Remote Observed Dosing of Suboxone to Improve Clinical Practice
Phase: PHASE1
Conditions: Opioid-use Disorder, Opioid Dependence, Opiate Dependence
Sponsor: University of Pennsylvania

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REMOTE OBSERVED DOSING TO IMPROVE SUBOXONE 
COMPLIANCE IN CLINICAL PRACTICE 
 
 
 
Principal Investigator  
Brenda Curtis, PhD  
Department of Psychiatry 
University of Pennsylvania Treatment Research Center 
3535 Market Street, Suite 500 
Philadelphia, PA 19104 
215-746-7306 
Bcurtis@pennmedicine.upenn.edu 
 
 
Medical Director 
 
 
 
 
 
 
 
Regulatory Sponsor 
 
Kyle Kampman, MD 
Department of Psychiatry 
University of Pennsylvania Treatment Research Center 
3535 Market Street, Suite 500 
Philadelphia, PA 19104 
215-746-2764 
kampman@pennmedicine.upenn.edu 
 
Funding Sponsor 
 
National Institutes of Health/NIDA 
6001 Executive Boulevard 
Room 5213, MSC 9561 
Bethesda, Maryland 20892 
Study Product 
 
Remote Observed Medication Dosing (Adherence) 
Protocol Number 
830028 (JIT) 
IRB Number 
 
NIH Grant Number 
 
1R34DA045177 
 
 
 
 
Initial version 
 
       07/16/2018 
Amended 
 

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Table of Contents 
BACKGROUND AND STUDY RATIONALE .......................................................................... 5 
1 
INTRODUCTION .................................................................................................................. 5 
1.1 
BACKGROUND AND RELEVANT LITERATURE .................................................................. 6 
2 
STUDY OBJECTIVES......................................................................................................... 8 
2.1 
PRIMARY OBJECTIVE ...................................................................................................... 8 
2.2 
SECONDARY OBJECTIVES (IF APPLICABLE) .................................................................... 9 
3 
INVESTIGATIONAL PLAN ................................................................................................ 9 
3.1 
GENERAL DESIGN ........................................................................................................... 9 
3.2 
ALLOCATION TO INTERVENTIONAL GROUP ..................................................................... 9 
3.3 
STUDY MEASURES .......................................................................................................... 9 
3.4 
STUDY ENDPOINTS ....................................................................................................... 11 
3.4.1 
Primary Study Endpoint..................................................................................... 11 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ............................... 11 
4.1 
TOTAL NUMBER OF SUBJECTS AND SITES ................................................................... 12 
4.2 
INCLUSION CRITERIA ..................................................................................................... 12 
4.3 
EXCLUSION CRITERIA ................................................................................................... 12 
4.4 
SUBJECT RECRUITMENT ............................................................................................... 12 
4.5 
VULNERABLE POPULATIONS: ........................................................................................ 13 
5 
STUDY PROCEDURES .................................................................................................... 13 
5.1 
SCREENING ................................................................................................................... 13 
5.2 
STUDY INTERVENTION................................................................................................... 14 
5.2.1 
Visit 1 .................................................................................................................... 14 
5.2.2 
Visits 2-4 (Suboxone Induction) ....................................................................... 15 
5.2.3 
Visits 5-28 ............................................................................................................ 15 
5.2.4 
End of Study Visit ............................................................................................... 15 
5.3 
UNSCHEDULED VISITS .................................................................................................. 15 
5.4 
SUBJECT WITHDRAWAL ................................................................................................ 15 
5.4.1 
Data Collection and Follow-up for Withdrawn Subjects ............................... 16 
5.5 
EARLY TERMINATION VISITS ......................................................................................... 16 
5.6 
EFFICACY EVALUATIONS (ONLY IF APPLICABLE) ........................................................... 16 
5.7 
PHARMACOKINETIC EVALUATION .................................................................................. 16 
5.8 
GENETIC TESTING ......................................................................................................... 16 
5.9 
SAFETY EVALUATION (ONLY IF APPLICABLE) ................................................................ 16 
6 
STATISTICAL PLAN......................................................................................................... 16 
6.1 
SAMPLE SIZE AND POWER DETERMINATION ................................................................ 16 
6.2 
STATISTICAL METHODS................................................................................................. 17 

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6.3 
CONTROL OF BIAS AND CONFOUNDING (IF APPLICABLE, TYPICALLY OBSERVATIONAL 
STUDY OR IF RANDOMIZATION IS NOT TAKING PLACE) .............................................................. 17 
6.3.1 
Baseline Data ...................................................................................................... 17 
6.3.2 
Analysis of Primary Outcome of Interest ........................................................ 17 
6.3.3 
Pharmacokinetic Analysis (only if applicable) ................................................ 17 
6.3.4 
Interim Analysis (only if applicable) ................................................................. 18 
7 
SAFETY AND ADVERSE EVENTS ............................................................................... 18 
7.1 
DEFINITIONS .................................................................................................................. 18 
7.1.1 
Adverse Event..................................................................................................... 18 
7.1.2 
Serious Adverse Event ...................................................................................... 18 
7.2 
RECORDING OF ADVERSE EVENTS ............................................................................... 19 
7.3 
RELATIONSHIP OF AE TO STUDY .................................................................................. 19 
7.4 
REPORTING OF ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .......................... 19 
7.4.1 
Follow-up Report ................................................................................................ 19 
7.4.2 
Investigator reporting: notifying the study sponsor (if applicable) .............. 19 
7.4.3 
Data and Safety Monitoring Plan ..................................................................... 20 
8 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .......... 20 
8.1 
CONFIDENTIALITY .......................................................................................................... 20 
8.2 
DATA COLLECTION AND MANAGEMENT ........................................................................ 21 
8.3 
RECORDS RETENTION .................................................................................................. 22 
9 
STUDY MONITORING, AUDITING, AND INSPECTING ............................................ 22 
9.1 
STUDY MONITORING PLAN ........................................................................................... 22 
9.2 
AUDITING AND INSPECTING ........................................................................................... 22 
10 
ETHICAL CONSIDERATIONS .................................................................................... 23 
10.1 
RISKS ............................................................................................................................ 23 
Common side effects are categorized below: ................................................................ 23 
10.2 
BENEFITS....................................................................................................................... 23 
10.3 
RISK BENEFIT ASSESSMENT ......................................................................................... 24 
10.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ......................................... 24 
10.4.1 
Alterations to Typical Consent Process (only include if applicable) ........... 24 
11 
STUDY FINANCES ....................................................................................................... 25 
11.1 
FUNDING SOURCE ......................................................................................................... 25 
11.2 
CONFLICT OF INTEREST ................................................................................................ 25 
11.3 
SUBJECT STIPENDS OR PAYMENTS .............................................................................. 25 
12 
REFERENCES ............................................................................................................... 26 
13 
APPENDICES................................................................................................................. 32 
 

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Study Summary 
 
Title 
REMOTE OBSERVED DOSING TO IMPROVE SUBOXONE 
COMPLIANCE IN CLINICAL PRACTICE 
Short Title 
RODISC 
IRB Number 
 
Protocol Number 
830028 (JIT) 
Methodology 
Two-Group RCT examining remote observed dosing. All participants 
receive Suboxone. 
Study Duration 
13 weeks  
Study Center(s) 
University of Pennsylvania 
Objectives 
To test the preliminary efficacy of using remote adherence monitoring in 
buprenorphine (Suboxone®) treatment for OUD 
Number of 
Subjects 
40 subjects  
Main Inclusion 
and Exclusion 
Criteria 
Opioid use disorder.  Men and women over 18 years of age. Subjects 
must have current DSM 5 diagnosis of opioid use disorder. Subjects 
must be in good health and psychiatrically stable.  They must have no 
other substance use disorder except tobacco use disorder or cannabis 
use disorder. Comorbid alcohol use disorder will be accepted if alcohol 
use disorder is not severe enough to require a medical alcohol 
detoxification. Subjects must not have received buprenorphine 
maintenance treatment within the past 3 months and must not have a 
current diagnosis of chronic pain requiring opioids. 
Intervention  
 
2 Group RCT: 
Group 1 (control): Attention match group that mirrors current clinical 
care 
Group 2 (treatment): Remote observed dosing of Suboxone 

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Statistical 
Methodology 
Buprenorphine adherence will be measured using two-times-weekly 
creatinine normalized quantitative urine levels for buprenorphine and 
norbuprenorphine. Rates of illicit opiate use will be compared between 
the groups using combinations of urine drug screens(UDS) and TLFB 
self-reports obtained at each visit. At each office visit, subjects will 
complete standard questionnaires on mood, health behaviors, risky 
behaviors, and craving, and report all drug and alcohol use that has 
occurred since their last office visit. Submission of videos will be 
recorded (date and time) and assessed daily for compliance (i.e., taking 
the medication as prescribed). 
Data and Safety 
Monitoring Plan  
Data will be collected by trained study staff with standardized forms 
using only a study number and initials to identify the participant. A code 
that links the participant to the study will be kept confidential by the 
study team in a password protected secure database. The clinical 
research coordinator and fellow staff members will be responsible for 
collecting and checking all clinical data. This includes ensuring that all 
fields are completed appropriately, that the clinical database is 
complete and accurate and all corrections are done according to GCPs. 
Any inconsistencies/deviations will be documented and reviewed by the 
PI. 
 
All data collection is HIPAA compliant. The CSA supports the 
appropriate privacy of all clinical and research data collected as part of 
any study. We follow Penn’s policy in the use and disclosure of 
protected health information in research in a manner that respects the 
patient’s privacy in accordance with the “Privacy Rule” promulgated 
under the Health Insurance Portability and Accountability Act (HIPAA) 
and other applicable laws. All staff receive appropriate HIPAA training. 
All participants sign a combined Informed Consent and HIPAA-
authorization form, receive a copy of this form, and receive a notice of 
Penn’s privacy practice. HIPAA signed forms are retained in locked file 
cabinets with participants’ source documents. Data analysis will be 
conducted by the Center statistician, Dr. Kevin G. Lynch, with 
assistance from the PI. 
 
Background and Study Rationale 
This study will be conducted in full accordance with all applicable University of 
Pennsylvania Research Policies and Procedures and all applicable Federal and state 
laws and regulations including the following regulations as they apply 45 CFR 46, 21 
CFR Parts 50, 54, 56 All episodes of noncompliance will be documented. 
1 
Introduction 
Opioid Use Disorder is a major public health problem, with high relapse rates and a strong 
association with negative health consequences. Suboxone (buprenorphine + naloxone) is an 
efficacious medication that is typically administered in an office-based setting; however, 
compliance rates are near 50% and diversion is a significant problem. This project proposes to 
develop and test the use of remote compliance monitoring of Suboxone to improve medication 
adherence and treatment outcomes. 

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1.1 
Background and Relevant Literature  
Opioid use disorder (OUD) is a significant public health problem. About 2 million Americans 
meet criteria for opioid use disorder involving prescription pain relievers and an additional 
591,000 Americans meet criteria for a heroin use disorder (Center for Behavioral Health 
Statistics and Quality 2016). The rise in prescription opioid use in the US has resulted in a 
dramatic increase in heroin use, as prescription opioid users switch to heroin when their access 
to prescription opioids becomes limited (Peavy et al. 2012; Cicero, Ellis, and Surratt 2012; 
Cicero et al. 2014, 50). Opioids (including prescription opioids and heroin) killed more than 
33,000 people in 2015, more than any year on record (CDC 2016). Nearly half of all opioid 
overdose deaths involve a prescription opioid.(Rudd et al. 2016) In addition to opioid overdose 
deaths, opioid use is associated with a number of medical problems, especially when used 
intravenously. Needle sharing and sexual practices place heroin users at high risk for human 
immunodeficiency virus infection and hepatitis c as well as other infectious diseases (Chen et al. 
2015; Richard S. Garfein et al. 1996). Heroin use is associated with high utilization of 
emergency services (McGeary and French 2000).  
 
Effective treatments for OUD are available but underutilized. From 2004-2013 only 21% of 
patients with an OUD received any treatment (Saloner and Karthikeyan 2015). This is despite 
the fact that there are currently 3 efficacious medications available to treat this disorder: 
methadone, naltrexone (Vivitrol®), and buprenorphine (Suboxone®). Methadone maintenance 
treatment (MMT) has been available the longest of the three and has been shown to a very 
efficacious treatment (Ball and Ross 1991) As an opiate agonist, methadone is able to alleviate 
opiate withdrawal symptoms, reduce opiate craving and, at higher doses, reduce the ability of 
illicit opiates to cause intoxication (Ward et al. 2009).  However, there are a several aspects of 
MMT that are less attractive. For example, MMT occurs exclusively in the context of an Opiate 
Treatment Program (OTP), where dosing occurs daily at set times. Such programs require a 
large time investment from participants, as they must attend the clinic daily within set dosing 
hours. Another common problem with MMT relates to the associated side effects that can 
diminish patient compliance including weight gain and cognitive impairment (Curran et al. 2001; 
Mendelson et al. 1996; Nolan and Scagnelli 2007; Pirastu et al. 2006; Prosser et al. 2006). 
Lastly, federal regulations limit access to MMT making it logistically impractical for many 
patients (Johnson et al. 2000; Substance Abuse and Mental Health Administration 2015). 
 
Buprenorphine, a partial agonist that exerts significant actions at the mu opioid receptor, has 
also been shown to be effective for the treatment of OUD (Johnson et al. 1995; Liebson et al. 
1988; Johnson, Jaffe, and Fudala 1992). It offers agonist substitution that alleviates opiate 
withdrawal and reduces opiate cravings—thereby reducing opiate use (Gowing, Ali, and White 
2009; Greenwald et al. 2007; W Ling and Wesson 2003). Buprenorphine has a higher affinity for 
the mu opiate receptor than all available full opiate agonists offering antagonist blockade that 
prevents patients from experiencing a high from illicit opiates (Greenwald et al. 2007; W. K. 
Bickel et al. 1988; Warren K. Bickel and Amass 1995).   Because it is a partial agonist and not 
prone to overdose, it is considered to be safe enough to dispense out of a clinician’s office as 
opposed to an OTP (Center for Substance Abuse Treatment 2004). The availability of 
buprenorphine treatment outside of an OTP has significantly expanded the availability of 
effective treatment for OUD and is associated with reducing disparities related to treatment 
access (Bonhomme et al. 2012; Kumari et al. 2016; Stanton 2006).   
While initial studies reported little evidence of buprenorphine diversion (Stanton 2006), more 
recent studies have indicated buprenorphine is prone to diversion and poor adherence that can 
significantly diminish its safety and efficacy (Kumari et al. 2016; Tkacz et al. 2012).  In these US 
clinical trials, adequate adherence to buprenorphine has been shown to occur in fewer than 

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50% of subjects who are prescribed the medication. In a trial involving 50 African American 
subjects with opioid use disorder participating in office based buprenorphine treatment, it was 
found that only 48% of the subjects were adherent to the medication as defined as having 80% 
or more of their visits associated with a positive UDS for buprenorphine (Kumari et al. 2016). In 
another trial involving 703 subjects with opioid use disorder only 41% of the subjects took 
buprenorphine 80% of the days it was prescribed (Tkacz et al. 2012). Finally in an examination 
of medical and pharmacy claims data over a year, only 32% of patients participating in office 
based buprenorphine treatment took buprenorphine on 80% or more days (Tkacz et al. 2014).  
Poor adherence to buprenorphine treatment has been associated with a number of negative 
outcomes including poor treatment retention of patients participating in office based treatment 
(Matson et al. 2014). Compared to patients with good adherence, poorly adherent patients in 
office based buprenorphine treatment were ten times more likely to relapse to opioid use (Tkacz 
et al. 2012).  
The growth in cell phone use creates an unprecedented opportunity to improve medication 
adherence (Krishna, Boren, and Balas 2009; Lester et al. 2010; Horvath et al. 2012; Granholm 
et al. 2011; Pop-Eleches et al. 2011). The use of Remote Observed Dosing (ROD) allows us to 
reach underserved, at-risk populations (Hoffman et al. 2010). In a study with cannabis 
dependent patients using ROD that was directly observed (DOT) over Skype for three weeks, 
every morning 20 participants were video called by staff who observed consumption of the study 
medication. Adherence was confirmed 96% of the time and was also assessed with weekly 
face-to-face visits, pill counts, and plasma drug levels (DeWorsop et al. 2016). 
The ROD protocol we are proposing in this study is very similar to protocols used in studies with 
pediatric patients receiving iron chelation therapy and adult patients receiving anti-tuberculosis 
treatment that allows the user to video record dosing (Leonard et al. 2017; R. S. Garfein et al. 
2015). Leonard and colleagues conducted a pilot study to examine the feasibility of using a 
smartphone app to improve compliance to iron chelation. Self-report adherence rates to 
chelation therapy are around 71%-76% and are as low as 43% based on pharmacy refill rates 
(Leonard et al. 2017). The protocol these researchers used involved: 1) patient recording daily 
videos of at-home medication administration and 2) provider feedback through cell phone 
messaging. The mobile ROD protocol was feasibly implemented in a clinic setting and reported 
high levels of compliance, disease knowledge retention, and acceptance among patients. In 
another pilot study with adult patients in Mexico and the US who were receiving anti-
tuberculosis treatment, ROD was used to monitor compliance (R. S. Garfein et al. 2015). This 
protocol involved patients using a smartphone to record videos of themselves taking the 
medication and uploading the video to a secure website to document compliance. The research 
staff sent text message reminders—one before the doses were due and one after missed 
doses. Garfein and colleagues reported that adherence was similar in Mexico (96%) as in the 
US (93%) and ROD was preferred over observed in office dosing. In addition, ROD patients felt 
the technique was more confidential; never or rarely experienced problems recording the videos 
and 100% would recommend ROD to others (R. S. Garfein et al. 2015). 
  
To address this need we recently completed a feasibility study of remote observed Suboxone® 
dosing to determine whether we could enroll and retain participants in such a study (UPENN 
Protocol # 816651). The observed dosing protocol we used was similar to the ones used to 
examine the feasibility of directly observed therapy (DOT) (DeMaio et al. 2001; DeWorsop et al. 
2016). In our feasibility study, 10 participants were enrolled. Each participant received 12 weeks 
of Suboxone® during the study. Participants attended weekly in-office sessions where they took 
an observed dose of Suboxone® and then took the remaining weekday doses (M-F) while on a 

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video Skype call with study staff. Data from that study reveal low rates of continued opioid use 
while on Suboxone® and high rates of Skype-observed doses. All urines tested during the study 
were buprenorphine positive, demonstrating excellent adherence with the treatment. In addition, 
self-reports of opiate use corresponded to urine drug screen results, and only one participant 
continued to test positive for opioids intermittently during the study. Participants successfully 
completed 100% of required in-office visits, and 90% of scheduled Skype calls. Perhaps 
more important, participants did not find the daily Skype calls to be burdensome. 
However, the pilot study did not have a control group and because the clinic was only open 
Monday-Friday, we did not observe dosing on the weekends. While this is true for many 
physician offices and community based treatment providers, it is problematic because 
weekends are often a high risk time for drug users. It is important to observe dosing 7 days a 
week in order to ensure optimum adherence and avoid diversion. It is equally important to 
determine if ROD improves buprenorphine adherence compared to an attention-matched 
control group.  
Dr. Curtis has developed a protocol that uses a smartphone to video record buprenorphine 
dosing and automatically sends this recording through HIPAA compliant means to 
clinical staff who can then review it at a convenient time and location. Her protocol also 
uses SMS text messaging to communicate with patients. To address the feasibility of patients 
with an OUD using this technology, Dr. Curtis conducted a pilot study with 71 patients in OUD 
treatment locally regarding the feasibility and usability of such a technology. The preliminary 
data indicated: 
• 
While 95% of patients had a cell phone, the majority of them (76%) had “pay as you go” 
plans with limited data capabilities. In addition, 71% reported changing their cell phone 
regularly. 
• 
87% reported sending and receiving SMS text messages daily, 60% used the video 
option on their phones to send videos, 54% watched videos online, and 53% used an “instant 
message app”. 
• 
78% reported they would take part in a text messaging program to help prevent relapse 
and 75% reported they would be receptive to a cell-phone based OUD intervention. 
These findings suggest using the proposed platform to monitor buprenorphine dosing is 
both feasible and would be welcomed by patients undergoing opioid treatment.  
 
2 
Study Objectives 
ROD has the potential to 1) improve adherence, 2) reduce the risk of diversion, and 3) increase 
access to buprenorphine treatment. 
2.1 
Primary Objective 
• 
The overarching aim of this behavioral intervention is to test the preliminary efficacy of 
using remote adherence monitoring in buprenorphine (Suboxone®) treatment for OUD. 
For the ROD group, we will calculate the within-patient proportion of study days on which 
video captured adherence, as per protocol. We will use these data to compare observed 
adherence rates in this group to rates reported in prior studies and to the attention 
control group. 

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2.2 
Secondary Objectives (if applicable) 
• 
Rates of illicit opiate use will be compared between the groups using combinations of 
urine drug screens (UDS) and TLFB self-reports obtained at each visit. 
3 
Investigational Plan  
Forty patients with OUD, who are not currently prescribed buprenorphine, will be recruited 
through the University of Pennsylvania’s Center for the Studies of Addiction (CSA), an 
outpatient substance abuse treatment facility. Potential participants will be screened for physical 
and psychological appropriateness for inclusion in the study using the CSA standard intake 
procedures. This includes a psychosocial diagnostic evaluation, a medical exam, urine and 
blood tests, and an EKG (see Measures for full description of screening assessments). 
Participants who are appropriate for the trial will be inducted onto Suboxone® using standard 
office based induction as described in the ASAM National Practice Guideline for the Use of 
Medications in the Treatment of Addiction Involving Opioid Use (Kampman and Jarvis 2015).  
All patients will receive buprenorphine (Suboxone®; up to 24 mg daily) and will be randomly 
assigned to one of two groups. The experimental group (n=20) will receive daily remote 
observed dosing (ROD) via a secured video platform that records dosing using study-provided 
smartphones (approximately 5 minutes each session). ROD videos will be monitored daily for 
compliance. The attention control group (AC, n=20) dosing will not be observed. All subjects will 
attend 2 weekly study visits (3 study visits during the induction phase in Week 2). Study visits 
starting in Week 3, after the Induction phase, will consist of counseling in the form of weekly 
Medication Management (MM); buprenorphine distribution with medication management;and a 
urine screen. Study visit 4 will consist of a urine screen and phone management task 
(downloading study related videos) for those randomized to the Remote Observed Dosing 
Group. 
 
3.1 
General Design 
Participants will be randomized into one of two study groups. Both groups will receive standard 
buprenorphine maintenance treatment. Participants will attend study visits twice weekly for 12 
weeks and a close-out visit in week 13. One group will be assigned to Remote Observed Dosing 
(ROD) and will have all of their Suboxone® doses remotely observed using procedures 
described below. The attention control (AC) group will not have their dosing observed but will 
send a text message confirming they have taken their study medication to the study team daily 
matching contact with the study team. 
3.2 
Allocation to Interventional Group  
Participants will be randomized into one of two study groups based on proportion of use of 
prescription opiates and heroin, gender, and prior Suboxone® treatment. 
3.3 
Study Measures 
We will administer several standard assessments during the course of the study (shown below). 
At each office visit, subjects will complete standard questionnaires on mood, health behaviors, 
risky behaviors, and craving, and report all drug and alcohol use that has occurred since their 
last office visit: 
Addiction Severity Index (McLellan et al. 1992). The ASI is a 45-minute interview which 
yields composite scores, ranging from 0 to 1, of problem severity over the past 30 days in 7 
areas: medical, employment, drug use, alcohol use, legal, family/social, and psychiatric. Studies 

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have shown moderate to excellent interrater and test-retest reliability. The ASI was used to 
characterize baseline demographic and drug use variables for each subject. The composite 
scores will be used as secondary outcome measures. The ASI will be administered at baseline 
week 5, week 9 and at the end of study. 
Adverse events. Adverse events are queried and documented at each visit and recorded in 
the CRF.  
Clinical Global Impression Scale (Guy 1976). The CGI is a brief clinical rating of severity of 
illness (at time of interview) and global improvement (from admission) using a 7-point Likert 
scale. The CGI is done by an observer and the subject to assess clinical progress, global 
improvement and to assess the severity of the subject’s illness at regular contacts over the 
course of the study. The CGI is done once during baseline by the observer and participant, at 
week 9 and at the end of the study. 
Columbia Suicide Severity Rating Scale (Chappell et al. 2012). This is a 5-item scale with 
additional questions that may be asked based on the participant’s responses to the core items. 
This questionnaire will assess both lifetime and recent suicidal ideation and behavior, including 
both passive and active thoughts/plans. It is extensively used across clinical practices, 
hospitals, research institutions and schools to address potential thoughts of suicide expressed 
by the client. This questionnaire will be administered at baseline, and once a week through the 
trial. The CSSRS is a form that has been included in all pharmacotherapy trials as a safety 
measure.(U.S. Department of Health and Human Services n.d.) Note: This data will not be 
analyzed but will be included to help ensure the safety of the participants. 
Concomitant medications will be queried and recorded at each participant visit.  
Hamilton Depression Rating Scale (Hamilton 1967). The Ham-D is a 20-minute, 24-item 
interview that measures the severity of depression and changes in depressive symptoms. The 
Ham-D is administered at baseline, week 9 and at the end of the study. 
Locator Form. The locator form asks about addresses and phone numbers where the 
participant might be contacted, as well as names and addresses of other individuals who might 
know the participant’s whereabouts. The information is used to locate participants who do not 
respond to a calls and weekly text messages. 
Obsessive Compulsive Drug Use Scale (Franken, Hendriks, and van den Brink 2002). 
Adapted from the Obsessive Compulsive Drinking Scale(Anton, Moak, and Latham 1995) 
(OCDS), measures craving for heroin on a 12-item likert scale. Our version replaces heroin with 
opioids more generally. This will be administered at baseline and weekly throughout the trial. 
Risk Assessment Battery (Metzger et al. 1993). The RAB is a 38 item self-report 
questionnaire which assesses high risk behavior for exposure to the HIV virus. The RAB yields 
drug, sex and total risk scores and will be administered at baseline and at the end of the trial.  
Systems Usability Scale (Grindrod, Li, and Gates 2014). The SUS is a 10 item self-reported 
validated measure of learnability and user satisfaction that we will use to evaluate the remote 
medication monitoring protocol. It uses a 5-point Likert scale to provide a quantitative measure 
of the usability of the ROD protocol and provides an overall score between 0 and 100. This 
scale will be administered at the end of the study.  
Timeline Follow Back Interview (Sobell and Sobell 1995). The TLFB is a 15-30 minute, semi-
structured interview adapted by our laboratory to collect information about daily drug, alcohol, 
and nicotine use. The TLFB will be given by trained research staff at baseline to cover 3 months 
immediately preceding treatment entry and will be updated at each research visit to determine 
any time spent in a controlled environment and cocaine, nicotine, and other drug use during the 

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period since the last visit. The composite of these assessments are additive over the course of 
the study so that we will have continuous data.  
Video Compliance. Submission of videos will be recorded (date and time) and assessed 
daily for compliance (i.e., taking the medication as prescribed). In addition, videos will be saved 
off the micro-SD cards at each office visit.  
Laboratory Measurements (in alphabetical order) 
Blood chemistry, Complete Blood Count (CBC), and Urinalysis are obtained to assess for 
adverse events. Enzyme levels will be obtained once at baseline and end of the study.  
Pregnancy Testing. Urine pregnancy tests will be obtained from all women at baseline, week 
5, week 9, and end of study.  
Urine Drug Screen and Urine Buprenorphine and Norbuprenorphine Screen. Quantitative 
urine buprenorphine and norbuprenorphine levels (using gas chromatography) with urine 
creatinine used as a control for urinary concentration will be assessed twice weekly throughout 
the trial. Urinary buprenorphine levels have been used extensively to establish buprenorphine 
adherence (Fox, Tetlow, and Allen 2006; Vincent et al. 1999). Quantitative levels of methadone 
have been used successfully to establish methadone compliance in a methadone maintenance 
program (Preston et al. 2003). Our toxicology consultant will assist us in interpreting urine 
creatinine controlled quantitative buprenorphine levels to establish medication adherence. Data 
from this trial will be used in optimizing the use of quantitative urine buprenorphine and 
norbuprenorphine levels in the subsequent efficacy trial. Qualitative (emit) urine toxicology for 
other drugs (benzodiazepines, barbiturates, opiates, marijuana, methadone, and amphetamine) 
is done at baseline and weekly throughout the trial.  
 
3.4 
Study Endpoints  
3.4.1 Primary Study Endpoint 
For the ROD group, we will calculate the within-patient proportion of study days on which video 
captured adherence, as per protocol.  
Secondary Study Endpoints 
We will use a combination of self-report and (nor)buprenorphine levels to classify patents in the 
AC group as adherent or non-adherent for each study day to compare their rates of adherence 
to the (video-verified) rates in the ROD group. These comparisons will give a direct estimate of 
the improvement in adherence likely to be observed between the proposed method and 
standard methods.  
Rates of illicit opiate use will be compared between the groups using combinations of urine drug 
screens (UDS) and TLFB self-reports obtained at each visit. 
4 
Study Population and Duration of Participation  
This study will involve 40 individuals with Opioid Use Disorder (OUD) who will receive three 
months (12 weeks) of buprenorphine (Suboxone®) (standard dose will be up to 24 mgs/day, 
adjusted as necessary on an individual basis). Suboxone® is a form of buprenorphine with 
naloxone added to reduce the potential for buprenorphine abuse.   

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4.1 
Total Number of Subjects and Sites  
Recruitment will end when approximately 40 subjects are enrolled at the University of 
Pennsylvania. It is estimate that we will need to approach approximately 160 participants. Of 
these potential participants, we anticipate 80 will undergo screening to recruit 40 participants.   
4.2 
Inclusion Criteria 
 Inclusion Criteria (prior to induction): 
• 
Voluntarily provide written informed consent prior to the conduct of any study-related 
procedure  
• 
Male, female, or transgender  
• 
18 – 45 years of age 
• 
Meet DSM 5 criteria for opioid use disorder moderate to severe 
• 
Women of childbearing potential must use a reliable means of contraception 
4.3 
Exclusion Criteria 
Exclusion Criteria (prior to induction): 
• 
Current diagnosis of AIDS 
• 
Participation in buprenorphine maintenance treatment within the past 3 months 
• 
Presence of AST and/or ALT equal to or > 3X upper limit of normal 
• 
Total bilirubin and/or creatinine equal to or > 1.5X upper limit of normal 
• 
Current diagnosis of chronic pain requiring opioids 
• 
Pregnant or lactating women 
• 
Previous hypersensitivity or allergy to buprenorphine 
• 
Current use of agents metabolized through CYP 3A4 such as azole antifungals (e.g. 
ketoconazole), macrolide antibiotics (e.g. erythromycin), and protease inhibitors (e.g. 
ritonavir, indinavir, saquinavir) 
• 
Meet DSM - 5 criteria for current use disorder for any psychoactive substances other 
than opioids, marijuana, cocaine or nicotine (e.g. alcohol, sedatives) 
• 
Current use of benzodiazepines 
• 
Significant medical or psychiatric symptoms or dementia which in the opinion of the 
investigators would preclude compliance with the protocol, adequate cooperation in the 
study, or obtaining informed consent 
• 
Concurrent medical conditions (such as severe respiratory insufficiency) that may 
prevent the patient from safely participating in the study; and/or any pending legal action 
that could prohibit  participation and/or compliance in study procedures  
4.4 
Subject Recruitment  
The project will be conducted at the Center for the Study of Addiction at the University of 
Pennsylvania. The CSA has a community-based (non-veteran) outpatient addiction treatment-
research program that is part of the University of Pennsylvania (CSA, Dr. Henry Kranzler, 
Director). The CSA offers outpatient addiction treatment for individuals from the greater 
Philadelphia area who are seeking treatment for their addiction and who qualify for one of our 
grant-sponsored treatment studies on alcohol, cocaine, dual cocaine-alcohol, opioid or nicotine 
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professional, and self-referrals from the greater metropolitan Philadelphia area. We will also 
recruit through placing flyers at Penn Medicine and Penn Medicine outpatient clinics. All patients 
enrolled at the CSA receive medical monitoring and high-quality treatment-at no cost. Female-
focused recruitment strategies including direct appeals to female-medical specialties such as 
OB-GYN offices, has increased our ability to recruit women with OUD. In addition to Dr. 
Kampman’s office based-buprenorphine practice, The University of Pennsylvania Health 
System supports office based buprenorphine treatment at the Charles O’Brien Center for 
Addiction Treatment and at nearby Penn Presbyterian Medical Center. 
 
4.5 
Vulnerable Populations:  
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research 
study 
 
5 
Study Procedures  
See Measures for Description of Study Assessments 
See Table 1 for Assessment Schedule 
 
 
Regular evaluation visits.  Subjects will have appointments with study staff two times weekly 
throughout the 12-week medication phase of the trial.  A telephone reminder call and/or text 
message will be used to enhance attendance. Urine drug screens (UDS) for buprenorphine and 
norbuprenorphine will be obtained at each visit, along with concomitant medications, adverse 
events, and time line follow back (TLFB). The Columbia Suicide Severity Rating Scale (CSSRS) 
will be obtained at baseline and weekly. Other measures completed routinely but not weekly are 
listed in Table 1. A description and schedule of assessments is provided in the study measures 
section of the protocol.  Each patient will meet weekly with the clinician who will assess clinical 
status, dispense study medications and monitor adverse events and concomitant medications.   
 
After the completion of Week 13, or at the termination for patients who discontinue from the trial 
prematurely, we will conduct the following procedures: physical exam, electrocardiogram, 
monitor adverse events and concomitant medications, obtain blood samples for chemistry, 
CBC, obtain a urinalysis (and a pregnancy test for women), and complete other measures (See 
Table 1). The Systems Usability Scale will be conducted at the end of study visit.  Safety follow 
up visit will be conducted one month after the completion of the medication phase.  
 
Psychosocial Treatment. Subjects will participate in weekly Medication Management (MM), an 
intervention developed as part of NIAAA’s Project COMBINE study, that provides advice and 
support from medical practitioners concomitantly with dispensing medications, safety checking 
and compliance (Pettinati et al., 2004). The main goal of MM is to increase the likelihood that 
patients will reduce their opioid use. The initial MM session is an hour; subsequent sessions are 
15-30 minutes.  
 
5.1 
Screening  
The University of Pennsylvania Center for the Study of Addictions, CSA, is home of the 
Treatment Research Center (TRC) (Dr. Henry Kranzler, Director) at 3535 Market Street, 
Philadelphia, PA 19104 will be the primary recruitment site.  Subjects have been steadily 
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recruitment is ongoing and accomplished through community, professional, and self-referrals 
from the greater metropolitan Philadelphia area.   Most of the TRC callers seeking treatment 
who are approved for intake (via center IRB-approved phone pre-screen) come in to consent to 
the General Screening Consent (Protocol #701074) for an intake appointment to review general 
medical and psychosocial criteria prior to consenting to a specific study. All participants enrolled 
at the TRC receive medical monitoring and high-quality treatment-at no cost. The TRC recruits 
through ads in local papers, radio ads, flyers at approved locations in the area, information at 
health fairs, online social media platforms, and other recruitment methods we have had success 
with in prior trials.  Uniform screening procedures will be used. A standardized telephone 
interview is followed by an appointment for those who meet general study criteria.  Participants 
who are ineligible for our studies, or participants who cannot be accommodated in one of our 
studies are instead referred to the outpatient clinic of nearby Presbyterian Hospital, which is a 
major part of the University of Pennsylvania Health System or to their insurance provider for 
treatment options.   
 
After signing a screening consent, persons will be screened to verify that they meet all 
inclusion/exclusion criteria. A medical history, physical and laboratory examination will be 
conducted. The research clinician will offer eligible patients participation in the study. The study 
staff member obtaining informed consent will ensure that the patient understands the 
risks/potential benefits of the study prior to signing the consent form. Individuals will not be 
enrolled in the study until they successfully pass a “quiz” about the content of the informed 
consent. 
 
Contacting Subjects: Subjects are informed during the informed consent process that contact 
information provided to the research staff may be used at a later date to contact them by phone 
or mail. Reasons for contact include but are not limited to: missed appointments, appointment 
reminders, requests for follow-up visits, notifications of medical testing results, or other clinical 
reasons. Subjects are instructed to notify study staff if they no longer wish to be contacted. 
Procedure for contacting subjects include but are not limited to: three attempts to reach the 
subject by phone by study staff, the Emergency Contact provided by the subject will be called 
by a clinical staff member, and an IRB approved letter asking the subject to come to the center 
and/or call the study team. 
 
5.2 
Study Intervention  
5.2.1 Visit 1  
 
• 
Medical Exam and EKG, CBC and blood chemistry Urinalysis (UA), Risk Assessment 
Battery 
• 
Pregnancy Test (women), Addiction Severity Index (ASI) 
• 
Urine Toxicology and Urine Buprenorphine and Norbuprenorphine Screen, Timeline 
Follow back (TLFB) 
• 
Clinical Global Impression Scale (CGI), Hamilton Depression Rating Scale (HAM-D) 
• 
Columbia Suicide Severity Rating Scale (C-SSRS), Obsessive Compulsive Drug Use 
Scale (OCDUS) 
• 
Concomitant medications 
 

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5.2.2 Visits 2-4 (Suboxone Induction) 
Participants who are appropriate for the trial will be inducted onto Suboxone® using standard 
office based induction as described in the ASAM National Practice Guideline for the Use of 
Medications in the Treatment of Addiction Involving Opioid Use (Kampman, Kyle and Jarvis, 
Margaret 2015). 
• 
Concomitant medications  
• 
Medical Management, Pill Distribution 
• 
Adverse Events  
• 
Visit 4: Randomization & Distribution of Smartphone w/ intervention training 
 
5.2.3 Visits 5-28 
Patients will be seen twice weekly. For each in-office visit, patients will provide a urine sample 
that will be tested for drugs of abuse and for quantitative buprenorphine and norbuprenorphine 
levels. At each office visit, patients will also complete questionnaires about craving and 
depression. They will be asked about other medications they are using, about their drug and 
alcohol use since their last visit, and about any side effects they may be experiencing. Dosage 
adjustments will be made as needed at the discretion of their clinician. Subjects will also 
participate in weekly, manualized Medication Management. After induction, all patients will 
receive open-label Suboxone® for 12 weeks. Patients in both groups will receive a weeks’ worth 
of Suboxone® at each medication management visit. After the 12 weeks of Suboxone®, 
subjects will be referred to on-going treatment options in the community. 
5.2.4 End of Study Visit 
After the completion of Week 14, or at the termination for patients who discontinue from the trial 
prematurely, we will conduct the following procedures: physical exam, vital signs and weight, 
electrocardiogram, monitor adverse events and concomitant medications, obtain blood samples 
for CBC, blood chemistry, obtain a urinalysis (and a pregnancy test for women), Urine drug 
screen and urine buprenorphine and norbuprenorphine levels, CGI, Timeline folllowback, and 
system usability screen (SUS). At the completion of the trial patients will be referred to MAT in 
the community, or if they decline they will receive a tapering dose of suboxone for one week.  
5.3 
Unscheduled Visits 
Unscheduled visits will be accommodated based on staff availability. 
5.4 
Subject Withdrawal  
 Subjects may withdraw from the study at any time without impact to their care.  They 
may also be discontinued from the study at the discretion of the Investigator for lack of 
adherence to intervention or study procedures or visit schedules, AEs, or due to 
worsening of opioid use disorder. The Investigator may also withdraw subjects who 
violate the study plan, to protect the subject for reasons related to safety or for 
administrative reasons.  It will be documented whether or not each subject completes 
the study. Subjects who withdraw early will have one final visit to collect final 
evaluations and assess adverse events.   

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5.4.1 Data Collection and Follow-up for Withdrawn Subjects 
Subjects who withdraw consent to participate in the study will be seen for one final 
study visit. During this visit, they will be asked for permission to have the study team 
look into their survival status via publically available means.   
5.5 
Early Termination Visits   
After the completion of Week 14, or at the termination for patients who discontinue from the trial 
prematurely, we will conduct the following procedures: physical exam, vital signs and weight, 
electrocardiogram, monitor adverse events and concomitant medications, obtain blood samples 
for CBC, blood chemistry, obtain a urinalysis (and a pregnancy test for women), Urine drug 
screen and urine buprenorphine and norbuprenorphine levels, CGI, Timeline folllowback, and 
system usability screen (SUS). At the completion of the trial patients will be referred to MAT in 
the community, or if they decline they will receive a tapering dose of Suboxone for one week.  
 
5.6 
Efficacy Evaluations (only if applicable)  
For the ROD group, we will calculate the within-patient proportion of study days on which video 
captured adherence, as per protocol.  
We will use a combination of self-report and (nor)buprenorphine levels to classify patents in the 
AC group as adherent or non-adherent for each study day to compare their rates of adherence 
to the (video-verified) rates in the ROD group. These comparisons will give a direct estimate of 
the improvement in adherence likely to be observed between the proposed method and 
standard methods.  
Rates of illicit opiate use will be compared between the groups using combinations of urine drug 
screens (UDS) and TLFB self-reports obtained at each visit. 
 
5.7 
Pharmacokinetic Evaluation  
Patients will provide a urine sample at each office visit that will test for quantitative 
buprenorphine and norbuprenorphine levels.  
5.8 
Genetic Testing  
Not applicable 
5.9 
Safety Evaluation (only if applicable) 
 Adverse events will be monitored at each visit. Concomitant medications will be queried and 
recorded at each visit. Safety laboratory measures include, complete blood count (CBC), blood 
chemistries, urinalysis, urine pregnancy tests (for women), EKG. 
6 
Statistical Plan 
 
6.1 
Sample Size and Power Determination 
One target of the study is to estimate the proportion of participants in the ROD group who 
adhere with their medication schedule for, say, 80% or more of their treatment days. If 90% of 
the 20 participants adhere, then our data will yield a 95% confidence interval of (68%, 98%) for 
the proportion adhering; if 95% are adherent, then our confidence interval will be (72%, 99%). 

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For the longitudinal comparisons of quantitative (nor)buprenorphine levels, transformed so that 
a linear model is appropriate, we use the methods of Hedeker and collegues. For an alpha level 
of 0.05, and assuming a within subject correlation of 0.4, and dropout of 10%, the sample size 
provides 80% power for a standardized linear group by time effect of d=0.65. Thus, the study is 
powered for medium to large effects in quantitative buprenorphine levels. 
6.2 
Statistical Methods 
For the ROD group, we will calculate the within-patient proportion of study days on which video 
captured adherence, as per protocol. We will use these data to compare observed adherence 
rates in this group to rates reported in prior studies.36,38,39 The primary comparison between the 
groups will use the creatinine normalized weekly quantitative urine levels for buprenorphine and 
norbuprenorphine. Exploratory analyses include the following: We will use a combination of self-
report and (nor)buprenorphine levels to classify patents in the AC group as adherent or non-
adherent for each study day, and use mixed effects logistic regression models to compare their 
rates of adherence to the (video-verified) rates in the ROD group. Rates of illicit opiate use will 
be compared between the groups using combinations of urine drug screens(UDS) and TLFB 
self-reports obtained at each visit. The ASI, CGI, and HAM-D scales are obtained monthly. To 
assess usability and acceptability of the ROD protocol and text messaging application, Dr. 
Curtis will conduct semi-structured interviews and analyze data from the Systems UsabilityScale 
(SUS) at the final office visit. 
 
6.3 
Control of Bias and Confounding (if applicable, typically observational study 
or if randomization is not taking place) 
Subjects will be randomly assigned to the two groups 
6.3.1 Baseline Data 
Baseline and demographic characteristics will be summarized by standard descriptive 
statistics (including mean and standard deviation for continuous variables such as age 
and standard percentages for categorical variables such as gender). 
6.3.2 Analysis of Primary Outcome of Interest 
The primary comparison between the groups will use the creatinine normalized weekly 
quantitative urine levels for buprenorphine and norbuprenorphine. For each response, we 
anticipate that a response transformation, such as the log transform, will yield responses 
appropriate for group comparisons based on linear mixed effects models, but we will consider 
generalized linear mixed effects models if necessary.88 Comparisons of BIC statistics across 
different covariance structures will be used to select the best model for within subject 
correlations – typically a model with random intercept and ar(1) residual correlations provides a 
good fit. The main explanatory variable will be a binary indicator for group (ROD vs AC). Time 
will be regarded as a continuous scale, and linear, quadratic or spline trends will be used as 
necessary, with group by time interactions examined for significance. Our primary analyses will 
examine the two sets of responses (buprenorphine and norbuprenorphine) separately, but we 
will also consider bivariate mixed effects models with cross-correlation structure to assess 
strength of dependence and concordance between the two sets of measures. These analyses 
will be performed using PROC GENMOD in SAS. 
6.3.3 Pharmacokinetic Analysis (only if applicable) 
Not Applicable  

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6.3.4 Interim Analysis (only if applicable) 
 Efficacy analyses will be conducted at the trial end.  There are no plans for interim 
analyses. 
 
7 
Safety and Adverse Events 
7.1 
Definitions 
7.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries 
should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
7.1.2 Serious Adverse Event 
Study definition of serious adverse event. Potential definition that may be used if 
applicable: 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any 
AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• required intervention to prevent permanent impairment or damage 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.   They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, 
drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or 
intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 

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7.2 
Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all 
adverse events will be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period will be recorded.  The clinical 
course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study intervention or participation is not the cause.  Serious adverse 
events that are still ongoing at the end of the study period will be followed up to 
determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study intervention or study 
participation will be recorded and reported. 
7.3 
Relationship of AE to Study  
The PI or medical director will review each adverse event and determine if it is definitely related, 
probably related, possibly related, unlikely, or unrelated to study procedures. 
7.4 
Reporting of Adverse Events and Unanticipated Problems 
 
The Investigator will promptly notify the Penn IRB of all on-site unanticipated, Adverse Events 
that are related to the research activity. Other unanticipated problems related to the research 
involving risk to subjects or others will also be reported promptly. Written reports will be filed 
using the HS-ERA and in accordance with the Penn IRB timeline of 10 working days. The 
Investigator will notify the study sponsor and the DSMB as outlined in the sections below. 
 
7.4.1 Follow-up Report 
 
If an AE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant new 
or reassessed information (e.g., concomitant medication, medical history) will be submitted to 
the IRB. The investigator will ensure that all SAEs are followed until either resolved or stable. 
 
When additional clinical information becomes available, a follow-up and/or final SAE report will 
be filed with the UPENN IRB, NIDA, the DSMB, and the FDA  
7.4.2 Investigator reporting: notifying the study sponsor (if applicable) 
A serious adverse event will be reported to the study sponsor within 24 hours of the event. All 
SAEs will be submitted to the NIDA Medical Monitor within 24 hours.  The NIDA Program 
Official (PO) and the NIDA Project Scientist (PS) will be notified within 3 business days of 
learning of the SAE using the online SAETRS system.  In addition, all written documentation for 
all SAEs and unexpected AEs will be provided to the NIDA Medical Monitor within three (3) days 
of reporting the event. The investigator will keep a copy of an SAE report form on file at the 
study site.   
 

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7.4.3 Data and Safety Monitoring Plan 
 
The data and safety monitoring plan is comprised of the following: 
• 
Principal Investigator- Brenda Curtis 
• 
Study Medical Director- Kyle Kampman 
• 
NIDA Medical Monitor 
• 
Sponsor- NIDA 
• 
Penn Independent Monitor 
• 
Data Safety and Monitoring Board (DSMB) 
Please see the attached Data and Safety Monitoring Plan for further details. 
7.4.3.1 Data Safety Monitoring Board (if applicable) 
 
A safety monitoring board has been established at the Center for the Studies of Addiction with 
the following purpose (according to NIDA guidelines): to assure that the safety of study subjects 
is protected while the scientific goals of the ongoing studies are being met. Specifically, the 
DSMB is charged with monitoring the safety of participants and the quality of the data, as well 
as the appropriate termination of studies either when significant benefits or risks have been 
uncovered or when it appears that a clinical trial cannot be concluded successfully. The board is 
chaired by James McKay Ph.D. a faculty member within the Department of Psychiatry at the 
University of Pennsylvania. Other members of the board include Kevin Lynch, Ph.D. (senior 
statistician), David Metzger, Ph.D., Deborah Dunbar, MSN, CRNP and Cynthia Clark Ph.D. 
CRNP who are faculty members or staff of the University of Pennsylvania School of Medicine.  
 
When the current study is reviewed, Dr. Curtis will open the meeting with a report on the trial 
status, followed by a closed session under the direction of  Daniel Langleben, MD who will stand 
in for Dr. McKay who is in conflict for this project. In addition, Ian Barnett, PhD (biostatistician) 
will stand in for Kevin Lynch, PhD who is in conflict for this project. Issues related to recruitment, 
subject safety and efficacy, whether the primary study question is being answered, conflict of 
interest, confidentiality, and ongoing study review (including AEs, SAEs, and regulatory issues) 
are assessed. Following each DSMB meeting, The designated member standing in for the Chair 
will make recommendations to Dr. Curtis, and a final report (edited by all Board members not in 
conflict with this project) will be prepared and submitted to NIDA, the Penn IRB, and (if required) 
the FDA according to each bodies reporting requirements. 
 
The board meets every six months (unless more frequent meeting are deemed necessary). 
Safety data will be reviewed by the Data Safety Monitoring Board every six months. A Data 
Safety Monitoring Board report will be issued to the NIDA project officer with the annual 
progress report. 
8 
Study Administration, Data Handling and Record Keeping 
8.1 
Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  

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• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
 
The study has a Confidentiality Certificate. 
 
 
8.2 
Data Collection and Management  
. 
 
Data will be collected by trained study staff with standardized forms using only a study number 
and initials to identify the participant.  A code that links the participant to the study will be kept 
confidential by the study team in a password protected secure database.  The clinical research 
coordinator and fellow staff members will be responsible for collecting and checking all clinical 
data.  This includes ensuring that all fields are completed appropriately, that the clinical 
database is complete and accurate and all corrections are done according to GCPs.  Any 
inconsistencies/deviations will be documented and reviewed by the PI.   
 
All data collection is HIPAA compliant. The CSA supports the appropriate privacy of all clinical 
and research data collected as part of any study. We follow Penn’s policy in the use and 
disclosure of protected health information in research in a manner that respects the patient’s 
privacy in accordance with the “Privacy Rule” promulgated under the Health Insurance 
Portability and Accountability Act (HIPAA) and other applicable laws.  All staff receive 
appropriate HIPAA training.  All participants sign a Combined Informed Consent and HIPAA-
authorization form, receive a copy of this form, and receive a notice of Penn’s privacy practice.  
Combined Informed Consent and HIPAA Authorization signed forms are retained in locked file 
cabinets with participants’ source documents.  
 
A computerized data entry and management system will be developed during the initial project 
months by the Center’s data management unit (DMU).  All data will be entered into this web-
based entry system by the research staff or study participants (self-assessments only).   
 
A closed and password protected data entry system has been designed so that only the 
responsible data entry person and the DMU supervisor can enter and/or edit data and this can 
be done only be using the programs and/or utilities available on the menu system.  Data and 
user stamping are used to create an audit trail. Range checks, review screens, and various 
error trapping routines are built into the system as quality control procedures.  All possible 
relevant information on the forms is pre-coded and field-validated.  All specific instructions and 
choices are provided for all data forms. All errors on source documents must be initialed and 
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integrity of the data entry process. The investigator or study research staff can request the data 
at any point during the study so that audits of the study’s current data input can be conducted 
and the data’s integrity assessed. 
 
8.3 
Records Retention 
 
After entry of all data in the Case Report Forms, these source documents will be kept on 
location until study closeout at which point they may be moved to a secure long-term storage 
facility. 
9 
Study Monitoring, Auditing, and Inspecting 
9.1 
Study Monitoring Plan 
 
One primary monitor will be assigned for this trial and will be responsible to complete the 
monitoring process.  The monitor will be a Research Coordinator who is independent from the 
trial and the study team.  A CV for the monitor will be obtained and updated annually.  The CV 
will be kept on file in the Sponsor section of the Regulatory Binder to document the 
qualifications of the monitor. To train the independent Monitor, the Principal Investigator and the 
Research Coordinator actively overseeing this trial will schedule a monitoring training session to 
discuss the protocol, case report forms, the informed consent, and the monitoring plan. In 
addition a monitoring manual will be created, which includes the complete protocol with the 
approved informed consent form, approved CRF, and this monitoring plan. 
 
Enrollment will be complete when 40 subjects are enrolled into the trial.  Enrollment for this 
study means when a participant is found to be eligible and is started on the study medication. 
Approximately 2 subjects will be enrolled per month.  After the study initiation visit, further 
monitoring visits will be conducted periodically throughout the study as described below.  (Note: 
The specific data to be reviewed at each visit is indicated in section 7.3.2) 
 
• 
The first independent monitoring visit will occur when the first two subjects have completed 
the study. 
• 
The second independent monitoring visit will occur when 25% of the subjects have been 
enrolled.   
• 
A third independent monitoring visit will be conducted when approximately 50% of the 
subjects have been enrolled.   
• 
A fourth independent monitoring visit will be conducted after 100% of the subjects have 
been enrolled.  This visit may be conducted after the subjects have completed the study and 
can also serve as the close-out monitoring visit 
9.2 
Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents.  The investigator will ensure the capability for inspections 
of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). Please see 
DSMP for additional info. 
 
 

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10 Ethical Considerations 
 
This study is to be conducted in accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies 
and procedures. 
 
This protocol and any amendments will be submitted to the Penn Institutional Review Board 
(IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  The 
decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the sponsor before commencement 
of this study.  
 
10.1 
Risks 
 
The potential risks of this study include adverse reactions to the study medications, potential 
adverse interactions between the study medication and opiates, discomfort due to the interview 
process, risk of breach of confidentiality, and the small risk incurred by venipuncture.  
 
Buprenorphine: Buprenorphine is a safe and well-tolerated medication FDA approved for the 
treatment of opiate dependence  
Common side effects are categorized below: 
Adverse events commonly observed with the sublingual administration of 
buprenorphine sublingual film are  
o oral hypoesthesia 
o glossodynia 
o oral mucosal erythema 
o headache 
o nausea 
o vomiting 
o hyperhidrosis 
o constipation 
o signs and symptoms of withdrawal 
o insomnia 
o pain 
o peripheral edema 
To help minimize these risks subjects are asked about AEs at each study visit.  Any reported 
AEs are assessed by the Nurse Practitioner or Medical Director and followed until resolution.  
 
10.2 
Benefits 
Subjects will benefit from receiving Suboxone for their Opiate Use Disorder. They will benefit 
from close medical and psychiatric attention over and above that which they will receive in an 
intensive outpatient treatment program and the potential personal improvements in health 
resulting from a diminished desire for- and reduced-use or abstinence from opioid.  The indirect 
benefits are the potential benefits to society to include decreased opioid use with a resultant 
decrease in opioid morbidity and mortality, as well as a reduction in the overall societal cost of 
opioid dependence. 
 

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10.3 
Risk Benefit Assessment 
 
The risks of participating in the study are outweighed by the potential benefits of participating in 
the study.  
10.4 
Informed Consent Process / HIPAA Authorization  
 
Most of the TRC callers seeking treatment who are approved for intake (via center IRB-
approved phone pre-screen) come in to consent to the General Screening Consent (Protocol 
#701074) for an intake appointment to review general medical and psychosocial criteria prior to 
consenting to a specific study 
All subjects for this study will be provided a combined informed consent/HIPAA Authorization 
form describing this study providing sufficient information for subjects to make an informed 
decision about their participation in this study.  This consent form will be submitted with the 
protocol for review and approval by the IRB for the study.  The formal consent of a subject, 
using the IRB-approved consent form, must be obtained before that subject undergoes any 
study procedure.  The subject, or legally acceptable surrogate, must sign the consent form, and 
the investigator-designated research professional obtaining the consent. Subjects will be 
consented by the study Principal Investigator, or appropriate designee, in a private room we 
have selected in which to perform consent. Potential subjects will review the consent form in 
detail with the person designated to consent (either PI or CRC or Research Tech) and have the 
ability to take the consent home for further review. Subjects will be provided the opportunity to 
ask all of their questions prior to signing the consent form. Subjects will not be enrolled in the 
study until they successfully pass a “quiz” about the content of the informed consent. 
 
10.4.1 Alterations to Typical Consent Process (only include if applicable)  
Not applicable 
10.4.1.1 
Waiver of Consent (In some cases for screening/portions of that 
study that qualify as minimal risk, a waiver of documentation of consent 
may be permissible IRB SOP) 
Not applicable 
10.4.1.2 
Waiver of Written Documentation of Consent 
 
Not applicable 
 
10.4.1.3 
Waiver of HIPAA Authorization  
 
Not applicable 
 
 

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11 Study Finances 
11.1 
Funding Source 
 
This study is financed through a grant from the National Institutes of Health/ National Institute on 
Drug Abuse (NIDA). 
11.2 
Conflict of Interest 
 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on 
Conflicts of Interest Related to Research.  
11.3 
Subject Stipends or Payments 
 
Participants will be reimbursed $15 for the time and effort needed to complete the baseline 
assessment. For each in-office visit, participants will be reimbursed $20 for their participation 
including travel ($5). The total possible compensation for a subject who complete all visits is 
$555. As required by Perelman School of Medicine all reimbursements will be done with 
ClinCards which can be used as to obtain cash and as debit or credit cards. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12 References 
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13 Appendices  
 
Table 1: Assessment Schedule 
Assessment 
Baseline 
(V1) 
Week 
2 (V2-
V4) 
Weeks 3-14 
(V5-V28) 
End of 
Study 
(V29) 
Medical Exam and EKG, CBC and blood chemistry, 
Urinalysis (UA), Risk Assessment Battery 
1X 
 
 
1X 
Pregnancy Test (women), Addiction Severity Index 
(ASI) 
1X 
 
2X, weeks 5 
and 9 
1X 
Urine Toxicology and Urine Buprenorphine and 
Norbuprenorphine Screen, Timeline Follow back 
(TLFB) 
1X 
 
24X 
1X 
Clinical Global Impression Scale (CGI), Hamilton 
Depression Rating Scale (HAM-D) 
1X 
 
1X, week 9 
1X 
Columbia Suicide Severity Rating Scale (C-SSRS), 
Obsessive Compulsive Drug Use Scale (OCDUS) 
1X 
 
12X 
 
Systems Usability Scale (SUS) 
 
 
 
1X 
Concomitant Medications 
1X 
3X 
24X 
1X 
Medical Management, Pill Distribution 
 
3X 
12X 
 
Adverse Events 
 
3X 
24X 
1X 
Video Compliance/Attention Control (7 days per 
week, weeks 3-14) 
 
 
84X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 2: Study Schedule 
 
 
Baseline
1
1
2
2
2
3
2
4
3
5
3
6
4
7
4
8
5
9
5
10
6
11
6
12
7
13
7
14
8
15
8
16
9
17
9
18
10 
19
10 
20
11 
21
11 
22
12 
23
12 
24
13 
25
13 
26
14 
27
14 
28
EOS
15 
29
Visit 
Number
Study Phase
Study 
Week
Induction Phase
Medication Phase