methadone] AND no self-reported illicit opioid use, based
on weekly substance use self-report during the final 12 weeks (weeks 13-24) of
the study (6 is the highest possible number of negative oral fluid toxicology
screen time periods). Participants will be randomly selected to undergo a
live-online supervised oral fluid screen at a rate of once every 2 weeks.
Negative toxicology screens have been previously used to assess effectiveness
of OUD treatment14,222.
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9.5.2 Secondary Outcomes
Main Secondary Clinical Outcomes:
1. Patient Report Outcomes Measurement Information System – Anxiety Short
Form 8a (PROMIS-ASF)
2. Patient Report Outcomes Measurement Information System – Pain
Interference Scale (PROMIS-PISF)
3. Positive oral fluid toxicology tests for Cocaine during the final 12 weeks
(weeks 13-24) of the study.
4. Positive oral fluid toxicology tests for Benzodiazepines during the final 12
weeks (weeks 13-24) of the study.
Exploratory Self-regulation mechanistic outcomes
1. Brief Experiential Avoidance Questionnaire (BEAQ) (EMO)
2. Difficulties in Emotion Regulation Scale (DERS-16) (EMO)
3. Perceived Stress Scale (PSS) (EMO)
4. Self-Compassion Scale (SCS) (SRP)
5. Multidimensional Assessment of Interoceptive Awareness subscales 1, 4-8
(MAIA) (SRP)
6. Nonattachment to Self Scale (NTS) (SRP)
7. Self-Critical Rumination Scale (SCRS) (SRP)
8. Experiences Questionnaire- Decentering Subscale (COG/EMO)
Exploratory Other Mechanistic outcomes:
1. Five Facet Mindfulness Questionnaire (FFMQ)
2. Interpersonal Mindfulness Scale (IMS)
3. Group Cohesion Questionnaire (GCQ)
4. M-ROCC Qualitative Interviews
5. Credibility/Expectancy Survey (OUD)
6. Credibility/Expectancy Survey (Stress)
Exploratory Clinical Outcomes:
1.Intervention retention at 24 weeks, defined as any active BUP prescription
within the last 28 days (i.e., between Weeks 20-24 of participant enrollment).
2.Time to intervention discontinuation
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3. Weekly Survey reports of BUP non-adherence [a] and diversion [b]
4. Medication-assisted treatment status at 24 weeks (including methadone,
buprenorphine or naltrexone).
5. Self-reported average daily dose of BZDs prescribed over final 12 weeks
6. Beck Anxiety Inventory (BAI)
7. Pain Catastrophizing Scale (PCS)
8. Substance Craving Scale (SUBCS)
9. CAT-DI
10. CAT-ANX
11. CAT-PSY
12. CAT-MANIA
13. CAT-SUD
14. CAT- PTSD
15. CAT-SDOH
9.6 Data Analyses
Primary Outcome:
The main primary outcome is biochemically-confirmed illicit opioid abstinent
periods (defined by a negative oral fluid test [negative for opiate, oxycodone,
fentanyl, methadone] AND no self-reported illicit opioid use), during the final 12
weeks of the study (with 6 being the highest possible number of oral fluid tests during
that time period).
Negative toxicology screens have been previously used to assess effectiveness of
OUD treatment14,222. We will use an intent-to-treat design to evaluate the extent to
which M-ROCC impacts biochemically confirmed illicit opioid abstinence over 6
biweekly time periods during the final 12 weeks of the study, using Generalized
Estimating Equations (GEE)223,224, which accounts for the clustering of individual
observations over time, with covariates. This analytic approach provides reliable
estimates even when data are unbalanced. GEE is also robust against
misspecifications of the working correlation matrix when specifying the correct
dependent-variable distribution and canonical link function. The benefit of selecting
the best correlation structure is the gains in efficiency. The Quasi-likelihood Under
Independence Model Criterion (QIC) will be used to ensure the best fitting working
correlation structure225. For dichotomous outcomes, we will specify a binomial
distribution and a logit link function, and robust standard errors clustered at the
individual-level. For missing data, we will implement multiple imputation methods
in Stata (mi procedure). This technique creates multiple complete datasets, imputes
missing values using a probabilistic simulation method (e.g., chained equations),
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analyzes each dataset, and uses standard rules to combine estimates and adjust
standard errors for the uncertainty of imputation226.
Secondary Outcomes:
A main secondary outcome is change in PROMIS-ASF227 at 24 weeks. To evaluate
Anxiety as a secondary outcome, we will conduct a difference-in-differences,
Intent-To-Treat, repeated measures analysis using linear mixed effects models
(mixed) to evaluate time × intervention assignment interaction from baseline to 24
weeks, using a selected sample of participants with a baseline PROMIS-ASF> 16
(T-score > 55), which is the cutoff for mild anxiety disorder (since PROMIS-ASF is
non-linear below this score). An additional secondary outcome is change in
PROMIS-Pain Interference228 (PROMIS-PISF) at 24 weeks. Mixed effects models
account for clustering of multiple observations within participants. We will compute
contrasts of predictive margins to test for significant within-group changes and
difference-in-differences (between-group) estimates over time. Between-group and
within-group effect size (Cohen’s d) will be computed based on the predictive
margins generated from the mixed models. To address missing data, we will
implement multiple imputation methods in Stata (mi procedure). This technique
creates multiple complete datasets, imputes missing values using a probabilistic
simulation method (e.g., chained equations), analyzes each dataset, and uses standard
rules to combine estimates and adjust standard errors for the uncertainty of
imputation229. Other secondary clinical outcomes include the number of positive oral
fluid tests for BZD or cocaine during the final 12 weeks of the study.
For secondary and exploratory outcomes, we will use the Benjamini-Hochberg false
discovery rate (FDR) procedure230, which accounts for multiple comparisons. We will
implement FDR according to Cao et al.231 in which a cutoff p value is determined for
a family of similar variables and analyses (family-wise error rate = 0.05)166,232,233.
Statistical significance will be determined for the following analysis families:
between-group main secondary clinical outcomes (family size, n = 4), and
exploratory self-regulation outcomes (n=8), exploratory other mechanistic outcomes
(n=4), exploratory clinical/health outcomes (n=15), formal practices (n= 4), informal
practices (n = 7), and resource use (n= 7) (see section 9.5.2 for details).
Exploratory analyses:
We will conduct mixed effects model analyses as described above to analyze
self-regulation mechanistic outcomes, including Brief Experiential Avoidance
Questionnaire (BEAQ), Difficulties in Emotion Regulation Scale (DERS-16),
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Perceived Stress Scale (PSS)234, Self-Compassion Scale (SCS), Multidimensional
Assessment of Interoceptive Awareness (MAIA-2), Nonattachment to Self Scale
(NTS), Self-Critical Rumination Scale (SCRS), and Experiences Questionnaire-
Decentering Subscale (EQD).
We will collect other mechanistic outcomes, including interpersonal variables related
to the group as potential covariates or mediators, Group Cohesion, Attitude about
group leader, interpersonal mindfulness, as measured by the Interpersonal
Mindfulness Scale (IMS), and intervention expectancy as measured by the
Credibility/Expectancy Survey239. Adverse childhood experiences240, Substance
Abuse and Addiction Core Tier 1241 (substance use severity and demographics), and
distance from clinic242,243 will also be collected. We will also collect data on
participant mindfulness using the Five Facet Mindfulness Questionnaire (FFMQ).We
will collect weekly surveys about BUP adherence and drug use. We will ask about
mindfulness practice dose in M-ROCC and recovery skills use in control arms.
Attitudes about group leaders and group cohesion244 will be measured at 8, 16, and 24
weeks.
We will conduct mixed effects model analyses as described above to analyze several
exploratory clinical outcomes, including Beck Anxiety Inventory245, Pain
Catastrophizing Scale, Substance Craving Scale and CAT-MH outcomes (CAT-DI,
CAT-ANX, CAT-PSY, CAT-MANIA, CAT-SUD, CAT-PTSD, CAT-SDOH).
We will also analyze BUP non-adherence and diversion reports, as well as
self-reported average daily dose of BZDs prescribed over final 12 weeks.
We will compare intervention retention at 24-weeks, which is defined as having an
active BUP prescription in the past 28 days at the 24-week study visit. In the chance
case of imbalance of assignment, we will add the following variables as measurable
covariates in regression models since they are known to impact retention246:
psychiatric diagnosis, age, gender, race/ethnicity, unemployment, previous opioid
treatment242, Hepatitis C246, childhood trauma247, baseline cocaine use14, and injection
drug use history14. We will also add any other baseline characteristics that may be
significantly imbalanced after randomization. We will also include key data collected
during the first 4 weeks of the intervention, i.e., BUP non-adherence, self-reported
illicit opioid use.
We will also measure time to intervention discontinuation, and fit Cox proportional
hazard models that model the risk of time to intervention discontinuation, comparing
hazard rates across the intervention and control groups, adjusting for the covariates
described above in the logistic regression. All individuals that do not discontinue the
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intervention at the end of data collection will be considered to be right-censored. We
will assess the Cox proportional hazards assumptions using tests of Schoenfeld
residuals and by visual estimation of log-log plots of the estimated survival curves.
We will also use Wald tests to test significance in intervention vs. control group
hazard rate differences.
We will also conduct a minimum of 12 qualitative interviews for M-ROCC or control
group completers to examine themes regarding online mindfulness delivery and to
compare responses with our R21 qualitative outcomes from our in-person group
model.
Because little is known about the dose effect or the impact of long term (> 8 weeks)
mindfulness training, in exploratory analyses, we will evaluate the specific impact of
MTPC intensive mindfulness sessions among those in M-ROCC who choose to
continue their participation by joining MTPC, tracking their 24-week outcomes
compared to the control arm that receives no mindfulness and participants that only
did LDM. There is insufficient power to formally randomize and test this third arm
that receives intensive MTPC, so we opt for this naturalistic design to provide
exploratory data on dose effects (# of mindfulness sessions, total practice mins during
24-weeks, >12 group sessions, and participation in intensive MTPC-OUD). Those
who continue through MTPC are likely to differ at baseline from other study
participants. Employing propensity score (PS) methods248 allows us to minimize bias
by balancing the MTPC, LDM only, and control groups on observable intervention
eligibility criteria and potential outcome confounders. We will consider PS
approaches including weighting, matching (nearest neighbor, optimal, ratio, full), or
sub-classification249. We will select methods providing the best covariate balance
across potential groups, graphically (range/density) and empirically (%-standardized
difference in means ≤10%). 
10. DATA COLLECTION AND QUALITY ASSURANCE
10.1 Data Collection Forms
Sources of Research Materials for Participants:
The following research material will be obtained:
1. Responses to surveys stored in REDCap
2. Audio tapes of M-ROCC sessions for fidelity ratings
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3. Saliva samples (Oral Fluid Toxicology Screenings)
The following is the full list of measures for this study.
CAT-MH Interviews
Participants are sent a link to complete the CAT-MH (Computer Adaptive Testing for
Mental Health) interview on a computer, tablet or phone. They can read or listen to
the questions. The interview is delivered via a secure CHA IT-approved process using
CHA’s HIPAA-compliant REDCap server. ATT is the company who developed the
CAT-MH software for behavioral health measurement. For this study, we will have an
external module in REDCap that integrates CAT-MH into CHA’s existing REDCap
server. In this way, all patient data will exist on our side of the firewall. Since these
CAT-MH assessments will only be used for research purposes, there will be no need
for participants to have a direct connection to CHA in order to access the CAT-MH
questionnaires that will be distributed through REDCap. Items from each of the
modules for depression (CAT-DI)189,250, anxiety (ANX-CAT)251, mania and hypomania
(M/HM-CAT)189, PTSD (PTSD-CAT)189, psychosis (PSY-S-CAT), social determinants
of health (CAT-SDOH), and substance abuse (SUD-CAT) 252,253 are chosen from large
item banks based on multidimensional item response theory, adapting each item
presented to the individual’s severity so that different individuals are tested with
different items depending on their severity level250. This allows for rapid testing –
2-12 minutes, depending on the number of domains tested – compared to 1-1.5 hours
for a structured clinical interview, and greater precision. It is easy for patients to fill in
online189. We monitor CAT-MH results daily and any rapid change in psychiatric
symptoms is brought to the attention of study staff, including either medical director
or PI. Moderate or severe suicide risk immediately triggers an email sent to the RC,
M-ROCC clinical director (Fredericksen), medical director (Todd Grisworld) and the
PI, and appropriate outreach by a study clinician and referral to the appropriate level
of evaluation or psychiatric care will ensue. Duration: 2-12 min.
Montreal Cognitive Assessment - Blind (MOCA-BLIND)204: The MOCA was
designed as a rapid screening instrument for mild cognitive dysfunction. The
MOCA-BLIND is comprised of the same tasks as the original MOCA, with visual
elements removed. It assesses different cognitive domains: attention and
concentration, memory, language, conceptual thinking, calculations, and orientation.
The total possible score is 22 points; a score of 16 or above is considered normal in
substance use disorder context. Duration: 10 min.
A brief demographics survey will note participant race, ethnicity, primary language,
income, address (including the street, unit/apartment number if applicable, city, state,
and zip code), phone number and e-mail address of three close contacts, Facebook
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and Instagram handle, name and phone number of buprenorphine prescriber, and
other quantifiable attributes. Duration: 4 min.
Scheduling Acceptability Survey: This survey will ask participants to rate, on a
scale of 1-10, the likelihood that they can attend the day/time that the current control
and LDM/MTPC groups are being held.
Baseline Battery for Participants:
A Survey of Meditation and Mindfulness Experience (SMME) will assess the
participant’s previous experience with meditation and Mindfulness-based
interventions, both over their lifetime and in the past two weeks. This will be a brief
questionnaire. Duration: 3 min.
Adverse Childhood Experiences (ACE) Questionnaire: The Adverse Childhood
Experienced (ACE) Questionnaire254 is a 10-item self-report measure that identifies
childhood experiences of physical, sexual, and emotional abuse; neglect by parents
or caregivers; violence between parents or caregivers; other kinds of serious
household dysfunction such as alcohol and substance abuse; and peer violence,
witnessing community violence, and exposure to collective violence. Participants
indicate “yes” or “no” to having experienced each type of ACE, and the score is
calculated by summing up the number of questions to which they responded “yes.”
Duration: 4 min
Substance Abuse and Addiction Core: Tier 1. We will use questions from this
PhenX (www.phenxtoolkit.org) core toolkit related to assess age of initiation of first
use, lifetime use, and past 30 days use, for all major substances of abuse, including
alcohol and tobacco. We will only ask participants the items that are not redundant
with the demographic survey above. The Core Collection includes highly
recommended measures deemed by the SAA Scientific Panel (SSP) as broadly
relevant to addiction research. This will be assessed verbally with a member of the
study staff asking the questions out loud to the research participants.
Duration: 10
min.
Clinical Assessment Battery for Participants:
The Patient Reported Outcomes Measurement Information System – Anxiety
Short Form 8a (PROMIS-ASF)255 is an 8-item scale used to assess patient-reported
health status for anxiety. PROMIS instruments are funded by the National Institutes
of Health (NIH), developed using Item Response Theory (IRT) and used to reliably
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and validly measure patient-reported outcomes for clinical research and practice.
Participants are asked to rate their experience of the item in the past seven days on a
5-point scale from 1 (Never) to 5 (Always). With use of the PROMIS Assessment
Center Scoring Service, a T score is generated from participant responses. A sample
item includes “My worries overwhelmed me.” Duration: 3 min.
The Patient Reported Outcomes Measurement Information System – Pain
Interference 8a (PROMIS-PISF)255,256 The PROMIS Pain Interference instruments
measure the self-reported consequences of pain on relevant aspects of one’s life.
This includes the extent to which pain hinders engagement with social, cognitive,
emotional, physical, and recreational activities. Pain Interference also incorporates
items probing sleep and enjoyment in life, though the item bank only contains one
sleep item. The Pain Interference short form is universal rather than disease-specific.
It assesses pain interference over the past seven days. each question has five
response options ranging in value from one to five (for pediatrics and parent proxy it
is 0 to 4). To find the total raw score for a short form with all questions answered,
sum the values of the response to each question. For example, for the adult 6-item
form, the lowest possible raw score is 6; the highest possible raw score is 30. A
higher PROMIS T-score represents higher consequences of pain. Duration: 3 min.
The Beck Anxiety Inventory (BAI) consists of 21 items with a Likert scale ranging
from 0 to 3 and raw scores ranging from 0 to 63. It was developed in 1988257 and a
revised manual was published in 1993 with some changes in scoring245. The BAI
scores are classified as minimal anxiety (0 to 7), mild anxiety (8 to 15), moderate
anxiety (16 to 25), and severe anxiety (30 to 63). Duration: 5 min.
Oral Fluid Toxicology Testing95:
The minimally invasive nature of sample collection is a key advantage of oral fluid
over traditional biospecimens. An IDE is not required for these saliva tests because
they are non-invasive and are not being evaluated to determine safety or
effectiveness. The two dominant methods are collection of whole saliva by passive
drool and collection of saliva by absorbent material placed in the mouth. A sponge
method of collection will be used for oral fluid toxicology testing. Oral fluid
toxicology testing will be supervised via videochat with a study staff member to
ensure that there is no tampering with the collection.
Preparation: All subjects will be sent a package after enrollment and initial screening
with sponge-based oral fluid toxicology testing kits. Tests will be sent at screening to
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participants’ homes to be taken at randomly selected time points during the
intervention or control group (at least 9 samples will be collected for each participant
with at least 6 between weeks 13-24).
Prior to the online group, each group will also include a weekly check-in time before
group or during group, during which oral fluid tests will be performed via Zoom in
supervised breakout rooms with 3-6 randomly selected individuals each week
(during the last 12 weeks of the intervention or control group). This process takes
about 15 minutes in total. During this time, participants are required to video chat
with a research coordinator to ensure that the results are properly recorded and that
there is no tampering with the samples. First participants will unscrew the collector
cap and pull out the collection stick with the sponge from the collection chamber.
Next, participants will put the collector stick between their tongue and cheek to
collect oral fluid by swabbing the inside of their mouth and then gently chewing the
sponge until the saturation stick turns red; this takes a total of 3 minutes. Once this is
complete, participants remove the sponge from their mouth, and place the collection
stick into the collection chamber. Finally, participants secure the cap and shake three
times. At this time, the research coordinator will start the timer for 10 minutes and
ensure that the collection chamber will be in clear view. Afterwards, the research
coordinator will ask the participant to peel off the label. Results will be recorded by
a saved screenshot image using the secure HIPAA compliant tool “Droplr” 258. These
screenshots will be uploaded to Droplr’s cloud server before being transferred to
CHA’s secure google drive with the study ID and acrostic and date of test as the only
identifiers. The research coordinator will record the results in REDCap, which will
be double checked by another RC. Duration: 15 min.
These oral fluid toxicology screens can only be used for research purposes, as they
are not FDA cleared for clinical use. We will be clear with patients and providers
that these tests are only for research purposes. We will not provide any patient’s oral
fluid screen data to their provider, however we will refer to these results where
necessary to provide the full context of an AE and encourage them to conduct a
toxicology test with a clinically-approved urine toxicology screen. We will be clear
that providers cannot make a clinical decision that impacts their patients’ treatment
plan based on this research screen.
Weekly Survey: Participants will receive a weekly password protected REDCap
survey gathering information about their substance use in the last week, retention,
buprenorphine adherence, their level of care (e.g., at a detox residential place,
regular outpatient, primary care, etc.), enrollment in medication-assisted treatment,
as well as their Buprenorphine and Benzodiazepine (if applicable) dosages. This
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survey will be sent via an email link to the secure, encrypted REDCap database. If
this is impossible this information will be collected using a CHA-IT approved
device. Duration: 4 min
Pain Catastrophizing Scale (PCS): The Pain Catastrophizing Scale (PCS)259 is a
13-item scale designed to facilitate research on the mechanisms by which
catastrophizing impacts pain experience. Participants will be asked to indicate the
degree to which they experience certain thoughts and feelings when experiencing
pain (e.g. “I feel I can’t go on”) on a scale from 0 (“Not at all”) to 4 (“All the time”).
Duration: 3 min.
Substance Craving Scale (SUBCS): The Substance Craving Scale (SUBCS) is a
6-item scale adapted from the Opioid Craving Scale (OCS)260,261. The SUBCS
assesses participant craving for Opioids (including fentanyl, heroin, methadone,
oxycodone or other opioids) and other substance use (including illicit drugs [e.g.,
cocaine, methamphetamine, etc.], using unprescribed pills [e.g., Adderall, etc.],
using prescribed medication in ways or at doses for which they were not prescribed
[e.g., Klonopin, etc.], or drinking alcohol). Duration: 2 min.
Self-Regulation Battery:
Brief Experiential Avoidance Questionnaire (BEAQ)262: The 62-item
Multidimensional Experiential Avoidance Questionnaire (MEAQ) was recently
developed to assess a broad range of experiential avoidance (EA) content. However,
practical clinical and research considerations made a briefer measure of EA
desirable. Using items from the original 62-item MEAQ, a 15-item scale (BEAQ)
was created that tapped content from each of the MEAQ’s six dimensions. Items
were selected on the basis of their performance in 3 samples: undergraduates (n =
363), psychiatric outpatients (n = 265), and community adults (n = 215). These items
were then evaluated using 2 additional samples (314 undergraduates and 201
psychiatric outpatients) and cross-validated in 2 new, independent samples (283
undergraduates and 295 community adults). The resulting measure (Brief
Experiential Avoidance Questionnaire; BEAQ) demonstrated good internal
consistency. It also exhibited strong convergence with respect to each of the
MEAQ’s 6 dimensions. The BEAQ demonstrated expected associations with
measures of avoidance, psychopathology, and quality of life and was distinguishable
from negative affectivity and neuroticism. Duration: 3 min
The Difficulties in Emotion Regulation (DERS-16) Scale263,264 is a 16-item
self-report scale designed to assess emotional dysregulation. The scale is a shortened
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version of the original 36-item scale. The scale assesses 5 aspects of emotional
dysregulation: non-acceptance of emotional responses (“When I’m upset, I feel like
I am weak”), difficulties engaging in goal directed behavior (“When I’m upset, I
have difficulty thinking about anything else”), impulse control difficulties (“When
I’m upset, I lose control over my behaviors”), limited access to emotion regulation
strategies (“When I’m upset, ﻿I believe that there is nothing I can do to make myself
feel better”), and lack of emotional clarity (“﻿I have difficulty making sense out of my
feelings.”). Duration: 3 min.
The Perceived Stress Scale (PSS) Scale234 uses 14 items to measure the degree to
which situations in life are stressful. Items are designed to evaluate how overloaded,
unpredictable, and uncontrollable one finds one’s life. Each item is scored on a
5-point Likert scale from 0 (Never) to 4 (Very often). An example question is, “In
the last month, how often have you felt difficulties were piling up so high that you
could not overcome them?” Positively stated items are reverse scored before all
scale items are summed to yield a total score. Duration: 3 min.
The Self-Compassion Scale (SCS)265 is a 26-item Self-Compassion Scale. This
scale evaluates six different aspects of self-compassion: Self-Kindness (e.g., ‘‘I try to
be understanding and patient toward those aspects of my personality I don’t like’’),
Self-Judgment (e.g., ‘‘I’m disapproving and judgmental about my own flaws and
inadequacies’’), Common Humanity (e.g., ‘‘I try to see my failings as part of the
human condition’’), Isolation (e.g., ‘‘When I feel inadequate in some way, I try to
remind myself that feelings of inadequacy are shared by most people”), Mindfulness
(e.g., ‘‘When something painful happens I try to take a balanced view of the
situation’’), and Over-Identification (e.g., ‘‘When I’m feeling down I tend to obsess
and fixate on everything that’s wrong.’’). The scale is scored on a 5-point Likert
scale (1 = Almost never; 5 = Almost always), and negative subscale items are
reverse scored. Duration: 5 min.
The Multidimensional Assessment of Interoceptive Awareness (MAIA-2)266is a
37-item self-report scale designed to assess multiple aspects of interoception and
interoceptive awareness. This study will ask participants to complete 26 items
including subscales 1,4-8 of the MAIA. The adapted scale assesses 6 aspects of
interoceptive awareness: noticing (“I notice when I am uncomfortable in my body”),
attention regulation (“When I am in conversation with someone, I can pay attention
to my posture”), emotional awareness (“I notice that my breathing becomes free and
easy when I feel comfortable”), self-regulation (“When I am caught up in thoughts, I
can calm my mind by focusing on my body/breathing”), body listening (“I listen to
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my body to inform me about what to do”), and trusting (“I feel my body is a safe
place”). Duration: 5 min.
The Nonattachment to Self Scale (NTS)267 comprises 7 items rated on a
seven-point Likert scale (1 = strongly disagree; 7 = strongly agree) measuring the
degree to which the person releases fixation on self-related thoughts and feelings.
Sound psychometric properties were established including good reliability
(Cronbach's α = 0.84; test-retest reliability: r = 0.80), construct validity and criterion
validity267. Internal consistency was good in the present samples (Cronbach's α =
0.88 and 0.87 in the BD and general population sample respectively), and NTS was
found to be negatively associated with hypomanic symptoms in bipolar
population267,268. Duration 2 min.
The Self-Critical Rumination Scale (SCRS)269 is a 10-item scale measuring the
degree to which the person repeatedly evaluates themselves negatively. Specifically,
the scale measures constructs such as shame and self-criticism. Participants respond
on a 7-point Likert scale from “not at all” to “very well.” Sample items from the
scale include, “My attention is often focused on aspects of myself that I’m ashamed
of” and “I criticize myself a lot for how I act around other people.”
Experiences Questionnaire Decentering Subscale (EQD)
This is a subset of the 20-item self-report measure of experiences, consisting of 11
questions measuring decentering80. Decentering is conceptualized as a protective
factor and capable of measuring resilience to depressive relapse. The EQD uses a
5-point Likert scale with responses from “never” to “all the time”. A sample item
from the decentering subscale is “I can observe unpleasant feelings without being
drawn into them.” Psychometric properties are: reliability: Cronbach’s α = .89;
convergent validity: r > .46; and divergent validity: r < −.35270. Duration: 5 min.
Mechanism Battery
Interpersonal Mindfulness Scale (IMS)239: This is a 27-item scale that assesses
trait mindfulness in the context of interpersonal interactions and relationships.
Factors include Presence, Awareness of Self and Others, Nonjudgmental
Acceptance, and Nonreactivity. Sample items include: “I think about the impact my
words may have on another person before I speak” and “When I receive an angry
text/email from someone, I try to understand their situation before responding.”
Participants are asked to rate their response from 1 (almost never) to 5 (almost
always). Duration: 4 min.
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The Five Facet Mindfulness Questionnaire (FFMQ)271 is a 39-item scale that
examines five factors that represent aspects of the current empirical conception of
mindfulness.  These five facets include: observing, describing, acting with
awareness, non-judging of inner experience, and non-reactivity to inner experience.
An example item is “I pay attention to how my emotions affect my thoughts and
behavior.” Participants rate their degree of agreement with each of the items on a
Likert-type scale ranging from 1 (Never or very rarely true) to 5 (Very often or
always true), with higher scores indicating higher experience of mindfulness.
Duration: 6 min.
Attitudes about group survey:
The Attitudes about group survey is an adapted version of the Group Cohesion
Questionnaire (GCQ)272 which uses only the engagement subscale, consisting of 5
Likert scale questions that describe positive working group atmosphere. Duration: 2
min
Weekly Mindfulness Practice Diary Card:
The Weekly Mindfulness Practice Diary Card will be completed weekly while the
participant is attending groups (for participants in the M-ROCC intervention group).
Carmody et al273 emphasizes that improvements in mindfulness, symptoms, and
wellbeing are significantly related to formal and informal mindfulness practice.
This card is a 4-item survey that asks participants to specify the type and duration of
formal mindfulness techniques they completed each day for the past week, as well as
the type and frequency of informal techniques each day. Formal mindfulness
techniques include body scan, sitting meditation, loving kindness, mindful
movement, and informal mindfulness practices include techniques like connecting
with breath and mindful awareness of eating. The survey also asks about the type
and frequency of use community or mobile mindfulness resources. Mobile resources
might include apps such as Headspace, Stop/Breath/Think, or Insight Timer, and
community resources would include online recordings from the CMC or UCSD
websites. A participant’s total practice for the week will be calculated by study
personnel, based on the information on the diary card that will collected by group
leaders weekly. This will also be completed by all participants during the Follow-up
Survey Sessions, at participant study weeks 8, 16, and 24. This survey will be sent
via an email link to the secure, encrypted REDCap database. Duration: 2 min.
Weekly Recovery Skills Diary:
The Weekly Recovery Skills Diary will be completed weekly while the participant is
attending groups. This 5-item survey asks participants to specify the average number
of times per day (over the past week) that they have engaged in recovery-related
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activities. Sample items include “Choose to be honest with myself and others,” “Call
or meet up with other people in recovery or attend mutual support meetings,” and
“Avoid high-risk situations, such as triggers, people, or places that remind me of
opioids.” This survey will be sent via an email link to the secure, encrypted, password
protected REDCap database. Duration: 2 min.
Adverse Events Self-Reporting Battery:
The Adverse Event Patient Participant Self-Report Form will be systematically
assessed at each assessment time point (8-weeks, 16-weeks, and 24-weeks). In
addition, group leaders and research coordinators will be trained to identify and report
any adverse events that occur or are reported during weekly live-online group visits.
All AEs will be reviewed monthly by the PI, and SAE’s will be reviewed within 24
hours. Please see adverse events section (7.3) above. Duration: 2 min
Credibility/Expectancy Survey (OUD)
The Credibility/Expectancy Survey will be completed at week 2, after the
participant has been randomized to their study arm. This 6-item survey will assess
intervention expectancy and rationale credibility for the participant’s assigned
intervention arm in regards to opioid use reduction. An example question is “At this
point, how much do you really feel that this program will help you to reduce your
opioid use?”. Duration: 3 min.
Credibility/Expectancy Survey (Stress)
The Credibility/Expectancy Survey will be completed at week 2, after the
participant has been randomized to their study arm. This 6-item survey will assess
intervention expectancy and rationale credibility for the participant’s assigned
intervention arm in regards to stress reduction. An example question is “At this point,
how much do you really feel that this program will help you to reduce your stress?”.
Duration: 3 min.
10.2
Data Management
Data Storage and Data Sharing/Transfer
The below outlines data storage in this study, which data will be stored, and what PHI
will be stored if applicable. Only CHA IRB approved study staff will have access to
the below, which summarizes the entirety of data collected in this study. Data will not
be shared from CHA to primary care sites at other institutions. ATT will send
downloads of the coded CAT-MH data through a previously CHA IT-approved
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process on a weekly basis to our G-Drive. All data collection will be centralized to
the following locations below. Study staff will be the only individuals who have
access to the sources below. We will not collect any data that is not outlined below.
Data will flow one-way from participants to the data storage location, which will be
maintained and overseen by CHA. This information will be outlined in the participant
ICF. Participants may request access to their own attendance and oral fluid toxicology
screen results. The study team will mail these results on a monthly basis, and will not
make any recommendations for what constitutes appropriate use of these results.
CHA Secure G-Suite Databases: Secure CHA G-suite database access will be
granted through secure logins to CHA IRB approved study staff only. All data kept in
G-suite databases will be identified by study number only, with the exception of the
one linking sheet that links name and study number, and the G-suite folder where the
pdfs of consent form signatures are kept. CAT-MH data will be transferred by ATT to
a confidential G-suite Drive for CHA MindWell that they have access to deliver file
drops once a week. Study status tracking for each participant will be maintained on a
G-suite database. Audio-video recordings of group sessions will be recorded by
Zoom, saved to a coordinators computer but only accessible within the CHA Zoom
research account on the coordinator’s computer, then uploaded to a G-suite database
and erased from the coordinator’s computer Zoom account. Study status tracking for
each participant will be maintained on a G-suite database. Any notes taken by study
staff during any portion of the study will be recorded in a google document within our
secure G Drive. All study staff will be alerted to the fact that no paper notes will be
recorded throughout the trial due to privacy issues related to working from home
during COVID-19.
PHI kept on Secure G-suite databases:
Study Inquiry Contact Form: Name, phone number, email address
Screening database: Name, birthday, medical diagnosis, phone number,
email address
Uploaded recordings of zoom group sessions
Linking database: Name, study number, study acrostic
Consent form folder, stored in secure G-Suite drive separate from all
other study documents: PDFs of consent form signature pages uploaded
Secure REDCap Databases:
Electronically signed informed consent forms and informed consent assessments will
be stored in REDCap and completion will be visible from REDCap dashboard. All
participant survey responses will be kept in a secure REDCap database. Only CHA
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IRB-approved study staff will have access to these databases. REDCap (Research
Electronic Data Capture)274 is a secure, HIPAA compliant, web-based application
designed to support data capture for research studies. This platform provides the
following elements: 1) an intuitive interface for validated data entry; 2) audit trails for
tracking data manipulation and export procedures; 3) automated export procedures for
seamless data downloads to common statistical packages; and 4) procedures for
importing data from external sources. The REDCap software was developed by
Vanderbilt University and has been obtained and installed for usage at the Cambridge
Health Alliance. Online REDCap surveys will be emailed to participants using a
password protected link.
PHI kept on REDCap database: demographic and survey response data (home
address including street, unit/apartment number if applicable, city, state, and zip code,
e-mail address, and age), oral fluid toxicology screen results, BUP prescription
information (dose, frequency, dispense number, prescription date).
Online Database Storage: Given the online nature of this study and complications
associated with the COVID-19 pandemic, all data will be stored using online secure
databases.
CHA IT Electronic Device: If a participant does not have internet and video camera
access, they may receive a CHA IT approved iPhone SE smartphone with unlimited
data for the duration of the study in order to facilitate survey completion and group
adherence. Participants will be mailed these study phones after randomization to their
study arm. Alternatively, participants may receive reimbursement towards an
unlimited data upgrade in the form of an online gift card to facilitate survey
completion and group adherence, should they provide documentation of their data
plan upgrade. Participants will be able to use the phone to access REDCap survey
links, and to participate in groups via Zoom.
PHI kept on electronic devices: None.
Data Linkage to participants and access to data:
The secure web application REDCap will be used for data collection. Data will be
entered directly into REDCap by participants. Any data entry not conducted by
participants will be conducted only by members of the research team. All data
collection will take place under the supervision of the Principal Investigator (Dr.
Schuman-Olivier, MD) or a Research Coordinator. Substitute codes will be used to
label all sources of participant information and access to identifiable data will be
limited to researchers directly involved in the study. The Data Analyst will be
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responsible for coding data and exporting coded data from REDCap to STATA (14 or
newer version), R (3.5.3 or newer version), or SAS (9.4 or newer version). All
identifiable data will be destroyed 7 years after study completion and will not be
maintained for future uses not specified in this research plan.
Data Sharing
The data generated in this grant will be presented at national or international
conferences and published in a timely fashion. All final peer-reviewed manuscripts
that arise from this proposal will be submitted to the digital archive PubMed Central.
Primary outcome data will be deposited to appropriate public repositories (e.g.,
Harvard Dataverse, Open Science Framework) prior to the time the main study
findings are accepted for publication. This will be listed in the consent form.
We will ensure that the clinical trial is registered to ClinicalTrials.gov no later than 21
days after enrollment of the first participant, and that a summary of study results will
be available on ClinicalTrials.gov no later than 12 months after the primary
completion date. Informed consent documents for the study will include a specific
statement relating to posting of study information and results at ClinicalTrials.gov.
CHA has an internal policy in place to ensure that clinical trials registration and
results reporting occur in compliance with policy requirements.
Description of Plan for Data Quality and Management:
The PI and data analyst will review data collection, data completeness and accuracy
as well as protocol compliance on a monthly basis.
Survey session data will be entered by participants into REDCap only. The data
analyst will review all REDCap data collection forms on an ongoing basis for data
completeness and accuracy as well as protocol compliance and provide a monthly
report to the PI about missing data.
Adherence with expected study assessment visits will be reviewed twice monthly
with PI, and twice yearly by the study statistician and DSMB.
Frequency of Review―The frequency of data review for this study differs according
to the type of data and can be summarized in the following Data Quality Monitoring
Table.
Table 3. Data Quality Monitoring Table
Data type
Frequency
of review
Reviewer
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Study progress, recruitment, ICF
and I/E review, and safety
Weekly
Senior Research Coordinator
(SRC)
Data collection, data
quality/completeness/accuracy
protocol compliance
Weekly
Senior Research Coordinator
(SRC)
Study progress, recruitment,
participant accrual (including
compliance with protocol
enrollment criteria)
Monthly
PI, SRC,
Data Analyst
Data collection, data
quality/completeness/accuracy
protocol compliance
Monthly
Data Analyst, SRC, PI,
Participant accrual (including
compliance with protocol
enrollment criteria)
Twice-yearly
PI, Investigator Meeting,
DSMB
Status of all enrolled
participants, as of date reporting
Twice-yearly
PI, Investigator Meeting,
DSMB
Adherence data regarding study
visits and intervention
Twice-yearly
PI, Study Methodologist,
DSMB
AEs and study safety
Per occurrence &
Monthly
PI
Minor Protocol Deviations
Per occurrence &
Monthly
PI
Major Protocol Violations
Per occurrence
PI, IRB, DSMB, NCCIH
SAEs
Per occurrence
PI, IRB, DSMB
SAEs (unanticipated, serious,
and possibly related to study)
Per occurrence
PI, IRB, DSMB, NCCIH
10.3 Quality Assurance
10.3.1
Training
Intervention group leaders will be clinical staff. Groups will be co-led by a trained
CHA clinical staff member, along with a co-leader from either CHA or one of our
affiliated primary care sites, trained by CMC to administer M-ROCC. Group leaders
will not have access to any study documents or information. They will act in a study
capacity. Control group leaders will be required to have at least 1 year of prior
experience leading recovery support groups for patients with OUD.
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M-ROCC Group Leader Training:
M-ROCC has particular competencies which enable its effective delivery, including
use of MBI: TAC (Teaching Assessment Criteria)275 during group leader training and
fidelity
checklists from MTPC that include the inquiry behavior count fidelity structure
adapted from MBRP276. All group leaders have the capacity to embody the qualities
and attitudes of mindfulness within the process of the group leadership, to respond
deftly to affect emerging within the group with a mindful and compassionate stance.
All group leaders will have engaged in appropriate training, consisting of 8 weeks of
personal MBSR, at least 6 months of regular personal practice, and 40- hours of
MTPC group leader training, including a one-day workshop focused on the
application of mindfulness theory to the OUD MAT population. Every group leader
will commit to weekly mentorship for the first two MTPC-OUD cohorts and must
maintain an ongoing personal practice. Finally, group leaders recognize that the group
is part of a participatory learning and healing process, underpinned by recognition of
our ‘common humanity’277.
M-ROCC Group Leader Fidelity and Adherence
Fidelity and Adherence: MROCC group leaders will participate in videoconference or
in-person weekly mentorship during the time they are leading first two M-ROCC
groups (LDM and MTPC). All groups will be audio-recorded via zoom. In order to
prevent drift from the manual, 10% of session audio records will be reviewed by
trained experts, and all sessions will be assessed for adherence to the manual using
fidelity checklists that are completed by research coordinators participating in the
group.
We have enrolled 16 clinicians from five OBOT sites around Massachusetts into our
group leader training pipeline and 12 clinicians across eight sites completed the
four-day MTPC group leader training in March 2019, with future trainings planned
for sites to expand their group leader capacity. Additional training is available if new
staff join the site are interested in working with program. Within each institution,
there is the capacity for a clinician to help cover multiple primary care sites, but
clinicians can’t be shared between institutions. The Clinical Director at CHA may be
able to help with site coverage as a co-leader, if a time-limited coverage issue arises.
These trained group leaders at each site will have the opportunity to co-lead a group
with a trained CHA clinician with supervision.
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10.3.2
Quality Control Committee
The Senior Research Coordinator will review enrollment reports, adverse events, data
quality, missing data, database quality, event reports from group leaders, and other
aspects of quality control address study each week.
An MTPC Faculty mentor (Gawande) will review 10% of audio-recordings of the
intervention and review adherence checklists to ensure fidelity to the intervention.
Dr. Schuman-Olivier meets monthly with the senior research coordinator and data
analyst to review enrollment, adverse events, data quality, missing data, database
quality, event reports from group leaders, and other aspects of quality control.
10.3.3
Metrics
All self-report survey items for both primary and secondary measures are coded as
required fields in REDCap to prevent missed items. During the RCT group leader
fidelity checklists are reviewed each week by the clinical director or other member of
the fidelity assessment team. All data are checked each month for missingness within
each measure and for missing surveys, by the data analyst.
10.3.4
Protocol Deviations
Protocol deviations are captured weekly in the research assistant and research
coordinator meeting, which is overseen by the senior research coordinator, and in the
study implementation weekly meeting, which is overseen by the PI. Deviations are
documented in the Protocol Deviation log, which is reviewed monthly by the PI and
is reviewed twice yearly by the DSMB, and annually by the CHA IRB.
10.3.5
Monitoring
Data Safety Monitoring Board:
We will have a Data Safety Monitoring Board that meets twice yearly, consisting of 3
members, with at least one substance use clinician researcher with expertise in
Buprenorphine treatment (Joji Suzuki, MD), at least one member who has expertise in
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mindfulness-based interventions (Sarah Bowen, PhD), and at least one
epidemiologist/statistician (Linda Valeri, PhD).
Safety Review Plan:
Study progress and safety will be reviewed monthly (and more frequently if needed).
Progress reports, including participant recruitment, retention/attrition, and AEs, will
be provided to the DSMB every 6 months for the DSMB meeting. An Annual Report
will be compiled and will include a list and summary of AEs. In addition, the Annual
Report will address (1) whether AE rates are consistent with pre-study assumptions;
(2) reason for dropouts from the study; (3) whether all participants met entry criteria;
(4) whether continuation of the study is justified on the basis that additional data are
needed to accomplish the stated aims of the study; and (5) conditions whereby the
study might be terminated prematurely. The Annual Report will be sent to the DSMB
and will be forwarded to the IRB. The IRB and other applicable recipients will review
progress of this study on an annual basis. The PI will also send copies of signed
recommendations and comments from the DSMB to the NCCIH Program Officer
within 30 days of each monitoring review.
Study Report Outline for the DSMB (Interim or Annual Reports):
The study team will generate Study Reports for the DSMB and will provide
information on the following study parameters: rate of participant accrual and
compliance with inclusion/exclusion criteria, status of all enrolled participants,
adherence data regarding study visits and intervention, AEs, and protocol violations.
Study report tables will be generated only from aggregate (not by group assignment)
baseline and aggregate safety data for the study population. A separate Closed Safety
Report, with masked group baseline and safety data, will be generated for the DSMB
by a designated unmasked member of the team but will not be reviewed by the study
PI.
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) any new
information becomes available during the trial that necessitates stopping the trial; or
(3) other situations occur that might warrant stopping the trial.
The PI will include an assessment of futility (if relevant) in the annual progress report
to NIH (using statistical means such as predictive probability, if appropriate) and will
consult with the study monitors to assess the impact of significant data loss due to
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problems in recruitment, retention, or data collection. The study may also be
discontinued at any time by the IRB, the NCCIH, or other government agencies as
part of their duties to ensure that research participants are protected.
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY
11.1
Institutional Review Board (IRB) Review
This protocol and the informed consent document and any subsequent modifications
will be reviewed and approved by the IRB or ethics committee responsible for
oversight of the study.
11.2
Informed Consent Forms
Informed consent will be obtained during the Informed Consent Session as described
in Section 6 above. The consent session will begin with a verbal review of key
information about the study. The consent form will describe the purpose of the study,
the procedures to be followed, and the risks and benefits of participation. All
informed consent documents are approved and reviewed on an annual basis by the
CHA IRB. A signed consent form will be obtained from each participant. Given that
the intervention requires a 7th grade reading level and only adult participants can
enroll, we will not obtain informed consent for this study from a person who requires
a guardian.
11.3
Participant Confidentiality
All participants will be protected by a certificate of confidentiality automatically
issued through the NIH. Confidentiality will be ensured by use of a unique numeric
identification code and an acrostic that are unique to each study participant.
All research session data will be collected using standardized electronic forms on
designed using the REDCap database hosted by Cambridge Health Alliance. REDCap
(Research Electronic Data Capture) is a secure, web-based application designed to
support data capture for research studies, providing an intuitive interface for validated
data entry and export procedures to common statistical packages. All data
management will be conducted by the research team operating from CHA. All data
collection will take place under the supervision of the Dr. Schuman-Olivier or the
research coordinator. Data will only be collected by members of the research team.
Only CHA IRB-approved study staff will have access to the study REDCap
databases, including the Research Coordinators. All REDCap access will be password
protected. Site clinical staff will not have access to REDCap databases.
The name and birthday, will be entered into an initial CHA secured G-Suite database
strictly for the purpose of screening and consent process. A unique numeric identifier
and acrostic will be created for all participants who have completed an informed
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consent. The list linking any personal identifying information with the participant’s
study number and acrostic will be kept in a CHA secured G-suite file. All data will be
linked to these identifiers and no direct participant identifiers will be transmitted from
REDCap to STATA 14, R 3.5.3 or SAS 9.4 for analysis.
All further study data from survey sessions will be collected in a second REDCap
database, which will reference this unique numeric identifier and acrostic.
Database Protection:
Participant informed consent, screening forms, and course documents will be stored
in double-locked lockboxes or filing cabinets at each site. Copies of consent forms
will be transferred to double-locked file cabinets at the Center for Mindfulness and
Compassion.
Access to identifiable data will be limited to researchers directly involved in the
study. All identifiable data will be destroyed 7 years after study completion and will
not be maintained for future uses not specified in this research plan.
Minimization:
The risk of loss of confidentiality is judged to be minimal. Confidentiality will be
maintained by disguising identifying information through the assignment of a
numeric study number and an alphabetic study acrostic, and by keeping all data in the
secure REDCap application. Any coded or de-identified data will be maintained in
password protected databases. Participant information will be accessible only to study
staff. Information about study participants will not leave our institution in any form
that would identify individual participants. Data will be transmitted to STATA 14 or
SAS 9.4 in a pooled form with participants identified only by numeric code and
acrostic. In addition, we will ask group participants to agree to a group confidentiality
agreement. This agreement would require that information shared within the group
remain solely within the group. Study staff will also be required to use password
protected computers connected to password protected WiFi when working remotely.
Confidentiality During Adverse Event (AE) Reporting
AE reports and annual summaries will not include participant- or group-identifiable
material. Each report will only include the unique M-ROCC numeric identifier and
acrostic.
11.4
Study Discontinuation
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
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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.
During the funding of this study, any action by the IRB or one of the study
investigators that results in a temporary or permanent suspension of the study will be
reported to the NCCIH Program Official within 1 business day of notification.
12. COMMITTEES
The DSMB for this study includes Sarah Bowen, PhD, Linda Valeri, PhD, and Joji
Suzuki, MD. See DSMP for details.
13. PUBLICATION OF RESEARCH FINDINGS
Any presentation, abstract, or manuscript will be made available for review by
NCCIH prior to publication.
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