Distress Tolerance and Benzodiazepine Discontinuation in Opioid Agonist Therapy, Phase 2
Phase: PHASE2
Conditions: Substance Use Disorders
Sponsor: Boston Medical Center

Distress tolerance and benzodiazepine discontinuation in opioid agonist therapy, Phase 2  Version 1.15, 
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Distress tolerance and benzodiazepine discontinuation in opioid agonist 
therapy, Phase 2 
NCT04109118 
Statistical Analysis Plan pages 22-23 
 
Principal Investigator: Tae Woo Park, MD, MSc 
Phone: (617) 414-1906 
E-mail: taewoo.park@bmc.org 
 
Protocol Version Number: 1.15 
Protocol Version Date: 6.1.21 
Funding Mechanism:  BU Grant # 9500306840 
 
 
 
 
CONFIDENTIAL 
 
 
This document is confidential and the property of Boston University/Boston Medical Center. No part 
of it may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. 
 
 

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TABLE OF CONTENTS 
1 List of Abbreviations .............................................................................................................. 3 
2 Protocol Summary .................................................................................................................. 3 
3 Background/Rationale & Purpose ....................................................................................... 4 
3.1 
Background Information .............................................................................................. 4 
3.2 
Rationale and Purpose ................................................................................................ 5 
4 Objectives ................................................................................................................................ 5 
4.1 
Study Objectives ........................................................................................................... 5 
4.2 
Study Outcome Measures ........................................................................................... 5 
4.2.1 
Primary Outcome Measures ......................................................................... 5 
4.2.2 
Secondary Outcome Measures ................................................................... 5 
5 Study Design ........................................................................................................................... 5 
6 Potential Risks and Benefits ................................................................................................. 6 
6.1 
Risks ............................................................................................................................... 6 
6.2 
Potential Benefits .......................................................................................................... 8 
6.3 
Analysis of Risks in Relation to Benefits ................................................................... 8 
7 Study Subject Selection ........................................................................................................ 8 
7.1 
Subject Inclusion Criteria ............................................................................................. 8 
7.2 
Subject Exclusion Criteria ........................................................................................... 9 
8 Study Intervention .................................................................................................................. 9 
9 Study Procedures ................................................................................................................. 11 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) ................................ 17 
10.1 Definitions .................................................................................................................... 17 
10.2 Safety Review ............................................................................................................. 18 
10.3 Reporting Plans .......................................................................................................... 19 
10.4 Stopping Rules ............................................................................................................ 19 
11 Data Handling and Record Keeping .................................................................................. 19 
11.1 Confidentiality .............................................................................................................. 19 
11.2 Source Documents ..................................................................................................... 21 
11.3 Case Report Forms .................................................................................................... 22 
11.4 Study Records Retention .......................................................................................... 22 
12 Statistical Plan ...................................................................................................................... 22 
12.1 Study Hypotheses ...................................................................................................... 22 
12.2 Sample Size Determination ...................................................................................... 22 
12.3 Statistical Methods ..................................................................................................... 23 
13 Ethics/Protection of Human Subjects ................................................................................ 23 
14 Literature References .......................................................................................................... 23 
15 Appendix ................................................................................................................................ 26 

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1 
List of Abbreviations 
 
 
Abbreviation 
Abbreviation definition 
BZD 
Benzodiazepine 
OAT 
Opioid agonist therapy 
SUD 
Substance use disorder 
DT 
Distress tolerance 
DT-BD 
Distress Tolerance – Benzodiazepine Discontinuation 
ACT 
Acceptance and commitment therapy 
BU 
Boston University 
BMC 
Boston Medical Center 
BHC 
Behavioral Health Clinic 
OBAT 
Office Based Addiction Treatment 
RA 
Research assistant 
 
2 
Protocol Summary 
 
Title: 
Distress tolerance and benzodiazepine discontinuation in opioid 
agonist therapy (OAT), Phase 2 
Population: 
4 individuals receiving OAT who are regularly using benzodiazepines 
and are interested in discontinuing benzodiazepine use 
Intervention: 
This study conducts a 13-week Distress Tolerance – Benzodiazepine 
Discontinuation (DT-BD) psychosocial intervention paired with 
benzodiazepine taper with the aim of assisting individuals receiving 
OAT discontinue benzodiazepine use.  
 
This psychosocial treatment intervention uses a combination of 
interoceptive exposure therapy and elements of acceptance and 
commitment therapy (ACT) to assist individuals in tolerating 
benzodiazepine withdrawal symptoms and teaching skills to 
prevent relapse to benzodiazepine use. It will also provide 
psychoeducation about benzodiazepine use in OAT. 
  
Objectives: 
Primary Objective: To pilot the DT-BD intervention in OAT patients 
discontinuing BZD use and assessing the strengths and limitations of 
the intervention. 
Design/Methodology: 
Implementation study, 13 weeks, 14 visits (1 baseline assessment + 
13 study visits) 
Total Study Duration: 
Approximately 1 year 
Subject Participation Duration: Approximately 3 hours for baseline assessment, 30 minutes for 
each physician visit (13 physician visits) and 60 minutes for each 
therapy visit (9 therapy visits) 
 

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3 
Background/Rationale & Purpose 
 
3.1 
Background Information 
 
The use of benzodiazepines (BZDs) among opioid agonist treatment (OAT) patients has been 
associated with lower treatment retention1, use of cocaine2, and overdose mortality3,4. As such, there is 
great concern that BZD use makes OAT less safe and less effective. BZD use is common among OAT 
patients, varies by region and OAT type, and ranges from 13-74% among methadone patients and 20-
43% among buprenorphine patients3,5-7. The most common motivations for BZD use in opioid users are 
to manage anxiety, to get high, and to manage sleep8-11. Because BZD use among OAT patients is often 
felt to be therapeutic, motivation to discontinue BZDs may be expected to be low. Yet when OAT 
patients who were using BZDs were asked if they would consider reducing or stopping BZD use, 40% 
reported they would10. 
Given the high prevalence of BZD use and its negative consequences in the OAT population, there 
has been surprisingly little work investigating strategies to discontinue BZD use in this group. Efficacious 
strategies to reduce long-term regular BZD use typically involve a gradual BZD taper, but more than half 
of patients do not tolerate the withdrawal period and approximately half of those that do, relapse 
within a month12,13. Augmenting the BZD taper with a psychosocial intervention is more effective than a 
taper alone in general population studies14-16.  
The standard of care for BZD discontinuation typically involves only a gradual BZD taper that can 
last from 4-16 weeks, and sometimes longer. Research supports augmenting the taper with a 
psychosocial intervention such as relaxation therapy (RT) or cognitive behavioral therapy (CBT) for 
benzodiazepine discontinuation but neither are typically offered in most settings, including at Boston 
Medical Center. This is often because of unavailability of evidence-based psychosocial interventions in 
many settings where patients are tapered off of BZDs. Other non-BZD pharmacological treatments are 
sometimes given such as antidepressants and non-hypnotic benzodiazepines to treat anxiety and 
insomnia symptoms brought on by the BZD taper.  
Regarding the psychosocial intervention, little is known about which type of approach might be 
most effective in assisting OAT patients to discontinue BZDs. Two trials have tested a psychosocial 
intervention aimed at assisting BZD discontinuation which have explicitly included substance use 
disorder (SUD) patients17,18, one of which was in a group of methadone maintenance patients18. Both 
tested a traditional cognitive behavioral approach and neither was effective in reducing BZD use 
compared to control. One approach that may be more effective involves improving their Distress 
Tolerance (DT), defined as an individual’s perceived ability to experience and endure negative emotional 
and physical states. DT-based approaches, which typically involve a combination of exposure therapy 
and Acceptance and Commitment Therapy (ACT)19-22, have increased abstinence in smokers23 and 
improved DT in SUD patients21. ACT aims to elicit acceptance of negative thoughts, feelings, and 
sensations that are interfering with the ability to behave in a way that is consistent with one’s values. 
Additionally, use of exposure therapy, particularly interoceptive exposure (exposure to somatic 
sensations of anxiety), improves BZD discontinuation in panic disorder patients24,25. Furthermore, ACT 
has been found to be effective for treatment of anxiety disorders26 and is a promising intervention for 
relapse prevention in SUD patients27 and insomnia28,29, the three most common motivations for BZD use 
among OAT patients (anxiety, euphoria, sleep). Thus an approach involving interoceptive exposure and 
ACT may help patients tolerate BZD withdrawal symptoms and the underlying anxiety, BZD cravings, and 
insomnia that led to the initial BZD use by facilitating acceptance of the negative thoughts, feelings and 
sensations caused by these conditions and increasing engagement in values-oriented behaviors. 

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This study will be conducted in compliance with the protocol, applicable regulatory requirements, and 
BMC/BU Medical Campus Human Research Protection policies and procedures. 
 
3.2 
Rationale and Purpose  
The rationale for this line of research is that a DT-focused approach may help teach OAT patients who 
use BZDs the skills to improve their ability to tolerate the distress from BZD withdrawal symptoms and 
the symptoms that lead to BZD relapse (e.g. anxiety, cravings). The overall goal of this line of research is 
to develop a DT-based intervention in order to help OAT patients who use BZDs to improve their distress 
tolerance and thereby 1) increase likelihood of BZD discontinuation and 2) decrease risk of later relapse 
to BZD use.  
 
The goal of this proposed study is to pilot test a Distress Tolerance – Benzodiazepine Discontinuation 
(DT-BD) intervention for OAT patients using BZDs, and to assess the applicability and feasibility of this 
intervention through treatment retention and qualitative interviews of 4 participants receiving OAT who 
regularly use BZDs. Participants will be interviewed to assess strengths and limitations of intervention. 
Data from the interviews will be used to refine the intervention condition. 
 
 
4 
Objectives 
 
4.1 
Study Objectives 
 
Primary Objective: We aim to pilot the DT-BD intervention in patients currently receiving OAT who 
regularly use BZDs, in order to assess feasibility of the intervention and assess strengths and limitations 
of the DT-BD intervention. Our primary goal of this pilot study is to gather data in order to revise the 
intervention conditions so that we can test these conditions in a later randomized controlled trial. 
 
4.2 
Study Outcome Measures 
 
4.2.1 Primary Outcome Measures 
 
This study is a pilot study of the DT-BD intervention with the aim of assessing its strengths and 
limitations. Thus, the primary outcome is the acceptability and feasibility of the interventions assessed 
by qualitative interviews of the participants. During and at completion of the intervention, participants 
will be asked to provide extensive feedback on the content of the intervention, method of delivery, and 
structure. 
 
4.2.2 Secondary Outcome Measures 
 
The study’s secondary outcome measures include completion of intervention, BZD use by urine drug 
tests and self-report, use of illicit drugs or alcohol by urine drug test and self-report, BZD withdrawal 
symptoms, anxiety and depression symptoms, sleep quality, and distress tolerance measures. 
 
5 
Study Design 

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This is a pilot clinical trial of the DT-BD intervention, which is an adjunctive psychosocial intervention in 
people seeking to discontinue BZD use. The study population will consist of outpatients receiving OAT 
for opioid use disorder who are also using BZDs regularly. All participants will receive the same BZD 
discontinuation protocol. This discontinuation protocol, or taper, is a usual clinical care benzodiazepine 
taper. We are piloting the DT-BD intervention as it has never been utilized in BZD discontinuation trials. 
The intervention consists of 14 study visits: the first visit consists of the baseline assessment and the first 
therapy visit, 4 subsequent weekly therapy visits, then a 9-week BZD taper which includes therapy visits 
(see Study Intervention section). Some participants may be prescribed non-benzodiazepine medications 
to treat the underlying conditions for which they were using BZDs [e.g. selective serotonin reuptake 
inhibitors (SSRI) for anxiety or hypnotics for insomnia] as per standard clinical care. Data collection will 
occur starting at the baseline assessment.  
 
 
6 
Potential Risks and Benefits 
 
6.1 
Risks 
 
Participants will be carefully screened at the beginning and closely monitored during the study 
procedures. Eligible individuals will be informed of each study procedure and the associated potential 
risks. Participants will be informed about the risks associated with the study itself, as well as the risks 
involved with the benzodiazepine taper. Participants will be informed that risks involved with the taper 
are happening as a part of their clinical care and not for research purposes. Potential risks will include: 
a. Subjective discomfort. It is possible that a specific focus on participants’ BZD use and other drug 
use behaviors could produce some distress. Other subjective distress may be related to the 
interoceptive exposure procedures and administration of the distress tolerance laboratory tasks 
(breath-holding and mirror tracing persistence task – computerized version [MTPT-C]) including 
temporary discomfort, such as frustration and other temporary symptoms of psychological 
stress. Any distress will be minimized by assurances that participant responses are confidential, 
that they can refuse to answer any particular question they do not want to answer, discontinue 
any laboratory task, and are free to withdraw from the study at any time without penalty. In 
addition, referrals will be provided to participants during consent and will be available upon 
request, in the event that participants are experiencing distress related to the study protocol or 
otherwise. Any distress will be minimized by assurances that participant responses are 
confidential, that they can refuse to answer any particular question they do not want to answer, 
discontinue any laboratory task, and are free to withdraw from the study at any time without 
penalty.  During the course of participation in the research, a participant may have questions 
about the assessment procedure, interoceptive exposure procedures, or distress tolerance 
tasks. A project staff member or therapist will be available to answer questions. To prevent 
discomfort or embarrassment, staff undergoes considerable training in building rapport and 
skillful interviewing. Research staff members will available to answer questions subjects may 
have about the assessment. Subjects are informed prior to the assessment that they may 
choose to skip any question or procedure they find uncomfortable. Discomfort experienced 
during the distress tolerance tasks is expected to dissipate soon after participants terminate the 
tasks. The close monitoring of objective and subjective effects by direct observation, 
interviewing, and self-ratings will allow emergent adverse effects to be detected immediately. If 

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any individual becomes overly distressed or distraught, the assessment will be stopped 
immediately and a staff clinician will talk privately with the affected individual(s). In addition, 
referrals will be provided to participants during consent and will be available upon request, in 
the event that participants are experiencing distress related to the study protocol or otherwise. 
b. Coercion. There is a potential for issues related to coercion to participate in this study. 
Participants may feel that receipt of OAT or their standing in the OAT clinic is dependent on 
participation in the study. Participants will be reminded throughout the study that participation 
is voluntary and that the study team will assist the participant in reconnecting with their 
outpatient BZD provider. Additionally, the study physician will bridge the participant’s 
medication as needed so that there is no gap in treatment.  
c. Breach of confidentiality. It is possible that data collection could result in breach of 
confidentiality. For participants in the proposed study, breach of confidentiality in self-report 
data could reveal that they are engaging in illegal behavior (i.e., breaking laws against 
possession and use of controlled substances in Massachusetts). However, the risk of breach of 
confidentiality is also modest, given the safeguards protecting the participants’ data. 
d. Overdose. When the BZD taper begins, participants will begin to be provided a week’s worth of 
BZD medication on a weekly basis until the taper is completed. BZDs when taken in high doses in 
combination with OAT can cause over sedation and respiratory depression, and can increase the 
risk of overdose death. The risk of causing overdose by providing a week of BZD medication in 
those already prescribed BZDs is the same or less than usual, given these participants are 
already receiving BZDs on a weekly or longer basis. For those not prescribed BZDs, there is an 
increased risk of overdose if participants take BZDs in greater quantity than we prescribe to 
them or if they are combining the BZDs we prescribe with other respiratory depressants. But 
there are risks of not prescribing BZDs to this group; these participants have reported regularly 
using BZDs obtained illicitly and may already be taking them in overdose or are at risk of BZD 
withdrawal. We will minimize overdose risk by excluding people with recent illicit opioid use 
which suggests instability in someone’s addiction disorder. We will obtain weekly urine drug and 
breathalyzer tests to monitor for substance use including respiratory depressants such as illicit 
opioids and alcohol. We will also be monitoring for over sedation during weekly physician visits 
which may lead to a temporary hold of BZD medication. And finally, we will be conducting a pill 
count at the beginning and the end of the study to help determine if participants are taking 
more medication than prescribed (see Study Intervention). 
e. Benzodiazepine withdrawal. All participants in this study will undergo gradual discontinuation 
of BZDs. All participants will be informed of potential risks, including those related to adverse 
effects from the BZD discontinuation process. Possible adverse effects of BZD taper include: 
anxiety, insomnia, irritability, nightmares, sensory disturbances, tremor, tinnitus, anorexia, 
diarrhea, and nausea. If the BZD taper is improperly administered (too rapid), then possible 
adverse effects include hypertension, fever, delirium, hallucinations, seizures, and death. 
Participants in prior BZD discontinuation trials very rarely required hospitalization as a direct 
result of the BZD taper. All participants will receive a medical alert bracelet and emergency card 
to inform medical providers that they are receiving a BZD taper. Comprehensive screening will 
exclude participants who would be placed at significant risk, such as prior benzodiazepine 
withdrawal seizures, as a result of participation in this study. 
f. Medication Adverse Effects. Some participants will receive SSRIs for anxiety/mood symptoms 
and/or non-benzodiazepine hypnotics for insomnia, if these symptoms occur during the BZD 
taper. Side effects of SSRIs may include: nausea, diarrhea, weight gain, dizziness, blurred vision, 

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dry mouth, headaches, and sexual dysfunction. The hypnotics, used in the proposed study, 
trazodone and mirtazapine, may also have side effects. For trazodone, side effects may include: 
dizziness, sweating, blurred vision, and less commonly, confusion, headache, change in heart 
rate, and shortness of breath. For mirtazapine, side effects may include: decreased or increased 
movement, confusion, shortness of breath, and rash. 
g. Interoceptive Exposure Risks: Interoceptive exposure approaches focus on providing patients 
additional practice in tolerating somatic sensations that trigger benzodiazepine use and will be 
personalized to each participant. The participant may be asked to hyperventilate, head roll, or 
jog in place. The participants will be provided with a description of the tasks, sensations the 
exercises will evoke, and strategies to attend to and tolerate these symptoms. Participants will 
also be existed to inform research staff of any pre-existing conditions that the tasks may 
exacerbate, so the research team may personalize the exercise. There are associated risks with 
these tasks, if the participants has pre-existing physical health concerns (e.g. high blood 
pressure, heart problems, or joint pain). Hyperventilation may have dizziness, light-headedness, 
numbness, blurred vision, and hot flashes or sweating. Participants may be asked to jog in place, 
which will increase heart rate and may cause joint, muscle or ligament strain (depending on the 
physical shape of the participant). These tasks will be very low impact and for brief time spans, 
and the study provider will terminate the exercise as needed. If the participant is unable to 
complete these tasks at all, due to previous health conditions, the study PI may determine they 
are not the right fit for the study and recommend discontinuation.  
 
6.2 
Potential Benefits 
 
Anticipated benefits are as follows: 1) all participants may have lower risk of BZD misuse, overdose 
death, and OAT treatment failure as a result of discontinuing BZD use, 2) if found to be effective, this 
treatment could reduce the health risks of BZD use in the population of patients receiving OAT, and 3) 
the results will be used to advance understanding of the roles of distress tolerance in BZD 
discontinuation. 
 
6.3 Analysis of Risks in Relation to Benefits 
 
The largest risks to participants are related to the BZD taper, which is happening as part of the 
participant’s clinical care and not for research purposes. If the BZD taper is properly administered, the 
risk of serious adverse effects is low. Because BZD use has been associated with negative consequences 
including overdose death in the patients taking OAT, the risks are judged to be acceptable relative to the 
anticipated benefits. 
 
 
7 
Study Subject Selection 
 
7.1 
Subject Inclusion Criteria 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
a) Age 18 or older 
b) Receiving OAT (methadone or buprenorphine) for at least 2 weeks 

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c) Regular BZD use defined by BZD use 3 or more times per week in past month by self-report and 
positive urine screen at time of recruitment  
d) Provides permission to contact current BZD prescriber if being prescribed BZDs 
e) Speaks English 
f) Wants to discontinue BZD use  
 
7.2 
Subject Exclusion Criteria 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
a) Pregnant, confirmed by urine pregnancy test 
b) Cognitive impairment, as indicated by Montreal Cognitive Assessment  
c) Any past month illicit opioid, barbiturate, cocaine, unprescribed z-drug, unprescribed amphetamine, 
or synthetic cannabinoid use determined by self-report or urine drug test 
d) Receiving ongoing psychosocial treatment for BZD use disorder 
e) Uncontrolled seizure disorder (i.e. seizure in prior 90 days), or past BZD withdrawal seizure  
f) Current suicidality or homicidality 
g) Current psychotic symptoms 
 
8 
Study Intervention 
 
Experimental condition 
 
In the study’s experimental condition, Distress Tolerance - Benzodiazepine Discontinuation (DT-BD), is a 
psychosocial intervention paired with a gradual benzodiazepine taper. The aim of the psychosocial 
intervention is to improve individuals’ ability to tolerate distress in order to assist benzodiazepine 
discontinuation in patients treated with OAT. There will be 5 sessions between therapist and participant 
prior to the start of the benzodiazepine taper. The taper occurs over 9 weeks and involves weekly 
meetings with a benzodiazepine prescriber during which a gradual benzodiazepine dose reduction will 
take place. 
 
The DT-BD intervention combines elements of existing psychosocial interventions. Specifically, 
interoceptive exposure techniques will be paired with elements of acceptance and commitment therapy 
(ACT) and relapse prevention (RP). Interoceptive exposure involves inducing symptoms that trigger 
benzodiazepine use and will be personalized to each participant (eg. Hyperventilation, head rolling, and 
jogging in place to mimic the dizziness and shortness of breath commonly observed in people who are 
having a panic attack). The purpose of interoceptive exposure is to decrease the fear of symptoms 
associated with benzodiazepine withdrawal and potentially the condition for which the participant was 
using benzodiazepines to treat. ACT teaches people skills in accepting distress in the service of their 
values rather than resisting or avoiding that distress, which may make distress worse or prolong it. Thus, 
these ACT-based skills are the ideal partner for interoceptive exposure exercises in that they will assist 
participants in enduring the distress induced by exposure exercises and ultimately, the symptoms of 
benzodiazepine withdrawal. 
 
After the baseline visit, in the first 5 sessions prior to the start of the benzodiazepine taper, the therapist 
will clarify the participant’s values, discuss the role of benzodiazepines in the treatment of anxiety 

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disorders, introduce interoceptive exposure exercises, explore thoughts and feelings about stopping 
benzodiazepine use, and introduce acceptance as an alternative to distress related to stopping 
benzodiazepine use. In the final 9 sessions, the therapist will continue to work with the participant on 
interoceptive exposure exercises and the importance of participant’s values, introduce mindfulness, 
teach relapse prevention skills, and do ACT-based exercises that teach cognitive defusion and 
willingness.  
 
Session 
Number  
Goals 
Themes 
1  
(Week -4) 
Introduction to intervention and treatment philosophy 
1) Introductions  
2 
(Week -3) 
Discuss nature of anxiety and BZDs, discuss risks of BZD use in 
OAT, discuss problems with BZD discontinuation, discuss BZD 
taper schedules , clarify participant’s values, values used to 
increase motivation for BZD discontinuation  
1) Psychoeducation 
2) Values clarification 
3) Motivation 
3 
(Week -2) 
Review costs of avoidance of anxiety including BZD use, 
discuss acceptance as alternative to controlling BZD 
withdrawal symptoms, introduce mindfulness to assist in 
observing rather than controlling symptoms, introduce 
interoceptive exposure with aim of practicing ACT-based skills 
while experiencing BZD withdrawal-like symptoms 
1) Problems with control  
2) Acceptance  
3) Mindfulness 
4) Exposure techniques 
4 
(Week -1) 
Introduce cognitive diffusion, discuss value-driven behavior as 
alternative to avoidance, further develop ability to observe 
one’s thoughts without judgment, in particular thoughts about 
anxiety/BZD withdrawal, conduct interoceptive exposure 
1) Cognitive diffusion  
2) Value-driven behavior 
3) Self as context 
5 
(Week 0)  
Taper begins 
Learn to use mindfulness during BZD withdrawal symptoms as 
a form of exposure, identify situations that might lead to a 
greater chance of relapse and developing coping skills if a 
lapse occurs, conduct interoceptive exposure 
1) Mindfulness 
2) Relapse Prevention  
6 
(Week 1) 
Introduce concept of willingness, help participant choose to 
experience anxiety/BZD withdrawal without trying to change 
that experience, conduct interoceptive exposure  
1) Willingness  
7 
(Week 2) 
Introduce concept of committed action, identify goals 
regarding BZD use, link goals to actions, conduct interoceptive 
exposure 
1) Committed Action 
8-10 
(Weeks 3-5) 
Review previous concepts, extend previous concepts to 
anxiety in general, dealing with setbacks through mindful 
acceptance, prepare for end of treatment 
1) Review concepts 
2) Dealing with setbacks 
11-14 (Weeks 
6-9) 
Monitor progress, address setbacks through mindful 
acceptance, review coping skills 
1) Review concepts 
2) Monitor progress 

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Description of Distress Tolerance – Benzodiazepine Discontinuation content 
 
 
BZD taper 
 
All participants will undergo BZD discontinuation. For those participants prescribed BZDs, we will obtain 
permission from those participants to contact the participants’ outpatient prescribers. We will inform 
those prescribers of the participants’ intent to discontinue BZD use and we will ask those prescribers not 
to continue prescribing BZDs during the study.  
 
The following description of the BZD taper protocol is a usual clinical care BZD taper. Patients at Boston 
Medical Center (BMC) might receive such a taper, though there may be slight differences based on 
clinician or patient preferences. Other clinicians at BMC have been consulted about this taper who agree 
that this protocol fits in the range of usual clinical care. 
 
We will check the Massachusetts prescription monitoring program to determine the recent BZD dose. 
For those participants not prescribed BZDs, we will determine the baseline BZD dose through self-
report. Once the starting BZD dose is determined, we will maintain participants on this dose until the 
start of the BZD taper (likely week 2 and 3 of study). Participants will see a study physician weekly to 
receive their BZD medication for the week until the taper is completed. BZD discontinuation in this study 
will consist of a gradual BZD taper in dose over 9 weeks. No RCTs have compared the safety and 
effectiveness of different BZD taper lengths in outpatient settings though most trials used a gradual 
taper of 8-10 weeks. Typical BZD tapers in clinical settings can range from 4 to 16 weeks, and sometimes 
longer (though research suggests that very long tapers of >6 months in OAT patients rarely lead to 
successful discontinuation18). The taper will be flexible in that the study physician will utilize clinical 
judgement to lengthen the taper if necessary, depending on the severity of the participant’s withdrawal 
symptoms. Anchor points will be set (33% reduction in dose after 2 weeks, 50% mid-treatment, 100% by 
week 8) to emphasize the time-limited nature of the taper.  
 
Safety monitoring for participants will be supervised by the study physician. Participants may have BZD 
medication temporarily held if the participant is felt to be over-sedated or tests positive for illicit drugs 
that are respiratory depressants (typically opioids). We will also conduct pill count at the beginning and 
the end of the study. If a participant’s number of pills is short by >20%, then the study team will meet 
and discuss the possibility of the participant’s discontinuation from the study. 
 
Participants are required to attend all 14 study visits including the baseline assessment. If a participant 
misses a study visit and research study staff are unable to get in contact with them up until 14 days after 
their missed appointment, they will be considered discontinued from the study. If a participant decides 
to discontinue participation during the study before the BZD taper is completed, we will contact their 
BZD prescriber and provide a bridge BZD prescription until they can be treated by their BZD prescriber. 
 
 
9 
Study Procedures 
 
See the Appendix for the schedule of events.  
 

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9.1 
Recruitment  
Patients will be recruited from Health Care Resource Centers (HCRC) Boston, Faster Paths to Treatment 
Urgent Care Center at Boston Medical Center (BMC), the Behavioral Health Clinic (BHC) clinic at Boston 
Medical Center (BMC), and the Office Based Addiction Treatment (OBAT) Program at BMC. HCRC Boston 
provides OAT treatment for over 650 patients, the BHC clinic for over 150 patients, and the OBAT 
Program for over 600 patients. We will advertise the study by making an announcement of the study at 
clinic staff meetings. The research team will work with physicians and clinicians to ensure that they are 
aware of this research opportunity in order to facilitate their ability to refer potential participants to the 
study team. Potential participants identified by clinical staff can be given a study flier, which will detail 
the purpose of the study, eligibility criteria, and research staff contact information. Interested patients 
will be able to call the phone number or contact the email address for the research team included on 
these advertisement materials in order to learn more information about the study. In addition, providers 
may obtain verbal consent from patients to have study staff call to invite them to participate. If the 
patient provides verbal consent to have research staff contact them, providers will then inform study 
staff that the patient is interested and expecting a phone call, and will pass along their name and 
contact information to the research staff. Providers may additionally obtain verbal consent from the 
patients to have study staff wait outside patients’ clinical appointments in one of the above referenced 
settings to ask if they would be interested in learning more about a research opportunity. If the patient 
indicates interest, then a member of the research team will bring them to an identified private space in 
the clinic that does not interfere with their clinical appointment. Any discussion of the study will only 
occur in a private space. In the private space, they will be provided more details about the research 
study. If they are interested, potential participants will be asked to complete a brief screening interview 
using the study screening script that will involve asking questions based on the inclusion and exclusion 
criteria. If no private space is available, interested participants will be given a study flier with study 
details and research contact information, and/or collect their contact information and ask permission to 
contact them at a later time to provide more information about the study and conduct the screening 
interview over the phone.  
Participants who appear to meet study criteria and are interested in participating, will be scheduled for 
a more comprehensive baseline assessment. At the baseline assessment, before delivering informed 
consent, research staff will review/confirm eligibility criteria previously done during initial screen. If the 
participant does not meet eligibly criteria (e.g. recently becoming pregnant), they will be unable to 
participate in the study and the eligibility data collected at baseline will be destroyed. For those who are 
eligible and consent, the eligibility criteria checklist will be saved along with their research study 
documentation. For those who are eligible but do not consent, their eligibility checklist will be 
destroyed.  
IRB approved advertisements/fliers may be posted throughout Boston Medical Center or its network of 
affiliated behavioral health clinics with permission. IRB approved advertisements may also be placed in 
newspapers. 
 
9.2 
Consent 
Candidates will be asked for informed consent before the comprehensive baseline assessment. 
Informed consent will be conducted in person in a private office in the BMC Department of Psychiatry’s 
Research Center in the Doctor’s Office Building or in the Behavioral Health Clinic (BHC) clinic in the 
Dowling Building at Boston Medical Center (BMC). Participants will then be asked to sign a consent form. 

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Informed consent will involve providing candidates an IRB-approved copy of the Informed Consent Form 
to read, or participants will be able to access an electronic version of these forms and can provide an e-
signature through drawing their signature on the screen (phone, computer, or tablet/Ipad) with their 
finger, mouse, surface pen, etc.  Appropriately qualified and trained study personnel will explain all 
aspects of the study in lay language and answer all of the study candidate’s questions. Study staff 
members are trained in Boston University Medical Center (BUMC) IRB policy and will closely follow 
consent procedures as outlined by the BUMC IRB. Research staff will explain all aspects of the study, 
including the intervention approach, experimental nature of the research, potential risks and benefits, 
and the expected duration and time commitment of their participation.   Potential participants will be 
permitted to take an unsigned consent form home with them to think about whether or not they’d like 
to participate. From the time of explanation of the research study, potential participants will be allotted 
7 days to decide whether they would like to participate in the research study. Potential participants will 
be given study contact information, should they have any questions or concerns, during those 7 days. 
Candidates who remain interested after receiving an explanation of the study will be delivered the 
Assessment of Capacity to Participate in Clinical Research to test his/her understanding of the project, 
the purpose and procedures involved, and the voluntary nature of his/her participation. Those who 
cannot successfully answer the items on the Capacity Questionnaire will have the study re-explained by 
research staff with a focus on aspects they did not understand. Those who demonstrate understanding 
of the study and voluntarily agree to participate will be asked to sign the Informed Consent Form. 
Participants will be given, mailed, emailed (depending on preference) a copy of their signed consent 
form. No baseline assessments will begin until after a signed research consent form is obtained.  
 
 
9.3 
Baseline Assessment 
See schedule of events for breakdown of assessments and study timeline 
 
 
Baseline Assessment:  
 
After informed consent is obtained, participants will begin their baseline assessments. The baseline 
assessments will be delivered in person, either at our research office or at a BMC clinical space.  
 
First, participants will be delivered a urine drug test and pregnancy test, and the 30-day Timeline 
Followback (TLFB), which will be used to measure drug use in the past 30 days. Participants will not be 
eligible to continue with the study a) if their urine drug screen shows use of illicit drugs (including 
opioids, cocaine, barbiturates, unprescribed z-drugs, unprescribed amphetamines, or synthetic 
cannabinoids), b) if they report use of illicit drugs (including opioids, cocaine, barbiturates, unprescribed 
amphetamines, unprescribed z-drugs, or synthetic cannabinoids) in the past month, or c) if their urine 
drug screen shows that they are currently pregnant. The urine pregnancy screen results will be available 
immediately during their visit. However, the urine drug screen results may take up to several days to 
process.  
• 
If the urine screen shows that the participant is currently pregnant, the participant will not be 
eligible to continue with the study and baseline assessments. These participants can return after 
30 days, if they choose, where they will be asked to re-screen with the urine drug test, 
pregnancy test, and the TFLB. If at that second visit, their pregnancy test is negative and they 

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report no illicit drug use in the past 30 days, they will be able to take the baseline assessments. 
Pending the results of their urine drug screen, they will be able to continue with their follow up 
study visits.  
• 
If the participant is not currently pregnant, but reports use of illicit drugs (including opioids, 
cocaine, barbiturates, unprescribed amphetamines, unprescribed z-drugs, or synthetic 
cannabinoids) in the past month on the TLFB, the participant will not be eligible to continue with 
the study and baseline assessments. These participants will have the opportunity to return in 30 
days where they will re-take the urine drug test, pregnancy test, and the TLFB. If at the re-
screen, they are not pregnant and report no use of illicit drugs in the past month, they will be 
able to take the baseline assessments. Pending the results of their urine drug screen, they will 
be able to continue with their follow up study visits. 
• 
The urine drug screen results may take up to several days to process. If the pregnancy screen 
shows the participant is not currently pregnant, and the participant reports no use of illicit drugs 
in the past 30 days, the participant may complete the baseline assessments and receive the $30 
payment. When research staff receive the results for the urine drug screen and it shows use of 
illicit drugs (including opioids, cocaine, barbiturates, unprescribed z-drugs, unprescribed 
amphetamines, or synthetic cannabinoids), they will not be eligible to continue with the study. 
However, if they would still like to participate in the study, they will have the opportunity to 
return in 30 days where they will re-take the urine drug screen, pregnancy test, and TLFB. If at 
the second screen, they are not currently pregnant, report no illicit drug use in the past 30 days, 
and there is no presence of illicit drugs from their urine screen, they will be enrolled in the 
study.  
 
For those who are not eligible to be in the study and/or choose not to return after 30 days for a re-
screen, we can provide referrals and contact information for alternative services at Boston Medical 
Center for urgent care and benzodiazepine use, including the Outpatient Behavioral Health Clinic at BMC 
and Faster Paths to Treatment Center at BMC. These programs are listed in the consent form under the 
Treatment Alternatives Section.  
 
Those who are eligible to continue with the study will be asked to complete baseline assessments. These 
could be completed at our research office or in the clinic through REDCap survey links, whichever is 
most convenient and appropriate for the patient. Participants who complete the surveys online will be 
sent REDCap survey links to their emails or mobile phone. A trained research assistant (RA) will collect 
demographic information and administer the Mini-International Neuropsychiatric Interview (MINI)30, a 
brief, 15-minute psychiatric diagnostic interview. Motivation for BZD use, alcohol and other drug use by 
self-report, BZD withdrawal symptoms, distress tolerance measures, affect and sleep symptoms, and 
suicidal ideation will also be assessed during the baseline assessment. Participants who complete the 
baseline assessments will receive a $30 payment in the form of a BMC Clincard for their time and 
participation.  
 
Daily assessment: In addition to the assessments listed in the table above, we will measure substance 
use, BZD medication adherence, and sleep duration and quality on a daily basis. Each participant will be 
sent a daily REDCap survey link either to their mobile phone number or email, and asked to complete a 
brief questionnaire for the previous day.  Participants will be sent the survey link through REDCap to 
their email address or, if preferred, to their mobile phone number using Twilio, a third party service, 

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that enables SMS text survey link distribution to phone numbers through REDCap. If they do not own a 
mobile phone, we will provide a phone free of charge for use during the study. After the completion of 
the study or study drop out, participants will be asked to return the phone. 
 
After informed consent is obtained and baseline assessments are completed, participants will begin with 
their first session of the intervention.  
 
9.4 
Assessment Tools 
 
BZD and Other Drug Use. We will measure benzodiazapine history using the BZD history 
questionnaire32,33. At baseline and weekly through the taper, we will measure alcohol, BZD, OAT, and 
illicit drug use with urine screening and self-report. The 30-day Timeline Followback (TLFB)34 will be used 
to measure self-report of drug use at baseline. We will send a REDCap survey link to the participants’ 
mobile phone number or email to measure substance use during the week. Urine BZD tests will include 
immunoassay for all BZDs and liquid chromatography–mass spectrometry for lorazepam and 
clonazepam, as these BZDs have a high false negative rate on immunoassay tests35,36. A breathalyzer test 
will be performed at each visit. We will assess for BZD withdrawal symptoms using the Clinical Institute 
Withdrawal Assessment-Benzodiazepines (CIWA-B)37.  
 
BZD Medication Adherence. We will send a daily REDCap survey link to the participant’s email or mobile 
phone to assess daily BZD medication adherence.   
 
Affect and Sleep. At each visit, anxiety symptoms will be assessed using the Overall Anxiety Severity and 
Impairment Scale (OASIS)38 and the Patient Health Questionnaire (PHQ-9)39 will be used to assess 
depression symptoms. Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI)40 at 
baseline and on a weekly basis. Additionally, sleep duration and sleep quality will be measured on a daily 
basis using a REDCap survey link.   
 
Distress Tolerance. Self-reported DT measures will include the Distress Intolerance Index41, the 
Acceptance and Action Questionnaire-II42 and the Anxiety Sensitivity Index43. Behavioral DT measures 
will include breath holding and the computerized Mirror Tracing Persistence Task (MTPT-C)44.  
 
Suicidal Ideation:  At the baseline assessment, we will measure suicide risk, severity and immediacy of 
risk, and level of support needed using the Columbia-Suicide Severity Rating Scale (C-SSRS).  
 
Feasibility and Acceptability. We will measure recruitment and retention rates, number of visits  
attended, and participant feedback of intervention during an in-depth qualitative exit interview.  
 
In this study, data will be collected from participants who are or may present to assessment and 
intervention appointments intoxicated. Upon arrival to intervention and assessment appointments, all 
participants will receive a Breathalyzer test prior to assessment interviews; if a participant appears 
intoxicated or impaired, the RA will reschedule the interview. If participants experience anxiety and 
insomnia during the BZD taper, we will offer an SSRI or a dose increase if already prescribed for anxiety, 
and non-BZD hypnotics (e.g. trazodone or mirtazapine) for insomnia. 
 
9.5 
Exit Interview 

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Exit interview – At the end of the taper, participants will undergo an in-depth qualitative exit interview. 
Interviews will be audio recorded, and written notes containing no individual participant identifiers will 
be taken by the RA. Participants will be asked to provide extensive feedback during exit interviews to 
assess what was/was not helpful, what would have been helpful, and any feedback on intervention 
content, method of delivery, or structure.  
 
Participants will receive $30 at baseline visit and will be paid $2 for each daily mobile assessment from 
week 2 to week 13 (earning up to $168).  They will additionally receive a $50 ClinCard for a post-
intervention interview. Participants can earn up to $248 for participating in the study. 
Safety Assessment  
If the study staff learns of any acute safety concerns, such as current thoughts about suicide, self-harm, 
or intent to harm others, abuse, neglect, or other reportable conditions, research study staff will 
interrupt study activities and utilize the Standard Operating Procedure for Safety Assessments 
Endorsement of Suicidality, Risk to Self or Others (SSOP) Safety Assessment Form. If the participants 
brings up thoughts of suicide or self-harm, research staff will utilize the Columbia-Suicide Severity Rating 
Scale (C-SSRS) to assess participant risk. If the participant brings up intent or harm others, abuse, neglect 
or other reportable conditions, research staff will complete the Acute Safety Assessment to probe 
frequency and severity of the concern to identify participants who may be at immediate risk and require 
further intervention. Upon completion of the C-SSRS and/or Acute Safety Assessment, research staff will 
contact the study PI who will conduct an acute safety assessment over the phone or in person. PI will 
then utilize clinical judgement to determine further course of action.  
 
Removal of Participants 
All instances of study drop out will be documented, including reason for dropout, who decided the 
participant would drop out (participant, study staff or PI), and whether the drop out resulted from 
burden of intervention, study assessment, or another reason. Withdrawn participants will be 
encouraged to participate in the exit interview to provide feedback on why the intervention did not 
work for them and suggestions for improvement. Participants may withdraw voluntarily at any time for 
any reason. If the participants withdraw from the study or the intervention, they will be asked to return 
the mobile phones.  
 
There are two types of participant withdrawal: “intervention withdrawal” and “study withdrawal”.  
 
1. Intervention withdrawal: A participant drops out of the treatment (either because they are no 
longer interested or because the study PI feels the intervention is no longer appropriate), but 
still provides the research team with post-intervention data by completing assessments and exit 
interview. 
2. Study withdrawal: A participant (or provider on behalf of participant) explicitly communicates 
that they are no longer interested in being a part of the study at all, including future 
assessments and compensation. Cases of intervention withdrawal are not automatically 
considered to be study withdrawal unless the participant specifically states that they never wish 
to be contacted again by the study, or if the study investigator deems any future contact would 
be inappropriate.  
 

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Participants may be removed if:  
• 
If the results of their urine drug screen tests positive for illicit drugs.  
• 
If the number of benzodiazepine medication during the pill count is short of the expected 
amount by over 20% at both visits.  
• 
If the participant tests positive for cocaine, synthetic cannabinoids, non-prescribed opioids, 
barbiturates, z-drugs (for example, Ambien), or amphetamines during the urine drug screen or 
they report using these substances a total of 3 times during the study. 
• 
If there is evidence of ongoing substance use of illicit substances, they may be removed and 
referred to a higher level of treatment including inpatient detoxification or residential 
treatment. 
• 
If the participant becomes pregnant over the course of the study.  
• 
If the study investigator or treating provider feels the study is negatively impacting the 
participant’s health or wellbeing resulting in increasing severity of illness that is clinically 
assessed as such by the study PI. Such cases will be assessed clinically and study PI will 
determine whether the participant should be removed from the study. 
• 
If the participant becomes suicidal and presents with clinically determined safety risk to self or 
others.  
 
 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
 
10.1 Definitions 
 
The following definitions will be used in the assessment of safety: 
 
Adverse Event (AE) is any untoward or unfavorable medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. 
 
Serious Adverse Event (SAE) is any adverse event that  
(1) results in death; 
(2) is life-threatening; 
(3) results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) results in a persistent or significant disability/incapacity; 
(5) results in a congenital anomaly/birth defect; or 
(6) based upon appropriate medical judgment, may jeopardize the subject's health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse).  
 
Life-threatening means that the event places the subject at immediate risk of death from the event as it 
occurred.  
 

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Unanticipated Problem is defined as an event, experience or outcome that meets all three of the 
following criteria:  
• 
is unexpected; AND 
• 
is related or possibly related to participation in the research; AND 
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
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 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
• 
the known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol–related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as product labeling and 
package inserts; or 
• 
the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the 
adverse event. 
 
10.2 Safety Review 
 
Both the risks listed in Section 4.1 and unknown risks will be monitored as follows:  
 
The study PI, Tae Woo Park, will review and update this protocol and all procedures as needed and will 
provide oversight. Monitoring will be done by the PI in consultation with mentors, the IRB and NIDA, the 
study sponsor. 
 
What is Monitored. All procedures will be monitored to ensure that they conform to the approved 
protocol. In addition, monitoring will be done of all unforeseen circumstances that might arise and 
affect safety; of all reports of serious adverse events as defined above; of other significant adverse 
events (adverse events that lead to drop out by the participant or termination by the investigator); and 
of unexpected adverse events resulting from the study. 
 
Frequency of Monitoring. Monitoring of adherence to the study protocol and emergent unanticipated 
adverse events will be conducted by the PI on an ongoing basis. This monitoring will be discussed with 
mentors during regularly scheduled meetings. Participants will be given contact information so that they 
can inform study staff of events that occur in between study visits. In addition, monitoring by the IRB is 
conducted at the annual continuing reviews as scheduled by the IRB and upon receiving reports of 
adverse events from the PI. 
 
Oversight. The PI is responsible for the general oversight for all research activities. Each intervention 
project will have a yearly review of its DSMP during the regular continuing review process, outlining the 
following points: (a) reassessment of the risks and benefits to study participants, (b) participant 
recruitment, accrual, and retention, (c) data quality and confidentiality, (d) consideration of external 
scientific or therapeutic developments with impact on the safety of participants or the ethics of the 

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study, (e) review any adverse events. The PI will update the general DSMP procedures as needed. All 
modifications to the protocol or DSMP will be communicated to NIDA, the study sponsor. 
 
 
10.3 Reporting Plans 
 
The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems, safety 
monitors’ reports, and Adverse Events to the BMC/BU Medical Center IRB in accordance with IRB 
policies: 
• 
Unanticipated Problems occurring at BMC/BU Medical Campus involving a fatal or life-threatening 
event will be reported to the IRB within 2 days of the investigator learning of the event. 
• 
Unanticipated Problems occurring at BMC/BU Medical Campus not involving a fatal or life-
threatening event will be reported to the IRB within 7 days of the investigator learning of the 
event. 
• 
Reports from safety monitors with recommended changes will be reported to the IRB within 7 
days of the investigator receiving the report.  
• 
Adverse Events (including Serious Adverse Events) will be reported in summary at the time of 
continuing review, along with a statement that the pattern of adverse events, in total, does not 
suggest that the research places subjects or others at a greater risk of harm than was previously 
known. 
• 
Reports from safety monitors with no recommended changes will be reported to the IRB at the 
time of continuing review.  
 
10.4 Stopping Rules 
 
The study has no pre-defined stopping rules. Should a fatal or life-threatening overdose/withdrawal 
event occur, the PI will revise or withhold the research plan and discuss with mentors, the IRB, and 
NIDA. 
 
 
11 Data Handling and Record Keeping 
 
11.1 Confidentiality 
 
Coded data: A unique ID will be used to identify individual records, and all data and samples will be 
labeled only with this study ID number (i.e., not the participant’s name, date of birth, medical record 
number, etc). The unique study ID will be linked to participant identifiers via a mastercode/key. 
Restricted access to participant contacts information and the mastercode/key will be limited to 
members of the research staff as necessary to complete their duties. Locator/contact information and a 
master enrollment list will include identifiers, but participant names will not be entered into the 
analytical database. The mastercode/key that links study data to identifiers will be stored separately 
from the study data (i.e., in separate physical files and separate databases) and protected as described 
below. 
 

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Data Management and Security to Protect Privacy: The research study team will assure high quality 
forms, monitor data quality, and track and link the multiple data sources. Data will be linked and 
entered using multiple checks. The research study team will manage data collection forms, design the 
database management system for data entered and for participant tracking, implement procedures for 
quality control, and provide statistical programming. 
All data for study purposes will be collected with Apple iPad tablets or electronic survey links using the 
Boston University Medical Campus’ installation of REDCap data collection system, a software tool 
developed at Vanderbilt University and made available through the Clinical and Translational Science 
Awards network (CTSAs). To help protect and secure the data stored in REDCap’s database, the software 
application employs several methods to protect against malicious users who may attempt to identify 
and exploit any security vulnerabilities in the system. Access to the REDCap data entry website will be 
based on permissions granted by username and password which will be managed by the Boston 
University Clinical and Translational Sciences Institute for the Medical Campus Office of Information 
Technology (OIT). Only authorized study members will be able to enter or view data. The login 
information (username) of the person submitting the information, the date and time submitted, and 
other navigational information will be automatically obtained and stored in the database.   
Boston University’s installation of REDCap is HIPAA compliant. Information posted on forms will be 
electronically encrypted using secure socket layering (SSL) encryption technology so that only the 
intended recipient can decode the data.  Data will reside on a secure, password protected server at 
Boston University Medical Center (BUMC) to which only designated individuals have access, thus 
providing a secure environment for all project data.  The database will be automatically backed up on a 
nightly basis.  Files stored on BUMC servers will be protected by electronic ‘firewalls’ that restrict access 
to designated users.  Restrictions and permissions to update the database will be controlled through the 
REDCap web application. 
Because the server will be part of the BUMC network NT domain, only connections from users 
authenticated from the domain controller are accepted, thus providing a secure environment for all 
Center data. Specifically, the policy for computer systems security implemented at BUMC: 
• 
Provide physical security of data.  All central systems are physically secured behind locked doors 
with access restricted to key personnel in the OIT.  Access through the primary door is also 
protected by an alarm system that is tied directly into the on-site central emergency response 
security control center.  Written policies exist for contingencies to provide access to the room to 
those not explicitly authorized. 
• 
Provide virtual security via connectivity.  Internal access to all systems is done via Microsoft 
Challenge Handshake Authentication Protocol.  With the exception of internet provider-based 
services, external client access must first gain access to the internal network before connecting 
to the systems.  This connection is initiated via a Virtual Private Network connection using Point-
to-Point Tunneling Protocol or through the University's modem pool which require Kerberos 
authentication. 
All data are protected with disaster recovery via several methods: 
• 
Hardware redundancy:  Several stages of redundancy exist at the hardware level to minimize 
failure:  dual-redundant power supplies exist on each disk array; hot-spare disk is configured to 
automatically self-heal in the event of a disk failure in the array; emergency power generators 

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ensure a 100% electrical uptime; and uninterrupted power supplies present the systems with 
conditioned steady-state power. 
• 
Data backup:  The data are backed up on a regular schedule.  All tapes are moved off-site on a 
daily basis and are stored in a fire-proof safe.  Cycle-time of backups is approximately two 
months with the exception of a yearly archive which is retained for a one-year period. 
• 
Data Security:  All data are stored on NT File Systems with password-protected files and 
directories. 
The BUMC REDCap Server has implemented a mix of preventive and detective security measures: 
• 
Two factor authentication required for both admin and user access 
• 
Require a password change every quarter for users 
• 
Server is placed behind data center firewall 
• 
Requires two-factor authentication and only permits for specific admin(s) that need to access 
the server 
• 
Inform PIs that they need to remove investigators who are no longer involved, and periodically 
(ideally quarterly) review accounts 
• 
Server is protected by intrusion prevention measures (firewalls/snort)   
• 
Server is part of change management and vulnerability management programs to ensure server 
is patched within 30 days of vulnerability notification 
 
Electronic survey links will be sent to participant's emails or phone numbers using REDCap and REDCap 
enabled feature, Twilio. Twilio is a third-party web service that provides the functionality for researchers 
to send REDCap survey invitations via SMS text messaging.  Twilio will have access to the participant's 
phone number.  When a BU REDCap admin enables Twilio for a REDCap project, BU REDCap verifies that 
the Twilio Request Inspector has been disabled.  This setting ensures that survey participants' phone 
numbers do not get permanently logged on Twilio's servers, but instead remain securely in the BU 
encrypted REDCap server. Twilio will not have access to participant PHI data. 
 
The qualitative interviewers will be audiotaped, with subjects’ permission, using a digital voice recorder 
or audio recording program on our BMC encrypted study laptops. Each digital audio file will be coded 
with subject unique identifiers, only connected to identifiers (PHI) via a separate, password-protected, 
master code. These files will be stored on a password-protected, encrypted BMC network. The coded 
audio file will additionally be sent to a commercial service for transcription.  
 
All paper records (i.e. signed consent forms) will be stored in locked storage spaces (cabinets or 
drawers) in a secure research office. Only study staff will have access to the key to get into these storage 
spaces. Participant forms will be stored in a single folder that is labeled with their respective study ID 
number. 
 
 
11.2 Source Documents 
 

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Study records will include consent forms, transcriptions of participant exit interviews, and participant 
interviews that will be audio recorded on a digital voice recorder. The audio recordings will be 
transcribed by a commercial transcription service. These transcriptions will be the primary source 
documents for this study. The interviewer, the PI or a trained research assistant, may also take notes on 
the qualitative interview guide during the interview and these notes may also serve as source 
documents for study data. Additional participant data will consist of a brief, 15-minute psychiatric 
diagnostic interview, measurement of motivation for BZD use, a urine drug test, alcohol and other drug 
use by self-report, BZD medication adherence by self-report, BZD withdrawal symptoms, distress 
tolerance measures, and affect and sleep symptoms. REDCap, described more generally below, will be 
used to assess BZD medication adherence, substance use, and sleep (sleep duration and sleep quality). 
We will ask participants to provide once daily reports via REDCap survey link sent to participant’s email 
or mobile phone.   If participants do not own a phone, we will provide them with a phone with one.   
 
This study will utilize REDCap (Research Electronic Data Capture), a software toolset and workflow 
methodology for electronic collection and management of clinical and research data, to collect and 
store assessment data. The Boston University School of Medicine Research Department will be used as a 
central location for data processing and management. REDCap provides a secure, web-based application 
that provides an intuitive data manipulation interface, custom reporting capabilities, audit trail 
functionality, real-time data monitoring/querying of participant records, and variations of data 
exporting/importing. 
 
11.3 Case Report Forms 
 
This study will not utilize case report forms. 
 
11.4 Study Records Retention 
 
The transcriptions and notes from the interviews, as well as assessment data, will be retained for at 
least seven years after the completion of the study and will be destroyed after the publication of the 
final journal article that uses this data. The audio files will be destroyed after they have all been 
transcribed. 
 
 
12 Statistical Plan 
 
12.1 Study Hypotheses 
 
DT-BD intervention will be found to be acceptable and feasible treatment arm for OAT patients 
discontinuing BZDs.  
 
12.2 Sample Size Determination 
 
This is a small pilot study to assess the acceptability and feasibility of the DT-BD intervention. A total of 
four participants will be recruited. If there is early dropout from the study, we will replace participants 
until we have an adequate rate of completion that allows for evaluation of all of the DT-BD intervention 

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modules. Interviews from this pilot study will be used to further refine our interventions in preparation 
for a larger, randomized pilot trial testing DT-BD vs. a control condition in this patient population.  
 
12.3 Statistical Methods 
 
The primary outcome for this study is the acceptability and feasibility of the intervention. The primary 
outcome data will consist of transcribed, in-depth interviews after the completion of the BZD taper. A 
qualitative research approach will be used to analyze this data. The analysis plan is centered on several 
domains, and within each of the domains, the investigator will draw comparisons, looking for overlap 
and differences, themes and trends. In addition, the investigator will continually look for newly 
emerging topics and patterns. Though we are collecting quantitative data including substance use, 
affect, sleep, and distress tolerance, we are only doing this for acceptability and feasibility purposes. 
This is in preparation for a future, larger trial during which we will be using these proposed measures for 
quantitative analysis. 
 
 
13 Ethics/Protection of Human Subjects 
 
This study is to be conducted according to applicable US federal regulations and institutional policies 
(which are based in federal regulations, guidance, and ICH Good Clinical Practice guidelines). 
 
This protocol and any amendments will be submitted to the Boston Medical Center and Boston 
University Medical Campus IRB, for formal approval of the study conduct. The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator.  
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. The 
consent form will be submitted with the protocol for review and approval by the IRB. The consent of a 
subject, using the IRB-approved consent form, must be obtained before that subject is submitted to any 
study procedure. Consent will be documented as required by the IRB.   
 
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15 Appendix 
 
Schedule of Events 
 
Visit 1: 
Baseline 
Assessment 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6* 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Taper 
Ends 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Questionnaire  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BZD History Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine BZD Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Timeline Follow-back (TLFB) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Institute Withdrawal 
Assessment-Benzodiazepines 
(CIWA-B) 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Distress Intolerance Index DII 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Acceptance and Action 
Questionnaire-II (AAQ-II) 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Anxiety Sensitivity Index 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Breath holding and Mirror 
Tracing Persistence Task (MTPT-
C) results 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Overall Anxiety Severity and 
Impairment Scale (OASIS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient health Questionnaire 
(PHQ-9) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pittsburgh Sleep Quality Index 
(PSQI) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-suicide severity rating 
scale (c-ssrs) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acceptability – Attendance, 
treatment retention, participant 
feedback 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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June 2021  
 
Page 27 of 27 
In depth qualitative exit 
interview  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
* First visit after start of taper