A Randomized Clinical Trial of Comprehensive Cognitive Behavioral Therapy (CBT) Via reSET-O for a Hub and Spoke Medication Assisted Treatment (MAT) System of Care.
Phase: NA
Conditions: Opioid-use Disorder
Sponsor: Milton S. Hershey Medical Center

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HRP-592 - Protocol for Human Subject
Research with Use of Test Article(s)
Protocol Title:
A Randomized Clinical Trial of Comprehensive Cognitive Behavioral Therapy (CBT) via reSET-O for a Hub and 
Spoke Medication Assisted Treatment (MAT) System of Care.
Principal Investigator:
Name: Sarah Kawasaki, MD
Department: Psychiatry
Telephone: 717-782-2781
E-mail Address: sxk865@psu.edu
Version Date:
8/23/2022
Clinicaltrials.gov Registration #: NCT04129580
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Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Data and Safety Monitoring Plan
10.0
Risks
11.0
Potential Benefits to Subjects and Others
12.0
Sharing Results with Subjects
13.0
Subject Payment and/or Travel Reimbursements
14.0
Economic Burden to Subjects
15.0
Resources Available
16.0
Other Approvals
17.0
Multi-Site Study
18.0
Adverse Event Reporting
19.0
Study Monitoring, Auditing and Inspecting
20.0
Future Undetermined Research: Data and Specimen Banking
21.0
References
22.0
Confidentiality, Privacy and Data Management
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1.0
Objectives
1.1
Study Objectives
The overall goal of this RCT is to conduct a patient-level community-based effectiveness trial of the 
comprehensive, mobile app-based cognitive-behavioral intervention reSET-O, to determine whether this 
intervention improves the adherence to and outcome of medication assisted treatment (MAT)for opioid 
use disorder (OUD) in the setting of a Hub and Spoke implementation system.
This RCT is part of an R21/R33 NIH grant. The R21 pilot trial is currently underway (IRB: 00009931) with 
some subjective positive observations in terms of subject participation and engagement with the app. 
The R21 trial has laid the ground work for the R33 to be conducted successfully. 
The primary hypothesis is that a greater proportion of patients assigned to Treatment As Usual (TAU) + 
reSET-O, compared to those assigned to TAU alone, will complete 6 months of MAT.
The Pennsylvania Psychiatric Institute (PPI) is committed to providing a wide range of high quality 
behavioral health services, including an Opiate Treatment Program (OTP) established in October 2017. 
Through the Pennsylvania Coordinated Medication Assisted Treatment (PACMAT) system, PPI functions 
as the “Hub,” herein referred to as the PPI Hub, offering medication assisted treatment (MAT) with 
methadone, dispensed and prescribed buprenorphine-naloxone (suboxone) and buprenorphine 
(Subutex).  The PPI Hub also offers extended release naltrexone to a limited number of patients.  The PPI 
Hub also offers counseling with individual and group settings to the level of intensive outpatient 
treatment using evidence-based Cor-12 and Matrix model programs for groups to start.  Treatment 
continues either at the PPI Hub or at one of the outlying spokes, depending on geography and patient 
clinical needs.  Whether at PPI Hub or spokes, patients are assigned a case manager who meets with 
them regularly and coordinates their care with the prescribing physician.  
The study test article, reSET-O (Pear Therapeutics, Inc.), is a commercially available version of the web-
based Therapeutic Education System (TES).
1.2
Primary Study Endpoints
The primary outcome measure will be retention in treatment on MAT for 6 months after initiation. 
1.3
Secondary Study Endpoints
The secondary outcome measures will be opioid use and other substance use (urine and self-report), 
craving, and measures of quality of life including mental health symptoms and social functioning.  
Exploratory analyses will examine whether the effect of reSET-O on 6-month adherence is mediated by 
improvements in quality of life outcomes.
2.0
Background 
2.1
Scientific Background and Gaps
Medication assisted treatment (MAT) is a cornerstone of an effective national response to the epidemic 
of opioid use disorder (OUD).  A key goal of the SAMHSA-funded State Targeted Response (STR) grants is 
to make MAT widely available to patients with OUD throughout the U.S. by reducing systemic barriers 
and increasing local capacity.  However, a major barrier to the effectiveness of MAT is patient 
adherence.  Studies show that 50% or more of patients with OUD initiating MAT will drop out of 
treatment within the first 3 to 6 months.  Dropout is associated with a high risk of relapse and overdose, 
and 6 months of treatment is considered a minimum needed for most patients to enter into long term 
abstinence and recovery.
2.2
Previous Data
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The Opioid Epidemic and Medication Assisted Treatment (MAT)
The opioid epidemic has spread rapidly over the past decade, reaching virtually every region of the U.S.  
It is estimated that 2.4 million Americans are currently addicted to opioids, and the prognosis is poor, if 
left untreated, including mortality from opioid overdose (Hser et al., 2001). Different types of MAT such 
as buprenorphine-naloxone, buprenorphine, methadone, and extended-release naltrexone, may be 
remarkably effective if patients adhere to treatment, the challenge is adherence to treatment.  Studies 
of buprenorphine-naloxone, specifically, typically show less than 50% of patients retained in treatment 
for 6 months (Hser et al., 2014; Lee et al., 2017), and dropout from treatment is associated with relapse 
(Weiss et al., 2011; 2015; Hser et al., 2016; 2017).  Hence, to combat the opioid epidemic, it is critical 
that MAT become universally available, and that patients’ adherence to MAT be improved.  
The digitally delivered intervention to be tested in this proposed study, reSET-O, targets treatment 
adherence, keeping appointments, and adherence to medication, while utilizing techniques of cognitive 
behavioral therapy and skills to avoid drug use and address problems with cravings, mood, and 
relationships, in order to avoid relapse, and rebuild a healthy lifestyle to support long term recovery. 
Barriers to Implementation of MAT and the Penn State Hub and Spoke System
Three evidence-based Medication Assisted Treatment (MAT) approaches for treatment of opioid use 
disorder are approved in the U.S., methadone, buprenorphine, and extended release injection 
naltrexone. Maintenance treatment with methadone, a full opioid agonist, has been available for 
treatment of opioid use disorder since the 1970s.  Methadone can only be prescribed under special 
regulations that are burdensome to patients (e.g. daily attendance at clinic required initially). 
Buprenorphine, approved in the U.S. in 2002, is a partial opioid agonist with less abuse potential, similar 
effectiveness, and more widespread availability than methadone, since it can be prescribed by any 
licensed physician who completes a modest training requirement.  However, the supply of physicians 
actively prescribing buprenorphine remains limited.  New prescribers need to be trained and supported 
within a variety of available clinical settings.  The SAMHSA Opioid STR grants awarded to the States 
beginning in 2017 provided additional funding for MAT and encouraged the use of implementation 
models to address the shortage of prescribers, case managers, and associated services.  With STR 
funding to the State of Pennsylvania, the Penn State-Hershey Medical Center established a Hub and 
Spoke (described below), based at Pennsylvania Psychiatric Institute, which is modeled on the Vermont 
program (Brooklyn and Sigmon 2017).  This Hub and Spoke offers methadone, buprenorphine and 
buprenorphine-naloxone.  It is within this system that the study proposed here will unfold, so that the 
findings may generalize to other States and regions around the U.S. utilizing similar models that support 
expansion of MAT through specialty clinic Hubs and primary care Spokes.  All three forms of MAT are 
subject to substantial rates of dropout from treatment, and dropout carries a high risk of relapse to 
opioid use.  It is our hypothesis that reSET-O will reduce dropout and hence improve the effectiveness of 
MAT treatment. 
Barriers to Implementation of MAT: The Importance of Behavioral Therapy
Another key systemic barrier that has been identified is lack of access to behavioral intervention and 
counseling to accompany MAT prescribing (Quest et al., 2012; Hutchinson et al., 2014; DeFlavio et al., 
2015).  Provision of counseling is a regulatory requirement for methadone, buprenorphine, and 
buprenorphine-naloxone treatment.  Further, evidence suggests that counseling and behavioral 
treatments improve adherence to and effectiveness of MAT (McLellan et al., 1993), particularly 
contingency management approaches (Peirce et al., 2006; Nunes et al., 2006; Carroll and Weiss 2017).  
Primary care practices and other clinical settings new to treating addictions typically lack staff with 
expertise in relevant behavioral treatments.  Even addiction treatment programs serving as “hubs” may 
struggle to deliver more than rudimentary counseling due to time constraints and lack of expertise in 
the latest evidence-based interventions.  The intervention to be tested in this proposed study, reSET-O, 
is a comprehensive cognitive behavioral treatment, with a strong evidence-base to suggest that it can 
improve adherence and outcome of MAT treatment for opioid use disorder (OUD), compared to 
standard counseling.  Since it is a mobile app, delivered through patients interacting with a smart phone, 
it does not require a large time commitment or behavioral health expertise of clinical staff.  Thus, reSET-
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O has the potential to address the need for behavioral treatment as part of STR efforts to rapidly expand 
MAT, while improving the effectiveness of MAT at ushering patients into stable recovery.  
2.3
Study Rationale
The study proposed here would be the first randomized controlled clinical trial of a comprehensive 
cognitive behavioral therapy to increase the effectiveness of MAT for the treatment of OUD in the 
context of a regional Hub and Spoke system to expand access to MAT. Programs like the Penn State Hub 
and Spoke have been set up to serve rural and impoverished small urban communities that have 
become the epicenter of the opioid epidemic.  The need to deliver evidence-based psychosocial 
treatment has been identified as one of the key barriers to implementing MAT in such primary care 
settings, where the time and expertise needed to deliver such interventions are scarce.  A digitally 
delivered cognitive behavioral intervention such as reSET-O has the potential to fill this gap. Since reSET-
O is a commercially available mobile app, if found effective in supporting MAT, it has the potential to be 
rapidly disseminated across the U.S. health system in support of the STR initiative.
The study of reSET-O proposed here would be the first test of a randomized control trial of 
comprehensive cognitive behavioral therapy (CBT) to increase the effectiveness of MAT for the 
treatment of OUD in the context of a regional effort to expand implementation of MAT.  As a 
comprehensive CBT treatment, reSET-O focuses not only on drug use, craving, and medication 
adherence, but also on skills to help patients address common problem areas, such as relationships, 
mood and related problems, and social functioning, in order to rebuild a healthy lifestyle.  It is also 
individualized in that patients can select and repeat therapy lessons relevant to their most pressing 
problem areas.  Most evidence-based behavioral interventions are delivered by clinicians and require 
training and supervision of clinical staff to deliver the intervention correctly, and substantial time of 
clinical staff to actually deliver the intervention to patients at scale.  Clinicians’ time and expertise are 
resources that are in short supply in community-based efforts to expand implementation of MAT and 
have been identified as significant barriers to delivering MAT to date.  If found effective in the trial 
proposed here, reSET-O has the potential to lead the field of MAT implementation toward a new 
paradigm where a behavioral intervention becomes a resource that can be down-loaded from the web 
and prescribed to patients, rather than an intervention that needs to be learned and painstakingly 
delivered by clinicians.  This has the potential to promote widespread implementation of MAT both by 
reducing barriers to delivering behavioral therapy, and by improving adherence to MAT and overall 
treatment outcome.  This effort may also in the long run encourage the development of other web-
based behavioral interventions to support implementation of MAT.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria

18 years of age or older

Diagnosis of opioid use disorder (OUD) as determined through routine clinical care

Recently starting outpatient treatment for OUD within the PACMAT Hub and Spoke System of 
Care.

Initiating MAT with buprenorphine-naloxone (suboxone), buprenorphine (Subutex), or 
methadone.  Since buprenorphine (Subutex) is an FDA approved MAT for pregnant women with 
OUD, pregnant women are eligible to participate in the research study, assuming they meet all 
other eligibility requirements. 

Ability to read, write, and comprehend English

Providers who are engaged with the reSET-O app and talking to their patients who have agreed 
to participate in the study and also assigned to use the reSET-O app.
3.2
Exclusion Criteria
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
Initiating maintenance treatment that does not include MAT or switching to a maintenance 
treatment that does not include MAT (i.e.: detoxification and counseling treatment only without 
MAT).

Planning an outpatient detoxification

Judged by the evaluating physician or allied clinician to need a higher level of care (i.e.: 
residential or inpatient treatment)

Less than 18 years of age

Unable to read, write, and comprehend English
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
There are a number of reasons for potential subject withdrawal from the research study. If 
funding for the research study ends, then all subjects will be withdrawn from the research study. 
If it appears as though their OUD diagnosis is becoming worse, then subject will be withdrawn 
from the research study. This information will also be outlined in the consent form. 
3.3.2
Follow-up for withdrawn subjects
Withdrawn subjects will be categorized by why they withdrew (disease progression, etc.), and 
the timing of withdrawal at the 1, 3, and 6-month time points. Withdrawn subjects will not be 
replaced. Withdrawn subjects will have the opportunity to have a follow-up visit with the study 
doctor if there are any concerns regarding next steps and/or treatment.
4.0
Recruitment Methods
4.1
Identification of subjects
Patients will be identified at the PPI Hub clinic through the PACMAT Hub and Spokes system of care. 
Patients are categorized as either Hub or Bridge/Spoke patients, depending on if they routinely seek 
treatment at the PPI Hub or a Spoke site.  The PACMAT Hub and Spokes system of care has a strong 
track record of recruiting patients with substance abuse disorders. These centers are already providing 
treatment for patients with opioid use disorder (OUD), making them a primary source of treatment and 
attracting a high volume of patients.  Additionally, the PPI Hub has a valued partnership with the 
Recovery-Advocacy-Service-Empowerment (RASE) Project and Just for Today (JFT) Recovery Services 
that connect clients to the PPI Hub and Spokes in our continuum of care and provides Case Managers for 
patients receiving their MAT care at Spoke practices.
All patients entering treatment for OUD within the PACMAT Hub and Spoke system will be verbally 
introduced to the study by the treating clinician who is also a study team member. Patients who are 
interested in participating in the study will be taken to the research office in the clinic and will engage in 
a phone call/zoom session with a research assistant to begin the recruitment process (if the research 
assistant is working remotely). If the research assistant is on site, then they will escort the patient to the 
research room for in-person recruitment. Those interested in learning more about the study will be 
scheduled for an appointment to ask questions about the study, go through the consenting process. 
Complete baseline questionnaires, and be randomized. Recruitment appointments will be scheduled 7-
21 days after the patient completes clinic intake and provides contact information to research staff. 
Research activities will occur remotely with the patient at the PPI Hub or in a place of the patient’s 
choosing (i.e. patient’s home). All in-person research activities will occur at the PPI clinic. 
In addition, research staff will place project flyers and handouts in the PPI OTP waiting room and 
research rooms (submitted with this modification). Flyers and handouts will introduce the project and 
provide contact information (email and phone) for research staff. If patients reach out to research staff 
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directly, research staff will verify eligibility before discussing the project and beginning the consent 
process.
Providers at PPI will be engaged in the app. Providers at PPI continue to function in-house and through 
telehealth procedures. Providers will login to the clinician dashboard to discuss modules completed with 
patients (either virtually or in-person) who have agreed to participate and have also been assigned to 
use the app. Once the study is complete, these providers will also be asked to engage in an open-ended 
discussion about the research study and complete a brief survey regarding the feasibility and 
acceptability of the app intervention. This open-ended discussion and survey may be done remotely or 
in-person, depending on the status of the current COVID19 pandemic at the end of this study.
Providers will only use the clinician dashboard side of the app to review their patient-completed 
modules and discuss these modules with their appropriate patients. Providers will not use the app for 
their patients who do not wish to be in the research or who have decided to quit the research study. 
Providers will receive a running list from research staff of their patients who are enrolled in the study 
and assigned to the use the app. This will be updated and provided on a monthly basis. 
4.2
Recruitment process
4.2.1
How potential subjects will be recruited.
New patients at the OTP at PPI are required to present in-person to the clinic. Potential patients 
will be recruited first by being verbally introduced to the study at their first intake clinical 
appointment by a treating clinician who is also a study team member. Patients coming to the PPI 
Hub clinic for treatment and who use or plan to use MAT will be identified through physician 
referral.  The PPI Hub clinic currently has five part-time physicians and one full-time nurse 
practitioner.  Patients who are interested in the study will be asked to talk with a research 
assistant via phone, zoom session, or in-person in a private room (within the clinic). 
4.2.2
Where potential subjects will be recruited.
Patients will be recruited at the PPI Hub clinic, and RASE and Just for Today spoke sites in 
southern Central PA.
4.2.3
When potential subjects will be recruited.
Patients will be recruited during their routine clinical care appointments.
4.2.4
Describe the eligibility screening process and indicate whether the screening process will 
occur before or after obtaining informed consent. Screening begins when the investigator 
obtains information about or from a prospective participant in order to determine their 
eligibility.  In some studies, these procedures may not take place unless HIPAA Authorization 
is obtained OR a waiver of HIPAA Authorization when applicable for the screening procedures 
is approved by the IRB.  [For FDA regulated studies, consent for any screening activities would 
need to be obtained prior to screening unless specifically waived by the IRB.]
Screening a patient medically/psychiatrically to determine appropriate type of MAT is a clinical 
decision that is part of routine care, so that the research study is not responsible for erecting 
criteria that MAT is safe and appropriate at the outset. 
Eligibility criteria are broad with minimal exclusionary criteria in keeping with the goals of an 
effectiveness trial to select a fully representative sample of patients seeking treatment in real 
world community-based treatment settings. Inclusion criteria include being over 18 years of age, 
being fluent in English, being interested in participating in research about opioid use and having 
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started Methadone or Suboxone within the past 42 days. Exclusion criteria include not being 
fluent in English and staying at a treatment facility or program where the use of cell phones or a 
tablet device is prohibited. 
5.0
Consent Process and Documentation 
5.1
Consent Process:
Check all applicable boxes below:
 Informed consent will be sought and documented with a written consent form [Complete Sections 
5.2 and 5.6] 
 Implied or verbal consent will be obtained – subjects will not sign a consent form (waiver of 
written documentation of consent) [Complete Sections 5.2, 5.3 and 5.6] 
  Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception). [Complete section 5.2, 5.4 and 5.6] 
 Informed consent will not be obtained – request to completely waive the informed consent 
requirement. [Complete Section 5.5]
5.2
Obtaining Informed Consent 
5.2.1
Timing and Location of Consent 
Consent will occur 0-42 days after the intake appointment. Consenting will occur through a 
remote zoom session conversation (when the research assistant is working remotely) and in-
person (when the research assistant is on site) while the prospective participant is at the PPI 
Hub. The baseline research appointment will be scheduled as a remote session during a time 
that is conducive for both the research staff and potential research subject. The subject and 
research coordinator will review the consent form over a zoom session or in-person. The subject 
will be offered either an electronic version of the consent form or a hard copy of the consent 
form to review on their own before the consent meeting and/or during the meeting. Subjects 
will be given time to review the consent form and all questions will be answered by the research 
coordinator. IRB approved hard copy consent forms will be stored in unlocked cabinets in 
research rooms where the zoom consenting session will take place, in which a research assistant 
may instruct the participant to retrieve if appropriate. The consent form may also be emailed or 
mailed to the subject (before the meeting or during). The subject will be allowed to take the 
consent form home for further review or to discuss with family, friends, or a provider actively 
involved in their care if they wish. 
If participants are interested in participating in the study, they will have three different options 
for completing the consent process (depending on if the research assistant is working on-site or 
remotely):
1.
Patients will be sent a REDcap link via personal email or text message on the PPI OTP 
clinic smartphone, a personal cell phone, or a personal tablet device. This REDcap link 
will ask for participant consent including the date and time, entry of their first and last 
name, as well as their signature as drawn through a computer mouse or finger. The 
individual obtaining consent will also complete a REDcap form indicating the date, time, 
and signature that the consent form was explained to the participant. REDcap has the 
ability to data-lock fields. As soon as the participant and consenter sign the REDcap 
consent form, the consenter will lock the data fields. 
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2.
If there are technological challenges using the e-signature process or if the patient 
prefers to use a different option, the patient will have the option of signing a hard copy 
of the consent form. If the patient chooses this option, then research staff will also 
complete the “Phone Consent to Participate In a Research Study Signature Page.” Once 
both forms have been collected, the baseline process (baseline surveys) can continue. 
3.
If research staff are on-site, research staff will provide the patient with a hard copy of 
the consent form and both the patient and research staff will sign the same consent 
form. 
Upon obtaining consent, participants will be asked to complete a brief quiz with questions 
related to the consent form. It is estimated that this quiz will take 5-10 minutes to complete and 
is used to ensure the participant’s understanding of the consent form and the research study 
overall. There is no penalty for incorrect answers to the consent quiz questions. For any consent 
quiz question that is answered incorrectly, the research staff conducting the consent 
appointment will review the respective areas to ensure the participant’s understanding. A copy 
of the signed consent form will be emailed or mailed to the participant. If in person, a copy of 
the signed consent form will be handed to the patient. We may also email the signed consent 
form to the participant’s PPI clinical provider, who is also a study team member, to print the 
form at the clinic and physically hand the form to the participant. Method of delivery of the 
signed consent form will be based on participant preference. 
Providers engaging with the app as appropriate will be provided a summary of explanation for 
research to provide an overall synopsis of the study as well as their involvement. This summary 
of explanation will be emailed to all providers engaging with the app. Provider questions may be 
answered via email or over the phone.
We will ensure that the participant is completing the correct version of the consent by dating 
the consent database within the reSET-O project based on the IRB approval date. This will be 
noted/filed in the regulatory binder to ensure smooth quality assurance checks and monitoring. 
This way, there is no confusion as to which consent form database needs to be used, which will 
be particularly helpful once the consent IRB stamp of approval changes as a result of continuing 
reviews, modifications, etc.
If updated versions of the consent and/or addendums are required, we will generate new 
consent and/or addendum databases within the reSET-O project in REDcap. We will be sure to 
date the databases with the most recently approved IRB version to avoid confusion on which 
REDcap consent database should be used. Newly enrolled participants from that point would 
then complete the new, updated consent form. Established participants would then be 
contacted to complete an e-signature through REDcap for an addendum if necessary. The same 
steps above, as outlined for consent completion, will occur for addendum review and signature. 
5.2.2
Coercion or Undue Influence during Consent 
Prospective participants will have the opportunity to read the consent form, the requirements 
for participating in the project will be reviewed with prospective participants by the research 
coordinator, any questions will be answered, and written informed consent will be obtained by 
study staff. Participants may request a copy of the consent form to take home and review with 
significant others, and be rescheduled for a second visit for additional discussion. They will have 
a chance to read the informed consent document, ask any remaining questions, and provide 
signed consent. 
For pregnant subjects or subjects who may become pregnant, per HRP-412, each individual 
providing consent is fully informed regarding the reasonably foreseeable impact of the research 
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on the fetus or neonate. There is no prospect of benefit to the fetus, the risk to the fetus is NOT 
greater than Minimal Risk and the purpose of the research is the development of important 
biomedical knowledge which cannot be obtained by any other means.
Providers will have the opportunity to review the summary of consent of research and may ask 
questions at any point in time. They may refuse to participate in the open-ended discussion and 
they do not have to answer any questions on the survey that they do not wish or feel 
comfortable answering.
Consent is obtained only by research staff (research coordinator, research assistants), and not 
by any clinical staff, in order to ensure that patients do not feel obligated to their clinicians to 
consent to the research.  The consent form, and consent discussion with research staff, make it 
clear that research participation is voluntary and does not affect the ability to obtain treatment.
5.3
Waiver of Written Documentation of Consent 
Providers engaging with the app as appropriate will be provided a summary of explanation for research 
to provide an overall synopsis of the study as well as their involvement. Consent will be implied by 
providers engaging with the app with appropriate patients and, at the completion of the study, engaging 
in an open-ended discussion and completing the survey about feasibility and acceptability of the app 
intervention. Informed consent will be sought but some of the elements of informed consent will be 
omitted or altered (e.g., deception).
5.4
Informed consent will not be obtained – request to completely waive the informed consent 
requirement
N/A
5.5
Consent – Other Considerations 
5.5.1
Non-English-Speaking Subjects
N/A – Subjects are only eligible if they can read, write, and comprehend English. 
5.5.2
Cognitively Impaired Adults
5.6.2.1 Capability of Providing Consent
If a subject is unable to provide consent as a result of intoxication (i.e.: illegal 
substances or alcohol) as observed by the clinician during the routine clinical care 
appointment, then the study will not be introduced to the potential subject during 
that time. 
If a subject is unable to provide consent as a result of intoxication (i.e.: illegal 
substances or alcohol) as observed by the research coordinator or research 
assistant, then the consent process will stop and be rescheduled at the potential 
participant’s discretion.  
5.6.2.2 Adults Unable to Consent
N/A
5.6.2.3 Assent of Adults Unable to Consent
N/A
5.5.3
Subjects who are not yet adults (infants, children, teenagers) 
5.6.3.1 Parental Permission
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N/A
5.6.3.2 Assent of subjects who are not yet adults
N/A
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or disclosed in this 
study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the only box 
checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical records 
will be accessed to determine eligibility before consent/authorization has been obtained). [Complete 
all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies). [Complete all 
parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization (verbal 
authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
We plan to obtain verbal authorization only from provider participants; however, PHI of 
providers will not be collected. The following sections do not apply to the patient participants 
who may receive the app intervention (based on randomization).
6.2.1.1
Plan to protect PHI from improper use or disclosure
Information is included in the “Confidentiality, Privacy and Data 
Management” section of this protocol.
6.2.1.2
Plan to destroy identifiers or a justification for retaining identifiers 
We do not plan to obtain identifiers of participant providers. Data collected 
from providers will be self-report surveys, which will be entered into 
REDcap. Completed paper surveys by providers will be stored in a secure 
and locked research office. 
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
We are not collecting PHI of participant providers. 
6.2.3
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
The verbal authorization and waiver of documentation of authorization is required, because the 
application intervention is being randomly administered to clinic-patients who wish to be a part 
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of the research study, and it is expected that the providers will engage in the application 
intervention with those specific research subjects.
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations. 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) 
per federal regulations. 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented.
7.0
Study Design and Procedures
7.1
Study Design
This RCT trial will be conducted to test the effectiveness of reSET-O as a cognitive behavioral therapy to 
enhance MAT treatment adherence among opioid use disorder (OUD) patients.  All participants will be 
randomly assigned to receive reSET-O along with treatment as usual (TAU) or TAU alone.  
We are collaborating with Columbia University who has worked closely with Pear Therapeutics, Inc. 
(owners of the reSET-O app program).  Analysis of the patient survey data via REDCap as well as data 
collected from the reSET-O phone app, received from Pear Therapeutics through a Penn State approved 
file sharing system (i.e.: Accelion, File Drop, Kitedrive, etc.), will be conducted by a senior PhD-level 
statistician and master’s level analyst located in the Clinical and Translational Science Institute (CTSI) at 
Penn State College of Medicine. The Columbia University biostatistician will be available for consultation 
and guidance throughout data analysis; Columbia University will not be directly handling study data 
beyond that required of routine quality assurance procedures and weekly study team meetings.  
We are also collaborating with the Research Foundation for Mental Health (RFMH) as affiliated with 
Columbia University. RFMH will be providing quality assurance for the project including monitoring of 
data collection of both non-PHI and PHI, as well as monitoring the regulatory binder. All monitoring 
reports completed for QA will be submitted to the Penn State IRB.
7.2
Study Procedures
7.2.1
Visit 1 (Intake/Baseline) 
During the subject’s intake appointment, eligibility is confirmed by the provider and subjects are 
directed to a private research room. Research staff will introduce the research study to the 
participants and schedule a research appointment to discuss the project further in 7-21 days. 
Subjects can take a physical copy of the consent form home with them or request one be 
emailed to them. 
During the first research appointment, research staff will confirm eligibility, complete the 
consent process, complete the baseline questionnaires, and randomize the subject (TAU + 
reSET-O or TAU alone). Participants will be asked to undergo research assessments consisting of 
an interview and self-report questionnaires (described below), as well as urine samples collected 
at all visits (baseline, week 4(+/- 2 weeks), week 8(+/- 2 weeks), week 12(+/- 2 weeks), and week 
24(+2/- 4 weeks)). Urine toxicology for opioids and other drugs is collected at PPI as part of 
routine clinical care; however, urine collected at these specific clinic visits will also be used for 
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research purposes and used to confirm self-reports of abstinence.  This will be outlined in the 
consent form and discussed with the participant. 
Participants who are assigned to TAU + reSET-O will be briefed on the reSET-O app and will 
download the reSET-O app onto their smartphone or tablet device. Penn State research 
assistants will have the capability to generate and provide app access codes through the Pear 
Therapeutics clinician dashboard. This allows for instant access and entry into the app for the 
research subject, as opposed to waiting for several hours or even days for onboarding through 
the Patient Services Center.  However, participants will still be required to complete the Pear 
Therapeutics reSET-O patient services center (PSC) enrollment form (completed with the 
research assistant), which will be transferred to the PSC via secure file transfer (e.g. Accellion or 
Kitedrive) or by fax. The PSC is affiliated with Pear Therapeutics, the owners of the reSET-O app. 
The following information is collected on the enrollment form and faxed to PSC:

The enrollment form collects information that is used by the PSC to verify the identity of 
the subject including the patient’s first and last name, and a date of birth, which will be 
a “dummy” date of birth (i.e.: 01-001-1999; dd-mmm-yyyy).   The first and last name of 
the participant is required because PPI Hub clinicians who are also part of the research 
team will not be able to identify their patients who are engaged in the app through the 
clinician dashboard via subject IDs due to the volume of patients seen. Thus, the PPI Hub 
providers need to be able to see participant patient names in their clinician dashboard 
in order to engage with subject about their app use. The PSC form clearly indicates that 
this individual is enrolled in a research study, which allows staff at the PSC and Pear 
Therapeutics, Inc. to understand that services are not to be billed to any insurance. 

A phone number is also required for the enrollment form, which may be a phone 
number most commonly used by the participant, or a phone number associated with a 
research assistant’s office phone (for participants who do not have an operating phone 
number).   The phone number is needed because the PSC will call the subject weekly to 
ensure that that the participant is able to use the app without technical difficulty. The 
participant may opt out of these calls, which will be outlined in the consent form. reSET-
O, Pear Therapeutics, Inc. (owners of reSET-O), and other entities affiliated with reSET-O 
do not use phone numbers for any other purpose including selling the phone number to 
third parties, sales calls, etc.

An email is also required for the enrollment form, which may be an email most 
commonly used by the participant, or the research coordinator/research assistant may 
help the participant set up a free email account for purposes of this study. An email is 
needed because should the participant forget their username and/or password to login 
to the app, they will be able to reset their login credentials via email.  reSET-O, Pear 
Therapeutics, Inc. (owners of reSET-O), and other entities affiliated with reSET-O do not 
use email addresses for any other purpose including selling the email  to third parties, 
marketing or other advertisements, etc.
Participants, who do not own a smartphone, will be provided with an inexpensive tablet device 
that will be able to access reSET-O for the duration of the trial. These devices will be obtained 
and managed by research study staff. Should a participant lose or sell the tablet device, or if the 
device is stolen, they will be afforded a second chance with a new tablet device as provided by 
the study. Should the participant lose or sell the second device, or if the second device is stolen, 
they will not receive a third tablet device. They will still be enrolled in the study and asked to 
complete questionnaires at the appropriate time points; however, they may not be able to 
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engage with the app, reSET-O, unless they provide their own device that is compatible for use 
with the reSET-O app (e.g., smart phone, table).  This will also be outlined in the consent form.
After obtaining consent, randomized assignment, and getting set-up with the reSET-O app (if 
applicable) as outlined above, all participants will complete the electronic surveys listed below. 

Eligibility checklist to assess a potential participants eligibility via inclusion and exclusion criteria. 

Demographics form will be used to collect basic demographic information on each participant 
(i.e.: DOB, gender, education level, etc.), and will only be collected at baseline.

Locator form collects information that will be useful in helping research staff to locate a 
participant for assessment should they stop attending treatment, including address, phone 
number(s), and contact information of significant others who would know how to locate the 
participant.  This is important scientifically to minimize missing data due to loss to follow up. In 
order to protect confidentiality of participants, if listed significant others are contacted, no 
information will be divulged by research staff about the participant, other than that they were 
participating in a survey at Penn State and the research team in attempting to contact them for 
follow up survey. During consent participants will be informed that it is important for research 
staff to be able to contact them to find out how they are doing and conduct assessments, even if 
they have dropped out of treatment, and the procedures for contacting significant others for 
locator purposes are explained.

Timeline Follow-Back (TLFB) (Sobell and Sobell, 1992; 2000) assesses self-reported alcohol and 
other drug use (frequency, quantity) using calendars and memory aids to enhance recall. We will 
not be able to provide printed calendars; however, the participant will be encouraged to use 
their phone or tablet device to view a calendar app to help enhance their recall of past 
substance use. The TLFB has good psychometric properties, including test-retest reliability with 
multiple populations, and content, criterion, and construct validity across multiple related 
measures. Additional questions will assess intensity and number of days of urges/cravings for 
opioids and other substances, and HIV risk as a result of IV drug use and sharing of 
needles/works. Per the recommendation of the NIH, staff who are blinded to the randomization 
assignment of participants should complete the TLFB. Penn State research staff will complete 
the TLFB during baseline because it will be completed before randomization occurs. Columbia 
research staff will be completing the TLFB via phone/WebEx session with all subjects beginning 
with the 4-week follow-up visit. During the follow-up visits, Penn State research staff will 
complete all research tasks with the participants and help facilitate the TLFB with the Columbia 
team by:
o
Transferring the participants to the Columbia team by phone, text or email;  
o
Providing a phone number or meeting room link so participants could reach out to the 
Columbia team directly; and/or 
o
Providing the Columbia team with the participant’s contact information (at the 
participant’s request). 
o
The research tasks with the Columbia team will occur through the participant’s phone or 
an office phone via WebEx. Columbia University requires the use of WebEx for research 
outreach to participants. 

Coping Strategies Scale (CSS) (Litt et al., 2003) is a 23-item, self-report measure (originally 
adapted from the Processes of Change (Proschaska et al., 1998)), assessing change processes, 
coping skills, and problem-solving related to urges to use substances. It has good reliability 
across samples (=.83 to .87). Two versions with only slight differences in directions will be 
administered. At intake, the directions will ask subjects to think about the last three months 
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when answering the questions. For all follow-up research appointments, the directions will ask 
the subject to think about their coping strategies used since the last research appointment. 
Question/prompt items remain the same between the two versions.

PROMIS is a well validated and widely used scale that measures the quality of social and 
occupational functioning. 

Social Connectedness Scale (SCS) (Lee and Robbins 1995; 1998) is a 20 item, 6-point scale, self-
report assessing psychological belonging or interpersonal closeness with good reliability (=.91).

Patient Health Questionnaire (PHQ) (Spitzer et al., 1999) was developed for use in primary 
health settings and screens for DSM psychiatric diagnosis of major depression and generalized 
anxiety at baseline. 

The Kessler 10 (K10) (Kessler et al., 2003) is a brief, 10-item self-report measure of general 
psychiatric distress will be collected at baseline and follow up points to address change in 
psychiatric symptoms over time. K10 has good reliability and is used in World Health 
Organization mental health surveys in 30 countries.

HIV Risk from the Sexual Experiences and Risk Behavior Assessment Schedule (SERBAS): A 
summary item from the Sexual Experiences and Risk Behavior Assessment Schedule (SERBAS), 
used as primary outcome in large HIV risk reductions studies (Tross et al., 2010), elicits the 
number of episodes of occasions of vaginal or anal intercourse without a condom over the last 
90 days using time-line follow back cues for recall.  

Time Line Follow-Back (see above) will query intravenous drug use, and episodes of sharing 
needles.

Columbia Suicide Severity Rating Scale (C-SSRS; Posner et al., 2008):  The C-SSRS will be 
administered only to subjects who have endorsed suicidal ideation (SI) per the Patient Health 
Questionnaire (PHQ). There is one item on the PHQ that assesses self-reported SI using a Likert 
scale of 0-3 (0 = not at all; 3= nearly every day). A score of 1 or higher is considered an SI 
endorsement, which will warrant administration of the C-SSRS. Should the C-SSRS results 
indicate an SI presence/plan, a Hub PPI provider (physician or nurse practitioner) will take over 
the evaluating situation and follow PPI’s SI policy.

Intervention Acceptability/Feedback Form (IAFF) is a 7-item self-report measure comprised of 
indicators of treatment acceptability on 10-point scales: interesting, useful, new information, 
easy to understand, satisfaction, relevance to life, and likability. This will only be administered to 
patients who have been assigned to TAU + reSET-O. 

TAU Tracking Form (TTF) –completed by research staff in order to capture services received in 
TAU per week over past 4 weeks, including modality and frequency. Research staff will verify the 
information with the patient for accuracy.  

reSET-O Implementation and Adherence: For participants who have been assigned to TAU 
+reSET-O, we will collect data from the reSET-O data system and dashboard for each patient on 
utilization of reSET-O features (how many and which therapy lessons are completed, incentives 
earned, use of the communication features).

Weiner Intervention Appropriateness, Acceptability and Feasibility Survey: This survey will be 
completed by providers who are engaged with the app. This survey evaluates acceptability, 
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appropriateness, and feasibility of intervention implementation using a 5-point Likert scale 
(1=lowest score; 5=highest score).  
In cases where the Timeline Follow-Back assessment cannot be completed (patient cannot 
access the Columbia team’s WebEx room, patient must leave the research visit before 
completing), Penn State research staff will pull data from the Demographic Questionnaire Form 
that the patient completes during their intake process (attached to this modification). This 
questionnaire is also administered by Penn State research staff as part of routine intake. This 
data query is necessary because of the time sensitive nature of self-reported alcohol and drug 
use data (i.e. asking about a patient’s alcohol and drug use in the last 30 days). 

HITS (Hurt-Insult-Threaten-Scream Screening Tool): This assessment screens for domestic 
violence in participants who have a romantic partner. It will be used at both the baseline and 
endpoint visits. 

BARC-10 (Brief Assessment of Recovery Capital): This is a 10-item measure that assesses the 
level of personal, social, physical and professional resources that someone has available. 

PCL-C (PTSD Checklist – Civilian Version): A self-report rating scale for symptoms of PTSD over 
the past 1 month. 

Overdose History: This assessment asks patients if they have ever overdosed on a substance and 
then goes into branching logic for details of the incident if they have, with questions like 
“when?”, what substance, etc. 

First Response Opioid Survey Tool (FROST): This survey has questions for all research 
participants about the first time they used opioids. 
7.2.2
Week 4 (+/- 2 weeks), Week 8 (+/- 2 weeks), Week 12 (+/- 2 weeks), & Week 24 (+2/- 4 weeks)
The same procedures and measures listed above will be repeated again at the Week 4 (+/- 2 
weeks), 8(+/- 2 weeks), 12(+/- 2 weeks) & 24(+2/- 4 weeks) follow up visits – measured from 
completion of baseline questionnaires and randomization. Given the predicted scheduling 
challenges with this population, we plan to incorporate a 2-week window for completion of 
specific visits. For the last visit, we plan to allow for a +2/-4 window in the event that we need to 
allow for time to locate specific subjects who have been lost to follow-up.
A qualitative interview will be conducted and recorded with patients who have been assigned to 
TAU + reSET-O (n=100) at week 4 to gather their initial thoughts on the app and identify factors 
contributing to time spent on the app. Qualitative interviews will also be conducted at weeks 8 
and 12 to elicit personal accounts of their experience using the program, acceptability of the 
program, and suggestions for improvement.  The total time to administer these qualitative 
interviews is estimated at 20-30 minutes.  The interview will be audio recorded. The audio 
recording will be stored on the Hershey Network server, accessible only by assigned study staff 
and the PI. The interview does not ask for PHI and therefore PHI is not expected to be in the 
recording; however, transcriptionists will be trained to remove PHI from any interviews.
reSET-O only works for 12 weeks at a time.  Therefore, at week 12, subjects who have been 
randomly assigned to TAU + reSET-O will repeat the reSET-O enrollment process again, which 
includes the PSC form, for the continuation of their access to reSET-O. Information on the first 
enrollment form will be identical to the second enrollment form, with the exception of phone 
number and email in the event that this information has changed. There is no change in 
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completion of modules within the app or contingency management provided by the app from 
access time point 1 to access time point 2. The extended access allows the subject’s account to 
rollover into the extended access account, enabling subjects to pick up where they left off with 
their contingency management, modules, and revisiting completed modules.
There will be two phone check-ins with the research coordinator/ research assistant. The phone 
check-ins will occur during the 16th week and again during the 20th week of the study.  The 
phone check-in will be a simple 5-10-minute conversation to ask the subject how they are doing 
and determine if their contact information has changed in order to facilitate contact for the 24-
week follow up. 
At the completion of the study, providers (i.e.: physicians, case managers, etc.) will be complete 
a five-minute survey regarding the feasibility, acceptability, barriers, and facilitation of using 
reSET-O. They will also be asked to engage in an open-ended discussion (approximately 1-1.5 
hours) to provide suggestions for improvement of the app itself or facilitation of 
implementation.  No personal information will be collected from providers about themselves. 
The open-ended discussion and survey may be done remotely, depending upon the status of the 
COVID19 pandemic
7.3
Duration of Participation
All participants are asked to participate in 5 remote or in-person research visits over 24 weeks as listed 
above, as well as participate in two phone check-ins at week 16 and week 20.  The baseline visit will take 
about 1 to 1.5 hours for subjects assigned to reSET-O +TAU, and 45 minutes to 1hour for subjects 
assigned to TAU only. For reSET-O + TAU subjects, follow-up appointments will last 30 to 45 minutes, 
with the exception of the visit that accounts for the addition of a qualitative interview (weeks 4, 8 or 12), 
which will last approximately 50 to 65 minutes to account for the qualitative interview. For subjects who 
have been assigned to TAU only, follow-up visits will take 20-30 minutes to complete.
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
reSET-O: Mobile App Delivering Cognitive-Behavioral Intervention to Enhance Implementation 
of MAT
reSET-O is the commercially available version (Pear Therapeutics, Inc.) of the Therapeutic 
Education System (TES) originally developed by Bickel, Marsch and colleagues (2008). It was 
recently approved by the FDA as the first digital therapeutic adjunct for the treatment of 
substance use disorders.  Pear Therapeutics has agreed to provide reSET-O for this proposed 
project without cost and to collaborate on any modifications that arise during the R21 phase.  
reSET-O (TES) combines two empirically supported treatment approaches, Community 
Reinforcement Approach (CRA) and Contingency Management (CM), translating them onto a 
computer-interactive learning environment, delivered by smartphone or tablet, without the 
direct involvement of a human therapist. CRA is based on the model that substance use 
disorders develop when drug reinforcers grow in salience and displace an individual’s normal 
healthy sources of reinforcement, such as friends, family, employment, and recreation.  CRA 
teaches patients cognitive-behavioral coping skills to resist drug use and to address factors such 
as craving, depression and other mood problems, and relationship issues that are associated 
with risk of relapse, in order to rebuild their lives and relationships without drugs. CM provides 
concrete monetary rewards (e-giftcards) contingent on performance of one or several key target 
behaviors, such as urine-confirmed abstinence from drugs or attendance at treatment 
appointments.  CRA and CM are both highly researched therapeutic interventions for substance 
use disorders with broad empirical support individually (Hunt & Azrin 1973; Budney & Higgins 
1998; Miller & Meyers 1998; Stitzer & Petry 2006). When delivered together, CRA and CM have 
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been shown to contribute uniquely to outcomes, suggesting complementary therapeutic 
elements that enhance overall treatment effectiveness (Roozen et al., 2004; Higgins et al., 1994; 
2003). 
MAT treatment (treatment as usual) when combined with counseling has a decent success rate 
at greater than 50% patient retention over a 6-month period.  Patients retained in MAT 
treatment typically experience substantial improvement in their opioid use, while those who 
discontinue MAT typically relapse to opioid use.  Therefore it is important to try to improve the 
rate of retention in treatment, which is why the reSET-O intervention is proposed. Patients 
enrolling in the study will have been prescribed their appropriate MAT as their standard of care 
and is not part of the research study.
7.4.2
Treatment Regimen
reSET-O is delivered as a mobile app and can be downloaded to and used by a smart phone or 
tablet. Buprenorphine-naloxone and buprenorphine dosing ranges from 2-24mg/day, is 
administered sublingually, and in combination with counseling.  Methadone dosing ranges from 
60-250mg/day, is administered orally, and in combination with counseling. For buprenorphine-
naloxone, buprenorphine, and methadone, initial doses are started low to avoid precipitated 
withdrawal and titrated upwards to achieve relief of withdrawal symptoms and avoid cravings.
7.4.3
Method for Assigning Subject to Treatment Groups
Subjects will be randomly assigned to TAU alone or TAU + reset-O, but stratified by MAT into 
three arms:  methadone, buprenorphine initiated at the Hub and buprenorphine initiated as a 
bridge appointment with continuation of treatment at the spoke.
Randomization will be determined through a web-based data management system. The 
stratification data will be entered and the data management system will conduct the 
randomization and communicate back with the treatment assignment within the same web-
based interface.
7.4.4
Subject Compliance Monitoring
The Contingency Management system developed in TES, and adapted in reSET-O, utilizes the 
“prize bowl” method developed by Petry to deliver contingency management at lower cost (cost 
of the incentives) to make it more feasible for community-based treatment.  When a target 
behavior is performed (completing a therapy lesson, attending a clinic appointment), the patient 
earns a “draw”, where some draws yield motivational messages, some are low cost prizes, with 
the occasional higher value prize.  The program keeps track of the draws earned and prizes, so 
that, again, burden on clinical to organize the CM intervention is minimized.  Completion of 
therapy lessons automatically earns draws.
In order to further support buprenorphine adherence, reSET-O contains communication 
features, where the patient receives a daily prompt to take their buprenorphine dose, and can 
record taking each dose, as well as any drug use or craving.  This information, along with 
information on which therapy lessons a patient has completed, is summarized on a dashboard 
for each patient available that is available on line to the prescribing physician and other 
clinicians (research coordinator/research assistant in the study proposed here) to help track 
progress and stimulate discussion between patients and their clinicians.
7.4.5
Blinding of the Test Article
Per the recommendation of NIH, the TLFB should be completed by staff blinded to the 
randomized assignment of the participants. Penn State research staff will complete the TLFb 
with participants because this occurs before randomization. All TLFB conducted after the 
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baseline visit will be conducted by an external research team member who is blinded to the 
randomization assignments. Upon completion of the TLFB, the external staff member will 
transmit files to the Penn State research team via Accellion/ Kite Drive for e-storage of the 
document (on the Hershey Medical Network server, accessible through role-based security 
only), and entry into REDcap. No PHI is collected or exchanged during the TLFB process.
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
Participating patients assigned to TAU + reSET-O will download the free 
reSET-O app to their own smartphones, but for those who do not own a 
smartphone, a smartphone will be provided for the duration of the trial.
7.4.6.2
Storage
Approximately 75 inexpensive smartphones or tablets will be maintained by
study personnel.
7.4.6.3
Preparation and Dispensing
N/A
7.4.6.4
Return or Destruction of the Test Article
N/A
7.4.6.5
Prior and Concomitant Therapy
N/A
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
We will recruit and enroll 200 patients with OUD within the Penn State Hub and Spoke System 
(Pennsylvania Coordinated Medication Assisted Treatment (PACMAT), for this RCT. 
Due to the possibility of turnover and new hires, we expect approximately 12-15 providers to engage 
with and provide feedback on the app. Any new hires will not engage with the app until CITI and HIPPAA 
training is completed and a modification reflecting a team member change has been approved by this 
IRB. The team member form will be reviewed on a bi-monthly basis and updated as appropriate with 
any changes, and the IRB will be notified as soon as possible regarding these updates.
Research subjects will not be assigned to any newly hired provider until the said provider has completed 
the appropriate CITI and HIPPAA training, and has officially been added to the study team and approved 
through the Penn State IRB. 
8.2
Sample size determination
Previous studies of MAT treatment of OUD indicate substantial drop out rates--typically in the 40% to 
50% range still retained in treatment at 24 weeks.  Assuming 40% retention in the TAU treatment group, 
a sample size of 100 patients per treatment group (total N = 200) is selected to ensure sufficient power 
of 80% with a two-sided level of significance of 5% to be able to detect a difference of at least 19.7% 
between the TAU vs reSET-O + TAU treatment groups (i.e., 40% retained in TAU vs 59.7% retained in 
reSET-O + TAU).  This difference of 19.7% is equivalent to an odds-ratio of 2.22 and would be clinically 
meaningful.
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8.3
Statistical methods
Outcome Measures and Covariates
Primary outcome: The primary outcome will be a binary indicator of whether or not the patient is 
retained on MAT (methadone, buprenorphine, or buprenorphine-naloxone) treatment through 24 
weeks. For those who drop out before 24 weeks, time (week) of dropout will be recorded, and they will 
be considered as not retained. 
Secondary outcomes: 1) weeks of treatment retention (time to drop-out 0-24 weeks, survival; number 
of weeks retained, continuous); 2) urine-confirmed abstinence from opioids in the last 4 weeks 
(longitudinal (weeks 4, 8, 12, and 24), binary); 3) Days using opioids in the last 4 weeks (longitudinal, 
continuous); 4) Days using other drugs/alcohol in last 4 weeks (longitudinal, continuous); 5) coping 
strategies (CSS mean score; longitudinal, continuous); 6) social functioning (EuroQol, SCS, global scores 
and subscales; longitudinal, continuous); 6) overall mental health symptoms (K10; longitudinal, 
continuous); 7) HIV risk behavior—days in past 30 of vaginal or anal sex without a condom (longitudinal, 
continuous); Any needle sharing in past 4 weeks (longitudinal, binary); 7) Treatment satisfaction at week 
24 (IAFF; continuous); 8) Serious adverse events (binary).
Additional variables: Covariates, primary and secondary analyses: Stratification factors: 1) any 
intravenous drug use (binary); 2) treatment with methadone vs buprenorphine at Hub vs buprenorphine 
at Spoke (categorical). Moderators: 1) both stratification factors will be explored as moderators; 2) 
demographic characteristics (gender, age, ethnicity etc.); 3) prescription opioid use only vs any heroin or 
fentanyl use (binary); 4) other substance use at baseline (any cannabis, any stimulant, any heavy 
drinking days; binary); 5) Probable major depression at baseline (binary based on PHQ score); 6) history 
of prior treatment for opioid use versus first treatment episode (binary). Mediators: 1) social functioning 
(EuroQol; continuous); 2) social connectedness (SCS; continuous); 3) opioid craving (continuous); 4) 
coping (CSS; continuous); and 5) mental health symptoms (K10; continuous).
Intent to Treat, Dropouts, and Missing Data
All analyses will be on the Intent-to-treat (ITT) sample, i.e., all randomized subjects (N=200) according to 
the treatment arm to which they were assigned.  For the primary outcome, patients that dropped out 
before 24 weeks will be considered not retained. For the secondary outcome urine-confirmed 
abstinence, missing data (patients who cannot be located) will assumed to be opioid positive (not 
abstinent), a typical assumption which is reasonable based on the high rate of relapse among patients 
with OUD who discontinue medication treatment (Weiss et al., 2011; 2015; Hser et al., 2016; 2017).  For 
other secondary outcomes, missing data will be treated as missing at random. Longitudinal mixed 
effects models do not require complete data to provide estimates of the outcome, and the estimates 
are considered valid under the assumption that the data are missing at random (Little & Rubin, 2002). 
We will additionally perform sensitivity analysis for the secondary outcomes to examine the influence 
on the outcomes of dropout and missing data by performing several imputation methods, for instance 
imputing missing weeks as all abstinent or all non-abstinent.  Comparison of the inferences from 
assuming various models for the missingness provides a measure of the validity of the efficacy estimate 
from the initial model.
Significance Testing and Preliminary Analyses
All tests for main effects will be performed at two-sided significance level of 5%. Before performing 
specific analyses, we will examine the distribution of outcome measures and covariates and investigate 
for outliers. The distributions of continuous variables will be checked for normality, and transformed, if 
necessary. Distribution of demographic variables will be examined and described in terms of means, 
standard deviations, proportions and 95% confidence intervals. Covariates will be examined for 
association with treatment outcome. Covariates associated with treatment outcome will be adjusted for 
in models used to test study hypotheses.
Primary outcome
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Statistical Model:  Hypothesis: Adding reSET-O to TAU (reSET-O + TAU arm) will promote greater 24 
week retention in treatment on buprenorphine compared to the TAU arm. The positive effect of 
randomization to the reSET-O+TAU group compared to TAU group will be estimated using logistic 
regression with the binary outcome of retention in treatment for 24 weeks (yes/no) modeled as a 
function of treatment condition (reSET-O + TAU vs TAU) and stratification factors (methadone 
treatment; buprenorphine treatment at Hub; buprenorphine treatment initiation at hub and 
continuation at spoke) and intravenous drug use in last 30 days (yes/no).  The odds ratio of the 
treatment term and its confidence limits will estimate the treatment effect.  The raw retention rates in 
each treatment group and rate differences will be computed for descriptive purposes.  
Secondary outcomes
Statistical Models: For each of the secondary outcomes (see above) the effect of randomization to the 
reSET-O+TAU arm compared to the TAU arm will be estimated with a model of the same general form as 
for the primary outcome (three independent variables: treatment assignments (reSET-O+TAU vs TAU) 
and the two stratification factors) using logistic regression model (for binary outcomes), generalized 
linear model (for continuous outcomes), or longitudinal generalized mixed effects model (for 
longitudinal outcomes) with appropriate link functions (e.g. logit for binary outcomes). Longitudinal 
outcomes analyzed using a mixed effects models will utilize a generalized estimating equation with an 
autoregressive correlation structure to account for within subject correlation over time, as well a 
random intercept accounting for between subject variability. Retention data will be displayed with 
Kaplan-Meier curves that show the observed probability of retention in the program until time t, over 
time across the 24-week trial. The time to not-retained (dropout) data for reSET-O +TAU and TAU groups 
will be analyzed using proportional hazards models with covariates. If proportional hazard assumption is 
not satisfied, the data will be analyzed using a non-parametric log-rank test. In addition to stratification 
factors, covariates that are found to be related to the outcomes will be also added to the models to 
improve the power for detecting significant differences.
Moderation and Mediation
Moderation Statistical Models: The effect of randomization to the reSET-O+TAU arm will be estimated 
for subpopulations based on the demographic and baseline characteristics selected as moderators (see 
above). We will estimate the moderation effect on primary outcome using a similar model to Aim 1 
primary outcome with the inclusion of moderator by treatment interaction: Yi= 0+1Trxi+2Mi 
+3TrxiMi+4Ci+si where Mi is the moderator status for ith subject and Trxi is subject’s treatment 
assignment. Regardless of the significance of the interaction term, we will use the model to estimate the 
95% confidence interval of the treatment effect for each level or category of the moderator variable. 
The moderator analyses are exploratory and hypothesis generating, but significant moderator effects 
can be useful in planning future efforts at implementation of reSET-O by identifying subgoups that may 
particularly benefit.  Identifying subgroups where there is less benefit may suggest future modifications 
to reSET-O or its implementation strategy to achieve better effect in those subgoups.
Mediation Statistical Models: The effect of randomization to the reSET-O +TAU arm will be estimated 
when accounting for potential mediators (see above).  In particular, we are interested in testing whether 
an impact of treatment on the primary outcome of 24 week buprenorphine retention is mediated by 
craving and by coping skills (CSS), which are targets of the therapy lessons or modules of reSET-O, as 
well as social functioning (PROMIS) and social connectedness. We will simultaneously estimate both the 
total effect of treatment assignment on primary outcome and the indirect of treatment assignment on 
primary outcome mediated through the intended target mediators using structural equation modeling 
(SEM) in software MPlus (Taylor, MacKinnon and Tein 2008). The indirect effect is estimated by the 
product of the effect of treatment assignment on the mediator and the effect of the mediator on the 
primary outcome while adjusting for treatment assignment. SEM will provide an estimate of the indirect 
effect of each mediator as well as its bootstrapped 95% confidence interval. These mediational analyses 
explore whether the effect of reSET-O on the primary outcome is being channeled through reSET-O 
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having an impact on its intended targets (abstinence/relapse prevention, and psychosocial functioning) 
(i.e. main effects of treatment assignment on mediator).  This can, again, be of heuristic value in 
suggesting aspects of either reSET-O itself or its implementation that might need strengthening in future 
research or implementation efforts.
Implementation Outcomes
Measures of reSET-O utilization and adherence (number and types of therapy lessons completed, 
incentives earned, utilization of communication features) will be summarized with descriptive statistics, 
and associations with baseline covariates explored to understand what factors may drive reSET-O 
utilization, including patient characteristics and clinical setting (Hub vs Spoke).
 
Qualitative Interviews conducted with reSET-O patients will elicit personal their experiences with reSET-
O and its acceptability, feasibility, barriers and facilitators, and suggestions for improvement. A 
Qualitative Interview was previously developed in consultation with the Advisory Board, for the R21 
pilot trial (Penn State IRB 00009931). Qualitative data analyses from the result of the qualitative 
interview, as well as using experiences from the R21 pilot trial and adaptation process, may indicate 
changes to improve the current qualitative interview that is expected to be used and incorporate 
standard implementation outcomes (Glasgow et al., 1999). Using Atlas.ti software and a coding 
framework developed from the qualitative interview, research staff (Campbell, Aydingolo) will 
systematically code transcripts of the interviews, resolving discrepancies in consensus discussion. The 
descriptive implementation data and interviews will be presented to the Advisory Board and used to 
help understand the feasibility of future implementation efforts across the State and beyond.  
9.0
Data and Safety Monitoring Plan
9.1
Periodic evaluation of data
Data is directly entered into REDcap by the research assistants.  The research coordinator will 
periodically check the data as it is entered to ensure REDcap is working properly and recording the data 
as appropriate.  Regular quality assurance monitoring will be conducted by Ms. Aydingolo (Columbia) 
who will remotely review regulatory documentation, data collection and data management procedures, 
and review other study documentation (e.g., progress notes, error corrections, contingency 
management logs). These reviews will also include: 100% review of informed consents, eligibility criteria, 
AE and SAE documentation, and protocol violations. 
9.2
Data that are reviewed
Data reviews include regulatory documentation, data entered directly into REDcap, progress notes, 
error corrections, contingency management logs, informed consent and eligibility criteria, AE and SAE 
documentation, and protocol violations. 
9.3
Method of collection of safety information
Study progress and safety will be reviewed weekly via conference call with the Study PIs and research 
team.  Progress reports, including patient recruitment, retention/attrition, and AEs, will be provided to 
PIs following each of the QA monitoring visits. An Annual Report will be compiled and will include a list 
and summary of AEs.  The Annual Report will be submitted to the data safety monitoring board (DSMB), 
IRB and NCCIH per their requirements.  The IRB and other applicable recipients will review progress of 
this study on an annual basis. 
9.4
Frequency of data collection
Data collection is ongoing as it includes cumulative data (data received from the reSET-O app) and 
discrete data (data collected by surveys as completed at the research visits – baseline and week 4, 8, 12, 
and 24 visits).
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9.5
Individuals reviewing the data
Oversight of data management, including data collection, storage, and export, security, tracking, data 
analysis software and hardware, and quality assurance will be the responsibility of Drs. Kawasaki and 
Nunes. A senior (bio)statistician and master’s level analyst from the CTSI at Penn State College of 
Medicine will conduct analysis of REDCap survey data as well as app data from Pear Therapeutics. Dr. 
Pavlicova, senior Biostatistician at CUMC, will be available for consultation as needed throughout the 
data analysis process but will not play an active role in the analysis itself. Ms. Aydingolo, under 
supervision of Drs. Kawasaki and Nunes, will be responsible for monitoring of data export, storage, and 
management. Weekly remote meetings will take place between Drs. Kawasaki and Nunes, Ms. 
Aydingolo, and study site research staff. 
9.6
Frequency of review of cumulative data
Cumulative data includes data collected by the app, reSET-O. Data checks will occur regularly including 
anytime a subject who has been assigned to reSET-O+TAU meets with a research coordinator for a 
research appointment or meets with their clinician involved in their substance abuse treatment and is 
affiliated with the PPI Hub and/or RASE or JFT These clinicians are defined as reSET-O research study 
coordinators, PPI Hub counselors, PPI Hub physicians, PPI Hub nurse practitioners, JFT “Certified 
Recovery Specialist’s" or RASE care coordinator. These clinicians will login to the clinician dashboard side 
of the app and view how many modules the client has completed and the amount of rewards the client 
has earned, as well as logging urine drug screens as favorable or unfavorable. If a subject reports 
problems with the app or a clinician notes problems with the app and how data may be recorded, Pear 
Therapeutics, Inc. will be notified immediately to mitigate the issue(s). 
9.7
Statistical tests
Drs. Kawasaki and Nunes will provide oversight to the statistical analysis process, ensuring timely 
provision of cleaned and locked data to the statistics team; data will be shared with the CTSI statistician 
and analyst following data lock, and Dr. Pavlicova (Columbia) will provide as needed consultation on 
data and statistical issues throughout the trial.  Detailed statistical analysis plan is described under 
Section 8.3, above 
9.8
Suspension of research
This study will be stopped prior to its completion if: (1) the intervention is associated with adverse 
effects that call into question the safety of the intervention; (2) difficulty in study recruitment or 
retention will significantly impact the ability to evaluate the study endpoints; (3) any new information 
becomes available during the trial that necessitates stopping the trial; or (4) other situations occur that 
might warrant stopping the trial.  
10.0
Risks
In general, risks associated with research comprised of behavioral interventions are low.  reSET-O is a behavioral 
intervention that provides education about skills for avoiding drug use and otherwise improving health, modest 
incentives for adherence to treatment, and enhanced communication with providers, features which entail little 
anticipated risk. Potential risks for the research participation include psychological discomfort, answering 
sensitive questions related to substance use, mental health, and sexual behaviors, loss of confidentiality, and 
disclosure of information that meets reporting requirements.  The interventions (reSET-O + TAU; TAU alone) 
may be ineffective, and patients’ opioid use or associated problems may get worse.  
There is a risk of loss of confidentiality as absolute confidentiality cannot be guaranteed. However, research staff 
will take precautions and maintain data created by participants to the degree permitted by the technology used 
in order to attempt to prevent loss of confidentiality. 
There is a risk of randomization as only half of the participant population will receive reSET-O + TAU (n=100). 
Therefore, subjects who are assigned to TAU alone will not be exposed to the content affiliated with the reSET-O 
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app, including psychoeducation about skills for avoiding drug use and otherwise improving health. These 
subjects will also not receive the monetary incentives for adherence to treatment as affiliated with the app, or 
the monetary incentive to complete the qualitative interview as this interview is specific to the use of the reSET-
O app. 
All of the assessment surveys or questionnaires outline above may lead to some psychological discomfort as 
participants discuss sensitive areas related to high risk drug or sexual behaviors. They may feel uncomfortable 
answering such questions and/or become distressed when faced with reviewing their involvement in high risk 
behaviors. 
Some of the questionnaires and interview questions will ask about participant feelings, such as depression, 
sadness, and anxiety. If responses indicate suicidal thoughts or risks of the subject hurting themselves or others, 
then we may need to break confidentiality and contact a licensed mental health professional or law 
enforcement officer. All subjects who express any suicidal thoughts will be referred for follow-up mental health 
counseling.
For subjects assigned to TAU + reSET-O, reSET-O should not induce any more discomfort than other treatments 
offered as part of outpatient substance abuse treatment. If participants become overly distressed, they will be 
directed to clinical staff working at their treatment program.  Research staff (Research Coordinator and Research 
Assistants) will be trained in a safety protocol, so that if patients reveal acute distress or serious symptoms (e.g. 
depression or suicidal ideation) during a research assessment, the research staff will alert clinical staff at 
PACMAT, who will take over evaluating the situation and determine the severity of distress and if any additional 
evaluation or treatment is needed.
Subjects assigned to TAU + reSET-O will interact with reSET-O on the participant’s mobile device (smartphone or 
tablet). A patient may interact with all the functionalities of reSET-O whether or not in the presence of a wireless 
signal or wifi.  The program will update whenever coming in contact with wifi.    Although information and 
answers within reSET-O cannot be accessed, the reSET-O website could become known and someone could look 
up the general website of the developer. They would be able to see that reSET-O (in general) and Pear 
Therapeutics, Inc. (the company that developed the reSET-O) are generally linked to substance abuse prevention 
and treatment.
Providers who are also considered subjects as a result of providing data about the app may be exposed to 
minimal risk. For instance, providers may find it cumbersome and time consuming to add some study related 
tasks to their overall workload; however, the goal of this study is not to add a significant amount of work to the 
providers; rather, the goal is to have the providers incorporate the use of the app during their clinical 
appointments with appropriate participants. We expect this workload to add approximately 6-12 minutes of 
additional time related to work tasks. Providers are free to engage in the app for longer than this if they plan to 
explore the app more and its resources. Providers may also find the open-ended discussion time consuming; 
however, they will only be asked to do this once. 
The consent process will indicate the potential risks of participating in the study and participants will be advised 
that they do not have to answer questions with which they do not feel comfortable. The assessment will allow 
participants to skip any question they do not want to answer. The consent form will also indicate that 
participants are free to discontinue the study at any time for any reason with no explanation.
The summary of explanation of research for providers will outline any risks. It will be explained to providers that 
they are not required to participate in the open-ended discussion. They are not required to answer any 
questions about the app on the survey that they do not feel comfortable answering. 
11.0
Potential Benefits to Subjects and Others 
11.1
Potential Benefits to Subjects
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There may be no benefit to participants in the research.  Prior evidence suggests reSET-O may improve 
adherence with appointments, adherence to medication, and skills to avoid drug use and relapse.  
However, the purpose of the research is to determine whether this benefit will be observed when 
reSET-O is implemented within a Hub and Spoke system. 
There is no benefit to the provider subjects. 
11.2
Potential Benefits to Others
This study addresses one of the key barriers to implementation of MAT within efforts to expand MAT 
into underserved communities and primary care settings, namely the need to deliver evidence-based 
psychosocial treatment to help prevent relapse and foster a healthy lifestyle when behavioral health 
specialists are rarely co-located.  Since reSET-O is a commercially mobile app, downloadable from the 
web, if found effective in supporting MAT in the Hub and Spoke setting under this research, it has the 
potential to be rapidly implemented across the U.S. health system in support of the STR initiative.
 
12.0
Sharing Results with Subjects
N/A
13.0
Subject Payment and/or Travel Reimbursements
All patients will be compensated for their time spent completing research evaluations, with $40 for the 
intake/baseline visit and $25 for each of the week 4, 8, 12, and 24 research visits (regardless if all tasks are 
completed onsite or if some tasks are completed remotely). An extra $25 will be provided at the week 8 or 12 
visit, when a participant completes the qualitative interview. Since the qualitative interview is specific to the use 
of the reSET-O app, only subjects who have been assigned to TAU + reSET-O will participate in the qualitative 
interview. Thus, total compensation will be $165 in the form of gift cards for individuals assigned to TAU + 
reSET-O, and the total compensation for individuals assigned to TAU alone will be $140 in the form of gift cards. 
Gift cards earned based on completed research appointments will be printed and handed to the participant or 
emailed to the participant – based on participant preference. If emailed, research assistants will follow-up with 
the participant to ensure that the gift card was received; however, it will be outlined in the consent form that 
“lost” gift cards will not be replaced. This study does not plan to use Greenphire because the ability to withdraw 
actual cash from the Greenphire card would allow a vulnerable patient with addiction to potentially withdraw 
money to purchase drugs or alcohol. Gift cards provided in this study are never associated with vendors that sell 
alcohol, drugs, or weapons (e.g., Target).  
Additionally, patients assigned to TAU + reSET-O may receive contingency management rewards as part of the 
reSET-O application program. Participants also have the possibility of earning monetary prizes ranging from $5 
to $100, in the form of a vendor gift card (e.g. Amazon or Starbucks), on a varying reinforcement schedule. 
Participants may earn prizes through a wheel-spin gaming system as coded within the app. Wheel-spins are 
earned from having favorable urine drug screens, meaning no illegal substance is present in the participant’s 
urine, and learning module (within the app) completion.  Urine drug screens are evaluated based on urine 
screens collected at visits 4, 8, 12, and 24, in which the assessing clinician or research coordinator will use the 
Clinician Dashboard on the reSET-O app to activate the lottery-based reward.  The reSET-O app will manage the 
administration and activation of lottery-based rewards for participant completed modules.  
Half of the lottery-based rewards will be e-language positive reinforcement (i.e.: “Good Job!”). 41.8% of the 
rewards will be $5 electronic gift cards; 8.0% of the rewards will be $20 electronic gift cards; and 0.2% of the 
rewards will be $100 electronic gift cards (see uploaded power point document as an example of e-gift card 
administration from the reSET-O app).  All electronic gift cards are managed and administered by the reSET-O 
application and ultimate owners (Pear Therapeutics, Inc.). Participants may earn a maximum of approximately 
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$599 if they earn all possible draws; however, based on prior experience with such schedules, we predict that 
they will likely earn about 45%-65% of possible earnings (approx. $270-$390). 
Provider subjects will not be compensated. 
14.0
Economic Burden to Subjects
14.1
Costs
N/A
14.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers. 
15.0
Resources Available 
15.1
Facilities and locations
The study sites will be the SAMHSA STR funded Pennsylvania Psychiatric Institute (PPI)-based Hub and 
Spoke system, called Pennsylvania Coordinated Medication Assisted Treatment (PACMAT), for which Dr. 
Kawasaki is the Principal Investigator. The PACMAT PPI Hub is a new specialized Addiction Treatment 
Program at Pennsylvania Psychiatric Institute (PPI) in Harrisburg, PA, and Spokes are medical practices in 
the surrounding, largely rural counties of central Pennsylvania, including Dauphin, Cumberland/Perry, 
Franklin/Fulton, Lancaster, and Lebanon counties.  
All research procedures will occur in a hybrid of remote and in person, depending on patient preference 
and the current COVID situation in Dauphin County, PA. 
15.2
Feasibility of recruiting the required number of subjects
Since the opening of the PACMAT PPI Hub in and collaboration with spoke providers through RASE in 
November 2017, over 700 OUD patients have been treated at the PPI Hub, whereas Spoke providers 
have treated over 900 OUD patients collectively. The majority of this combined patient population use 
MAT. Thus, the patient flow appears adequate especially given the broad eligibility criteria. We are 
excited about our new collaboration with Just for Today for this research project as they have locations 
in several counties in southern Central Pennsylania and have a broad reach of patients on MOUD. 
15.3
PI Time devoted to conducting the research
20% research time
15.4
Availability of medical or psychological resources
Medical and psychological resources are available at PPI should a subject endorse suicidality on the 
PHQ-9 and subsequent C-SSRS. If a subject endorses suicidality, trained and certified research staff will 
administer the C-SSRS. If the C-SSRS administration determines that suicidal ideation and plan are 
present, then the research staff will contact a doctor or nurse practitioner to take over the evaluating 
situation.  At the opioid treatment program at PPI, there are currently three medical doctors and one 
nurse practitioner.
15.5
Process for informing Study Team
N/A
16.0
Other Approvals
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16.1
Other Approvals from External Entities
This study is being considered for funding through NIH and, as such, has undergone scientific review as part of 
the application approval process.
16.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Penn State Health only – Research involves the collection of tissues or use of 
pathologic specimens. Upload a copy of “HRP-902 - Human Tissue For Research Form” in CATS IRB. 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of human 
tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens in a PSU 
research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or gene therapy).
  Clinical Laboratories – Penn State Health only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that had been 
collected for clinical purposes but are no longer needed for clinical use. Upload a copy of “HRP-901 - Human 
Body Fluids for Research Form” in CATS IRB. 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of CRC 
services in any way.
  Conflict of Interest Review – All campuses – Research has one or more of study team members indicated as 
having a financial interest.
  Radiation Safety – Penn State Health only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a copy of “HRP-
903 - Radiation Review Form” in CATS IRB. 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or intends to 
hold the IND or IDE.
  Scientific Review – Penn State Health only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific review 
requirement may be fulfilled by one of the following: (1) external peer-review process; (2) department/institute 
scientific review committee; or (3) scientific review by the Clinical Research Center Advisory committee.  NOTE: 
Review by the Penn State Health Cancer Institute (PSCI) Protocol Review Committee or the PSCI Disease Team is 
required if the study involves cancer prevention studies or cancer patients, records and/or tissues. For more 
information about this requirement see the IRB website.
17.0
Multi-Site Study
17.1
Other sites 
N/A
17.2
Communication Plans
N/A
17.3
Data Submission and Security Plan
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N/A
17.4
Subject Enrollment
N/A
17.5
Reporting of Adverse Events and New Information
N/A
17.6
Audit and Monitoring Plans
N/A
18.0
Adverse Event Reporting
18.1
Adverse Event Definitions
For drug studies, incorporate the following definitions into the below responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
Suspected adverse 
reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”.

Reasonable possibility.  For the purpose of IND safety 
reporting, “reasonable possibility” means there is 
evidence to suggest a causal relationship between the 
drug and the adverse event.
Serious adverse 
event or Serious 
suspected adverse 
reaction
Serious adverse event or Serious suspected adverse reaction: An adverse event 
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or research 
subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that had it occurred in a more severe form, might 
have caused death.
Unexpected 
adverse event or 
Unexpected 
suspected adverse 
reaction.  
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified.
For device studies, incorporate the following definitions into the below responses, as written:
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Unanticipated 
adverse device 
effect
Any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or IDE application (including a supplementary plan 
or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.
18.2
Recording of Adverse Events
N/A
18.3
Causality and Severity Assessments
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event.
If the investigator’s final determination of causality is “unknown and of questionable relationship to the study drug(s) or 
device(s)”, the adverse event will be classified as associated with the use of the study drug(s) or device(s) for reporting 
purposes.  If the investigator’s final determination of causality is “unknown but not related to the study drug(s) or 
device(s)”, this determination and the rationale for the determination will be documented in the respective subject’s 
case history.
18.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
18.4.1 Written IND/IDE Safety Reports
N/A
18.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
N/A
18.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
18.6
Unblinding Procedures
N/A
18.7
Stopping Rules
N/A
19.0
Study Monitoring, Auditing and Inspecting
19.1
Study Monitoring Plan
19.1.1 Quality Assurance and Quality Control
Monitoring will be done by the PI. RFMH team staff member Nicole Aydingolo will periodically 
monitor Penn State’s regulatory binder and data collection for quality assurance purposes.
19.1.2 Safety Monitoring
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N/A
20.0
Future Undetermined Research: Data and Specimen Banking
20.1
Data and/or specimens being stored
N/A
20.2
Location of storage
N/A
20.3
Duration of storage
N/A
20.4
Access to data and/or specimens
N/A
20.5
Procedures to release data or specimens
N/A
20.6
Process for returning results
N/A
21.0
References
Bickel WK, Marsch LA, Buchhalter AR, Badger GJ. Computerized behavior therapy for opioid-dependent
outpatients: a randomized controlled trial. Exp Clin Psychopharmacol. 2008 Apr;16(2):132-43. doi:
10.1037/1064-1297.16.2.132.
Brigham GS, Feaster DJ, Wakim PG, Dempsey CL. Choosing a control group in effectiveness trials of
behavioral drug abuse treatments. J Subst Abuse Treat. 2009 Dec;37(4):388-97.
Brooklyn JR, Sigmon SC. Vermont Hub-and-Spoke Model of Care for Opioid Use Disorder: Development,
Implementation, and Impact. J Addict Med. 2017 Jul/Aug;11(4):286-292.
Budney, A. J., & Higgins, S. T. (1998). Therapy manuals for drug addiction, a community reinforcement plus
vouchers approach: Treating cocaine addiction. Rockville, MD: National Institute on Drug Abuse.
Campbell AN, Nunes EV, Matthews AG, Stitzer M, Miele GM, Polsky D, Turrigiano E, Walters S, McClure EA,
Kyle TL, Wahle A, Van Veldhuisen P, Goldman B, Babcock D, Stabile PQ, Winhusen T, Ghitza UE.
Internet-delivered treatment for substance abuse: a multisite randomized controlled trial. Am J Psychiatry.
2014 Jun;171(6):683-90.
Carroll KM, Weiss RD. The Role of Behavioral Interventions in Buprenorphine Maintenance Treatment: A
Review. Am J Psychiatry. 2017 Aug 1;174(8):738-747.
Christensen DR, Landes RD, Jackson L, Marsch LA, Mancino MJ, Chopra MP, Bickel WK. Adding an 
Internetdelivered
treatment to an efficacious treatment package for opioid dependence. J Consult Clin Psychol.
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Page 31 of 33 (V.01/21/2019) 
2014 Dec;82(6):964-72.
DeFlavio JR, Rolin SA, Nordstrom BR, Kazal, Jr LA. Analysis of barriers to adoption of buprenorphine
maintenance therapy by family physicians. Rural and Remote Health 15: 3019. (Online) 2015.
Dolezal C, Meyer-Bahlburg H, Liu X, et al. Longitudinal changes in sexual risk behavior among HIV+ and HIV−
male injecting drug users. Am J Drug Alcohol Abuse. 1999;25(2):281–303.
Glasgow, R. E., Vogt, T. M., & Boles, S. M. (1999). Evaluating the public health impact of health promotion
interventions: the RE-AIM framework. American Journal of Public Health, 89, 1322-1327.
Higgins, S. T., Budney, A. J., Bickel, W. K., Foerg, F.E., Donham, R., & Badger, G. J. (1994). Incentives
improve outcome in outpatient behavioral treatment of cocaine dependence. Archives of General
Psychiatry, 51, 568-576.
Higgins, S. T., Sigmon, S. C., Wong, C. J., Heil, S. H., Badger, G. J., Donham, R., et al. (2003). Community
reinforcement therapy for cocaine-dependent outpatients. Archives of General Psychiatry, 60, 1043-1052.
Hser YI, Hoffman V, Grella CE, Anglin MD. A 33-year follow-up of narcotics addicts. Arch Gen Psychiatry.
2001 May;58(5):503-8.
Hser YI, Saxon AJ, Huang D, Hasson A, Thomas C, Hillhouse M, Jacobs P, Teruya C, McLaughlin P, Wiest K,
Cohen A, Ling W. Treatment retention among patients randomized to buprenorphine/naloxone compared
to methadone in a multi-site trial. Addiction. 2014 Jan;109(1):79-87.
Hser YI, Evans E, Huang D, et al. Long-term outcomes after randomization to buprenorphine/naloxone versus
methadone in a multi-site trial. Addiction 2016;111:695-705.
Hser YI, Huang D, Saxon AJ, et al. Distinctive Trajectories of Opioid Use Over an Extended Follow-up of
Patients in a Multisite Trial on Buprenorphine + Naloxone and Methadone. J Add Med 2017;11:63-9.
Hunt, G. M., & Azrin, N. H. (1973). A community-reinforcement approach to alcoholism. Behavioral Research
Therapy, 11(1), 91-104.
Hutchinson E, Catlin M, Andrilla CH, Baldwin LM, Rosenblatt RA. Barriers to primary care physicians
prescribing buprenorphine. Ann Fam Med. 2014 Mar-Apr;12(2):128-33.
Israel, B. A., Schulz, A. J., Parker, E. A. & Becker, A. B. (1998). Review of community-based research:
assessing partnership approaches to improve public health. Annual Review of Public Health, 19(1), 173–
202.
Kessler, R.C., Barker, P.R., Colpe, L.J., Epstein, J.F., Gfroerer, J.C., Hiripi, E., Howes, M.J, Normand, S-L.T.,
Manderscheid, R.W., Walters, E.E., Zaslavsky, A.M. (2003). Screening for serious mental illness in the
general population. Archives of General Psychiatry, 60(2), 184-189.
 Lang, A.J., Stein, M.B. (2005) An abbreviated PTSD checklist for use as a screening instrument in primary care. 
Behaviour Research and Therapy, 43, 585-594
 Lang, A. J., Wilkins, K., Roy-Byrne, P. P., Golinelli, D., Chavira, D., Sherbourne, C., Rose, R. D., Bystritsky, A., 
Sullivan, G., Craske, M. G., & Stein, M. B. (2012). Abbreviated PTSD Checklist (PCL) as a Guide to Clinical 
Response. General Hospital Psychiatry, 34, 332-338.
STUDY00012685
Approval: 3/26/2024

Page 32 of 33 (V.01/21/2019) 
Lee, R. M. & Robbins, S. B. (1995). Measuring belongingness: The Social Connectedness and the Social
Assurance scales. Journal of Counseling Psychology, 42(2), 232.
Lee, R. M. & Robbins, S. B. (1998). The relationship between social connectedness and anxiety, self-esteem,
and social identity. Journal of Counseling Psychology, 45, 338–345.
Litt, M. D., Kadden, R. M., Cooney, N. L. & Kabela, E. (2003). Coping skills and treatment outcomes in
cognitive-behavioral and interactional group therapy for alcoholism. Journal of Consulting and Clinical
Psychology, 71(1), 118.
Little RJA, Rubin DB. Statistical Analysis with Missing Data, 2nd Edition. Wiley. 2002.
Marsch LA, Guarino H, Acosta M, Aponte-Melendez Y, Cleland C, Grabinski M, Brady R, Edwards J. Web-based
behavioral treatment for substance use disorders as a partial replacement of standard methadone
maintenance treatment. J Subst Abuse Treat. 2014 Jan;46(1):43-51.
McLellan AT, Arndt IO, Metzger DS, Woody GE, O'Brien CP. The effects of psychosocial services in substance
abuse treatment. JAMA. 1993 Apr 21;269(15):1953-9.
Meyer-Bahlburg H, Ehrhardt A, Exner T, et al. Sexual Risk Behavior Assessment Schedule—Adult—Armory
Interview. New York: New York State Psychiatric Institute and Columbia University; 1991.
Miller, W. R., Meyers, R. J., & Hiller-Sturmhofel, S. (1998). The community-reinforcement approach. Alcohol
Research and Health, 23, 116-121.
Miller WR, Sorensen JL, Selzer JA, Brigham GS. Disseminating evidence-based practices in substance abuse
treatment: a review with suggestions. J Subst Abuse Treat. 2006 Jul;31(1):25-39.
Nunes EV, Ball S, Booth R, Brigham G, Calsyn DA, Carroll K, Feaster DJ, Hien D, Hubbard RL, Ling W, Petry
NM, Rotrosen J, Selzer J, Stitzer M, Tross S, Wakim P, Winhusen T, Woody G. Multisite effectiveness
trials of treatments for substance abuse and co-occurring problems: have we chosen the best designs? J
Subst Abuse Treat. 2010 Jun;38 Suppl 1:S97-112.
Peirce JM, Petry NM, Stitzer ML, Blaine J, Kellogg S, Satterfield F, Schwartz M, Krasnansky J, Pencer E,
Silva-Vazquez L, Kirby KC, Royer-Malvestuto C, Roll JM, Cohen A, Copersino ML, Kolodner K, Li R.
Effects of lower-cost incentives on stimulant abstinence in methadone maintenance treatment: a National
Drug Abuse Treatment Clinical Trials Network study. Arch Gen Psychiatry. 2006 Feb;63(2):201-8.
Petry NM, Peirce JM, Stitzer ML, Blaine J, Roll JM, Cohen A, Obert J, Killeen T, Saladin ME, Cowell M, Kirby
KC, Sterling R, Royer-Malvestuto C, Hamilton J, Booth RE, Macdonald M, Liebert M, Rader L, Burns R,
DiMaria J, Copersino M, Stabile PQ, Kolodner K, Li R. Effect of prize-based incentives on outcomes in
stimulant abusers in outpatient psychosocial treatment programs: a national drug abuse treatment clinical
trials network study. Arch Gen Psychiatry. 2005 Oct;62(10):1148-56.
Quest TL, Merrill JO, Roll J, Saxon AJ, Rosenblatt RA. Buprenorphine therapy for opioid addiction in rural
Washington: the experience of the early adopters. J Opioid Manag. 2012 Jan-Feb;8(1):29-38.
Prochaska, J. O., Velicer, W. F., DiClemente, C. C., Fava J. (1988). Measuring processes of change:
applications to the cessation of smoking. Journal of Consulting Clinical Psychology, 56(4), 520-528.
Roozen, H. G., Boulogne, J. J., van Tulder, M. W., van den Brink, W., De Jong, C. A. J. & Kerkhof, A. J. F. M.
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Approval: 3/26/2024

Page 33 of 33 (V.01/21/2019) 
(2004). A systematic review of the effectiveness of the community reinforcement approach in alcohol,
cocaine and opioid addiction. Drug and Alcohol Dependence, 74(1), 1-13.
Sobell, L. C. & Sobell, M. B. (1992). Timeline follow-back: a technique for assessing self-reported alcohol
consumption. In J. Allen & R. Z. Litten (Eds.), Measuring Alcohol Consumption: Psychosocial and
Biological Methods (pp.41-72). Totowa, NJ: Humana Press.
Sobell, M. B. & Sobell, L. C. (2000). An excellent springboard. Addiction, 95(11), 1712-1715.
Spitzer, R. L., Kroenke, K., Williams, J. B. W. (1999). Validation and Utility of a Self-report Version of PRIMEMD:
The PHQ Primary Care Study. JAMA, 282(18), 1737-44.
Stitzer, M. & Petry, N. (2006). Contingency management for treatment of substance abuse. Annual Review of
Clinical Psychology, 2, 411–434.
Taylor, A.B., D.P. MacKinnon, and J.-Y. Tein, Tests of the Three-Path Mediated Effect. Organizational
Research Methods, 2008. 11(2): p. 241-269.
Tross S, Campbell AN, Cohen LR, Calsyn D, Pavlicova M, Miele GM, Hu MC, Haynes L, Nugent N, Gan W,
Hatch-Maillette M, Mandler R, McLaughlin P, El-Bassel N, Crits-Christoph P, Nunes EV. Effectiveness of
HIV/STD sexual risk reduction groups for women in substance abuse treatment programs: results of NIDA
Clinical Trials Network Trial. J Acquir Immune Defic Syndr. 2008 Aug 15;48(5):581-9.
Weathers, F., Litz, B., Herman, D., Huska, J., & Keane, T. (October 1993). The PTSD Checklist (PCL): Reliability, 
Validity, and Diagnostic Utility. Paper presented at the Annual Convention of the International Society for 
Traumatic Stress Studies, San Antonio, TX.
Weiss RD, Potter JS, Fiellin DA, Byrne M, Connery HS, Dickinson W, Gardin J, Griffin ML, Gourevitch MN,
Haller DL, Hasson AL, Huang Z, Jacobs P, Kosinski AS, Lindblad R, McCance-Katz EF, Provost SE,
Selzer J, Somoza EC, Sonne SC, Ling W. Adjunctive counseling during brief and extended
buprenorphine-naloxone treatment for prescription opioi dependence: a 2-phase randomized controlled
trial. Arch Gen Psychiatry. 2011 Dec;68(12):1238-46.
Weiss RD, Potter JS, Griffin ML, et al. Long-term outcomes from the National Drug Abuse Treatment Clinical
Trials Network Prescription Opioid Addiction Treatment Study. Drug Alcohol Dep 2015;150:112-9.
Williams AR, Nunes E, Olfson M. To Battle the Opioid Overdose Epidemic, Deploy the Cascade of Care.
March 13, 2017; http://healthaffairs.org/blog/2017/03/13/to-battle-the-opioid-overdose-epidemic-deploythe-
cascade-of-care-model/
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