Brain Mechanisms of Reducing Polysubstance Use Following a Novel Body-mind Intervention
Phase: NA
Conditions: Multiple Drug Use
Sponsor: Texas Tech University

 
 
Brain Mechanisms of Reducing Polysubstance Use 
Following a Novel Body-mind Intervention  
Protocol Number: 03212020 
National Clinical Trial (NCT) Identified Number:  NCT04261504 
Principal Investigator: Yi-Yuan Tang, Ph.D. 
Sponsor: Texas Tech University 
Grant Title: Brain Mechanisms of Reducing Polysubstance Use Following a Novel 
Body-mind Intervention 
Grant Number: R61AT010138 
Funded by:  National Center for Complementary and Integrative Health 
Version Number:  v.1.1 
2020-03-21 
 
Summary of Changes 
Version 
Date 
1.0 
2019-02-27 
1.1 
2020-03-21 

Based on the NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the 
NIH terms of award.  
 

Brain Mechanisms of Reducing Polysubstance Use 
 
Version 1.1  
Protocol 0321020 
 
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Based on the NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 2 
1 
PROTOCOL SUMMARY ............................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................ 3 
1.2 
Schema ................................................................................................................................................. 3 
1.3 
Schedule of Activities .......................................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................................ 6 
2.1 
Study Rationale .................................................................................................................................... 6 
2.2 
Background ........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 6 
2.3.1 
Known Potential Risks ..................................................................................................... 6 
2.3.2 
Known Potential Benefits ................................................................................................ 7 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 7 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 8 
4 
STUDY DESIGN ............................................................................................................................................. 8 
4.1 
Overall Design ...................................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design ................................................................................................ 8 
4.3 
Justification for Intervention ............................................................................................................... 9 
4.4 
End-of-Study Definition ....................................................................................................................... 9 
5 
STUDY POPULATION .................................................................................................................................. 9 
5.1 
Inclusion Criteria .................................................................................................................................. 9 
5.2 
Exclusion Criteria ................................................................................................................................. 9 
5.3 
Lifestyle Considerations ...................................................................................................................... 9 
5.4 
Screen Failures .................................................................................................................................... 9 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 10 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ............................................ 10 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ...................................... 10 
6.1.1 
Study Intervention or Experimental Manipulation Description ................................. 10 
6.1.2 
Administration and/or Dosing ....................................................................................... 11 
6.2 
Fidelity ................................................................................................................................................. 11 
6.2.1 
Interventionist Training and Tracking .......................................................................... 11 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 11 
6.4 
Study Intervention/Experimental Manipulation Adherence .......................................................... 11 
6.5 
Concomitant Therapy ........................................................................................................................ 12 
6.5.1 
Rescue Therapy ............................................................................................................. 12 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................................... 12 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................. 12 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 12 
7.3 
Lost to Follow-Up ............................................................................................................................... 12 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 13 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 13 
8.2 
Safety Assessments .......................................................................................................................... 13 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 13 
8.3.1 
Definition of Adverse Events ........................................................................................ 13 
8.3.2 
Definition of Serious Adverse Events .......................................................................... 14 

Brain Mechanisms of Reducing Polysubstance Use 
 
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8.3.3 
Classification of an Adverse Event .............................................................................. 14 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 15 
8.3.5 
Adverse Event Reporting .............................................................................................. 15 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 15 
8.3.7 
Reporting Events to Participants ................................................................................. 15 
8.3.8 
Events of Special Interest ............................................................................................. 16 
8.3.9 
Reporting of Pregnancy ................................................................................................ 16 
8.4 
Unanticipated Problems .................................................................................................................... 16 
8.4.1 
Definition of Unanticipated Problems .......................................................................... 16 
8.4.2 
Unanticipated Problems Reporting .............................................................................. 16 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 17 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 17 
9.1 
Statistical Hypotheses ....................................................................................................................... 17 
9.2 
Sample Size Determination .............................................................................................................. 17 
9.3 
Populations for Analyses .................................................................................................................. 17 
9.4 
Statistical Analyses Plan................................................................................................................... 18 
9.4.1 
General Approach .......................................................................................................... 18 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 18 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 18 
9.4.4 
Safety Analyses .............................................................................................................. 18 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 18 
9.4.6 
Planned Interim Analyses ............................................................................................. 18 
9.4.7 
Sub-Group Analyses ..................................................................................................... 19 
9.4.8 
Tabulation of Individual Participant Data .................................................................... 19 
9.4.9 
Exploratory Analyses ..................................................................................................... 19 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 19 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 19 
10.1.1 
Informed Consent Process ........................................................................................... 19 
10.1.2 
Study Discontinuation and Closure ............................................................................. 19 
10.1.3 
Confidentiality and Privacy ........................................................................................... 20 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 21 
10.1.5 
Key Roles and Study Governance .............................................................................. 21 
10.1.6 
Safety Oversight ............................................................................................................. 21 
10.1.7 
Clinical Monitoring .......................................................................................................... 21 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 22 
10.1.9 
Data Handling and Record Keeping ............................................................................ 22 
10.1.10 
Protocol Deviations ........................................................................................................ 23 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 24 
10.1.12 
Conflict of Interest Policy .............................................................................................. 24 
10.2 
Additional Considerations ................................................................................................................. 24 
10.3 
Abbreviations and Special Terms ................................................................................................... 24 
10.4 
Protocol Amendment History ........................................................................................................... 26 
11 
REFERENCES ............................................................................................................................................. 27 
12 
ATTACHMENT ............................................................................................................................................. 28 
 

Brain Mechanisms of Reducing Polysubstance Use 
 
Version 1.1  
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Based on the NIH Protocol Template for Behavioral and Social Sciences Research 
 
1 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form(s) will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
 

Brain Mechanisms of Reducing Polysubstance Use 
 
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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines, as described in the Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
03-18-2024 
 
Name: Yi-Yuan Tang 
 
 
Title: Professor  
 
Investigator Contact Information 
Affiliation: Arizona State University 
Address: 425 N 5th St, Phoenix, AZ 85004  
Telephone: 4807903577 
Email: yiyuan@asu.edu 
 
 
 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Brain Mechanisms of Reducing Polysubstance Use Following a Novel 
Body-mind Intervention 
Grant Number: 
R61AT010138 
Study Description: 
The R61 phase of the study aims to understand the mechanisms and 
training effects of evidence-based body-mind training on self-control in 
polysubstance use. Specifically, it aims to understand brain mechanisms 
of improved self-control following an evidence-based preventive 
intervention - integrative body-mind training (IBMT). 
Objectives: 
 
Primary Objective: This study aims to examine brain mechanisms of 
improved self-control following IBMT. 
Endpoints: 
Primary Endpoint: Brain outcome 
Study Population: 
70 adults (both sexes) who are at least 18 years old with polysubstance 
use in the Lubbock, TX. 
Phase or Stage: 
N/A  
Description of 
Sites/Facilities Enrolling 
Participants: 
The participating site/facility is Texas Tech University, where 
enrollment of participants happens. There is no foreign site.  
Description of Study 
Intervention/Experimental 
Manipulation: 
Experimental manipulation is evidence-based preventive intervention - 
integrative body-mind training (IBMT) and will be offered as a group 
for 10 sessions across 4 weeks. 
Study Duration: 
12 months 
Participant Duration: 
3 months 
1.2 
SCHEMA  
 
 
 

Brain Mechanisms of Reducing Polysubstance Use 
 
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Figure 1. Flowchart of screening, inclusion, and assessment process 
 
Screening 
 
 
 
Visit 1 
Day 1 
 
 
 
 
 
 
 
 
 
 
 
 
Visits 2-11 
Day 3 ± 1 to  
Day 30 ± 1 
 
Visit 12 
Day 31 ± 2 
 
Visit 13 
Day 90 ± 2 
 
Total N: 70 
screen potential participants by inclusion and exclusion criteria; schedule Visit 1. 
Conduct informed consent process. Perform baseline assessments. 
 
Details refer to Section 1.3, Schedule of Activities 
Arm 2 
N = 35  
Arm 1 
N = 35  
Administer study intervention Session 1 to Session 10 
Randomize 
Post-Intervention assessments  
Follow-up assessments 
Details refer to Section 1.3, 
Schedule of Activities 

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1.3 
SCHEDULE OF ACTIVITIES  
 
 
 
 
Pre-screening 
 
 
Visit 1 
Day 1 
Visit 2 to Visit 
11 
Day 3 ±1 to Day 
30±1 
Visit 12 
 Day 31 ±2 
Visit 13 
Day 90 ±2 
Review Eligibility 
X 
 
 
 
 
Informed Consent 
 
X 
 
 
 
Demographics 
 
X 
 
 
 
Outcome Evaluation 
 
 
 
 
 
Brain Assessment (MRI 
scan) 
 
X 
 
X 
X 
Cognitive Assessment 
(Self-control tasks) 
 
X 
 
X 
X 
Randomization 
 
X 
 
 
 
Control & Experimental Interventions  
 
X 
X 
 
 
Adverse Events Reporting 
 
X 
X 
X 
X 

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2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
Polysubstance use ties with numerous consequences for adults, including poor performance, impaired 
driving, injuries, risky behaviors (e.g., unsafe sex), increased risk for substance use disorders (SUDs), and 
heightened risk for morbidity and mortality. Treatment outcomes, however, are far from optimal since 
treatments often fail to capitalize on important target domains linked to addiction outcomes. We propose 
to address this urgent and critical public health issue by examining the effectiveness of a brief evidence-
based mindfulness intervention – Integrative Body-Mind Training (IBMT) in adults with polysubstance use 
through randomized clinical trials (RCTs). We will examine if the intervention can improve brain function 
and structure in self-control related regions and networks, thereby reducing polysubstance use. 
Outcomes from this study will inform prevention and treatment option to promote health and well-being 
for individuals with polysubstance use. 
2.2 
BACKGROUND  
Tobacco use is the leading cause of cancer and the leading preventable cause of death. Alcohol use is 
responsible for ~88,000 deaths each year in the U.S. and is another primary preventable cause of cancer. 
The combined use of cigarettes and alcohol is associated with an increased risk of mortality and 
morbidity.1 Previous research shows that one target domain (mechanism) for polysubstance use involves 
deficits in self-control networks including the prefrontal cortex (PFC), the anterior cingulate cortex (ACC), 
and the ACC-Striatum circuit.31-33 Deficits in self-control have been linked to SUDs, and can be ameliorated 
through interventions.11,29-36 Mind Body Interventions such as mindfulness meditation (MM) have shown 
to decrease substance use and have the potential to minimize negative outcomes resulting from deficits 
in self-control.2,11,31-36 Although research suggest MM is efficacious at reducing problematic use, some 
studies are replete with limitations including the lack of: adequate control conditions, effective 
mindfulness programs, and assessments for biomarkers of change.37-39 As a result, the support for MM 
has been less robust in some work,40 thereby warranting more rigorous randomized controlled trials using 
appropriate MM program and active control, as well as standardized and theoretically driven 
assessments. Self-control/EF and attention deficits can be improved through brief intervention. Our 
preliminary RCTs in healthy adults provide support for our clinical trial by showing improvement in self-
control/EF, attention, cognitive functioning, emotion, stress reduction, and quality of life following brief 
IBMT intervention, 2-30 suggesting its potential effectiveness in adults with polysubstance use. 
2.3 
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
The study includes behavioral, cognitive, and brain assessments, as well as mindfulness-based 
intervention. 
Behavioral and Cognitive Assessments 
• 
Immediate risks: Potential boredom from completing the questionnaires and interviews.  
• 
Long-term risks: Data including self-report, questionnaires and interview involve risk of breaches 
in confidentiality. 

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• 
Alternative procedures: There are no other available alternative procedures to assess behavior and 
cognition, since to assess the behavior and cognition, we have to use the actual assessments. To 
minimize immediate risks, breaks in between questionnaires and interviews are offered to reduce 
boredom. To minimize long-term risks, all information about the specific individuals will be 
maintained as confidential. Absolutely no names of subjects are used in published reports or in 
presentations in scientific meetings. All data will be kept in locked files and digital media in the PI’s 
laboratory. Reference to individual subject data will be made with a number and letter code for 
each subject. Any risks to participants are minimal and are outweighed by the benefits of 
increasing our scientific understanding of improving self-control and reducing polysubstance use. 
Brain Assessments 
• 
Immediate risks: Potential boredom from completing the MRI scan, the possibility of becoming 
uncomfortable in the enclosed space of the scanner. 
• 
Long-term risks: MRI data involves risk of breaches in confidentiality. 
• 
Alternative procedures: There are no other available alternative procedures to brain, since to 
assess the brain, we have to use the actual MRI assessments.  
 
Mindfulness-based Intervention 
• 
Immediate risks: Potential boredom from completing the intervention.  
• 
Long-term risks: No known risk based on our previous studies1. 
• 
Alternative procedures: There are no other available alternative procedures, since the goal is to 
test the effects of the mindfulness-based intervention. To minimize immediate risks, breaks during 
the session are offered to reduce boredom.  
2.3.2 KNOWN POTENTIAL BENEFITS  
Immediate potential benefits 
The immediate potential benefits from participant in this study include that participants generally 
find the experimental paradigms enjoyable (i.e. meditation and relaxation state) during the 
intervention sessions1.  
Long-term potential benefits 
The long-term potential benefits include that participants have the opportunity to learn more 
about approaches and methods of improving self-control during the intervention and may be able 
to apply the learned knowledge in their everyday life and reduce polysubstance use.  
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Because this is a study that examines the effects of an intervention on behavior, cognition, and behavior, 
it is inevitable to expose participants to risk of boredom during their assessments and interventions, as 
these assessments and intervention are necessary for us to evaluate the effects of the intervention.  
 
To minimize immediate risks of potential boredom from completing the behavioral and cognitive 
assessments, brain assessments, and mindfulness-based intervention, breaks during the assessments and 
interventions are offered to reduce boredom and give participants time to rest. To minimize long-term 
risks, all information about the specific individuals will be maintained as confidential. Absolutely no names 
of subjects are used in published reports or in presentations in scientific meetings. All data will be kept in 

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locked files and digital media in the PI’s laboratory. Reference to individual subject data will be made with 
a number and letter code for each subject.  
Based on the risks of boredom and breach in confidentiality, as well as our approaches to minimize these 
risks, we conclude that any risks to participants are minimal and are outweighed by the benefits of 
increasing our scientific understanding of improving self-control in adults with polysubstance use, as well 
as the benefits of potentially having the participants learning ways to improve self-control and potentially 
reduce polysubstance use in their everyday life. 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
This study aims to investigate 
the modulation effects of a 
novel body-mind intervention 
on brain outcomes. 
 
 
 
 
Baseline and post-
intervention 
assessments of 
brain outcomes 
(functional activity 
in anterior 
cingulate 
cortex/medial 
prefrontal cortex). 
The novel body-mind 
intervention should lead to 
improvement in brain 
outcomes at post-intervention 
compared to baseline. 
Secondary 
 
 
N/A 
N/A  
 
 
N/A   
Tertiary/Exploratory  
 
 
N/A 
N/A  
 
 
N/A   
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
The study is a randomized control trial (RCT) involving two groups – IBMT (Arm 1: experimental 
manipulation) and RT (Arm 2: control group) group. Participants in each group will be assessed at 
baseline and post-intervention using behavioral and brain assessments as described in Section 1.3. 
Automatic randomization will be conducted by study staff and used to assign participants to each 
arm/group condition using an algorithm before the baseline assessment. This randomization 
procedure ensures balance between groups on gender while also balancing total treatment numbers.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
To evaluate the effects of our experimental manipulation, we need an active control group for this RCT 
study design. The RT has been used as a control condition in many previous published studies and is an 

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accepted control intervention. Thus, we use it as a control condition in our study design. There are no 
known or potential problems associated with the control group.3-5,8-12 
4.3 
JUSTIFICATION FOR INTERVENTION 
The chosen 10-sessions of experimental manipulation - IBMT has been shown to improve behavior, 
cognition, and brain in previous RCTs in healthy adults. Thus, we choose to use the same setup and design, 
and expect the same length and frequency of the intervention would be appropriate for adults with 
polysubstance use.  
4.4 
END-OF-STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed the baseline 
assessment, 10 intervention sessions, and post-intervention assessment.  
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. At least 18 years old 
2. Free of any psychiatric diagnoses or medication (besides a SUD to alcohol, tobacco, or cannabis 
3. In the past month, at least 4 episodes of heavy episodic drinking; at least 3 occasion of cannabis 
use; and daily cigarette use for at least the past month 
4. Normal or corrected-to-normal vision 
5. Written informed consent 
6. No previous meditation or neurofeedback experiences 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Any psychiatric diagnoses other than an SUD 
2. Medical disorder(s) that may affect the central nervous system; medications that affect the 
central and autonomic nervous system; or a positive pregnancy test result (females) 
3. Excluding cannabis, evidence of recent (past month) illicit drug use. 
5.3 
LIFESTYLE CONSIDERATIONS 
N/A 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently assigned to the study intervention or entered in the study. Individuals who do not meet the 
criteria for participation in this trial (screen failure) because of meeting one or more exclusion criteria that 
are likely to change over time may be rescreened. Examples include the successful removal of metal 

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devices that previously made them ineligible for an MRI scan. Rescreened participants will be assigned 
the same participant number as for the initial screening. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
We anticipate to enroll 70 participants (males and females) who are at least 18 years old across different 
race and ethnicity based on local demographic characteristics. Subjects will be recruited through print and 
media ads within local community. This will include radio and online ads and recruitment through social 
media. Flyers will be distributed throughout the local community. Based on our and other’s previous  
experiences in longitudinal studies, about 5-10% of participants will dropout over the study period  
due to illness or relocation. We plan a dropout rate of 20% for this brief intervention given the population 
is polysubstance users. We propose to recruit 70 adults of which 56 (80%) will complete the study.  
Compensation and Retention. Participants will be financially compensated with $300 in total for 
completing the study protocol (approximately for 15 hours of time); participants who only partially 
complete the protocol will be compensated based on prorated hours. To maximize participant retention 
we will maintain contact with participants over time via frequent assessment intervals (e.g., requiring a 
functioning phone number and email address to contact participants by phone or email as needed, and 
obtaining the name, address, and phone number of at least 2 friends or classmates who can provide 
contact information for the participants, should we be unable to contact them during the study; emails 
and reminder phone calls prior to all study visits; offer flexible scheduling options for assessment (including 
weekends); provide fair compensation to participants; and maintain positive relations with participants. 
These procedures were used to maintain adequate participant retention in our prior NIH studies. 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
Experimental Manipulation – IBMT (Arm 1): IBMT emphasizes the cooperation between body and mind in 
facilitating and achieving a meditative state ecologically.2-12 Each IBMT session is facilitated by an 
experienced coach who has demonstrated the ability to attain the appropriate state of body and mind, 
and to lead the group to achieve a similar state. The coach creates a harmonious and relaxed atmosphere, 
observes facial and body cues to identify those who are struggling with the method, and gives proper 
feedback for effective practice. IBMT coach helps subjects attain desired state by first providing a brief 
period to induce a cognitive or emotional state that will facilitate the training. Then, coach helps subjects 
find an appropriate and balanced body posture and follow instructions to achieve deeper levels of relaxed 
body (physiology of relaxation) and experience a restful feeling and mental quiet (psychology of 
relaxation) mindfully. When the mind wanders, the coach helps subjects accept and be open to 
experiences without judgment, and further guides subjects to use a favorite mental image as a tool to 
return to the present moment gently. At last, the coach facilitates a brief group discussion to ensure 
subjects having positive experiences consistent with the intent of IBMT. The method stresses no effort to 
control thoughts, but instead emphasizes a state of restful alertness that allows a high degree of 
awareness of the body, mind, and environment. 2-12 

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Control Intervention – RT (Arm 2): For RT, each session includes pre-, post- and practice sessions, similar 
to IBMT procedure and is facilitated by a trained coach. However, RT involves relaxing different muscle 
groups over the face, head, shoulders, arms, legs, chest, back, and so on, guided by the experienced and 
certified coach. With eyes closed and in a sequential pattern, one concentrates on the sensation of 
relaxation, such as feelings of warmth and heaviness. Therefore, RT includes relaxation and imagery (no 
mindfulness component) and could serve as an ideal active control. Along with other groups, we have been 
using RT as active control in our RCTs. 2-12 The progressive training helps achieve physical and mental 
relaxation and calmness.  
6.1.2 ADMINISTRATION AND/OR DOSING 
Both arms of interventions will be administered face-to-face as a group by trained interventionists. Both 
interventions will have 10 group sessions, and the completion of all 10 sessions is considered to be having 
a “full-dose” intervention. Participants in the same arm/group will interact with a shared interventionist.  
6.2 
FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
Explicit coach selection criteria and on-going monitoring and supervision of treatment delivery and fidelity 
will ensure that the interventions are of the highest quality, follow the protocols precisely, and prevent 
coach drift and contamination. For IBMT and RT, the coach must have a minimum of a master’s degree in 
psychology, social work, or a related field and experience running group therapy. The coach will need to 
meet additional criteria: have completed the trainer course, had a daily practice of mindfulness, and 
attended a silent meditation retreat. To monitor coach’s adherence and competence, all sessions will be 
recorded and a random sample of 10% will be rated by the investigators using the modified Adherence 
Scale to ensure the interventionist has adequate competence and adherence to the protocols, and to 
prevent drift. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
To minimize potential biases, participants are randomized based on automatic covariate conducted by Co-
I using an adaptive algorithm. Participants are blinded to the intervention. Specifically, they were told that 
they will be engaged in body-mind intervention, without knowing whether or not the intervention they 
received is the experimental manipulation or control intervention. See methods of analysis in Section 9, 
Statistical Considerations for details on randomization. Additionally, research staff who assesses 
participants are also blinded of the participants’ intervention condition. Randomization code is maintained 
by the Co-I. A planned breaking of randomization code and blinding would occur for any participants who 
reported serious adverse events. The PI and Co-I will identify which group the participant is in, without the 
need for research staff to be involved in knowing the participant’s intervention group.  
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
Participants’ adherence with study procedures will be tracked by taking their attendance at intervention 
visits. Moreover, in each session, we use participant self-report and coach observation to calculate study 
intervention adherence by the participant based on their engagement and quality of practice.  

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6.5 
CONCOMITANT THERAPY 
N/A 
6.5.1 RESCUE THERAPY 
N/A 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
If a clinically significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant management 
is needed. Any new clinically relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods for 
determining the need to discontinue 
• 
If the participant is due to complete assessments within 1 weeks of being discontinued from the 
study intervention, those assessments will be administered at the time of discontinuation; if the next 
scheduled assessments are more than 1 week from the discontinuation date, the next scheduled 
assessment will not be administered. Thereafter, the participant will be not included in all future 
scheduled assessments, as they did not participate in the intervention. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance, unless varying compliance is an aspect of the study 
objectives  
• 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up  
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
The reason for participant discontinuation or withdrawal from the study will be recorded. Subjects who 
sign the informed consent form and are randomized but do not receive the study intervention may be 
replaced. Subjects who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are discontinued from the study, will not be replaced. 
7.3 
LOST TO FOLLOW-UP 

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A participant will be considered lost to follow-up if he or she fails to return for 1 scheduled visit and study 
staff are unable to contact the participant after at least 3 attempts.  
 
The following actions must be taken if a participant fails to return for a required study visit: 
 
• 
The site will attempt to contact the participant, reschedule the missed visit within 1 week, counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods).  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
The study involves assessing participants at baseline, post-intervention, and one-month follow-up. The 
participant will be screened for eligibility after consenting. They will fill out demographic questionnaires 
and MRI screening form to determine their eligibility. Next, they will undergo behavioral and brain 
assessments by trained research staff and/or MRI technician. All non-brain assessments will be conducted 
at PI’s lab for all participants to decrease variability. All brain assessments will be conducted at Barrow 
Neurological Institute for all participants to decrease variability.    
 
Below is a list and description of the assessments: 
• 
Imaging assessments  
MRI Scan – provides images of brain structure and function 
• 
Administration of questionnaires, interviews 
Behavioral assessments – demographic questionnaire, subjective reports of polysubstance use 
8.2 
SAFETY ASSESSMENTS 
N/A 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
 
This protocol uses the definition of adverse event from 21 CFR 312.32 (a): any untoward medical 
occurrence associated with the use of an intervention in humans, whether or not considered intervention-
related. 
 

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8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
 
This protocol uses the definition of serious adverse event includes: (a) Death; (b) Hospitalization (initial or 
prolonged); (c) Life-threatening condition; (d) Disability or Permanent Damage; (e) Other Serious 
(Important Medical Events). 
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will 
be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
All adverse events (AEs) will have their relationship to study procedures, including the intervention, 
assessed by an appropriately-trained clinician based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below.  
 
• 
Related – The AE is known to occur with the study procedures, there is a reasonable possibility 
that the study procedures caused the AE, or there is a temporal relationship between the study 
procedures and the event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study procedures and the AE. 
• 
Not Related – There is not a reasonable possibility that the study procedures caused the event, 
there is no temporal relationship between the study procedures and event onset, or an alternate 
etiology has been established. 
 
8.3.3.3 EXPECTEDNESS  
 
A clinician with appropriate expertise in medical care will be responsible for determining whether an 
adverse event (AE) is expected or unexpected. An AE will be considered unexpected if the nature, severity, 
or frequency of the event is not consistent with the risk information previously described for the study 
procedures. 

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8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report form 
(CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study procedures (assessed only by those with the training and authority to make 
a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study will be 
documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 
PI will record events with start dates occurring any time after informed consent is obtained until 7 (for 
non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed for 
outcome information until resolution or stabilization. 
8.3.5 ADVERSE EVENT REPORTING  
In consultation with the PI, a trained member of the study team will be responsible for conducting an 
evaluation of an adverse event and shall report the results of such evaluation to the NIH and the reviewing 
Institutional Review Board (IRB) as soon as possible, but in no event later than within 24 hours after the 
investigator first learns of the event. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
In consultation with the PI, a trained member of the study team will be responsible for conducting an 
evaluation of a serious adverse event and shall report the results of such evaluation to the NIH and the 
reviewing Institutional Review Board (IRB) as soon as possible, but in no event later than within 24 hours 
after the investigator first learns of the event. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
The PI will be responsible for reporting AEs or SAEs related to the study to participants as soon as possible, 
but in no event later than within 24 hours after the investigator first learns of the event. 

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For incidental findings from MRI brain scan, the MRI facility will inform the PI if there is incidental finding 
and the PI will report the finding to participants as soon as possible, but in no event later than within 24 
hours after the investigator first learns of the event. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
N/A 
8.3.9 REPORTING OF PREGNANCY  
N/A  
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human Research 
Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or others to 
include, in general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will include 
the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• 
A detailed description of the event, incident, experience, or outcome  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   

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• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor/funding agency within 10 business days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor/funding agency within 10 
business days of the investigator becoming aware of the problem  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 10 business days of the IRB’s receipt of the report of 
the problem from the investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
The PI will be responsible for reporting UPs related to the study to participants as soon as possible, but in 
no event later than 10 working days after the investigator first learns of the UP. 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Endpoint(s):  
We hypothesize that, compared to participants who receive a RT control intervention, participants 
who receive IBMT for improving brain outcomes will have improved anterior cingulate cortex/medial 
prefrontal cortex functional activity after completing the intervention at post-assessment. 
Alternatively, our null hypothesis is that there will be no difference in the effects of IBMT for improving 
brain outcomes and those of RT at post-assessment. 
9.2 
SAMPLE SIZE DETERMINATION 
Our RCT design is focused on determining if within-person brain changes significantly differ across the 
intervention groups. All participants in this study will be those who use polysubstance. In prior work 
involving smokers (N = 27), we detected significant fMRI signal changes in the ACC/mPFC (Cohen’s d= .90) 
after 2-wk of IBMT than before IBMT 11,24. Compensating for the expected variability of findings in 
ACC/mPFC activity in polysubstance use, we thus expect a conservative, medium to large (Cohen’s d = .80) 
effect (i.e., we expect the effect size between the intervention and control conditions to be 0.80 at post-
intervention) based on ours and other studies.8-11,41,42 However, we may expect polysubstance users to be 
somewhat more variable. Given the power considerations, we increased our sample size to 35 per group, 
which will give us 90% power to detect fMRI signal changes evoked by IBMT. The target sample size for 
the proposed study in the R61 phase (n = 70; 35/condition) is designed to provide sufficient evidence to 
detect significant brain changes in ATC users following interventions. Given we anticipate up to 20% 
attrition across the R61 phase of the study, power analysis suggests adequate power.  
9.3 
POPULATIONS FOR ANALYSES 
The analysis population will be Modified Intention-to-Treat Analysis Population. Specifically, these 
participants are those who completed the full-dose of the intervention (10 sessions) and have 
completed data for the primary endpoint.  

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9.4 
STATISTICAL ANALYSES PLAN 
9.4.1 GENERAL APPROACH 
Behavioral and brain data analysis will undergo separate analyzing streams to test intervention effects 
and underlying mechanisms at baseline and post-intervention. Given the scope of this 2-year R61 
project, the logical first step at this early stage of research is to examine the potential intervention 
effects and mechanisms, then move to the full scale RCTs for R33 phase. To address our study Aims, 
repeated-measures ANOVA will be used. By utilizing all assessment points, this approach allows for 
well-powered tests to detect significant differences in changes across the experimental conditions, 
even when assuming smaller magnitude effect sizes. Effect size measures (from the repeated-
measures ANOVA, Cohen’s d highlighting mean differences between treatment and control groups 
across assessments) will also be calculated to describe the intervention’s effect on study outcomes. 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
The primary endpoints are brain assessments and are all repeated measures assessed at baseline and post-
intervention. For brain assessment of brain assessment of functional activity, whole-brain analyses of fMRI 
timeseries during resting state will be calculated and for all endpoints based on standardized processing 
pipelines of fMRI data using REST software (www.restfmri.net). After these data preprocessing and 
calculation, numerical values will be generated for each brain voxel. Next, the effects of intervention (IBMT 
vs. RT) on primary endpoints will be examined using repeated-measures ANOVA with time x group 
interaction effect. Threshold-free cluster enhancement approach will be used to identify clusters showing 
significant effects. Variance and covariance across repeated measures will be calculated as part of the 
ANOVA. Age and sex will be included as covariates to control for potential confounding effects of age and 
sex on brain outcomes. Results will be presented as F values for the interaction effect, along with p values 
to indicate statistical significance. Normality and homogeneity of variance assumptions will be checked 
using SPSS built-in tools for ANOVA. Multiple comparison corrections will be conducted using FDR 
correction. Missing data will be handled with case-wise deletion. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
N/A 
9.4.4 SAFETY ANALYSES 
N/A 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Intervention groups will be compared on baseline characteristics including demographics and behavioral 
assessments of polysubstance use using independent samples t-tests.  
 
9.4.6 PLANNED INTERIM ANALYSES  
 N/A 
 

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9.4.7 SUB-GROUP ANALYSES 
Sub-group analyses will not be conducted for primary and secondary outcomes for this pilot study, as the 
sample size of sub-groups (N<10) based on age, sex, race/ethnicity or other demographic characteristic(s) 
will not be sufficient to conduct meaningful group analyses. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will not be tabulated as the goal of the study is to examine group effects. 
 
9.4.9 EXPLORATORY ANALYSES 
N/A 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to the 
participant and written documentation of informed consent will be completed prior to starting the study 
intervention.  The following consent materials are submitted with this protocol: 1. Consent Form. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent will be administered by a member of the study team to the participant. The team 
member will give the participant a brief overview of the consent form and summarize relevant information 
from each section of the consent form. Participants will then be given time to read the consent form on 
their own. The study population involves English speaking cognitively normal adults, so no special 
procedures are needed to obtaining the consent. Participants will be asked if they understand and 
comprehend the consent form and if they have any questions. These procedures serve as means for 
determining competency and assessing comprehension/understanding of the participants. Any questions 
the participants may have will be answered by the team member. Finally, participants are asked to indicate 
if they would like to enroll in the study or not by signing or not signing the consent form. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 

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by the suspending or terminating party to study participants, funding agency, and regulatory authorities. 
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform 
study participants, the Institutional Review Board (IRB), and sponsor/funding agency and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance of study staff to the protocol (ie, significant protocol violations) 
• 
Pandemic, such as COVID-19 
 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the funding agency, sponsor, IRB, Food and Drug Administration (FDA), or other relevant 
regulatory or oversight bodies (OHRP, DSMB). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a specific 
study participant will be held in strict confidence within the research team. No personally-identifiable 
information from the study will be released to any unauthorized third party without prior written approval 
of the sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor or funding agency, representatives of 
the Institutional Review Board (IRB), regulatory agencies, may inspect all documents and records required 
to be maintained by the investigator. The study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at the study site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a 
period as dictated by the reviewing IRB, Institutional policies, or sponsor/funding agency requirements. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should be made available 
to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms used to 
share data will include proper plans and safeguards for the protection of privacy, confidentiality, and 
security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not be 
traceable to a specific study participant). Plans for archiving and long-term preservation of the data will 
be implemented, as appropriate.  
 
Certificate of Confidentiality  

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To further protect the privacy of study participants, the Secretary, Health and Human Services (HHS), has 
issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, clinical 
or other human subjects research funded wholly or in part by the federal government.  Recipients of NIH 
funding for human subjects research are required to protect identifiable research information from forced 
disclosure per the terms of the NIH Policy (see https://humansubjects.nih.gov/coc/index). As set forth 
in 45 CFR Part 75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported research covered 
by this Policy are required to establish and maintain effective internal controls (e.g., policies and 
procedures) that provide reasonable assurance that the award is managed in compliance with Federal 
statutes, regulations, and the terms and conditions of award. It is the NIH policy that investigators and 
others who have access to research records will not disclose identifying information except when the 
participant consents or in certain instances when federal, state, or local law or regulation requires 
disclosure. NIH expects investigators to inform research participants of the protections and the limits to 
protections provided by a Certificate issued by this Policy. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at the study site. After the study is completed, 
the de-identified, archived data will be transmitted to and stored at the study site’s secured data storage 
space. The use of the de-identified data by other researchers including those outside of the study will be 
granted per reasonable requests.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Independent Data Safety 
Monitor 
Yi-Yuan Tang, Ph.D., Professor 
Elliot Stein, Ph.D., Investigator 
Arizona State University  
National Institute on Drug Abuse 
425 N 5th St, Phoenix, AZ 85004 
251 Bayview Boulevard Suite 
200, Baltimore, MD 21224 
4807903577 
4437402650 
yiyuan@asu.edu 
stein@mail.nih.gov 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including clinical trials and intervention. Members of the DSMB 
will be independent from the study conduct and free of conflict of interest. The DSMB will meet at least 
semiannually to assess safety and efficacy data from each arm of the study. The DSMB will operate under 
the rules of an approved charter that will be written and reviewed at the organizational meeting of the 
DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB 
will provide its input to NCCIH via annual report. 
 
10.1.7 CLINICAL MONITORING 

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Clinical site monitoring will be conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with International 
Council on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s). Monitoring activities will be conducted by the study site itself, so please see Section 
10.1.8, Quality Assurance and Quality Control. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The study site will perform internal quality management of study conduct, data collection, documentation 
and completion. Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process as well as 
a percentage of the completed consent documents.  This review will evaluate compliance with GCP, 
accuracy, and completeness.  Feedback will be provided to the study team to ensure proper consenting 
procedures are followed.  
 
Source documents and the electronic data --- Data will be initially captured on source documents (see 
Section 10.1.9, Data Handling and Record Keeping) and will ultimately be entered into the study 
database.  To ensure accuracy site staff will compare a representative sample of source data against the 
database, targeting key data points in that review. 
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and will 
implement corrective actions when the quantity or nature of deviations are deemed to be at a level of 
concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all trial related 
sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 

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Data collection will be the responsibility of study team at the site under the supervision of the site 
investigator. The investigator will be responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant consented/enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents will be consistent with the data recorded on the 
source documents.  
 
Clinical data (including adverse events (AEs) and SAEs will be entered into RedCap provided by the study 
site. The data system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents will be retained for a minimum of 2 years after the study completion date. These 
documents should be retained for a longer period, however, if required by local regulations. No records 
will be destroyed without the written consent of the sponsor/funding agency, if applicable. It is the 
responsibility of the sponsor/funding agency to inform the investigator when these documents no longer 
need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
International Council on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) 
requirements. The noncompliance may be either on the part of the participant, the investigator, or the 
study site staff. As a result of deviations, corrective actions will be developed by the site and implemented 
promptly.  
 
These practices are consistent with ICH GCP:  
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
 
It will be the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 10 working days of identification of the protocol deviation, or within 10 working days of 
the scheduled protocol-required activity. All deviations will be addressed in study source documents, 
reported to NCCIH Program Official and NCCIH. Protocol deviations will be sent to the reviewing 

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Institutional Review Board (IRB) per their policies. The site investigator will be responsible for knowing 
and adhering to the reviewing IRB requirements. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals.  Data from this study may be requested from other researchers 10 years after the completion of 
the primary endpoint by contacting PI Yi-Yuan Tang.  Considerations for ensuring confidentiality of these 
shared data are described in Section 10.1.3. 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this trial. The study leadership in 
conjunction with the NCCIH has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CFR 
Code of Federal Regulations 
COC 
Certificate of Confidentiality 
DSMB 
Data Safety Monitoring Board 

Brain Mechanisms of Reducing Polysubstance Use 
 
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EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
fMRI 
Functional Magnetic Resonance Imaging 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
IBMT 
Integrative Body Mind Training 
ICH 
International Council on Harmonisation  
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
RT 
Relaxation Training 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
SUD 
Substance Use Disorder 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
02/27/2019 
Initial protocol 
Initial protocol 
1.1 
03/21/2020 
Added COVID screening and updated 
subject payment 
Modification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. McGinnis, J. M., Foege, W. H. (1999). Mortality and morbidity attributable to use of addictive substances in the 
United States. Proceedings of the Association of American Physicians. 111(2), 109-118. 
2. Tang, Y. Y. (2017). The Neuroscience of Mindfulness Meditation: How the Body and Mind Work Together to 
Change Our Behavior? Springer Nature 
3. Tang, Y. Y., Ma, Y., Wang, J., Fan, Y., Feng, S., Lu, Q., Yu, Q., Sui, D., Rothbart, M. K., Fan, M., Posner, M. I. (2007). 
Short-term meditation training improves attention and self-regulation. Proceedings of the National Academy of 
Sciences, 104(43), 17152-17156. 
4. Tang, Y. Y., Fan Y, Lu Q, Tan LH, Tang R, Kaplan R, Pinho, M.C., Thomas, B.P., Che K, Friston KJ, Reiman EM. 
(2020). Comparison of long-term physical exercise and meditation practice in an aging population. Frontiers in 
Psychology. 11:358 
5. Tang, Y. Y., Ma, Y., Fan, Y., Feng, H., Wang, J., Feng, S., Lu, Q., Hu, B., Lin, Y., Li, J., Zhang, Y., Wang, Y., Zhou, L., 
Fan, M. (2009). Central and autonomic nervous system interaction is altered by short-term meditation. 
Proceedings of the National Academy of Sciences, 106(22), 8865-8870. 
6. Tang, Y. Y., Tang R, Gross JJ. (2019). Promoting emotional well-being through an evidence-based mindfulness 
training program. Frontiers in Human Neuroscience. 13:237 
7. Tang, Y. Y., Holzel, B.K., Posner, M.I. (2015). The neuroscience of mindfulness meditation. Nature Reviews 
Neuroscience, 16(4), 213-225  
8. Tang, Y. Y., Lu, Q., Geng, X., Stein, E. A., Yang, Y., Posner, M. I. (2010). Short-term meditation induces white 
matter changes in the anterior cingulate. Proceedings of the National Academy of Sciences, 107(35), 15649-15652. 
9. Tang, Y. Y., Lu, Q., Fan, M., Yang, Y., Posner, M. I. (2012). Mechanisms of white matter changes induced by 
meditation. Proceedings of the National Academy of Sciences, 109(26), 10570-10574. 
10. Tang, Y. Y., Tang Y, Tang R, Lewis-Peacock J. (2017). Brief mental training reorganizes large-scale networks. 
Frontiers in Systems Neuroscience, 11:6 
11. Tang, Y. Y., Tang, R., Posner, M. I. (2013). Brief meditation training induces smoking reduction. Proceedings of 
the National Academy of Sciences, 110(34), 13971-13975. 
12. Tang, Y. Y., Lu Q, Feng H, Tang R, Posner MI. (2015). Short-term meditation increases blood flow in anterior 
cingulate cortex and insula. Frontiers in Psychology, 6:212. 
13. Tang, Y. Y., Yang, L., Leve, L. D., Harold, G. T. (2012). Improving executive function and its neurobiological 
mechanisms through a mindfulness‐based intervention: Advances within the field of developmental 
neuroscience. Child development perspectives, 6(4), 361-366.14) Tang, Y. Y. (2009). Exploring the brain, 
optimizing the life. Beijing: Science Press. 
14. Tang, Y. Y. (2017). Brain-Based Learning and Education: Principle and Practice. Academic Press, 
Elsevier 
15. Tang, Y. Y., Tang R. (2020). The Neuroscience of Meditation: Understanding Individual Differences. 
Academic Press, Elsevier 
16. Tang, Y. Y., Posner, M. I. (2009). Attention training and attention state training. Trends in cognitive 
sciences, 13(5), 222-227. 
17. Fan, Y., Tang, Y. Y., Tang, R., Posner, M.I. (2014). Short term integrative meditation improves resting 
alpha activity and Stroop performance. Applied Psychophysiology and Biofeedback, 39(3-4), 213-7. 
18. Fan, Y., Tang, Y. Y., Tang, R., Posner, M.I. (2015). Time course of conflict processing modulated by 
brief meditation training. Frontiers in Psychology, 6: 911 
19. Ding, X., Tang, Y. Y., Cao, C., Deng, Y., Wang, Y., Xin, X., Posner, M.I. (2015). Short-term meditation 
modulates brain activity of insight evoked with solution cue. Social Cognitive and Affective 
Neuroscience, 10(1), 43-9. 
20. Ding, X., Tang, Y. Y., Tang, R., Posner, M.I. (2014). Improving creativity performance by short-term 
meditation. Behavioral and Brain Functions, 10:9 
21. Ding, X., Tang, Y. Y., Deng, Y., Tang, R., Posner, M.I. (2015). Mood and personality predict 
improvement in creativity due to meditation training. Learning and Individual Differences, 37, 217-221 

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22. Fan, Y., Tang, Y. Y., Posner, M. I. (2014). Cortisol level modulated by integrative meditation in a dose‐
dependent fashion. Stress and Health, 30(1), 65-70. 
23. Fan, Y., Tang, Y. Y., Ma, Y., Posner, M.I. (2010). Mucosal immunity modulated by integrative meditation in a 
dose dependent fashion. J Altern Complement Med. 16(2):151-5 
24. Tang, Y. Y., Posner, M. I., Rothbart, M. K., Volkow, N. D. (2015). Circuitry of self-control and its role in reducing 
addiction. Trends in cognitive sciences, 19(8), 439-444.  
25. Xue S, Tang, Y. Y., Tang R, Posner MI. (2014). Short-term meditation induces changes in brain resting EEG theta 
networks. Brain and Cognition, 87, 1-6.  
26. Xue S, Tang, Y. Y., Posner MI. (2011). Short-term meditation increases network efficiency of the anterior 
cingulate cortex. NeuroReport, 22(12): 570-4 
27. Tang, Y. Y., Rothbart, M. K., Posner, M. I. (2012). Neural correlates of establishing, maintaining, and switching 
brain states. Trends in cognitive sciences, 16(6), 330-337. 
28. Tang, Y. Y., Posner MI. (2014). Training brain networks and states. Trends in Cognitive Sciences, 18(7):345-50  
29. Tang, Y. Y., Tang, R., Posner, M. I. (2016). Mindfulness meditation improves emotion regulation and reduces 
drug abuse. Drug and alcohol dependence, 163, S13-S18. 
30. Fan, Y., Cui, Y., Tang, R., Sarkar, A., Mehta, P., Tang, Y. Y. (2024). Salivary testosterone and cortisol response to 
stress modulated by short-term meditation. Stress. 27:2316041. 
31. Baler, R. D., Volkow, N. D. (2006). Drug addiction: the neurobiology of disrupted self-control. Trends in 
molecular medicine, 12(12), 559-566. 
32. Posner, M. I., Rothbart, M. K., Sheese, B. E., Tang, Y. (2007). The anterior cingulate gyrus and the mechanism of 
self-regulation. Cognitive, Affective, Behavioral Neuroscience, 7(4), 391-395. 
33. Kelley, W. M., Wagner, D. D., Heatherton, T. F. (2015). In search of a human self-regulation system. Annual 
review of neuroscience, 38, 389-411. 
34. Goldstein, R. Z., Volkow, N. D. (2011). Dysfunction of the prefrontal cortex in addiction: neuroimaging findings 
and clinical implications. Nature reviews neuroscience, 12(11), 652-669. 
35. Bowen, S., Witkiewitz, K., Dillworth, T. M., Chawla, N., Simpson, T. L., Ostafin, B. D., Larimer, M. E., Blume, A. 
W., Parks, G. A., Marlatt, G. A. (2006). Mindfulness meditation and substance use in an incarcerated population. 
Psychology of addictive behaviors, 20(3), 343-347. 
36. Bowen, S., Witkiewitz, K., Clifasefi, S. L., Grow, J., Chawla, N., Hsu, S. H., Carroll, H. A., Harrop, E., Collins, S. E., 
Lustyk, K. M., Larimer, M. E. (2014). Relative efficacy of mindfulness-based relapse prevention, standard relapse 
prevention, and treatment as usual for substance use disorders: a randomized clinical trial. JAMA psychiatry, 71(5), 
547-556. 
37. Black, D. S. (2012). Mindfulness and substance use intervention. Substance use & misuse, 47(3), 199-201. 
38. Chiesa, A., Serretti, A. (2014). Are mindfulness-based interventions effective for substance use disorders? A 
systematic review of the evidence. Substance use & misuse, 49(5), 492-512. 
39. Zgierska, A., Rabago, D., Chawla, N., Kushner, K., Koehler, R., Marlatt, A. (2009). Mindfulness meditation for 
substance use disorders: a systematic review. Substance Abuse, 30(4), 266-294. 
40. Khoury, B., Lecomte, T., Fortin, G., Masse, M., Therien, P., Bouchard, V., Chapleau, M., Paquin, K., Hofmann, S. 
G. (2013). Mindfulness-based therapy: a comprehensive meta-analysis. Clinical psychology review, 33(6), 763-771. 
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12 ATTACHMENT  
 
 
 
 

Dear Participant: 
 
The funded ''Brain mechanisms of reducing polysubstance use following a novel body-mind intervention'' study is 
seeking your participation to understand brain mechanisms and training effects in those who may use alcohol, 
tobacco, or cannabis. The study will enable us to examine the potential mechanisms of meditation training and 
its effects on behavioral changes. 
 
What would I do if I participate? 
You will first take online questionnaires and interviews for qualifying the study, then you sit down a chair 
comfortably while receiving meditation and/or neurofeedback training. Prior to training, we will measure behavior 
via self-reports and simple physiological indexes such as breath rate or heart rate to reflect your states such as 
alert and sleepy using non-invasive portable equipment. We will measure brain activity using non-invasive and 
widely used fMRI (3 scans about 60 min each). This procedure is well-defined in the extant literature. The 
respective time for the first and last visit will be approximately 50-60 min. Without measurements, you will receive 10 
sessions of training lasting approximately 60 minutes each. The total study is expected to take about 15 hours. 
 
How will I benefit from participating? 
We would like to show our appreciation for your participation by giving you up to $300 in total after completion. If 
you do not complete the study, the payment will be prorated based on the time of task completed. You can also 
learn valuable information about how training may affect performance and behavior. 
 
Can I quit if I become uncomfortable? 
Your participation is completely voluntary, and you can choose to end the session at any time without penalty. 
While you will not receive the full incentive if you do not complete the study, you will receive a prorated incentive 
based on the time of task completed. We will use all available data unless you indicate otherwise. Because of the 
enclosed space, a few people become uncomfortable or anxious. If this happens to you, we will stop immediately.  
  
What are the risks and/or discomforts to me if I join this study? 
There is very little risk to you for participation in this study. Many individuals report experiencing relaxation and 
calmness. As part of the fMRI scan, you will be continuously monitored throughout the scan. If you have a 
pacemaker or some metal objects in your body, you will not be allowed to be in this study because of the strong 
magnet fields in the MRI scanner. Another risk is the possibility of metal objects being pulled into the magnet and 
potentially hitting you. To eliminate this risk, you will need to remove anything metal from your clothes, any metal 
piercings, and anything metal from your pockets. You will also walk through a metal detector (like airport 
scanners) when you come into the magnet chamber. It is important to know that no metal can be brought into the 
magnet room at any time. Once you are in the scanner, the door to the room will be closed so that no metal from 
outside accidentally goes near the magnet.   
  
How are you protecting privacy? 
Any information gathered for our study will remain confidential, and published reports will not mention individuals. 
Your file will be given a code number that will be used for identification, rather than a name. Only staff members 
working on this project have access, which will be used strictly for research purposes. The data collected, without 
any personally identifiable information, may be used in other research studying the effects of training in 
collaboration with this study. Any data that may be published in scientific journals will not reveal the identity of the 
participants. 
 
I have some questions about this study. Who can I ask? 
If you have any questions about the research, please call or write to Dr. Yi-Yuan Tang at yiyuan.tang@ttu.edu; 
806-742-3711. If you have any questions about your rights as a participant, or in the event of a research-related 
problem or concern, please contact TTU Human Research Protection at 806-742-2064.  
 
Your signature below indicates that you have read and understood the information provided above; that you willingly 
agree to participate; that you may withdraw your consent and discontinue participation at any time without penalty. 
 
Participant Name __________________________________________            Date_________________  
 
 
Participant Signature _____________________________________________