Conditions: Opioid-use Disorder Overdose
Keywords: opiate use disorder overdose medication assisted treatment
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 104
Healthy volunteers: no

Brief summary:
The proposed research will evaluate the ability of a mobile, rapid induction procedure to engage individuals in ongoing medication assisted treatment. A total of 250 untreated individuals meeting criteria for opioid use disorder and at high risk of opioid overdose will be enrolled in the study. Recruitment will take place in two targeted neighborhoods of Philadelphia (Kensington and South Philadelphia) with a high prevalence of fatal and non-fatal opioid overdose. A total of 250 participants will be engaged in the research. Following informed consent and determination of eligibility, 125 individuals will be enrolled as they engage with the mobile, rapid induction team and 125 individuals will be enrolled as they seek treatment from the CRC Episcopal Hospital (serving Kensington area) or BAC/CRC Hall Mercer Community Mental Health (serving South Philadelphia). The intervention group will receive four weeks of treatment with buprenorphine /naloxone and support for treatment engagement provided by a case manager and a peer recovery specialist. All participants will be assessed at baseline and then 1- and 6-month following enrollment. The primary endpoint for the study is continued enrollment in medication-assisted treatment at 6-month post-enrollment.

The proposed research will evaluate the ability of a mobile, rapid induction procedure to engage individuals in ongoing medication assisted treatment.

The specific aims are:

* Aim 1: To evaluate the impact of the mobile, transitional MAT intervention on its ability to engage participants in targeted, existing MAT treatment slots at 1- and 6-month post-enrollment.
* Aim 2: To evaluate the impact of the mobile intervention on subsequent drug use and overdoses at 6-month post-enrollment.
* Aim 3: To assess the acceptability and costs of the intervention. The program and patient costs of delivering and participating in the intervention will be documented.

Detailed description:
1. Study Objectives Aim 1: To evaluate the impact of the mobile, transitional MAT intervention on its ability to engage participants in targeted, existing MAT treatment slots at 1- and 6-month post-enrollment.

   Aim 2: To evaluate the impact of the mobile intervention on subsequent drug use and overdoses at 6-month post-enrollment.

   Aim 3: To assess the acceptability and costs of the intervention. The program and patient costs of delivering and participating in the intervention will be documented.

   Study participants who will receive buprenorphine/naloxone will be provided with information, counseling, and support for selection of ongoing treatment options including methadone maintenance (MMT), extended-release naltrexone (XR-NTX), or continued treatment with buprenorphine/naloxone.
2. Study design Duration of Study Participation The duration of study participation including screening/baseline assessments to follow-up will be 6 months.

   Total Number of Subjects A total of 250 participants will be engaged in the research at the time they seek treatment: 125 individuals will be enrolled as they engage with the mobile, rapid induction team and 125 individuals will be enrolled as they seek treatment from the BAC/CRC (treatment as usual).

   Subject Recruitment The recruitment of participants for this study will be accomplished using a community awareness campaign involving street outreach, targeted social media, and local advertisement. This campaign will begin one month before activation of the rapid induction intervention. During this time, the mobile assessment team will begin to be present in the designated location where the Mobile Clinical Trials Unit (MCTU) will be parked.

   Participant Education and the Informed Consent Process Potential participants who express interest in initiating treatment will be engaged in a structured approach to education about the study and its procedures. The information delivered at this point will be supportive and motivational and describe study participation as an opportunity to consider options for treatment. It will also be explained that their participation can contribute to a better understanding of the most effective ways to assist individuals who want to begin treatment. Staff will make it clear that even if they do not become engaged in treatment, their experiences are important and their contributions to the research will be valuable. This discussion will offer potential participants a chance to ask questions and receive prepared materials explaining the study and the requirements for participation.

   Those who appear to be eligible and express interest will begin the informed consent process to allow for screening. The informed consent process will give the participant an accurate understanding of the research procedures and make it clear that participation is voluntary. The informed consent document will be read and reviewed with the participant. The consent form includes clear language with special attention to the provision of permissions to contact the participant and individuals they identify as acceptable contacts if the research assistants are unable to make direct contact with the participant for the 1- and 6-month assessments.

   Screening assessments For those who remain interested following discussions and appear to meet eligibility criteria, the consent form will be signed and the screening visit will be conducted. This visit will include completion of assessments to confirm inclusion and exclusion criteria. The Nurse Practitioner will complete a medical history, a physical exam, a rapid blood test for HIV, a pregnancy test for women, and collect 10ml of blood for liver function tests. Research staff will complete baseline assessments. Those who are not eligible will receive a listing of treatment providers and encouraged to make contact for help with their substance use problems. For those who appear eligible following the screening visit, an appointment for initiating the intervention will be scheduled within 1 or 2 days.

   Study Measures All interviews will be administered by experienced research assistants trained in the administration of the proposed assessments. Following confirmation of eligibility, the mobile research assistants will complete the baseline assessment (described below). The participant assessments in this research will be sharply focused on the valid and reliable measurement of its primary endpoints i.e. ongoing treatment engagement will be the primary endpoint on which the study is powered. The two groups will be compared with respect to the rate of continued opioid use and subsequent overdoses. All assessments will be completed by trained research staff (not clinicians) at baseline, and again at 1- and 6-month post-enrollment. A follow-up rates of 95% and 90% at Month 1 and 6, respectively is anticipated. The assessments will take approximately 45 minutes to complete.
   * Physical history and examination including a blood test to evaluate the liver function.
   * Locator Data Collection: A detailed contact sheet (Locator Form) will be completed for all subjects as part of the baseline assessment. The form will be updated at each scheduled assessment visit.
   * DSM-5 Substance Use Disorder Checklist: This form is a listing of the eleven DSM-5 criteria for substance use disorder. Opioids, cocaine, and alcohol use disorders will be screened for confirmation of inclusion and exclusion criteria. A score of 4-6 is considered moderate severity and from 7-11 is considered severe substance use disorder. An opioid use disorder score of 4 or greater will be required for study eligibility. Alcohol use disorder and benzodiazepine scores of 4 or greater will be exclusionary.
   * A study specific questionnaire that gathers socio-demographic information (e.g. age, gender, race and ethnic identity, marital status, sexual orientation, educational level, employment status, income and income sources) and descriptive information about the subject's living situation and housing stability, history of involvement with the criminal justice system, drug use, and drug treatment history.

     o Addiction Severity Index (ASI) sections for Drugs and Alcohol and Medical Status: The ASI is a structured interview developed to assess the range of problems seen in drug users. The ASI produces severity ratings and composite scores in each of seven areas, and each type score has been assessed with regard to validity and reliability. Severity ratings and composite scores have demonstrated high levels of inter-rater, test-retest, and concurrent reliability (Cacciola et al., 2008; McLellan, Cacciola, Alterman, Rikoon, \& Carise, 2006; McLellan et al., 1992). The Medical and the Drug and Alcohol sections will be administered at baseline, 1- and 6-month follow-ups.
   * Patient Health Questionnaire (PHQ-9): Given the important role of depression in accessing and adhering to treatments for substance use disorder and other chronic medical problems (Mahajan, Avasthi, Grover, \& Chawla, 2014; Tavakkoli, Ferrando, Rabkin, Marks, \& Talal, 2013), the severity of depression using the 9-item Patient Health Questionnaire (PHQ-9) will be assessed. This brief assessment asks participants to indicate the frequency of occurrence of each of the nine DSM-IV diagnostic criteria for depression during the previous two weeks. This instrument has been widely used in clinical research and has strong psychometric properties. The PHQ-9 will be completed at baseline and month-1 and -6.
   * Urine drug screen using the CLIA waived® ACON Dip-and-Read 8-panel test for THC, cocaine, opiates, amphetamines, PCP, methamphetamine, benzodiazepines, barbiturates, and buprenorphine. The urine sample will be provided using standard procedures with temperature monitoring to preclude tampering and dilution.
   * HIV testing: Chembio SURE CHECK HIV 1/2® rapid-HIV test kits will be used to detect antibodies. These FDA approved and CLIA Waived kits produce results in 15 minutes from a blood drop. For those who test antibody positive, additional blood will be drawn for confirmatory testing via RNA viral load assay. Approximately 10% of participants will test positive for HIV.
   * Economic evaluation: The cost-effectiveness of the intervention will be performed using data collected with questionnaires widely used for cost-effectiveness analyses, the Drug Abuse Treatment Cost Analysis Program (DATCAP) and Non-Medical and Other Services Form (NSMOS). The DATCAP is a reliable instrument widely used by substance abuse treatment programs for the collection and organization of programmatic costs (French et al. 1997). The NSMOS is a questionnaire adapted from the Treatment Services Review (McLellan et al., 1992; Cacciola et al., 2008 ) for individuals receiving substance abuse treatment.

   Overview of Interventions Rapid Induction Intervention (RI) The rapid induction intervention will be delivered by the project's mobile team led by a nurse practitioner supported by a certified peer recovery specialist (CPRS), and a case manager (CM). Team members will work closely with each other and coordinate screening and treatment initiation, medication adherence monitoring, and assessment and linkage to ongoing MAT. Two half-time research assistants (RA) will participate as team members but will have intervention responsibilities. The RAs will assist with the community awareness campaign and recruitment and will conduct all assessments for the project. The mobile team will be based at Prevention Point Philadelphia and will receive clinical supervision from the mobile team's buprenorphine physician.

   Induction: Once eligibility has been determined, the NP will begin preparing the participant for induction, following the buprenorphine/naloxone induction protocol used by D'Onofrio et al., 2015.

   Medication Assisted Treatment (MAT) engagement during the month of intervention will be facilitated by the Peer Recovery Specialist (PRS). The purpose of a PRS is to support the participant in their recovery process. In addition, the project will provide intensive training and ongoing consultation on MAT. The PRS hired for this study will also receive intensive training focused on addiction as a chronic medical condition, motivational enhancement strategies and facilitating short-term behavioral contracts. The PRS will meet with the participant a minimum of 3 times per week and be available for telephone counseling and support throughout the one-month intervention period.

   The mobile team's Case Management (CM) function will be performed by a master's level social worker. The CM will have primary responsibility for identifying the treatment program that best meets the needs of the participant. The CM effort will be sharply focused on identifying and removing barriers to MAT treatment engagement. This will include completing medication authorization forms and insurance enrollment if necessary, and then making referrals to additional supports, including mental health treatment, housing, medical, legal support, and peer-based recovery supports in the community. The CM will work collaboratively with participants to remove barriers to care and to enhance program outcomes and to provide psychosocial support.

   The mobile team will insure that there is a clear plan for rapid engagement with ongoing treatment as soon as possible. Buprenorphine/naloxone will be provided during the time of transition to their long-term provider for up to 1 month. Telephone support will be available should participants have questions or need assistance and the mobile team will also have daily contact with participants until they complete contact with their ongoing provider.

   Comparison group - Treatment as usual During the same period of time, participants will also be recruited at the City of Philadelphia Behavioral Health System Behavioral Assessment Centers (BAC) and Crisis Response Centers (CRC) located at Episcopal Hospital serving Kensington area and Hall Mercer BAC/CRC (a University of Pennsylvania program) serving South Philadelphia area. Two research assistants from the TRI-PHMC will enroll and follow-up 125 participants at BAC/ CRC. The participants will complete the same assessments at baseline, 1- and 6-month follow-up. Authorization for the Philadelphia Department of Public Health to look shared information about their subsequent use of health department services (CARES database, http://www.phila.gov/hhs/data/Pages/Cares.aspx) will also be requested in the consent form. Research staff will only conduct assessments. Treatment engagement services will be provided by the staff of the BAC/CRC as usual.

   Subject Withdrawal Participants may choose to withdraw from the study at any time. They do this by providing verbal or written communication to this effect. Withdrawal from the study will not impact access to care. The Principal Investigator may withdraw subjects for reasons related to safety or for administrative reasons. It will be documented whether or not each subject completes the study. Subjects who do not complete the intervention will continue to be contacted to complete follow-up visits (Month 1 and 6) to collect final evaluations and to assess adverse events.
3. Statistical Plan 3.1. Data Quality Trained staff will review all forms prior to the completion of the study visit in an effort to minimize problems associated with missing values and incorrect skip patterns. All assessments will be recorded on final version of the electronic Case Reporting Forms (eCRFs). eCRFs will also be developed to capture the results of all biological assessments. All eCRFs will be completed using only participant identifying numbers and will not include names, addresses, or other data that could possibly be used to disclose the identity of the participant. Research staff will be responsible for entering all data into the secure web-based developed on REDCap (Research Electronic Data Capture). REDCap is designed to comply with HIPAA regulations. Data will be input with secure web authentication, data logging, and Secure Sockets Layer (SSL) encryption. REDCap allows multisite access. It allows real-time data entry validation (e.g. for data types and range checks), audit trails, and the ability to set up a calendar to schedule and track critical study events such as participant visits.

   The data quality control process associated with data processing will consist of the following stages: potential subject pre-screening for eligibility, registration, subject eligibility confirmation, first data entry, second data entry in the form of 100% interactive verification, data validation, and data auditing. A random 5% of the questionnaires in each wave of data collection (i.e., baseline, 1- and 6-month) will be subjected to database auditing throughout the trial. This data quality control process ensures that all stages of the data handling process will be subjected to data quality control.

   3.2. Data analyses Propensity score model to account for non-randomized allocation: The participants are not randomly assigned to the mobile rapid induction intervention and BAC/CRC groups, so it is possible that there will be confounding of the group effect with the effects of characteristics of the participants. Propensity score approach (Rosenbaum 2002, Rothman, Greenland et al. 2008) will be used to account for this. A broad range of baseline variables will be entered as covariates in a logistic regression model predicting treatment group, including age, race/ethnicity, gender, number of previous overdoses, number of previous treatments for opiate use disorder, type of opioid used, and depression. The model will yield predicted probabilities of BAC/CRC group for all participants (the propensity score), and a five-level ordinal variable based on the quintiles of the propensity score will be created. This ordinal variable will be included as a stratum variable in our models.

   Analyses for the primary aim: i.e. to evaluate the impact of the mobile, transitional MAT intervention on its ability to engage participants in targeted, existing MAT treatment slots at 1- and 6-month post-enrollment. For each of the 1- and 6-month time points, the participants will be classified as being engaged/not-engaged (where non-engaged will include dropped out or missing). The groups will be compared on engagement rates at the two time points using a repeated measures logistic regression model, incorporating the propensity score as described above (Diggle, Heagerty et al. 2002). The fixed effects will be binary indicators of treatment group and time point; test for a group by time interaction to assess whether the group effect differs at month 1 and month 6. As there are only two time points, the use an unstructured covariance matrix to accommodate within-participant covariance.

   Analyses for Aim 2: Repeated measures model will be run to compare the groups on the ASI (addiction severity index) drug composite score at month-1 and 6. The model will be similar to that described for the engagement analyses of Aim 1, but with a beta distribution assumed for the response, to accommodate the bounded range (zero to one) of the ASI composite scores. The groups will be compared on the number of overdoses per participants using repeated measures Poisson regression models, if there is sufficient variability in the number of overdoses reported. If a low rate of overdoses causes convergence issues for the Poisson model, participants will be classified as having no overdose versus at least one, and compare the groups using repeated measures logistic regression models.

   Missing data. For the longitudinal analyses described above, premature discontinuation from treatment and occasional missing daily use indicators will lead to incomplete data. The repeated measures models described above can make use of all available data provided by subjects, but the inferences drawn from them will be unaffected by the missing data only if the missing data can be regarded as ignorable, essentially meaning that missingness can be predicted/explained from the baseline data and from responses obtained prior to drop-out. The sensitivity of our main analyses to the presence of missing data will be assessed by performing a sensitivity analysis, in which estimates of the group effect will be obtained under various non-ignorability assumptions. Selection models will be used to examine the effects of missing data (Robins, Rotnitzky et al. 1995), in which the probability of premature discontinuation at a time point as a function of baseline characteristics and responses at previous time points will be modeled using logistic regression models, and incorporate the predicted probabilities into a weighted analysis of the main hypotheses.

   Analyses for Aim 3: The total costs and per-participant costs of rapid initiation of MAT for opioid treatment engagement will be estimated using a cost-offsets approach to determine the economic value of this novel strategy. A cost-offsets approach requires a comparison of the total cost of the intervention (proposed enhanced procedure or treatment as usual) to the future costs of healthcare utilization avoided (i.e., benefits) due to the intervention. Healthcare utilization and medical costs will be estimated before and after participants receive either rapid initiation of MAT for opioid treatment engagement or treatment as usual. Information on healthcare utilization will be collected from participants at each assessment when study-staff administer the Non-Medical and Other Services Form (NSMOS; detailed description in Instruments section). Medical costs associated with these treatments/services will be estimated using Medicaid data.
4. Safety and Adverse Events 4.1. Data Safety Monitoring Plan (DSMP) For this study, the University of Pennsylvania established procedures and infrastructure for data and safety monitoring will be used. During the course of the study, safety and data quality monitoring will be performed on an ongoing basis by the Principal Investigators and the study staff. Study staff members are responsible for collecting and recording all clinical data using the established MOP. This includes ensuring that all source documents exist for the data on the Case Report Forms, ensuring all fields are completed appropriately, and ensuring that all corrections are done according to Good Clinical Practice (GCP). Any inconsistencies/deviations will be documented. The study Key Personnel will review data on an ongoing basis and will document reviews by initialing and dating reports. Study staff members conduct 100% quality assurance on data.

Staff training will consist of an explanation of the protocol and review of the e-Case Report Forms. In addition, the duties of each staff person will be outlined and all applicable regulations will be reviewed. Senior personnel will supervise junior staff and provide re-training in the study protocol as needed.

The Independent Monitor for this study is the University of Pennsylvania Center for Studies on Addiction DSMB. The DSMB will review the study every 6 months for all the duration of the study. The DSMB form could be find in Appendix at the end of this document. The PI will provide a summary of the status of the project that occurs during the reporting period. These data will also be reported to CDC on an annual basis as part of the progress report. The DSMB report will include the participants' socio-demographic characteristics, expected versus actual recruitment rates, treatment retention rates, any quality assurance or regulatory issues that occurred during the past year, summary of SAEs, and any actions or changes with respect to the protocol.

4.2. Adverse Events Adverse events that occur at any point in the trial will be identified, managed, and documented in accordance with reporting requirements of the the City IRB (the IRB of record) and the sponsor (the CDC). Adverse events are defined as negative biologic events and/or social harms that occur during the course of the trial. When needed, referrals to medical treatment or specialists will be made. All patients will have comprehensive psychiatric and medical screening prior to randomization and at each counseling and assessment where evaluations for AEs will be routine. A member of the research team will be available at all times to answer questions and assess possible AEs. Participants will be withdrawn from the study if they show severe deterioration or if determined clinically necessary for other reasons.

4.3 Internal Monitoring and Auditing

Oversight and Monitoring: The City of Philadelphia IRB will monitor the protection of human subjects and the safe and secure collection and storage of data. This committee assesses all studies before study initiation and then reviews protocols annually. The committee ensures the scientific, technical, and statistical soundness of the research and guarantees that methods for the ethical and safe treatment of human subjects are in place. The committee scrutinizes the scientific and ethical aspects of protocols and provides for an objective and ongoing assessment of the study's scientific and ethical integrity.

Protocol monitoring will ensure that the research protocol specified is being followed without unauthorized deviations. Weekly meetings will be held to monitor the progress of the trial. These meetings will involve the Principal Investigators, Co-Investigators, Project Director, Site coordinator and other study staff. This will help to ensure standardized application of the protocol and will serve as an ongoing mechanism by which project staff and investigators will communicate in order to maintain a consistently high quality of study conduct. Concerns identified will be addressed through training and retraining of personnel.

Database Auditing: Project director and RAs will review data entered into the database versus that recorded on the CRFs. All accrued cases will be subjected to database auditing throughout the duration of the trial. Depending on the data management findings, re-training will be provided, should problems such as increased errors be detected.

Data Auditing: Project director and staff RAs will review safety data recorded on the CRF versus that contained on the actual source document (client chart, EHR). All accrued cases will be subjected to auditing throughout the duration of the trial. A Regulatory Binder Review by OHR will include the following essential documents: IRB Protocol, Consent Form and Amendment Approvals, IRB Closure Letter, List of Authorized Signatures, Laboratory Certifications, Protocol and Amendment Signature Pages, Financial Disclosure Questionnaires, and Monitoring Log. Additional monitoring by OHR may include: source documentation verification; adverse event documentation; and facility assessment.

Data Security: Using network firewall technologies, the database will prevent the three major sources of data security problems: unauthorized internal access to data, external access to data, and malicious intent to destroy data and systems. Controlled user access will ensure that only appropriate and authorized personnel are able to view, access, and modify trial data. All modifications to data will document user access and data associated with the modification, as well as values prior to modification.

Evidence of Training in Human Subject Research: All personnel working on this project will be required to review the protocol, complete training in the protection of human subjects and undergo training.

Confidentiality Since self-report and medical data will be collected and stored as part of this study, it is possible that subject privacy or confidentiality can be threatened. To address this concern, the Data Management System has set up several safeguards to prevent unauthorized access to study data. An automatically generated index number is assigned to a subject's study identification number (unique for personnel and clients). A linked subject identification table is created for the storing of subject name, address and telephone contact information. This table uses the automatically generated index number rather than the study identification number. The master subject map and subject identification information tables are maintained in a separate database. Using this method, no identifying subject information is directly linked to medical information or other study data. The present research team has not experienced the unauthorized use of study data. A web-based data collection procedure will minimize the possibility of loss of privacy or confidentiality. The risk of a potential breach of confidentiality is addressed in the informed consent documents.

Computers and Databases Trained staff will review all forms prior to the completion of the study visit in an effort to minimize problems associated with missing values and incorrect skip patterns. All assessments will be recorded on final version of the electronic Case Reporting Forms (eCRFs). eCRFs will also be developed to capture the results of all biological assessments. All eCRFs will be completed using only participant identifying numbers and will not include names, addresses, or other data that could possibly be used to disclose the identity of the participant. Research staff will be responsible for entering all data into the secure web-based developed on REDCap (Research Electronic Data Capture). REDCap is designed to comply with HIPAA regulations. Data will be input with secure web authentication, data logging, and Secure Sockets Layer (SSL) encryption. REDCap allows multisite access. It allows real-time data entry validation (e.g. for data types and range checks), audit trails, and the ability to set up a calendar to schedule and track critical study events such as participant visits.

Arms:
arm 1: Rapid initiation of buprenorphine/naloxone, counseling, peer support and case management arm 2: Seeking treatment from the BAC/CRC (treatment as usual)

Interventions: intervention 1: buprenorphine/naloxone
Intervention descriptions: intervention 1: A mobile team will be led by a nurse practitioner (able to prescribe buprenorphine/naloxone in PA) and include a peer recovery specialist (PRS), and a case manager. The team will rapidly confirm opioid use disorder and risk of overdose, complete informed consent, and begin induction procedures for a "transitional" (one month) course of buprenorphine/naloxone treatment. During this time, the dedicated case manager and PRS will work with the participants to help them become engaged in existing medication assisted treatment programs

Protocol document:
Prot_SAP_000.pdf: 
Rapid initiation of BUP/NX 
 
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Rapid initiation of buprenorphine/naloxone to optimize MAT utilization in Philadelphia 
 
 
Principal Investigator  
Dr. David S. Metzger 
Department of Psychiatry  
HIV Prevention Research Division 
3535 Market Street, Suite 4000, Philadelphia, PA 19104 
Phone: 215-746-7346 
Email: dsm@pennmedicine.upenn.edu 
Regulatory Sponsor 
 
Center for Disease Control and Prevention 
 
Funding Sponsor 
 
Center for Disease Control and Prevention 
CDC Grant Number 
 
1 R01 CE003049-01 
 
 
Initial version 
V1: NOV-15-2018 


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TABLE OF CONTENTS 
1 
STUDY SUMMARY 
4 
2 
INTRODUCTION 
6 
2.1 
RESPONSES TO THE EPIDEMIC 
6 
2.2 
MEDICATION ASSISTED TREATMENT 
7 
2.3 
INTERVENTIONS TO INCREASE UTILIZATION OF EXISTING MAT 
8 
2.4 
MAT ENGAGEMENT IN PHILADELPHIA 
8 
3 
THE PROPOSED STUDY 
8 
3.1 
PROJECT OVERVIEW 
8 
3.2 
INNOVATION 
9 
3.3 
COLLABORATIONS 
9 
3.4 
STUDY OBJECTIVES 
11 
3.5 
RATIONALE FOR STUDY DESIGN 
11 
3.5.1 
Why no Randomization? 
11 
3.5.2 
Why buprenorphine/naloxone for rapid treatment initiation? 
11 
3.6 
STUDY TIMELINE 
12 
3.7 
STUDY MEASURES 
12 
3.8 
STUDY ENDPOINTS 
14 
3.8.1 
Primary end-point 
14 
3.8.2 
Secondary Study Endpoints 
14 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION 
14 
4.1 
DURATION OF STUDY PARTICIPATION 
14 
4.2 
TOTAL NUMBER OF SUBJECTS 
14 
4.3 
INCLUSION CRITERIA 
15 
4.4 
EXCLUSION CRITERIA 
15 
4.5 
SUBJECT RECRUITMENT 
15 
4.6 
VULNERABLE POPULATIONS 
16 
4.7 
STUDY PROCEDURES 
16 
4.8 
PARTICIPANT SCREENING 
16 
4.8.1 
Subject recruitment 
16 
4.8.2 
Participant Education and the Informed Consent Process 
17 
4.8.3 
Screening assessments 
17 
4.9 
STUDY INTERVENTION PHASE 
17 
4.9.1 
Overview of Interventions 
17 
4.10 
SUBJECT WITHDRAWAL 
19 
5 
STATISTICAL PLAN 
19 
5.1 
DATA QUALITY 
19 
5.2 
SAMPLE SIZE AND POWER DETERMINATION 
19 
5.3 
STATISTICAL METHODS 
20 
6 
SAFETY AND ADVERSE EVENTS 
21 
6.1 
DATA SAFETY MONITORING PLAN (DSMP) 
21 
6.2 
ADVERSE EVENTS 
21 
6.3 
INTERNAL MONITORING AND AUDITING 
22 
7 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING 
23 
7.1 
CONFIDENTIALITY 
23 
7.2 
SOURCES OF RESEARCH MATERIAL 
23 
7.3 
COMPUTERS AND DATABASES 
23 
8 
ETHICAL CONSIDERATIONS 
23 
8.1 
RISKS 
23 
8.2 
RISK MINIMIZATION 
24 
8.3 
BENEFITS 
24 


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8.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION 
24 
9 
RESOURCES NECESSARY FOR HUMAN RESEARCH PROTECTION 
25 
9.1 
QUALIFICATIONS OF PRINCIPAL INVESTIGATOR 
25 
9.2 
RESEARCH STAFF 
26 
10 
STUDY FINANCES 
26 
10.1 
FUNDING SOURCE 
26 
10.2 
CONFLICT OF INTEREST 
26 
10.3 
SUBJECT COMPENSATION 
27 
11 
PUBLICATION PLAN 
27 
12 
REFERENCES 
28 
 


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1 
Study Summary 
 
Title 
Rapid initiation of buprenorphine/naloxone to optimize MAT utilization in Philadelphia 
 
Short Title 
Rapid initiation of BUP/NX  
Study overview 
The proposed research will evaluate the ability of a mobile, rapid induction procedure to 
engage individuals in ongoing medication assisted treatment. A total of 250 untreated 
individuals meeting criteria for opioid use disorder and at high risk of opioid overdose will be 
enrolled in the study. Recruitment will take place in two targeted neighborhoods of 
Philadelphia (Kensington and South Philadelphia) with a high prevalence of fatal and non-
fatal opioid overdose. A total of 250 participants will be engaged in the research. Following 
informed consent and determination of eligibility, 125 individuals will be enrolled as they 
engage with the mobile, rapid induction team and 125 individuals will be enrolled as they 
seek treatment from the CRC Episcopal Hospital (serving Kensington area) or BAC/CRC Hall 
Mercer Community Mental Health (serving South Philadelphia). The intervention group will 
receive four weeks of treatment with buprenorphine /naloxone and support for treatment 
engagement provided by a case manager and a peer recovery specialist.  All participants will 
be assessed at baseline and then 1- and 6-month following enrollment. The primary endpoint 
for the study is continued enrollment in medication-assisted treatment at 6 months post 
enrollment. 
Study Duration 
The estimated duration of study is 36 months. Individual study subject participation will last 6 
months. 
Study Center(s) 
The University of Pennsylvania will serve as the primary project location, and all recruitment 
and data collection efforts will be executed by University of Pennsylvania staff members. A 
subcontract has been established with Prevention Point Philadelphia and Public Health 
Management Corporation. 
Objectives 
The proposed research will evaluate the ability of a mobile, rapid induction procedure to 
engage individuals in ongoing medication assisted treatment.   
The specific aims are:  
• 
Aim 1:  To evaluate the impact of the mobile, transitional MAT intervention on its 
ability to engage participants in targeted, existing MAT treatment slots at 1- and 6-
month post-enrollment.   
• 
Aim 2: To evaluate the impact of the mobile intervention on subsequent drug use 
and overdoses at 6-month post-enrollment.  
• 
Aim 3: To assess the acceptability and costs of the intervention. We will document 
the program and patient costs of delivering and participating in the intervention. 
Number of 
Subjects 
A total of 250 participants will be engaged in the research at the time they seek treatment: 
125 individuals will be enrolled as they engage with the mobile, rapid induction team and 
125 individuals will be enrolled as they seek treatment from the BAC/CRC (treatment as 
usual).   


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Main Inclusion 
and Exclusion 
Criteria 
Inclusion Criteria: 
• 
Must be 18 years of age or older 
• 
Opioid overdose in the prior 12 months  
• 
Meet criteria for opioid use disorder  
• 
Resident of Philadelphia 
• 
Willingness and ability to participate in study procedures 
Exclusion Criteria: 
• 
Inability to comprehend or complete study procedures 
• 
Plans to relocate during study time frame 
• 
Diagnosis of serious liver disease (LFT >3x normal ranges) 
• 
Currently in medication assisted treatment (MAT) for substance use disorder 
• 
Pregnancy or lactation 
• 
Moderate to severe alcohol or benzodiazepine use disorder 
Intervention  
• 
The intervention consists in a rapid initiation of buprenorphine/naloxone, counseling, 
peer support and case management as a method for linkage to long-term, evidence-
based medication assisted treatment.   
• 
Inductions will be initiated in the individual’s home community, either on our mobile 
medical facility or via home visits.  
• 
The mobile team will be led by a nurse practitioner (able to prescribe 
buprenorphine/naloxone in PA) and include a peer recovery specialist (PRS), and a 
case manager. The team will rapidly confirm opioid use disorder and risk of overdose, 
complete informed consent, and begin induction procedures for a “transitional” (one 
month) course of buprenorphine/naloxone treatment.  During this time, the dedicated 
case manager and PRS will work with the participants to help them become engaged 
in existing medication assisted treatment programs.  
• 
The type of ongoing treatment will be determined on an individual basis and will 
include options of methadone maintenance, buprenorphine/naloxone treatment, or 
extended-release naltrexone (XR-NTX).   
Statistical 
Methodology 
• 
Comparison on engagement rates in ongoing opiate use disorder treatment at the 
two time points (1- and 6-months) using a repeated measures logistic regression 
model, incorporating the propensity score (to correct for non-randomized trial) 
• 
Evaluate the change in substance use and severity of addiction using a repeated 
measures model to compare the groups on the ASI drug composite score at months 
1 and 6.  
• 
Compare of the number of overdoses per participant between groups using repeated 
measures Poisson regression models, if there is sufficient variability in the number of 
overdoses reported. If a low rate of overdoses causes convergence issues for the 
Poisson model, we will classify participants as having no overdoses versus at least 
one, and compare the groups using repeated measures logistic regression models. 
• 
Evaluation of the sensitivity of our main analyses to the presence of missing data by 
performing a sensitivity analysis, in which we will obtain estimates of the group effect 
under various non-ignorability assumptions, using selection models to examine the 
effects of missing data, using logistic regression models, and incorporate the 
predicted probabilities into a weighted analysis of the main hypotheses. 
Data and Safety 
Monitoring Plan  
The study will be monitored by the PIs and co-investigators, and Philadelphia Department 
of Public Health Institutional Review Board, as well as by regulatory committees at the 
University of Pennsylvania (i.e., IRBs, OHR) and Center for Studies of Addiction Data Safety 
Monitoring Board (Penn DSMB). During the course of the study, safety and data quality 
monitoring will be performed on an ongoing basis by the Principal Investigator and the study 
staff.  
 


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2 
Introduction 
The information that follows constitutes the research protocol for the Rapid initiation of buprenorphine/naloxone to 
optimize MAT utilization in Philadelphia study. This study will be conducted in compliance with the provisions set 
forth in this document. This study will also be conducted in full accordance with all applicable University of 
Pennsylvania Research Policies and Procedures, Good Clinical Practice Standards and all applicable Federal and 
state laws and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56. All episodes of noncompliance will be 
documented. 
 
The proposed research will test a mobile intervention designed to initiate treatment and link individuals with opioid 
use disorder and a high risk of overdose to ongoing medication-assisted treatment (MAT).  Despite the high 
prevalence of opioid use disorder and elevated rate of fatal and non-fatal overdose in Philadelphia, over 20% of 
MAT capacity goes unused.  The proposed intervention will rapidly initiate treatment with buprenorphine/naloxone 
and provide one-month of medication coverage, peer support and case management sharply focused on linkage to 
ongoing MAT (i.e., methadone, buprenorphine/naloxone, extended-release naltrexone).   Several critical barriers to 
treatment (stigma, time, and distance) will be minimized by rapidly initiating MAT in the individual’s home 
environment.   
 
In 2016, a total of 63,632 Americans died of a drug overdose and opioids were involved in 66.4% of these cases 
(42,249 overdose deaths) (Seth, Scholl et al. 2018). At present, opioid-related overdoses are the leading cause of 
accidental death in the country with a mortality rate that has quadrupled since 2000 and increased by 44.1% from 
2015. In Pennsylvania, between July 2016 and September 2017, the CDC Enhanced State Opioid Overdose 
Surveillance system reported an 81% increase of the ED visits for suspected opioid overdoses. Statewide, there 
were 4,627 overdose deaths in 2016, an increase of 44.1% from 2015, the second highest rate of increase of any 
state during this reporting period (Centers for Disease Control and Prevention 2018). In Philadelphia, in 2017 there 
were 1,217 drug overdose deaths.  Medical examiner reports indicate that 88% involved opioids, including 
prescription opioids, heroin, and fentanyl (City of Philadelphia, 2018). The increasing presence of fentanyl is directly 
associated with the escalating numbers of fatalities and in 2017, fentanyl was found in over 80% of the opioid 
fatalities. The 2017 the age-adjusted opioid-related death rate (59.8 per 100,000) was more than twice that found in 
New York City and greater than any of the other largest cities in the country.  Conservative estimates suggest that 
there are 70,000 individuals using heroin in Philadelphia and approximately, 50,000 who misuse opioid prescription 
medications. According to the DEA, the heroin sold in Philadelphia has the highest purity and the lowest price in the 
country.  A bag of heroin in Philadelphia is now cheaper than a pack of cigarettes.   Philadelphia is an urban 
epicenter of the opioid epidemic in the United States.  
 
There is no demographic that remains unaffected by the opioid crisis in Philadelphia (City of Philadelphia, 2018).   
The age adjusted mortality rates have increased for all categories of age, race and gender.  The highest rates of 
increase over the past two years have occurred for women (49% increase) and 15 to 24-year old (62% increase).  
Using the City of Philadelphia Department of Health and Human Services’ integrated data system (CARES), 
analyses of fatal overdoses during the past 5 years indicated that 70% were males, 63% white, and 27% were ages 
25 to 34.  Importantly, 41.4% of these individuals had contact with at least one service of the Philadelphia 
Behavioral Health System within the 6 months of their death and 26.4% within 1 month of their death.  
Geographically, the opioid epidemic has affected all neighborhoods in the City.  Of relevance to this application, the 
two areas of highest concentration for fatal overdoses are the Kensington and South Philadelphia.  These are the 
target areas for the proposed intervention.  It is also important to note that nearly 75% of fatal overdoses took place 
in private residences.  The proposed intervention will be accessible to those with stabile as well as unstable 
housing.  
2.1 
Responses to the epidemic   
Beginning in the mid 1970’s, efforts directed at reducing the problems associated with drug use were led by the 
criminal justice systems.  The United States’ “War on Drugs” resulted in changes in law and enforcement policies 
leading to almost 3% of the US adult population being under some form of criminal justice supervision by the early 
2000’s (Peters, Young et al. 2017). These policies created a system of mass incarceration and relied on ineffective 
abstinence-only approaches, resulting in harmful consequences and in huge economic and human costs (Belenko, 
Hiller et al. 2013).  One of the consequences of these failed policies has been the neglect of evidence-based 
treatment approaches and systems.   
 


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Scientific and medical communities have advocated for increasing the availability of evidence-based 
pharmacotherapeutic approaches (Volkow, Frieden et al. 2014, Blum, Gold et al. 2016). In 2017, the US 
Department of Health and Human Services declared a public health emergency and announced a 5-point strategy 
to combat the opioid crisis. The strategy included improving access to evidence-based treatment and recovery 
services, promoting use of naloxone to prevent overdose, strengthening the understanding of the epidemic through 
better public health surveillance, providing support for cutting edge research on pain and addiction, and advancing 
better practices for pain management (US Department of Health and Human Services 2018).  The opioid epidemic 
is a complex public health issue that should be addressed with multifaceted approaches including harm reduction 
and evidence-based treatment of the opioid addiction. 
An important response to the opioid epidemic in Philadelphia has been the rapid scale up of naloxone access and 
training. When administered correctly and in time, can prevent death from opioid overdose. Different approaches 
for naloxone deliveries have been extensively examined and have concluded in the efficacy of the widespread 
coverage of naloxone to reduce overdose (Rowe, Santos et al. 2015, Kirane, Ketteringham et al. 2016, Wagner, 
Bovet et al. 2016, Fairbairn, Coffin et al. 2017, Faulkner-Gurstein 2017). In Philadelphia, naloxone has become 
widely available and has been used to reverse over 7,000 overdoses in 2017.  
Although an effective tool for fatal overdose prevention, naloxone is not a treatment of opioid addiction or a 
prevention for future overdose.  In fact, a recent publication showed that non-fatal overdose is the highest risk 
factor for subsequent fatal overdose (Caudarella, Dong et al. 2016). Consistent with these findings, the above map 
displaying the incidence of naloxone use is nearly identical to the one displaying the incidence of fatal overdose in 
Philadelphia. These findings support the importance of linking individuals to effective opioid addiction treatment 
after an overdose.  
2.2 
Medication Assisted Treatment 
 Opioid use disorder, or opioid addiction, is a chronic relapsing disease defined as the loss or reduced control of the 
use of substance and is expressed through persistence of this use despite the accumulation of negative 
consequences in health, social, financial, and family life (Auriacombe, Serre et al. 2018). Opioid addiction is most 
effectively treated as a chronic disease which cannot be cured and requires long-term management strategies 
(McLellan, Lewis et al. 2000, American Society of Addiction Medicine 2014). 
It is well-established that medication-assisted treatment for opioid use disorder, either with methadone, 
buprenorphine/naloxone, or, naltrexone is safe and effective in reducing and suppressing opioid use, improving 
health outcomes, and reducing all cause and overdose mortality (Mattick, Breen et al. 2014, Nielsen, Larance et al. 
2016). More recently, extended-release naltrexone (XR-NTX) has been approved by FDA for the treatment of 
opiate use disorder.  For those who initiate treatment, the effectiveness of XR-NTX appears comparable to 
methadone and buprenorphine/naloxone (Morgan, Schackman et al. 2018).  
 
Despite overwhelming evidence of efficacy and perceived potential to impact the opioid epidemic, it is estimated 
that less than 20% of the individuals with opioid use disorder have access to medication-assisted treatment and 
less than 10% actually receive treatment (CDC 2018) (Wu, Zhu et al. 2016).  Several barriers have been identified 
and can include financial (lack of insurance coverage, inability to pay), regulatory (limited treatment capacity, 
waivered physicians), geographic (limited providers, treatment access), attitudinal (stigma, negative attitude 
towards medication assisted treatment), and logistic (lack of transportation, hours of operation) (Huhn, Tompkins et 
al. 2017, Sharma, Kelly et al. 2017). The strict regulatory environment and the often-long waiting list to access 
outpatient methadone clinic is a major barrier to treatment engagement and has helped to promote the expansion 
of buprenorphine/naloxone treatment that is primarily delivered in physician offices (Stancliff, Joseph et al. 2012). 
Increased access to buprenorphine treatment was shown to dramatically reduce the overdose rate in France 
(Auriacombe, Fatseas et al. 2004, Fatseas and Auriacombe 2007, Dupouy, Palmaro et al. 2017), and studies have 
shown a link between buprenorphine prescriptions and reduced rates of opioid overdose (Knudsen 2015, Knudsen, 
Havens et al. 2017).  
 
The overall mortality in buprenorphine/naloxone treatment has been shown to no different than methadone 
treatment (Auriacombe, Franques et al. 2001, Kelty and Hulse 2017), and buprenorphine is safer than methadone 
during the 4-week period of induction (Kimber, Larney et al. 2015, Sordo, Barrio et al. 2017). Because 
buprenorphine is a partial agonist for mu opiate receptor and a kappa opiate receptor antagonist, the medication 
has a ceiling effect protecting from overdose (Fatseas and Auriacombe 2007). Increasing access to buprenorphine 
might raise concerns regarding diversion, however, previous studies have shown that illicit buprenorphine was not 


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linked with opioid overdose (Bretteville-Jensen, Lillehagen et al. 2015) and its use can enhance access to 
buprenorphine treatment (Cunningham, Roose et al. 2013, Fox, Chamberlain et al. 2015).  
2.3 
Interventions to increase utilization of existing MAT 
 Surprisingly little scientific attention has been devoted to evaluating interventions to increase the utilization of MAT. 
Several studies have focused on engaging individuals while they were in hospital (Sittambalam, Vij et al. 2014) or in 
the emergency department (D'Onofrio, O'Connor et al. 2015, D'Onofrio, Chawarski et al. 2017). These protocols 
have shown evidence of successful initial buprenorphine treatment engagement (21% to 74%) but without follow-up 
support after leaving the hospital, these rates were not sustained after 6 months.  However, not all the individuals 
who experienced non-fatal overdose go to the hospital or, if admitted, may leave prior to the delivery of any 
effective intervention or referral. A recent qualitative study in out-of-treatment opiate users showed that when they 
got insurance coverage (mostly Medicaid), they more likely to choose the treatment available in their local 
community (Huhn, Tompkins et al. 2017).  Community-based buprenorphine treatment intervention within harm 
reduction facilities (i.e. needle exchange program) was the most appealing strategy (Fox, Chamberlain et al. 2015, 
Fox, Sohler et al. 2017).  Another approach that has been reported was based on community outreach. This project 
used peer-recovery specialists to engage opiate users at high-risk for overdose and link them to methadone 
treatment.  They found that 76% initiated screening but only 54% stayed in treatment after 1 month (Scott, Grella et 
al. 2018). A similar strategy used a mobile unit and targeted individuals encountered at drug use venues (Daniels, 
Salisbury-Afshar et al. 2014) and linked the opiate users to local buprenorphine providers after helping them with 
insurance coverage. This program was able to link 49% of the participants to ongoing treatment but there was no 
measure of status at six months.  
 
While 
MAT 
treatment 
capacity 
continues 
to 
expand, 
primarily 
through 
increasing 
numbers 
of 
buprenorphine/naloxone providers (Substance Abuse and Mental Health Service 2016), there is growing 
recognition of the need for more effective strategies to link opiate users to treatment.  In February 2017, the 
Pennsylvania Department of Drug and Alcohol programs in partnership with the PA Department of Health, 
established a strategy for improving patient engagement in substance abuse treatment following hospital-based 
treatment for opioid overdose.  This strategy is called the “Warm Handoff”.  Overdose survivors who are treated in 
the emergency department (ED) receive counseling and a physician’s referral to be transferred directly from the ED 
to a drug treatment facility. The warm handoff is completed by a Peer Recovery Specialist who supports the patient 
and will accompany him/her to appointments for ongoing treatment following hospital discharge (Department of 
Drug and Alcohol Programs 2018). This strategy is being scaled up and has potential to improve the rate of 
completed referrals for individuals seen in the ED and needing substance abuse treatment services.  No data is yet 
available on the efficacy of this approach. 
 
2.4 
MAT engagement in Philadelphia 
 The City of Philadelphia Behavioral Health System has established Behavioral Assessment Centers (BAC) and 
Crisis Response Centers (CRC) as the point of entry into MAT. In cases of emergency related to addiction-related 
crisis, CRCs operate 24 hours a day, 7 days per week and do emergency evaluations to help determine the most 
appropriate level of care and services and provide linkages to these programs. BACs provide urgent assessments 
for addiction services during working hours. In many cases, they will help link individuals using opioids to a 
community-based MAT provider as appropriate. The Philadelphia Behavioral Health System outpatient MAT 
capacity is 8,707 slots, as of March 13, 2018, 1,846 (21%) MAT slots were still available (21%).   
3 
The proposed study 
3.1 
Project overview 
The proposed project will build upon and incorporate many of the same principles that have proven important to the 
success of the buprenorphine/naloxone program established by Prevention Point Philadelphia (PPP), a primary 
partner in this proposal. This treatment program, known as the “Stabilization, Treatment and Engagement Program” 
(STEP) is fully integrated within the PPP needle-exchange program that has been operational since 1991 
(Bachhuber, Thompson et al. 2018).  The STEP program was designed to provide treatment access to users of the 
syringe exchange program.  Individuals identified at exchange sites throughout the City were screened at PPP’s 
clinical offices in Kensington.  Following assessment and a mandatory training, individuals would meet with the 
program’s physician and receive an initial one-week prescription for buprenorphine/naloxone.  Weekly visits and 
prescription refills were required for the first month.  The STEP program has been able to successfully engage 124 
opiate users in long-term buprenorphine maintenance treatment with a retention of 65% at 6 months and 56% at 12 


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months.  More than 90% of those who remained in treatment at 12 months were opiate-abstinent (Bachhuber, 
Thompson et al. 2018).  Importantly, and in contrast to many other programs in the City, the STEP program has a 
waiting list of nearly 200 individuals. 
 
The proposed project incorporates the concept of rapid initiation of MAT and consequently, the rapid control of 
withdrawal symptoms. A mobile team (Nurse Practitioner, Certified Peer Recovery Specialist, and a Case manager) 
will provide medication, counseling and treatment engagement support for one month. During this time, individuals 
will be linked to community MAT providers with unused capacity.   
We will determine the economic value of the mobile intervention relative to treatment as usual from the perspective 
of the City of Philadelphia’s Department of Public Health. Dr. Julie Becher, a Health Economist in the HIV 
Prevention Research Division, Department of Psychiatry, Perelman School of Medicine at the University of 
Pennsylvania, will lead this portion of study activities with consultations with colleagues at the Center for Health 
Economics of Treatment Interventions for Substance Use Disorder, HCV, and HIV (CHERISH).  The results of this 
analysis will inform future policy decisions regarding implementation of this novel, mobile strategy for rapid initiation 
of MAT as a method for engagement in long-term evidence-based treatment.  If the intervention in this study shows 
positive economic value, the City of Philadelphia’s Department of Public Health may scale-up the intervention to 
reach more people throughout the city that may be at risk of opioid overdose. Enhanced interventions may require 
a greater amount of resources than alternative methods of more basic interventions or the usual standard of care.  
However, resource-intensive interventions may be justified through the achievement of better outcomes resulting 
from administering enhanced procedures.  
 
3.2 
Innovation  
Rapid induction with buprenorphine/naloxone in the community is the core innovation of the proposed research.  By 
reducing time and geographic barriers to treatment and the control of withdrawal symptoms, the intervention will 
provide a one-month opportunity to link participants to an appropriate, ongoing treatment provider. This use of MAT 
is an innovation designed to minimize common barriers to treatment engagement.  The use of buprenorphine will 
also allow for the transition to other MAT strategies that may be more appropriate for the individual, including 
methadone maintenance treatment, buprenorphine treatment, or treatment with extended-release naltrexone.  The 
ability to engage individuals with opioid use disorder in their home environment is another important innovation of 
the proposed research.  The mobile engagement team will include a Nurse Practitioner, a Case manager, and a 
Certified Peer Recovery Specialist and will begin inductions on the mobile medical unit or in the individual’s home.  
The mobility of the team is an innovation allowing easy access to individuals who indicate interest in treating their 
opioid use disorder.  We will assess treatment status at six months post enrollment as our primary outcome 
measure.  With the permission of the participant, the CARES Integrated Data Systems Service Utilization database 
will be available to identify involvement with drug treatment and other services provided by the City prior to and 
following the enrollment in the study.  
 
3.3 
Collaborations 
The proposed project will be led by investigators from the University of Pennsylvania (Metzger, Kampman, Becher, 
and Lynch) with over 60 years of collective experience in community-based substance use research in 
Philadelphia.   These investigators have had close and longstanding collaborations with investigators from TRI and 
Prevention Point Philadelphia.   
• 
Prevention Point Philadelphia (https://ppponline.org ):  Prevention Point Philadelphia (PPP) was founded 
in 1991 as an underground syringe exchange organization. Over the years, PPP has evolved into a multi-
service public health organization serving the most hard-to-reach populations in the toughest 
neighborhoods of Philadelphia.  PPP was founded as a community-based SEP to address the high 
incidence of HIV and hepatitis C infection among people who inject heroin. Its core services now include 
harm reduction through syringe distribution and exchange, overdose education and naloxone distribution, 
provision of HIV and hepatitis C virus testing, HIV care, housing, and assistance with social services. In 
2008, responding to client interest in addiction treatment and perceived lack of access by clients and 
program staff, PPP created a buprenorphine maintenance treatment program called the Stabilization, 
Treatment, and Engagement Program (STEP) that was fully integrated within the SEP. This program 
targets current SEP participants who express interest in cessation of heroin use.  PPP will hire and support 
to the mobile intervention staff and maintain responsibility for the integrity of the mobile treatment and 
engagement service modeled after the STEP program.  Jose Benitez and David Barclay have decades of 


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clinical and administrative experience in MAT delivery and  will provide clinical leadership for the mobile 
team. 
• 
TRI Center on Addictions at PHMC (https://www.tresearch.org ): The Treatment Research Institute (TRI) 
was founded in 1992 as a 501(c)(3) not-for-profit organization in Pennsylvania. TRI’s core mission has 
been to apply research to improve substance abuse policies and programs. TRI is committed to the 
development, evaluation, and dissemination of solutions designed to address issues related to substance 
use. As an independent treatment outcome evaluator, TRI has an extensive history of integrating its proven 
outcome assessment methods, measuring service delivery, and implementing evidence-based practices 
into clinical treatment programs nationally and internationally. TRI’s research focuses on integrating clinical 
care across the various sectors affected by substance use problems, including healthcare, criminal justice, 
education, and community-based services. TRI is highly regarded in the substance use and mental health 
fields and has a reputation as a leader in translating research into practical applications. TRI is also known 
as the ‘home’ of the Addiction Severity Index (ASI), one of the most widely used assessment tools in the 
field. Instruments developed by TRI are among the most widely utilized by clinicians, researchers, and 
justice systems throughout the world.  In June 2017, TRI merged with Public Health Management 
Corporation’s R&E Group, becoming the TRI Center on Addictions at PHMC (TRI-CA).   The investigators 
to be involved in theis project (Dugosh, Festinger, and Cos) have extensive experience in treatment 
research with a particular focus on MAT.    They will participate in the trainings and will help to manage the 
implementation of the research and maintain primary responsibility for the recruitment, follow-up, and 
assessment of individuals seeking treatment at the participating BAC/CRCs--the Treatment as Usual 
Group. 
• 
Center for Health Economics of Treatment Interventions for Substance Use Disorders, HIV, and 
HCV (CHERISH https://cherishresearch.org ):  CHERISH is an NIH-funded multi-institutional research 
center devoted to developing and disseminating economic evidence that informs substance use treatment 
policy and HCV and HIV care for people who use substances. The Center serves as a national resource to 
increase the impact of substance use economic research. Its infrastructure is designed to enhance existing 
research projects, promote state-of-the art economic research methods, and improve the ability of 
substance use economic researchers to communicate with decision makers and address changes in 
today’s healthcare system.  CHERISH will provide the research team with training and consultation in 
documenting the time and resources required to deliver and monitor the intervention, as well as potential 
downstream cost offsets associated with effective treatment. 
• 
Penn Injury Science Center (https://www.penninjuryscience.org ):  The Penn Injury Science Center is 
funded by a grant from the Centers for Disease Control and Prevention and brings together university, 
community, and government partners around injury and violence intervention programs with the greatest 
potential for impact. The Center promotes and perform the highest quality research, training and translation 
of scientific discoveries into practice and policy, in order to reduce injuries, violence and their impact to our 
region, the US, and locations around the world.  The Center’s diverse group of scientists, students, and 
staff are centrally co-located on the University of Pennsylvania campus in Philadelphia and represent 6 
Penn Schools, 12 other Penn Institutes and Centers, 2 Level 1 Trauma Centers, and 3 Research 
Laboratories.  The Center will provide consultation and support in geospatial analyses and mapping.   
Specifically, the Center will provide guidance on the initial location of the mobile treatment engagement 
unit. 
• 
Philadelphia Department of Public Health (PDPH):  This project has been planned and will be 
implemented in close cooperation with the Philadelphia Department of Public Health.  We will work closely 
with Kendra Viner, PhD, MPH and Jeffrey Hom, MD who co-manage the Opioid Surveillance, Epidemiology 
and Prevention Program (OSEPP) at PDPH.  This program focuses on collecting, analyzing, and reporting 
epidemiological trends in opioid abuse, including both fatal and nonfatal overdoses, use of addiction 
treatment services (e.g., detoxification, MAT), opioid prescribing practices, and medical consequences of 
drug use (HIV, hepatitis). All work is done in close collaboration with the Medical Examiner’s Office (MEO), 
which investigates and conducts comprehensive toxicology testing on all victims of fatal overdoses. 
OSEPP also conducts several prevention efforts, including managing community-based naloxone 
distribution programs, educating providers, pharmacists, and the public about opioid overdose prevention 
and reversal, and training primary care providers in screening and diagnosis of opioid misuse.  We will also 
work closely with Lia Pizzicato, MPH who created the city’s first Opioid Misuse and Overdose Report 
(https://hip.phila.gov/DataReports/Opioid) by building relationships with and securing timely information 
from the Medical Examiner’s Office, the Fire Department, the Police Department, and all major Philadelphia 
area emergency departments.   


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3.4 
Study Objectives 
The proposed research will evaluate the ability of a mobile, rapid induction procedure to engage individuals in 
ongoing medication assisted treatment.  Individuals meeting criteria for opioid use disorder and at high risk of opioid 
overdose will be enrolled in the study. Recruitment will take place in two targeted neighborhoods with a high 
prevalence of fatal and non-fatal opioid overdose. A total of 250 participants will be engaged in the research at the 
time they seek treatment.  Following informed consent and determination of eligibility, 125 individuals will be 
enrolled as they engage with the mobile, rapid induction team and 125 individuals will be enrolled as they seek 
treatment from the BAC/CRC.  All participants will be assessed at 1- and 6-month following enrollment. These 
assessments will provide data able to address each of the three aims.   
 
Aim 1:  To evaluate the impact of the mobile, transitional MAT intervention on its ability to engage participants in 
targeted, existing MAT treatment slots at 1- and 6-month post-enrollment.   
Aim 2: To evaluate the impact of the mobile intervention on subsequent drug use and overdoses at 6-month post-
enrollment.  
Aim 3: To assess the acceptability and costs of the intervention. We will document the program and patient costs 
of delivering and participating in the intervention. 
Assessments will also provide data on factors that are considered to be important determinants of retention in 
treatment—duration of opioid use; prior number of treatment attempts; frequency of recent use; and, depression.  In 
addition to age, gender, and race these variables will be used in the proposed propensity analyses. 
 
3.5 
Rationale for Study Design 
3.5.1 
Why no Randomization?   
 In the proposed project, individuals will contact our mobile team after learning about the opportunity to begin a 
rapid induction with buprenorphine/naloxone. As described in more detail later, awareness of the intervention will 
precede contact with the research team via social media, targeted advertisement, and word of mouth. This is an 
important feature of the research since we want to be able to measure the acceptability and demand for such a 
strategy. We believe that it would not be ethical to randomly assign individuals at this point to an alternative 
treatment option that would require additional time and referral to a different location to initiate screening and 
intervention. As an “open label” trial, any randomization process would also become widely known among potential 
participants and contaminate the perception of the mobile team as able to reliably initiate rapid treatment 
engagement.   
 
3.5.2 
Why buprenorphine/naloxone for rapid treatment initiation?    
 For this study, we choose to use buprenorphine/naloxone to initiate treatment. Buprenorphine, the active treatment 
agent in the buprenorphine/naloxone medication, is a partial mu-opioid receptor agonist with greater affinity than 
heroin, morphine or other prescription opioids (Johnson, Strain et al. 2003, Orman and Keating 2009, Hser, Evans 
et al. 2016). It provides anti-withdrawal and anti-craving effects for up to 36 hours on a single dose. As a partial 
agonist, the slower onset of effect diminishes the patient’s perception of euphoria (Mammen and Bell 2009, Dennis, 
Naji et al. 2014), while its safety profile, long half-life and binding duration make it useful for both short term use, 
tapering, and long-term opioid maintenance (Soyka 2015). Effectiveness has been demonstrated across diverse 
samples (Thomas, Fullerton et al. 2014). The initiation of treatment with buprenorphine is safer than with 
methadone and unobserved induction is widely adopted and has been shown to be as safe as supervised initiation 
(Lee, Vocci et al. 2014).  A recent Cochrane review showed no difference in retention at any duration with 
supervised compared to unsupervised dosing in retention in treatment at 1-month and at 3-month follow-up, no 
difference in abstinence at the end of treatment and no difference in diversion of buprenorphine (Saulle, Vecchi et 
al. 2017).  
 
Study participants who will receive buprenorphine/naloxone will be provided with information, counseling, and 
support for selection of ongoing treatment options including methadone maintenance (MMT), extended-release 
naltrexone (XR-NTX), or continued treatment with buprenorphine/naloxone (Baser, Chalk et al. 2011, Hartung, 
McCarty et al. 2014). 
 


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3.6 
Study Timeline 
As shown in the Table below, following start-up activities (approvals, hiring, training, and data collection 
preparations), recruitment activities (community awareness) will start in month 5 and implementation of the 
intervention will begin in month 6 and continue for 18 months.   
 
3.7 
Study Measures 
All interviews will be administered by experienced research assistants trained in the administration of the proposed 
assessments. Following confirmation of eligibility, the mobile research assistants will complete the baseline 
assessment (described below). The participant assessments in this research will be sharply focused on the valid 
and reliable measurement of its primary endpoints i.e. ongoing treatment engagement will be the primary endpoint 
on which the study is powered.  We will also carefully compare the two groups with respect to the rate of continued 
opioid use and subsequent overdoses.   All assessments will be completed by trained research staff (not clinicians) 
at baseline, and again at 1- and 6-month post-enrollment.  We anticipate follow-up rates of 95% and 90% at Month 
1 and 6, respectively. We anticipate that the assessments will take approximately 45 minutes to complete.   
 
• 
Physical history and examination including a blood test to evaluate the liver function.   
 
• 
Locator Data Collection: A detailed contact sheet (Locator Form) will be completed for all subjects as part 
of the baseline assessment.  We will ask participants to provide contact information on themselves and at 
least three additional people with whom they are most likely to stay in contact.  We will also ask about other 
places where participants might be able to be contacted in the future.  Participants will provide consent for 
research staff to contact individuals whose contact information they provide.  Contact information will also 
include e-mail addresses and mobile phone numbers for texting. The locator form will be updated at each 
scheduled assessment visit.   In addition, participants will be asked to call or visit the research staff 
whenever they have updates to provide regarding changes in contact information. 
 
• 
DSM-5 Substance Use Disorder Checklist: This form is a listing of the eleven DSM-5 criteria for substance 
use disorder.  We will screen for opioids, cocaine, and alcohol as each are necessary for confirmation of 
inclusion and exclusion criteria. A score of 4-6 is considered moderate severity and from 7-11 is considered 
severe substance use disorder. An opioid use disorder score of 4 or greater will be required for study 
eligibility.  Alcohol use disorder and benzodiazepine scores of 4 or greater will be exclusionary.  
 
  
• 
A study specific questionnaire that includes:  
o 
Socio-demographic Questionnaire:  This brief questionnaire will be administered by research staff 
and will collect demographic information (e.g. age, gender, race and ethnic identity, marital status, 
sexual orientation, educational level, employment status, income and income sources) and 
descriptive information about the subject's living situation and housing stability, history of 
involvement with the criminal justice system, drug use, and drug treatment history.  
 


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o 
Addiction Severity Index (ASI) sections for Drugs and Alcohol and Medical Status:  The ASI is a 
structured interview developed to assess the range of problems seen in drug users. The ASI 
produces severity ratings and composite scores in each of seven areas, and each type score has 
been assessed with regard to validity and reliability.  Severity ratings and composite scores have 
demonstrated high levels of inter-rater, test-retest, and concurrent reliability (Cacciola et al., 2008; 
McLellan, Cacciola, Alterman, Rikoon, & Carise, 2006; McLellan et al., 1992). The Medical and the 
Drug and Alcohol sections will be administered at baseline, 1- and 6-month follow-ups.  
 
• 
Patient Health Questionnaire (PHQ-9): Given the important role of depression in accessing and adhering to 
treatments for substance use disorder and other chronic medical problems (Mahajan, Avasthi, Grover, & 
Chawla, 2014; Tavakkoli, Ferrando, Rabkin, Marks, & Talal, 2013), we will also assess severity of 
depression using the 9-item Patient Health Questionnaire (PHQ-9). This brief assessment asks participants 
to indicate the frequency of occurrence of each of the nine DSM-IV diagnostic criteria for depression during 
the previous two weeks. This instrument has been widely used in clinical research and has strong 
psychometric properties. The PHQ-9 will be completed at baseline and months 1 and 6. 
 
• 
Urine drug screen:  We will use the CLIA waived® ACON Dip-and-Read 8-panel test for THC, cocaine, 
opiates, amphetamines, PCP, methamphetamine, benzodiazepines, barbiturates, and buprenorphine. The 
urine sample will be provided using standard procedures with temperature monitoring to preclude 
tampering and dilution.   
 
• 
HIV testing:  Chembio SURE CHECK HIV 1/2® rapid-HIV test kits will be used to detect antibodies. These 
FDA approved and CLIA Waived kits produce results in 15 minutes from a blood drop. For those who test 
antibody positive, additional blood will be drawn for confirmatory testing via RNA viral load assay. We 
anticipate that approximately 10% of participants will test positive for HIV. 
 
 
• 
Economic evaluation: The cost-effectiveness of the intervention will be performed using data collected with 
questionnaires widely used for cost-effectiveness analyses.  
• 
Drug Abuse Treatment Cost Analysis Program (DATCAP): The program-based Drug Abuse Treatment 
Cost Analysis Program (DATCAP) is a reliable instrument widely used by substance abuse treatment 
programs for the collection and organization of programmatic costs.  The instrument, by standardizing 
data collection procedures, enables direct comparison of data and cost estimates across different drug 
treatment programs and over time (French et al. 1997).  The program-based DATCAP is divided into 
different categories, each one pertaining to a particular area of standard universal economic resource 
and cost variables: personnel (e.g., percentage of time devoted to the program, annual salary, total 
cost of employee benefits, total overtime cost, any other personnel cost) supplies and materials (e.g., 
cost of medications, medical and office/mobile unit supplies, value of supplies and materials donated or 
received free of charge), major equipment (e.g., cost of all leased/rented equipment used by program, 
depreciation expense for equipment, value of any equipment donated or received free of charge), 
contracted services (e.g., cost of laboratory services, repairs and maintenance, advertising services), 
buildings and facilities (e.g., size of total usable space in building, percentage of that space used by the 
treatment program, percentage of time it was used by this program, annual lease/rental price per 
square foot), miscellaneous resources and costs (e.g., cost of utilities such as electricity, telephone, 
transportation, staff training, medical waste disposal) not recorded elsewhere  (French et al. 2004; 
Salome et al. 2003). The general categories of resources are universal and applicable to different 
programs in different locations. This instrument was designed to be flexible; individual items within 
each category may be added or deleted depending on specific aspects of a unique drug treatment 
program or geographical characteristics (Salome, French, Miller, McLellan 2003). The instrument is in 
the public domain and usage has not been monitored, so there is no readily available list of citations 
(Michael French, personal communication, August 18, 2008). Time to complete the instrument varies 
depending on specific characteristics of drug treatment programs.  This assessment is highly structured 
and will be completed over the course of a few days by Dr. Julie Becher and study staff. 
• 
Non-Medical and Other Services Form (NSMOS):  This questionnaire was adapted from the Treatment 
Services Review (McLellan et al., 1992; Cacciola et al., 2008 ) for patients receiving substance abuse 
treatment. It is designed to capture all medical and social services received by the participant between 
study visits. The NSMOS counts substance abuse treatment, medical services, employment visits, 
legal services, family services and psychological/emotional. It takes 5 to 10 minutes to complete. The 
Non-Medical and Other Services Form (NSMOS) will be used to collect information from participants on 


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their healthcare utilization.  This information will enable us to estimate costs incurred by the City of 
Philadelphia’s Department of Public Health. Participants will be asked about the medical services and 
other relevant resources they have utilized between assessments.   More specifically, participants will 
be asked about: visits and number of visits to an emergency room (not admitted to hospital); 
admittances (number and duration) to hospitals to detoxify from drugs or alcohol, or for other reasons; 
participation and number of days in outpatient treatment program for drug or alcohol problems; 
admittance (number and duration) in a residential program to detoxify or for other services; receipt, 
type, and prescribed dose, of medication to treat alcohol use disorder, opioid use disorder, or mental 
health disorder;  care (number of times) received by a psychiatrist or psychologist, counselor or social 
worker; number of visits to a medical office and number of visits with a doctor; amount spent out of 
pocket on healthcare (including prescriptions); and coverage and type of health insurance. Study staff 
will administer this form at each assessment. Time to complete will vary by participant. 
 
3.8 
Study Endpoints  
3.8.1 
Primary end-point 
Treatment engagement is the primary endpoint in this study.   
• 
Confirmation of enrollment in MAT:  Assessments will collect self-report of participation in MAT at the time 
of assessment as well as during the intervening time-period.  We will also collect confirmatory 
documentation from the identified treatment provider.  Permission to contact the treatment provider will be 
included in the consent and a specific release of information form signed by the participant will be included 
in the request for confirmation.  
• CARES Integrated Data Systems Service Utilization: Participants enrolled in this study will provide 
consent to allow the Health Department to review their records of utilization of city services prior to and 
following enrollment in the study.   
3.8.2 
Secondary Study Endpoints 
• 
Evaluate the impact on the number of overdose and evaluate the change in substance use and severity of 
addiction using a repeated measures model to compare the groups on the ASI drug composite score at 
months 1 and 6.  
• 
Cost evaluation: We will determine the economic value of the mobile intervention relative to treatment as 
usual from the perspective of the City of Philadelphia’s Department of Public Health. Dr. Julie Becher, a 
Health Economist in the HIV Prevention Research Division, Department of Psychiatry, Perelman School of 
Medicine at the University of Pennsylvania, will lead this portion of study activities with consultations with 
colleagues at the Center for Health Economics of Treatment Interventions for Substance Use Disorder, 
HCV, and HIV (CHERISH).  The results of this analysis will inform future policy decisions regarding 
implementation of this novel, mobile strategy for rapid initiation of MAT as a method for engagement in 
long-term evidence-based treatment.  If the intervention in this study shows positive economic value, the 
City of Philadelphia’s Department of Public Health may scale-up the intervention to reach more people 
throughout the city that may be at risk of opioid overdose. Enhanced interventions may require a greater 
amount of resources than alternative methods of more basic interventions or the usual standard of care.  
However, resource-intensive interventions may be justified through the achievement of better outcomes 
resulting from administering enhanced procedures. 
4 
Study Population and Duration of Participation  
4.1 
Duration of Study Participation  
The duration of study participation including screening/baseline assessments to follow-up will be 6 months.  
4.2 
Total Number of Subjects  
A total of 250 participants will be engaged in the research at the time they seek treatment: 125 individuals will be 
enrolled as they engage with the mobile, rapid induction team and 125 individuals will be enrolled as they seek 
treatment from the BAC/CRC (treatment as usual).   
 
 
 


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4.3 
Inclusion Criteria 
Participants must meet the following criteria for enrollment: 
• 
Must be 18 years of age or older 
• 
Opioid overdose in the prior 12 months  
• 
Meet criteria for opioid use disorder  
• 
Resident of Philadelphia 
• 
Willingness and ability to participate in study procedures 
4.4 
Exclusion Criteria 
• 
Inability to comprehend or complete study procedures 
• 
Plans to relocate during study time frame 
• 
Currently in medication assisted treatment (MAT) for substance use disorder 
• 
Evidence of serious liver disease (LFTs > 3 x the upper limit of normal)  
• 
Pregnancy or lactation 
• 
Moderate to severe alcohol or benzodiazepine use disorder 
 
There will be no exclusion based on gender or race/ethnicity. The participants to be recruited are expected to 
reflect the demographics of previous data provided by Philadelphia Department of Health on individuals who 
overdosed in the city of Philadelphia. Both men and women will be recruited for this study as both are affected by 
opioid epidemics. No gender restrictions are to be followed at recruitment. According to the available data, we are 
expecting enrolling about 30% of females.  Minority populations will not be excluded. We are expecting enrolling 
about 59% European-American/non-Hispanic, 25% African-American/non-Hispanic, 15% of Hispanic/Latino, and 
1% of Native American. 
 
4.5 
Subject Recruitment  
The recruitment of participants for this study will be accomplished using a community awareness campaign 
involving street outreach, targeted social media, and local advertisement.  This campaign will begin one month 
before activation of the rapid induction intervention.  During this time, the mobile assessment team will begin to be 
present in the designated location where we will park the Mobile Clinical Trials 
Unit (MCTU) – see picture. 
The MCTU is a medical vehicle is built on a heavy-duty truck frame that 
contains an expandable waiting area and two private examination rooms.  It 
has a sink area and a bathroom and is equipped with two locked refrigerators 
for specimen and medication storage. Dr. Ian Frank serves as the Medical 
Director for projects and services that take place on the MCTU. The unit is 
approved for use by the Pennsylvania Department of Health as a site for HIV 
testing and the exam rooms provide comfortable and private space for 
counseling, interviews, and data and specimen collections.     
 
The two neighborhoods with the highest concentrations of opioid overdose mortality will serve as our areas for 
engagement:  Kensington and South Philadelphia. The selection of parking l ocations for the MCTU is an important 
process and will be informed by issues of access to the target population, data regarding recent overdoses, and 
community support and permissions.   
 
For final site selection in this project, we will build on the work recently completed by the interdisciplinary “CUES 
Evaluation Working Group” of faculty, fellows, and stakeholders from the city and the drug-using community. The 
working group was funded by a grant from the Leonard Davis Institute for Health Economics (LDI) to support the 
development of an objective strategy for assisting the City in identifying potential locations for Comprehensive User 
Engagement Sites (CUES) where injections would be supervised and access to behavioral health and housing 
services would be provided.  
 
Using a mixed methods approach that combines geographic analyses and qualitative research methods, the 
working group asked stakeholders including municipal employees, healthcare providers, PWID, and residents from 
across Philadelphia for their thoughts about what features would make a location either well suited or not well 
suited for operating a CUES. That process revealed approximately 20 aspects of the built environment or the social 
environment that were used to classify each city block according to the presence or absence of each type of asset, 
barrier, or indicator of demand.   Assets for block selection included City Council District support, condom 


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distribution site, MAT site, HIV testing site, opioid support site, Public Health Center, pharmacy, pharmacy with 
Naloxone, public transit, social cohesion and syringe exchange site.   Barriers to block selection included schools, 
daycare centers, parks and recreation facilities, police station, fire station, alcohol outlet, gentrification pressures.  
Factors that indicated blocks with potential demand for the service include overdose deaths, naloxone (Narcan®) 
administration events, police narcotics arrest, and homeless encampments. Geocoding these location features, 
assigning a weight to each to represent its relative importance, and summing the values into a score produced a 
map of Philadelphia that identified 5 specific locations that appear to be most well suited for operating a CUES.  As 
depicted below, among these 5 locations, 1 good site is located in South Philadelphia and 1 best sites in the 
Kensington neighborhood. 
We believe that the factors that were developed for guiding the location of the CUES also apply to locating the 
MCTU for this research.  The circles on the map will be our preliminary target areas for exploration and finalization 
during the start-up phase of the research. 
4.6 
Vulnerable Populations 
Population protected under HHS regulations 45CFR46 Subparts B, C, & D Study Procedures:  Participants who are 
pregnant at the time of baseline assessments will not be eligible for the study.  
 
Populations vulnerable to undo influence or coercion: Educationally or economically disadvantaged persons are 
included but not solely targeted for recruitment. Cognitively impaired persons are not included in the current study.   
All the participants will be drug-dependent individuals. They are considered a vulnerable population due to the 
risks, both perceived and real, created through the use of illegal drugs. Care will be taken to ensure that they are 
treated with respect and consideration throughout the study process. 
4.7 
Study Procedures  
See Table below for a schedule of study procedures.  
 
 
4.8 
Participant Screening 
4.8.1 
Subject recruitment 
The recruitment of participants for this study will be accomplished using a community awareness campaign 
involving street outreach, targeted social media, and local advertisement.  This campaign will begin one month 
before activation of the rapid induction intervention. During this time, the mobile assessment team will begin to be 
present in the designated location where we will park the Mobile Clinical Trials Unit (MCTU). 
 
The MCTU is a medical vehicle is built on a heavy-duty truck frame that contains an expandable waiting area and 
two private examination rooms. It is approved for use by the Pennsylvania Department of Health as a site for HIV 
testing and the exam rooms provide comfortable and private space for counseling, interviews, and data and 
specimen collections. The selection of parking locations for the MCTU is an important process and will be informed 
Day 
P.S. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
180 
Pre-screening  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening/ 
Enrolment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent/ 
HIPAA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Locator form 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Physical exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood test – liver 
functions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nurse Practitioner* 
 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Case Manager* 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Recovery specialist* 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
BUP/NX delivery 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
BUP/NX dosing 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specific 
questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
PHQ-9 - Depression 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urine drug screen 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
HIV testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Engagement in MAT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Overdose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Cost analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DATCAP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
NMOS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Notes: 
P.S. = pre-screening day; 
* The mobile team (i.e. nurse practitioner, case manager, recovery specialist) will have contact with each participant at least 3 times per week.  


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by issues of access to the target population, data regarding recent overdoses, and community support and 
permission. We will work with the staff of Prevention Point that has an extensive access to the neighborhood to 
define the best locations within the neighborhood. 
4.8.2 
Participant Education and the Informed Consent Process 
 Potential participants who express interest in initiating treatment will be engaged in a structured approach to 
education about the study and its procedures.  The information delivered at this point will be supportive and 
motivational and describe study participation as an opportunity to consider options for treatment. It will also be 
explained that their participation can contribute to a better understanding of the most effective ways to assist 
individuals who want to begin treatment.  Staff will make it clear that even if they do not become engaged in 
treatment, their experiences are important and their contributions to the research will be valuable. We will inform 
participants that their direct involvement in the project will last for one year and that we will want to contact them at 
scheduled assessment visits regardless of their treatment status. This discussion will offer potential participants a 
chance to ask questions and receive prepared materials explaining the study and the requirements for participation.  
 
Those who appear to be eligible and express interest will begin the informed consent process to allow for 
screening. The informed consent process will give the participant an accurate understanding of the research 
procedures and make it clear that participation is voluntary. The informed consent document will be read and 
reviewed with the participant. The consent form includes clear language with special attention to the provision of 
permissions to contact the participant and individuals they identify as acceptable contacts if we are unable to make 
direct contact with the participant for the 1- and 6-month assessments. Since we will also need to confirm 
subsequent treatment engagement, the consent form will include permission to contact treatment providers to 
determine treatment status as well as permission for the Philadelphia Department of Public Health to look shared 
information 
about 
their 
subsequent 
use 
of 
health 
department 
services 
(CARES 
database, 
http://www.phila.gov/hhs/data/Pages/Cares.aspx). The consent form will also include a statement indicating that  
research staff will submit their names to the National Death Index for a record search should we be unable to make 
contact for a 90-day period. 
 
4.8.3 Screening assessments 
  For those who remain interested following discussions about the and appear to meet eligibility criteria, the consent 
form will be signed and the screening visit will be conducted.  This visit will include completion of assessments to 
confirm inclusion and exclusion criteria.  The Nurse Practitioner will complete a medical history, a physical exam, a 
rapid blood test for HIV, a pregnancy test for women, and collect 10ml of blood for liver function tests.  Research 
staff will complete baseline assessments described in section 3.7 of this protocol. Those who are not eligible will 
receive a listing of treatment providers and encouraged to make contact for help with their substance use problems.  
For those who appear eligible following the screening visit, an appointment for initiating the intervention will be 
scheduled within 1 or 2 days.  
 
4.9 
Study Intervention Phase  
4.9.1 
Overview of Interventions 
Rapid Induction Intervention (RI)  
The rapid induction intervention will be delivered by the project’s mobile team led by a nurse practitioner supported 
by a certified peer recovery specialist (CPRS), and a case manager (CM). Team members will work closely with 
each other and coordinate screening and treatment initiation, medication adherence monitoring, and assessment 
and linkage to ongoing MAT. Two half-time research assistants (RA) will participate as team members but  will 
have intervention responsibilities. The RAs will assist with the community awareness campaign and recruitment 
and will conduct all assessments for the project. The mobile team will be based at PPP and will receive clinical 
supervision from the mobile team’s buprenorphine physician (David Barclay, MD). As indicated throughout this 
application, access to the intervention will take place on the MCTU and during home visits following telephone 
contact.    
 
Induction:  Once eligibility has been determined, the NP will begin preparing the participant for induction. We will 
follow the buprenorphine/naloxone induction protocol used by D’Onofrio et al., 2015. In this protocol, the patient 
must be exhibiting signs and symptoms of opiate withdrawal, e.g., sweating, lacrimation, goose flesh, rapid pulse, 
before the first dose is administered. Withdrawal symptoms will be measured by the Clinical Opiate Withdrawal 


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Scale (COWS; Wesson & Ling, 2003), an 11-item scale designed to be administered by a clinician and that can be 
used in both inpatient and outpatient settings to reproducibly rate common signs and symptoms of opiate 
withdrawal and monitor these symptoms over time. The summed score for the complete scale will be used to 
determine the stage of opiate withdrawal and assess the level of physical dependence on opioids. Under the 
supervision of the NP, COWS will be used as an objective measure of withdrawal and buprenorphine/naloxone 
treatment will not initiate until the COWS score falls within the 8 -12 range. If the score is below 8, participants will 
be asked to the COWS will be re-administered in one hour and patients will receive a careful explanation of why 
medications cannot be started until clear withdrawal symptoms are present. When withdrawal symptoms are 
sufficient to initiate medication, patients will be given a 4 mg dose. In this trial, we will use generic 
buprenorphine/naloxone tablets or film that are easily administered by placing the tablets or film under the tongue 
and waiting for them to dissolve. The COWS will be repeated in one to three hours to assess the reduction in 
symptoms. It is expected based upon extensive clinical practice that participants will receive relief from opiate 
withdrawal symptoms with 4-8 mg doses of buprenorphine/naloxone on day 1 (e.g. a total day 1 dose of 8 mg). 
However, additional dose(s) may be given to those participants in whom withdrawal symptoms remain after 
receiving 8 mg of medication. In such cases, the Nurse Practitioner will increase the dosage but no more than 16 
mg of buprenorphine/naloxone will be given to a participant on day 1 of induction. As with any pharmacotherapy, 
the goal of buprenorphine/naloxone treatment is to use the minimum effective dose. The immediate goal of 
buprenorphine/naloxone therapy is to alleviate withdrawal symptoms, with longer-term goals of reducing drug 
craving, and reducing or eliminating use of opioids. If patients have problems adjusting to buprenorphine/naloxone 
(e.g., experience persistent withdrawal symptoms or continue to feel compelled to use illicit drugs), the dose may 
need to be increased. After stabilization, a three-day supply will be provided to the participant with simple 
instructions for self-administration.  
For those who fail to reach threshold for beginning induction while the mobile team is present and the participant in 
judged by the Nurse Practitioner to be appropriate for self-induction instructions for medication administration will 
be provided.  This “self-induction” procedure has now become quite common (Lee, Vocci, & Fiellin, 2014).  
Participants will be asked to maintain contact with the NP on the morning of the following day to assess symptoms 
of withdrawal. If the participant is not in withdrawal on the morning of day 2, the day 1 dosage will be maintained.  If 
the participant reports feelings of lethargy or sedation, on the next morning the day 2 dosage will be reduced.by 
2mgs.  If the participant reports feelings of withdrawal on the morning of the second, day the day 2 dosage will be 
increase by 4mgs. 
The final day of dose adjustment will typically be day 3.  On the morning of day 3, the participant will be assessed 
by the NP for signs of sedation or withdrawal and adjust dosages accordingly.  Once the stable dose has been 
determined, the participant will be given a one-week supply of medication and scheduled for an appointment the 
following week for assessment by the NP and receipt of the second week of medication. This procedure will be 
continued for the remainder of the treatment month.  Participants will meet with the NP weekly, and be invited to 
have telephone contact as needed.   
 
MAT engagement during the month of intervention will be facilitated by the Peer Recovery Specialist (PRS). The 
purpose of a PRS is to support the participant in their recovery process. In addition, the project will provide 
intensive training and ongoing consultation on MAT. The PRS hired for this study will also receive intensive training 
focused on addiction as a chronic medical condition, motivational enhancement strategies and facilitating short-
term behavioral contracts.  The PRS will meet with the participant a minimum of 3 times per week and be available 
for telephone counseling and support throughout the one-month intervention period.    
 
The mobile team’s Case Management (CM) function will be performed by a master’s level social worker. The CM 
will have primary responsibility for identifying the treatment program that best meets the needs of the participant. 
The CM effort will be sharply focused on identifying and removing barriers to MAT treatment engagement.  This will 
include completing medication authorization forms and insurance enrollment if necessary, and then making 
referrals to additional supports, including mental health treatment, housing, medical, legal support, and peer-based 
recovery supports in the community. The CM will work collaboratively with participants to remove barriers to care 
and to enhance program outcomes and to provide psychosocial support.   
The mobile team will insure that there is a clear plan for rapid engagement with ongoing treatment as soon as 
possible. Buprenorphine/naloxone will be provided during the time of transition to their long-term provider for up to 
1 month. Telephone support will be available should participants have questions or need assistance and the mobile 
team will also have daily contact with participants until they complete contact with their ongoing provider.  


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Comparison group – Treatment as usual 
During the same period of time, participants will also be recruited at the City of Philadelphia Behavioral Health 
System Behavioral Assessment Centers (BAC) and Crisis Response Centers (CRC) located at Episcopal Hospital 
serving Kensington area and Hall Mercer BAC/CRC (a University of Pennsylvania program) serving South 
Philadelphia area. Two research assistants from the TRI-PHMC will enroll and follow-up 125 participants at BAC/ 
CRC. The participants will complete the same assessments at baseline, 1- and 6-month follow-up. Authorization for 
the Philadelphia Department of Public Health to look shared information about their subsequent use of health 
department services (CARES database, http://www.phila.gov/hhs/data/Pages/Cares.aspx) will also be requested in 
the consent form.  Research staff will only conduct assessments.  Treatment engagement services will be provided 
by the staff of the BAC/CRC as usual.  
 
4.10 Subject Withdrawal  
Participants may choose to withdraw from the study at any time. They do this by providing verbal or written 
communication to this effect. Withdrawal from the study will not impact access to care. The Principal Investigator 
may withdraw subjects for reasons related to safety or for administrative reasons.  It will be documented whether or 
not each subject completes the study. Subjects who do not complete the intervention will continue to be contacted 
to complete follow-up visits (Month 1 and 6) to collect final evaluations and assess adverse events.   
 
5 
Statistical Plan 
5.1 
Data Quality 
Trained staff will review all forms prior to the completion of the study visit in an effort to minimize problems 
associated with missing values and incorrect skip patterns.  All assessments will be recorded on final version of the 
electronic Case Reporting Forms (eCRFs). eCRFs will also be developed to capture the results of all biological 
assessments.  All eCRFs will be completed using only participant identifying numbers and will not include names, 
addresses, or other data that could possibly be used to disclose the identity of the participant. Research staff will be 
responsible for entering all data into the secure web-based developed on REDCap (Research Electronic Data 
Capture). REDCap is designed to comply with HIPAA regulations. Data will be input with secure web 
authentication, data logging, and Secure Sockets Layer (SSL) encryption. REDCap allows multisite access. It 
allows real-time data entry validation (e.g. for data types and range checks), audit trails, and the ability to set up a 
calendar to schedule and track critical study events such as participant visits. 
The data quality control process associated with data processing will consist of the following stages: potential 
subject pre-screening for eligibility, registration, subject eligibility confirmation, first data entry, second data entry in 
the form of 100% interactive verification, data validation, and data auditing. A random 5% of the questionnaires in 
each wave of data collection (i.e., baseline, 1- and 6-month) will be subjected to database auditing throughout the 
trial. This data quality control process ensures that all stages of the data handling process will be subjected to data 
quality control. 
 
5.2 
Sample Size and Power Determination 
Our power analysis has been based on this primary aim. Our primary hypothesis is that participants who received 
rapid induction will more likely be engaged in ongoing treatment at 1- and 6-month follow-up than participants who 
sought treatment at BAC/CRC. We will test this hypothesis at a 5% level of significance.  Our principal interest is in 
the comparison of engagement rates between the mobile intervention and BAC/CRC groups, at months 1 and 6. 
Preliminary data suggest an engagement rate of about 20-30% in the BAC/CRC group. Assuming a steady loss to 
attrition that yields 80% completers, and a within-subject correlation of 0.3, the methods of Diggle et al. (Diggle, 
Heagerty et al. 2002) show that our sample size of 125 in each group yields 80% power for differences of about 
15% in engagement rates between the two groups (e.g., 80% power for BAC/CRC: 25% vs. Mobile: 40%, 
corresponding to a RR=1.6 and an OR=2.0) 
 
 


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5.3 
Statistical Methods 
Propensity score model to account for non-randomized allocation: The participants are not randomly 
assigned to the mobile rapid induction intervention and BAC/CRC groups, so it is possible that there will be 
confounding of the group effect with the effects of characteristics of the participants. We will use a propensity 
score approach (Rosenbaum 2002, Rothman, Greenland et al. 2008) to account for this. We will use a broad 
range of baseline variables as covariates in a logistic regression model predicting treatment group, including age, 
race/ethnicity, gender, number of previous overdoses, number of previous treatments for opiate use disorder, type 
of opioid used, and depression. The model will yield predicted probabilities of BAC/CRC group for all participants 
(the propensity score), and we will create a five-level ordinal variable based on the quintiles of the propensity 
score. We will then include this ordinal variable as a stratum variable in our models. 
 
Analyses for the primary aim: i.e. to evaluate the impact of the mobile, transitional MAT intervention on its ability 
to engage participants in targeted, existing MAT treatment slots at 1- and 6-month post-enrollment. For each of the 
1- and 6-month time points, we will classify participants as being engaged/not-engaged (where non-engaged will 
include dropped out or missing). We will compare the groups on engagement rates at the two time points using a 
repeated measures logistic regression model, incorporating the propensity score as described above (Diggle, 
Heagerty et al. 2002). The fixed effects will be binary indicators of treatment group and time point; we will test for a 
group by time interaction to assess whether the group effect differs at month 1 and month 6. As there are only two 
time points, we will use an unstructured covariance matrix to accommodate within-participant covariance.   
 
Analyses for Aim 2: We will also use a repeated measures model to compare the groups on the ASI drug 
composite score at months 1 and 6. The model will be similar to that described for the engagement analyses of Aim 
1, but with a beta distribution assumed for the response, to accommodate the bounded range (zero to one) of the 
ASI composite scores. We will compare the groups on the number of overdoses per patient using repeated 
measures Poisson regression models, if there is sufficient variability in the number of overdoses reported. If a low 
rate of overdoses causes convergence issues for the Poisson model, we will classify participants as having no 
overdoses versus at least one, and compare the groups using repeated measures logistic regression models.  
 
Missing data. For the longitudinal analyses described above, premature discontinuation from treatment and 
occasional missing daily use indicators will lead to incomplete data. The repeated measures models described 
above can make use of all available data provided by subjects, but the inferences drawn from them will be 
unaffected by the missing data only if the missing data can be regarded as ignorable, essentially meaning that 
missingness can be predicted/explained from the baseline data and from responses obtained prior to drop-out. We 
will assess the sensitivity of our main analyses to the presence of missing data by performing a sensitivity analysis, 
in which we will obtain estimates of the group effect under various non-ignorability assumptions. We will use 
selection models to examine the effects of missing data (Robins, Rotnitzky et al. 1995), in which we will explicitly 
model the probability of premature discontinuation at a time point as a function of baseline characteristics and 
responses at previous time points, using logistic regression models, and incorporate the predicted probabilities into 
a weighted analysis of the main hypotheses.  
 
Analyses for Aim 3:  We will estimate the total costs and per-participant costs of rapid initiation of MAT for opioid 
treatment engagement and use a cost-offsets approach to determine the economic value of this novel strategy. A 
cost-offsets approach requires a comparison of the total cost of the intervention (proposed enhanced procedure or 
treatment as usual) to the future costs of healthcare utilization avoided (i.e., benefits) due to the intervention.  
Healthcare utilization and medical costs will be estimated before and after participants receive either rapid initiation 
of MAT for opioid treatment engagement or treatment as usual.  Information on healthcare utilization will be 
collected from participants at each assessment when study-staff administer the Non-Medical and Other Services 
Form (NSMOS; detailed description in Instruments section).  Medical costs associated with these 
treatments/services will be estimated using Medicaid data.  Costs of the intervention will be collected by Julie 
Becher, PhD, using the Drug Abuse Treatment Cost Analysis Program (DATCAP; detailed description in 
instruments section).  She will interview staff in order to collect information on economic resource and cost 
variables such as staff salaries and benefits, study supplies and materials, major equipment, contracted services, 
building and facilities, and miscellaneous resources and costs.  Recognizing that full-time staff members may 
devote only part of their work time to the proposed study, she will conduct a time-in-motion study with relevant 
study staff in order to track their time devoted to this study.  Adjustments will then be made to salaries and benefits 
to reflect appropriate compensation attributed to this study.  Similar adjustments will be made to reflect the time that 
some equipment, buildings and facilities, and miscellaneous resources and costs are attributed to the proposed 
study.     
 


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Differences in pre-post medical costs will be used as an estimate of the value of downstream costs avoided due to 
the intervention.  We will compare these differences across groups for statistical significance.  We hypothesize that 
the medical costs after the intervention will be significantly lower for the participants that receive rapid initiation of 
MAT for opioid treatment than for the participants that receive treatment as usual.  The economic value of this novel 
intervention will be positive if the costs of this novel intervention are outweighed by the medical cost savings that 
result from participants obtaining long-term and consistent opioid treatment.  The proposed intervention is expected 
to aid with this process.  Therefore, we hypothesize that the cost of rapid initiation of MAT for opioid treatment will 
be outweighed by the resulting avoidance of healthcare utilization costs. 
 
We conduct our cost analyses from the perspective of the City of Philadelphia Department of Public Health since 
they may decide to scale-up the proposed services for other Philadelphia residents at risk of substance use 
overdose. Thus, we focus on healthcare utilization costs avoided as benefits of the proposed services.  We may 
extend our analysis later to use a societal perspective that would consider other economic costs, such as criminal 
justice costs, unemployment costs, and participant costs (e.g., travel, work time missed, childcare expenses, etc.). 
Inclusion of the economic costs avoided due to opioid use disorder treatment will make the economic value of the 
proposed intervention even more positive than it is hypothesized to be when considering only healthcare utilization 
costs avoided due to opioid use disorder treatment. 
6 
Safety and Adverse Events 
6.1 
Data Safety Monitoring Plan (DSMP) 
For this study, we will use established University of Pennsylvania procedures and infrastructure for data and safety 
monitoring. During the course of the study, safety and data quality monitoring will be performed on an ongoing 
basis by the Principal Investigators and the study staff. Study staff members are responsible for collecting and 
recording all clinical data using the established MOP. This includes ensuring that all source documents exist for the 
data on the Case Report Forms, ensuring all fields are completed appropriately, and ensuring that all corrections 
are done according to Good Clinical Practice (GCP). Any inconsistencies/deviations will be documented. The study 
Key Personnel will review data on an ongoing basis and will document reviews by initialing and dating reports. 
Study staff members conduct 100% quality assurance on data. 
Staff training will consist of an explanation of the protocol and review of the e-Case Report Forms. In addition, the 
duties of each staff person will be outlined and all applicable regulations will be reviewed. Senior personnel will 
supervise junior staff and provide re-training in the study protocol as needed. 
 
The Independent Monitor for this study is the University of Pennsylvania Center for Studies on Addiction DSMB. 
The DSMB will review the study every 6 months for all the duration of the study. The DSMB form could be find in 
Appendix at the end of this document. The PI will provide a summary of the status of the project that occurs during 
the reporting period.  These data will also be reported to CDC on an annual basis as part of the progress report. 
The DSMB report will include the participants’ socio-demographic characteristics, expected versus actual 
recruitment rates, treatment retention rates, any quality assurance or regulatory issues that occurred during the 
past year, summary of SAEs, and any actions or changes with respect to the protocol.  
6.2 
Adverse Events  
Adverse events that occur at any point in the trial will be identified, managed, and documented in accordance with 
reporting requirements of the the City IRB (the IRB of record) and the sponsor (the CDC). Adverse events are 
defined as negative biologic events and/or social harms that occur during the course of the trial. When needed, 
referrals to medical treatment or specialists will be made. All patients will have comprehensive psychiatric and 
medical screening prior to randomization and at each counseling and assessment where evaluations for AEs will be 
routine. A member of the research team will be available at all times to answer questions and assess possible AEs. 
Participants will be withdrawn from the study if they show severe deterioration or if determined clinically necessary 
for other reasons.   
 
Documenting Adverse and Other Negative Events 
We will document adverse events. The study will use an ANEF (Adverse and Negative Events Form), so that the 
distinction between an “adverse event” a “serious adverse event” (such as hospitalization or death), and a “negative 
event” (i.e., not meeting the criteria for adverse event) will be recorded. All adverse events will be documented on 
this form (along with a description of measures taken in response to the event).  Each time an adverse or serious 
negative event is identified, the project staff member who identified the event will complete an ANEF. The report 
form will include date, description of the event, duration, severity, measures used to ameliorate effects of the event, 


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and type of referral. Dr. Metzger will be notified immediately. The report form will be reviewed and signed by him 
and he will be responsible for ensuring that appropriate actions have been taken. 
 
In the event of a serious adverse event or a serious negative event, the Principal Investigator, Dr. Metzger will be 
notified via telephone or email within 8 hours of the event. The Principal Investigator will report the event to 
University of Pennsylvania IRB within 48 hours. If a serious adverse event occurs, the PIs will inform and consult 
with the Institutional Review Board within 24 hours of that event. 
 
Responding to Participant Needs Due to Adverse or Other Negative Events  
In all reports of adverse events, the research team’s first priority will be to ensure that appropriate responses to 
address the stated problem have been made. The project team has the ability to ensure access to available 
medical and social services. Staff will maintain contact with the participant until the problem is resolved or properly 
managed. 
6.3 
Internal Monitoring and Auditing 
Protocol monitoring will ensure that the research protocol specified is being followed without unauthorized 
deviations. Special emphasis will be placed on ensuring that the Consent Process is being completed properly and 
that adverse events are being properly reported.  Ongoing assessments of the data quality and timeliness will be 
undertaken. Participant recruitment and retention will be reviewed formally on a monthly basis.  Scientific or 
therapeutic developments that may have an impact on the safety of the participants or ethics of the trial will also be 
considered on an ongoing basis.  Weekly meetings will be held to monitor the progress of the trial.  These meetings 
will involve the Principal Investigators, Co-Investigators, Project Director, Site coordinator and other study staff.  
This will help to ensure standardized application of the protocol and will serve as an ongoing mechanism by which 
project staff and investigators will communicate in order to maintain a consistently high quality of study conduct.  
Concerns identified will be addressed through training and retraining of personnel.  
 
The study will be monitored by the PIs and co-investigators, and regulatory committees at Philadelphia Department 
of Public Health Institutional Review Board and University of Pennsylvania (i.e., IRBs, OHR). The following 
monitoring activities will be conducted according to standard operating procedures. These activities will be 
performed in association with database auditing and facilities monitoring by the PENN OHR and/or study staff. 
 
Database Auditing: Project director and RAs will review data entered into the database versus that recorded on the 
CRFs. All accrued cases will be subjected to database auditing throughout the duration of the trial. Depending on 
the data management findings, re-training will be provided, should problems such as increased errors be detected. 
 
Data Auditing: Project director and staff RAs will review safety data recorded on the CRF versus that contained on 
the actual source document (client chart, EHR). All accrued cases will be subjected to auditing throughout the 
duration of the trial. A Regulatory Binder Review by OHR will include the following essential documents: IRB 
Protocol, Consent Form and Amendment Approvals, IRB Closure Letter, List of Authorized Signatures, Laboratory 
Certifications, Protocol and Amendment Signature Pages, Financial Disclosure Questionnaires, and Monitoring 
Log. Additional monitoring by OHR may include: source documentation verification; adverse event documentation; 
and facility assessment. 
 
Data Security: Using network firewall technologies, the database will prevent the three major sources of data 
security problems: unauthorized internal access to data, external access to data, and malicious intent to destroy 
data and systems. Controlled user access will ensure that only appropriate and authorized personnel are able to 
view, access, and modify trial data. All modifications to data will document user access and data associated with 
the modification, as well as values prior to modification. 
 
Evidence of Training in Human Subject Research: All personnel working on this project will be required to review 
the protocol, complete training in the protection of human subjects and undergo training. 
 
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 (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance offices. 
 


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7 
Study Administration, Data Handling and Record Keeping 
7.1 
Confidentiality 
Since self-report and medical data will be collected and stored as part of this study, it is possible that subject 
privacy or confidentiality can be threatened. To address this concern, the Data Management System has set up 
several safeguards to prevent unauthorized access to study data. An automatically generated index number is 
assigned to a subject’s study identification number (unique for personnel and clients). A linked subject identification 
table is created for the storing of subject name, address and telephone contact information. This table uses the 
automatically generated index number rather than the study identification number. The master subject map and 
subject identification information tables are maintained in a separate database. Using this method, no identifying 
subject information is directly linked to medical information or other study data. For our multi-site trials, we have 
long-established protocols to guard against improper use of hard copies of data (e.g., locked files, numeric coding 
procedures). The present research team has not experienced the unauthorized use of study data. A web-based 
data collection procedure will minimize the possibility of loss of privacy or confidentiality. The risk of a potential 
breach of confidentiality is addressed in the informed consent documents. 
7.2 
Sources of Research Material 
All information will be derived from biological tests, standard clinical procedures, standardized interviews, and 
self-report questionnaires.  All subjects will receive a unique participant number that will be kept separate from 
any personal information that includes identifying variables such as name, address, relatives, place of work, etc.  
It is necessary for subject retention that personally identifying material be kept. 
7.3 
Computers and Databases 
Trained staff will review all forms prior to the completion of the study visit in an effort to minimize problems 
associated with missing values and incorrect skip patterns.  All assessments will be recorded on final version of the 
electronic Case Reporting Forms (eCRFs).  eCRFs will also be developed to capture the results of all biological 
assessments.  All eCRFs will be completed using only participant identifying numbers and will not include names, 
addresses, or other data that could possibly be used to disclose the identity of the participant. Research staff will be 
responsible for entering all data into the secure web-based developed on REDCap (Research Electronic Data 
Capture). REDCap is designed to comply with HIPAA regulations. Data will be input with secure web 
authentication, data logging, and Secure Sockets Layer (SSL) encryption. REDCap allows multisite access. It 
allows real-time data entry validation (e.g. for data types and range checks), audit trails, and the ability to set up a 
calendar to schedule and track critical study events such as participant visits.  
8 
Ethical Considerations 
8.1 
Risks 
The risks to participants in this study are related to: 1) side effects of buprenorphine/naloxone, 2) negative reactions 
to the questions asked, and, 3) violations of confidentiality and unwanted disclosures.    
 
• 
Risks associated with taking buprenorphine/naloxone: Because the medicine must be dissolved under your 
tongue, it may cause some mild irritation or leave a bad taste in your mouth.  The most common side effects 
of this FDA approved medication are headaches, pain, sweating, nausea, sleeping problems, stomach pains 
and constipation.  Buprenorphine/naloxone may impair mental and physical abilities involved in activities 
such as driving or operating machinery.  Buprenorphine/naloxone can cause breathing difficulties especially 
when mixed with other drugs like alcohol or benzodiazepines. The combination of buprenorphine/naloxone 
and alcohol is dangerous and combined use with benzodiazepines has been known to cause death. In rare 
cases, individuals have had allergic reactions to buprenorphine such as itching or rashes. 
 
• 
Unpleasant reactions to the assessment:  The questions about sexual activity and drug use might make 
some participants feel uncomfortable or embarrassed.  
 
• 
Unwanted disclosure:  It is possible that others might determine that an individual is in a study about 
treatment of opioid use disorder and assume that they are a drug user.  Some may react negatively and 
treat the participant unfairly, including family members and people in the community.  


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8.2 
Risk Minimization 
The following methods will be employed to minimize participant risk. 
 
Oversight and Monitoring: The PENN IRB will monitor the protection of human subjects and the safe and secure 
collection and storage of data. This committee assesses all studies before study initiation and then reviews 
protocols annually. The committee ensures the scientific, technical, and statistical soundness of the research and 
guarantees that methods for the ethical and safe treatment of human subjects are in place. The committee 
scrutinizes the scientific and ethical aspects of protocols and provides for an objective and ongoing assessment of 
the study’s scientific and ethical integrity. We will comply with all of the data and safety procedures outlined in the 
Data Safety Monitoring Plan and will seek regular recruitment advice from our Community Advisory Council. 
 
Quality Assurance Procedures and Participant Confidentiality: All subjects will be screened for eligibility using 
formal study forms and the Principal Investigator will regularly audit accrual to ensure that participants meet 
eligibility criteria. In addition, the Study Coordinator will audit all study files to ensure that questionnaires completed 
by subjects contain all items. Lastly, to protect confidentiality, all data will be numerically coded and information 
linking the numeric code to the subject’s name will be kept in a secured file cabinet and office. In addition, computer 
data files will be stored on password-protected computers and communication among the staff will use participant 
code numbers, not names. No information concerning data will be presented with participant names. Data will be 
collected in a private room or via telephone.  
 
Undue Influence/Coercion and Enrollment Status: In order to protect personnel participants from possible undue 
influence and coercion regarding enrollment in our study, the voluntary nature of the study is stressed throughout 
the informed consent documents.  
 
Adverse Event Reporting: In accordance with IRB guidelines, this protocol will employ the following mechanisms for 
adverse event reporting: 1) alert the IRB of any and all reports of serious adverse events; 2) informing all members 
of the study team of any and all reports of serious adverse events; and 3) notification to NIH of any actions taken by 
the IRB with regard to data safety monitoring. 
8.3 
Benefits 
The potential benefits of this study outweigh the potential risks. The study provides one-month of comprehensive 
treatment for opiate use disorder free of charge and link them to ongoing treatment.  
8.4 
Informed Consent Process / HIPAA Authorization  
Subjects will hear a study description where all study procedures, risks, and information about the study medication 
will be reviewed. Subject questions will be answered.  Following this presentation, the combined informed consent 
and HIPAA form will be completed by participants.  
 
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:  
• 
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 following personal health information will be collected as part of this study: 
1. Name 
2. Address 
3. Date of Birth 
4. Phone number(s) 
5. Electronic mail address 


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6. Dates of procedures and events (such as hospital admissions and discharges) relevant to side effect and 
adverse event reporting 
 
The following individuals and organizations may use or disclose personal health information: 
• 
The Principal Investigator (PI) and research staff 
• 
The Philadelphia Department of Public Health Institutional Review Board 
• 
The University of Pennsylvania Office of Regulatory Affairs 
• 
The University of Pennsylvania Office of Human Research (the office that monitors research studies) 
 
The Principal Investigators or research staff will inform participants if there are any changes to the list above during 
their active participation in the trial. 
 
Authorization for use of personal health information for this specific study does not expire while the study is no 
longer active (about 3 years). Paper research records are saved in an archive for 3 more years and are then 
destroyed. Study participant contact information may be held in a research database.  However, the School of 
Medicine may not re-use or re-disclose information collected in this study for a purpose other than this study 
unless: 
• 
The participant has given written authorization  
• 
The University of Pennsylvania or the Philadelphia Department of Public Health Institutional Review Boards 
grant permission 
• 
As permitted by law 
9 
Resources Necessary for Human Research Protection 
9.1 
Qualifications of principal investigator 
David S. Metzger Ph.D. (Principal Investigator): Dr. David Metzger, Ph.D. is Research Professor and Director of the 
HIV Prevention Research Division in the Department of Psychiatry of the Perelman School of Medicine at the 
University of Pennsylvania.  Dr. Metzger is currently the Co-Director of the Penn Mental Health AIDS Research 
Center and Director of its Developmental Core.  He is Director of the Prevention Science and Community 
Engagement Core of the Penn Center for AIDS Research and the Co-Director of the Prevention Clinical Research 
Site of the Penn Clinical Trials Unit funded by NIAID.  He began conducting research on the efficacy of substance 
abuse treatment in 1978.   Since 1989, he and colleagues from the HIV Prevention Research Division have been 
conducting AIDS related longitudinal trials among individuals at high risk of infection as well as those living with 
HIV.  Dr. Metzger’s research division has developed innovative community-based strategies for recruiting and 
retaining individuals into prospective research and clinical trials of biomedical and behavioral prevention 
interventions. He has led HIV prevention and treatment studies on agonist treatments and counseling strategies for 
opioid injectors in Philadelphia, China, Thailand, Vietnam and Indonesia. An overarching objective of his work has 
been to provide valid and reliable data that can increase understanding of the public health impact of participation 
in substance abuse treatment.  Currently, his work involves studies focused on understand the intersecting opioid 
and HIV epidemics in the US and testing strategies for the integration of the treatments for substance use disorders 
within HIV treatment and primary care settings. 


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9.2 
Research Staff 
The following research staff will be directly involved with the implementation and execution of the current study 
 
Name 
Study Role 
David Metzger, PhD 
Principal Investigator, University of Pennsylvania 
David Barclay, MD 
Study physician, Prevention Point Philadelphia 
Jose Benitez, MSW 
Site supervisor, Prevention Point Philadelphia 
Travis Cos, PhD 
Co-investigator, Public Health Management Corporation 
Karen Dugosh, PhD 
Co-investigator, Site supervisor, Public Health Management 
Corporation 
David Festinger, PhD 
Co-investigator, Public Health Management Corporation 
Kyle Kampman, MD 
Co-investigator 
and 
study 
expert 
physician, 
University 
of 
Pennsylvania 
Julie Kraut-Becher, PhD 
Co-investigator and health economist, University of Pennsylvania 
Kevin Lynch, PhD 
Co-investigator and Statistician, University of Pennsylvania 
Kendra Viner, PhD, MPH 
Co-investigator, Philadelphia Department of Public Health 
Brook Burkley, MSW 
Research coordinator, Public Health Management Corporation 
Cecile Denis, PhD 
Research Project Director, University of Pennsylvania 
 
 
Deb Dunbar, NP 
Nurse Practitioner, University of Pennsylvania 
Tiffany Dominique, BA 
Research Assistant, University of Pennsylvania 
Danielle Fiore, BS 
Database Manager, University of Pennsylvania 
Lia Pizzicato, MPH 
Database analyst, Philadelphia Department of Public Health 
TBN 
Research assistant, University of Pennsylvania 
TBN 
Nurse Practitioner, Prevention Point Philadelphia 
TBN 
Certified Recovery Specialist, Prevention Point Philadelphia 
TBN 
Case Manager, Prevention Point Philadelphia 
TBN 
Research Assistant, Public Health Management Corporation 
 
 
 
10 Study Finances 
10.1 Funding Source 
This study is funded through a grant from the Center for Disease Control and Prevention to the University of 
Pennsylvania. This study has a sub-contract with Prevention Point Philadelphia and another sub-contract with 
Public Health Management Corporation. Dr. Metzger will oversee all the finances.  
10.2 Conflict of Interest 
All investigators will follow the University of Pennsylvania Policy on Conflicts of Interest Related to Research. All 
Public Health Management Corporation and Prevention Point investigators will sign an agreement to follow the 
University of Pennsylvania rules.  


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10.3 Subject Compensation 
All participants will be compensated for participation (see Participant Compensation Schedules below). 
Compensation will be provided via debit card activated following completion of assessment visit.  
 
Participant Compensation Schedule 
Compensation Schedule 
Session 
Time Point 
Time and Effort 
Reimbursement 
Travel 
reimbursement  
1 
Baseline 
$30 
$5 
3 
Week 4 
$30 
$5 
8 
Week 24 
$30 
$5 
Total 
$90 
$15 
 
 
 
11 Publication Plan 
We will follow standard methods for publishing the results of this study and in accordance with any publication 
policies of the University, Department, Division or Research Center. Generally, University of Pennsylvania 
recommends that its researchers share data through communication channels such as speaking engagements and 
publications, postings on laboratory or institutional webpages, or data archives or enclaves, as appropriate. 
Because of the breadth and diversity of research supported by the NIH, the agency does not prescribe the 
formatting, presentation or mode of communication for research findings. However, it expects that data will be 
shared in a timely manner, typically no later than the acceptance for publication of the main findings from the final 
dataset.  
 
It is anticipated that the results of this study will be presented at scientific meetings and/or published in a peer 
reviewed scientific or medical journal. Dr. David Metzger will be the last author on abstracts and publications of the 
clinical data generated from this study. The investigators involved in the proposed protocol will fully adhere to the 
timeline stipulated in the NIH policy of dissemination of clinical trial information and publicly disseminate the 
research observations within 30 months from completion of the study. In addition, the investigators will ensure that 
the clinical trial as funded by the proposed award is registered and results information is submitted to 
ClinicalTrials.gov. 


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12 References 
 
1. American Society of Addiction Medicine. (2014). "Treating opioid addiction as a chronic disease." from 
https://www.asam.org/docs/default-source/advocacy/cmm-fact-sheet---11-07-14.pdf. 
2. Auriacombe, M., M. Fatseas, J. Dubernet, J. P. Daulouede and J. Tignol (2004). "French field experience 
with buprenorphine." Am J Addict 13 Suppl 1: S17-28. 
3. Auriacombe, M., P. Franques and J. Tignol (2001). "Deaths attributable to methadone vs buprenorphine in 
France." JAMA 285(1): 45. 
4. Auriacombe, M., F. Serre, C. Denis and M. Fatseas (2018). Diagnosis of Addictions. The Routledge 
Handbook of the Philosophy and Science of Addiction. H. Pickard and S. Ahmed, Routlege: 132-144. 
5. Bachhuber, M. A., C. Thompson, A. Prybylowski, J. Benitez, S. Mazzella and D. Barclay (2018). 
"Description and outcomes of a buprenorphine maintenance treatment program integrated within 
Prevention Point Philadelphia, an urban syringe exchange program." Subst Abus: 1-22. 
6. Baser, O., M. Chalk, D. A. Fiellin and D. R. Gastfriend (2011). "Cost and utilization outcomes of opioid-
dependence treatments." Am J Manag Care 17 Suppl 8: S235-248. 
7. Belenko, S., M. Hiller and L. Hamilton (2013). "Treating substance use disorders in the criminal justice 
system." Curr Psychiatry Rep 15(11): 414. 
8. Blum, K., M. Gold, H. W. Clark, K. Dushaj and R. D. Badgaiyan (2016). "Should the United States 
Government Repeal Restrictions on Buprenorphine/Naloxone Treatment?" Subst Use Misuse 51(12): 
1674-1679. 
9. Bretteville-Jensen, A. L., M. Lillehagen, L. Gjersing and J. B. Andreas (2015). "Illicit use of opioid 
substitution drugs: prevalence, user characteristics, and the association with non-fatal overdoses." Drug 
Alcohol Depend 147: 89-96. 
10. Caudarella, A., H. Dong, M. J. Milloy, T. Kerr, E. Wood and K. Hayashi (2016). "Non-fatal overdose as a 
risk factor for subsequent fatal overdose among people who inject drugs." Drug Alcohol Depend 162: 51-
55. 
11. Centers 
for 
Disease 
Control 
and 
Prevention. 
(2018). 
"Drug 
overdose 
death 
data." 
from 
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