Conditions: Opioid Use Disorder
Keywords: opioid use disorder Medication-assisted treatment Buprenorphine treatment Collaborative care model
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 71
Healthy volunteers: yes

Brief summary:
This pilot study examines the feasibility and acceptability of transitioning office-based buprenorphine treatment of opioid use disorder from physicians to pharmacists. Results from this study will inform the development of a future multi-site randomized clinical trial.

Detailed description:
The overall objective of this study is to explore the feasibility of transitioning the care of adult patients with opioid use disorder (OUD) who receive office-based buprenorphine treatment (OBBT) from physicians to pharmacists. Physicians will induce buprenorphine treatment and complete the stabilization phase before referring patients to pharmacists for the management of monthly maintenance visits. This study will assess the feasibility and acceptability of a collaborative care model between physician and pharmacist by measuring recruitment rate, treatment retention rate, treatment compliance rate, and participants' substance use. Other assessments measured will include treatment fidelity, participant, physician, and pharmacist satisfaction with OUD care, participant safety, and the pharmacists' use of electronic health records and the Prescription Drug Monitoring Program.

Arms:
arm 1: A single-arm study to evaluate the feasibility and acceptability of transitioning office-based buprenorphine treatment of adult patients with opioid use disorder from physicians to pharmacists.

Interventions: intervention 1: buprenorphine/naloxone intervention 2: Pharmacist-administered buprenorphine/naloxone maintenance care
Intervention descriptions: intervention 1: To relieve opioid withdrawal symptoms and craving, buprenorphine/naloxone will be prescribed by the study-physician and dispensed by the study-pharmacist on a monthly basis. The median expected dose is 16 mg daily, though adjustment by the study physician may be needed due to increased withdrawal and craving from previous study visits. Medication will be provided in the form of a sublingual film. intervention 2: Following buprenorphine/naloxone induction/stabilization with the physician, participants with opioid use disorder will be transferred to the care of pharmacists for the maintenance phase of treatment. Maintenance visits will occur monthly with the pharmacist at the pharmacy location for six months. Buprenorphine/naloxone will be dispensed by the pharmacist at the monthly study visits following participant assessment, communication with the physician, and prescription form the physician.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Study Protocol  
  
1/25/2019  
  
NIDA CTN-0075: Buprenorphine Physician-Pharmacist  
Collaboration in the Management of Patients with Opioid 
Use Disorder (Pharm-OUD-Care)  
  
NCT03248947  
 


 
 
 
  
  
  
NIDA CTN Protocol 0075  
  
Buprenorphine Physician-Pharmacist  
Collaboration in the Management of  
Patients with Opioid Use Disorder  
(Pharm-OUD-Care)  
  
 
Lead Investigator (LI):  
Li-Tzy Wu, ScD, RN, MA  
 
Co-LI:  
Paolo Mannelli, MD  
Protocol Date: January 25, 2019  
Version 7.0 
  
 


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PROTOCOL DEVELOPMENT TEAM  
  
Lead Investigator (LI):  
   
  
Li-Tzy Wu, ScD, RN, MA  
 
   
  
Mid Southern Node  
 
   
  
 
Duke University  
Co-LI:  
   
  
Paolo Mannelli, MD  
 
   
  
Mid Southern Node  
 
   
  
 
Duke University  
CCTN Scientific Officer:    
  
Udi Ghitza, PhD  
 
   
  
 
National Institute on Drug Abuse 
Data and Statistics Center (DSC):   
Paul Van Veldhuisen, PhD  
 
   
  
DSC Principal Investigator  
 
   
  
 
The Emmes Corporation  
Clinical Coordinating Center (CCC):  
Robert Lindblad, MD  
 
   
  
CCC Principal Investigator  
 
   
  
The Emmes Corporation  
  
 


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TABLE OF CONTENTS  
1.0  
LIST OF ABBREVIATIONS ............................................................................................ 1 
2.0  
STUDY SYNOPSIS AND SCHEMA ................................................................................ 3 
 2.1  
Study Objectives .......................................................................................................... 3  
 2.2  
Study Design ............................................................................................................... 3  
 
2.2.1  
Overview of Study Design ..................................................................................... 5  
 2.3  
Outcome Assessments ................................................................................................ 7  
 2.4  
Analyses ...................................................................................................................... 8  
3.0  
STUDY FLOWCHART .................................................................................................... 9 
4.0  
INTRODUCTION AND SIGNIFICANCE .........................................................................10  
 4.1  
Prescription (Rx) Opioid and Heroin Overdose Epidemic ............................................10  
 4.2  
Significance to the Field and Sustainability .................................................................13  
 4.3  
Policy Support for Transforming Pharmacy Practices to Address OUD .......................14  
5.0  
OBJECTIVES.................................................................................................................16  
 5.1  
Primary Objectives ......................................................................................................16  
 5.2  
Secondary Objectives .................................................................................................16  
 5.3  
Preliminary/Exploratory Objectives .............................................................................17  
6.0  
STUDY DESIGN ............................................................................................................18  
 6.1  
Overview of Study Design ...........................................................................................18  
 6.2  
Duration of Study and Visit Schedule ..........................................................................20  
 6.3  
The Rationale for Study Duration ................................................................................20  
7.0  
STUDY POPULATION ...................................................................................................21  
 7.1  
Inclusion Criteria .........................................................................................................21  
 7.2  
Exclusion Criteria ........................................................................................................21  
 7.3  
Participant Recruitment ...............................................................................................22  
 
7.3.1  
Special Populations to Consider ..........................................................................23  
 7.4  
Number of Sites ..........................................................................................................23  
 7.5  
Site Characteristics .....................................................................................................23  
 7.6  
Rationale for Site Selection .........................................................................................24  
8.0  
OUTCOME MEASURES ................................................................................................25  
 8.1  
Primary Outcome Measures .......................................................................................25  


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 8.2  
Secondary Outcome Measures ...................................................................................25  
 8.3  
Preliminary/exploratory Outcome Measures................................................................26  
9.0  
STUDY PROCEDURES .................................................................................................27 
 9.1  
Study Phases ..............................................................................................................27 
 9.2  
Screening and Baseline Procedures ...........................................................................27 
 
9.2.1  
Informed Consent Procedures (OBBT Clinic) .......................................................27 
 
9.2.2  
HIPAA Authorization and Medical Record Release Form .....................................27  
 
9.2.3  
Intake and Baseline Assessment (OBBT Clinic) ...................................................28  
 
9.2.4  
Randomization .....................................................................................................28  
 9.3  
Use of EHR Data ........................................................................................................28  
 9.4  
Study Interventions .....................................................................................................29  
 
9.4.1  
Overview of Study Interventions ..........................................................................29  
 
9.4.2  
Pharmacist Coaching Timeline and Procedures (see SOP for Pharmacist Coaching  
in the MOP) ........................................................................................................................30  
 
9.4.3  
SOP for the Management of Patients Receiving Pharmacy-Based OUD  
Management (Operational Care Agreement) (see MOP) ...................................................31  
 
9.4.4  
Replicability of Training and Treatment Structure .................................................31  
 9.5  
Buprenorphine Stabilization and Maintenance Visits ...................................................33  
 
9.5.1  
Buprenorphine Stabilization Visits ........................................................................33  
 
9.5.2  
Buprenorphine Maintenance Visits .......................................................................34  
 
9.5.3  
Early Termination Visit (at pharmacy) ..................................................................35  
 
9.5.4  
Counseling-Psychosocial Intervention .................................................................35  
 
9.5.5  
Other Medications and Concurrent Treatments ....................................................36  
 
9.5.6  
Handling of Missed Visits and Substance Use .....................................................36  
 9.6  
Participant Discontinuation ..........................................................................................36  
 9.7  
Blinding .......................................................................................................................37  
 9.8  
Participant Reimbursement .........................................................................................37  
10.0 STUDY ASSESSMENTS ...............................................................................................38  
 10.1  
Table 3: Study Assessment Timetable ........................................................................39  
 10.2  
Research Tasks: General Assessments .....................................................................41  
 10.3  
Research Tasks: Clinical Assessments .......................................................................42  


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 10.4  
Clinical Tasks ..............................................................................................................44  
 10.5  
Research Tasks: Safety Assessments ........................................................................45  
 10.6  Research Tasks: Treatment Compliance and Feasibility .............................................47  
11.0 STUDY TREATMENTS ..................................................................................................49  
 11.1  
Study Medication ........................................................................................................49  
 
11.1.1  
Study Medication Management ............................................................................49 
 
11.1.2  
Medication (Drug) Accountability Records ...........................................................49 
 
11.1.3  
Dispensing of Study Medication ...........................................................................49 
 
11.1.4  
Study Medication Storage ....................................................................................50 
 
11.1.5  
Used/Unused Medication .....................................................................................50  
 
11.1.6  
Lost Medication ....................................................................................................50  
 
11.1.7  
Medication Packaging ..........................................................................................50  
 
11.1.8  
Provisions for Access to Treatment after Study ....................................................50  
12.0 CONCOMITANT THERAPY ...........................................................................................51  
 12.1  
General Considerations ..............................................................................................51  
 12.2  
Prohibited Medications ................................................................................................51  
 12.3  
Medications Allowed During the Study ........................................................................51  
 
12.3.1  
Ancillary Medications ...........................................................................................51  
 
12.3.2  
Rescue Medications .............................................................................................51  
13.0 STATISTICAL ANALYSIS .............................................................................................52  
 13.1  
General Design ...........................................................................................................52  
 
13.1.1  
Study Hypothesis .................................................................................................52  
 
13.1.2  
Primary and Secondary Outcomes (Endpoints) ...................................................52  
 
13.1.3  
Recruitment .........................................................................................................52  
 
13.1.4  
Randomization and Factors for Stratification ........................................................52  
 13.2  Rationale for Sample Size and Statistical Power .........................................................52  
 
13.2.1  
General Approach ................................................................................................52  
 
13.2.2  
Projected Number of Study Sites .........................................................................53  
 
13.2.3  
Projected Number of Participants per Study Site .................................................53  
 
13.2.4  
Confidence Interval Estimation for Retention in Treatment...................................53  
 
13.2.5  Confidence Interval Estimation for Opioid Use  (self-report and UDS-based) .......55  


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 13.3  Statistical Methods for Primary and Secondary Outcomes ..........................................56  
 
13.3.1  
Recruitment Rate .................................................................................................56  
 
13.3.2  
Retention in Treatment ........................................................................................57  
 
13.3.3  
Substance Use ....................................................................................................57  
 
13.3.4  
Medication Compliance ........................................................................................57  
 13.4  
Significance Testing ....................................................................................................57  
 13.5  
Interim Analysis ..........................................................................................................57  
 13.6  
Exploratory Analysis ...................................................................................................57 
 13.7  
Missing Data and Dropouts .........................................................................................58 
 13.8  
Demographic and Baseline Characteristics .................................................................58 
 13.9  
Safety Analysis ...........................................................................................................58 
14.0 REGULATORY COMPLIANCE AND SAFETY ..............................................................59  
 14.1  
Regulatory Compliance ...............................................................................................59  
 14.2  
Statement of Compliance ............................................................................................59  
 14.3  
Institutional Review Board Approval ............................................................................59  
 14.4  
Informed Consent .......................................................................................................59  
 14.5  
Confidentiality .............................................................................................................60  
 
14.5.1  Health Insurance Portability and Accountability Act (HIPAA) ................................60  
 14.6  
Investigator Assurances ..............................................................................................60  
 
14.6.1  
Financial Disclosure .............................................................................................61  
 
14.6.2  
DEA Registration .................................................................................................61  
 14.7  
Clinical Monitoring.......................................................................................................61  
 14.8  
Inclusion of Women and Minorities .............................................................................62  
 14.9  
Regulatory Files ..........................................................................................................62  
14.10 Records Retention and Requirements ........................................................................62  
14.11 Reporting to Sponsor ..................................................................................................62  
14.12 Audits..........................................................................................................................63  
14.13 Study Documentation ..................................................................................................63  
14.14 Protocol Deviations .....................................................................................................63  
14.15 Safety Monitoring ........................................................................................................64  
 
14.15.1  
Safety Events ...................................................................................................64  


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14.15.2  
Reportable Safety Events .................................................................................64  
 
14.15.3  
Medical Monitor and Safety Monitor .................................................................64  
 
14.15.4  
Data and Safety Monitoring Board (DSMB) ......................................................64  
 
14.15.5  
Known Potential Toxicities of Study Drug .........................................................65  
 
14.15.6  
Potential Events Related to the Underlying Clinical Condition and/or Study  
Populations ........................................................................................................................65  
 
14.15.7  
Additional Study-Specific Risks ........................................................................65  
15.0 DATA MANAGEMENT AND PROCEDURES ................................................................67  
 15.1  
Design and Development ............................................................................................67  
 15.2  
Site Responsibilities ....................................................................................................67  
 15.3  
Data Center Responsibilities .......................................................................................67 
 15.4  
Data Acquisition and Entry ..........................................................................................67 
 15.5  
Data Editing ................................................................................................................67 
 15.6  
Data Transfer/Lock .....................................................................................................68 
 15.7  
Data Training ..............................................................................................................68  
 15.8  
Data Quality Assurance ..............................................................................................68  
16.0 TRAINING REQUIREMENTS ........................................................................................69 
17.0 PUBLICATIONS AND OTHER RIGHTS ........................................................................70 
18.0 SIGNATURES ................................................................................................................71 
19.0 REFERENCES ...............................................................................................................72 
20.0 APPENDIX A: DATA AND SAFETY MONITORING PLAN ...........................................79  
 20.1  
Brief Study Overview ..................................................................................................79  
 20.2  
Oversight of Clinical Responsibilities ..........................................................................79  
21.0 APPENDIX B: SUBOXONE® PACKAGE INSERT ........................................................81 
22.0 APPENDIX C: SIMULATION OF DATA FOR PRECISION ANALYSES ...................... 112  
  
  


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1.0  LIST OF ABBREVIATIONS  
Abbreviation  
Definition  
AACP  
American Association of Colleges of Pharmacy   
AE  
Adverse Event  
APhA  
American Pharmacists Association   
AST  
Aspartate Aminotransferase  
ALT  
Alanine Aminotransferase  
CARA  
Comprehensive Addiction and Recovery Act of 2016  
CCC  
Clinical Coordinating Center  
CDC  
Centers for Disease Control and Prevention   
CFR  
Code of Federal Regulations  
CLIA  
Clinical Laboratory Improvement Amendment   
CoC   
Certificate of Confidentiality   
CCTN  
Center for the Clinical Trials Network  
CDTM   
Collaborative Drug Therapy Management   
CMS  
Center for Medicare and Medicaid Services  
CPA   
Collaborative Practice Agreement  
CRF   
Case Report Form  
CTN  
Clinical Trials Network  
DEA  
Drug Enforcement Agency  
HHS  
Department of Health and Human Services  
DSC  
Data and Statistics Center  
DSM  
Diagnostic and Statistical Manual of Mental Disorders  
DSMB   
Data and Safety Monitoring Board   
ECG  
Electrocardiogram  
eCRF  
Electronic Case Report Form  
ED  
Emergency Department  
EDC  
Electronic Data Capture   
EHR  
Electronic Health Record  
ERC  
Ethics Review Committee  
FPFV  
First Participant First Visit  
FWA  
Federal Wide Assurance   
GCP  
Good Clinical Practice  
GEE  
Generalized Estimating Equation  
HIPAA  
Health Insurance Portability and Accountability Act   
IRB  
Institutional Review Board  
LFTs  
Liver Function Tests  
LI  
Lead Investigator  
LN  
Lead Node  
LPLV  
Last Participant Last Visit  
MAT  
Medication-Assisted Treatment  
MOP  
Manual of Operating Procedures  


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Abbreviation  
Definition  
MTM   
Medication Therapy Management  
NIDA  
National Institute on Drug Abuse  
OCA   
Operational Care Agreement  
OBBT   
Office-Based Buprenorphine Treatment  
OHRP  
Office for Human Research Protections  
OUD   
Opioid Use Disorder  
PDMP  
Prescription Drug Monitoring Program  
PI  
Principal Investigator  
RCT  
Randomized Controlled Trial  
Rx  
Prescription  
SAE  
Serious Adverse Event   
SAMHSA  
Substance Abuse and Mental Health Services Administration  
SOP  
Standard Operating Procedure  
SUD  
Substance Use Disorder  
SUSAR  
Serious Unanticipated Serious Adverse Reaction  
TLFB  
Timeline Followback   
UDS  
Urine Drug Screen   
US  
United States  
QA  
Quality Assurance  
 
 


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2.0  STUDY SYNOPSIS AND SCHEMA  
 
2.1  
Study Objectives  
The overall objective of this study is to explore the feasibility and acceptability of transitioning 
office-based buprenorphine treatment (OBBT) of adult patients with opioid use disorder (OUD) 
from physicians to pharmacists. Information generated from this pilot study will be used to inform 
the design of a future randomized controlled trial (RCT), which will test the effect of a 
physicianpharmacist collaborative care model in the management of patients with OUD. This pilot 
study will assess the feasibility and acceptability of the collaborative care model by measuring 
recruitment rate, treatment retention rate, treatment compliance rate, and participants’ substance 
use. Treatment fidelity; participant, physician, and pharmacist satisfaction with OUD care; 
participant safety; and the pharmacists’ use of electronic health records (EHR) and the 
Prescription Drug Monitoring Program (PDMP) will also be explored.   
The clinical significance of this pilot study is to explore a coordinated care model based on an 
operational agreement protocol among members of the same health care team that can shift the 
work burden from OBBT physicians to pharmacists during buprenorphine maintenance. Through 
this distribution of work, physicians are better enabled to treat a higher number of patients with 
OUD while helping pharmacists develop OUD and substance use disorder (SUD) care skills 
management, thus more effectively assisting in the reduction of medication diversion and doctor 
shopping among this patient population. This Operational Care Agreement (OCA; see SOP for 
OCA in the Manual of Operating Procedures (MOP)) defines the tasks and responsibilities of 
OBBT physicians and community pharmacists in the management of OUD. Under the OCA, a 
licensed OBBT physician diagnoses patients, supervises patient care, and refers patients to a 
pharmacist under a protocol that allows the pharmacist to perform specific patient care functions 
(Giberson et al., 2011). Under this agreement, pharmacists working within the context of a defined 
protocol are permitted to assume professional responsibility for performing patient assessments, 
administering medications, and monitoring medication regimens. The overall results of this study 
will open new research venues to accelerate collaborative opportunities among primary care 
providers, addiction providers and researchers, and pharmacists (e.g., NIDA, American 
Pharmacists Association).   
 
2.2  
Study Design  
This pilot study will use a non-randomized prospective design to collect feasibility data and 
operational information regarding the development of a physician-pharmacist collaborative care 
model defined by an operational care agreement for the management of patients with OUD. 
Pharmacists are health professionals. To explore the feasibility, this pilot study focuses broadly 
on licensed pharmacists in a variety of pharmacy settings, regardless of their prescriber status.  
The conceptual model of physician-pharmacist collaboration in the management of 
patients with opioid use disorder (Figure 1): This pilot study builds on existing evidence 
demonstrating the key role of the pharmacist within the health care team to help improve delivery 
and accessibility of medical treatment, as well as initial indications of a positive collaboration 
between physician and pharmacist in the management of OUD (APhA, 2014; DiPaula & 
Menachery, 2015). Specifically, pharmacists are ideally positioned to engage in efforts aimed at 
improving OUD care management and drug overdose prevention (APhA, 2014). Pharmacists not 
only dispense prescription medications (“gatekeepers”), but also may be involved in educating 
patients about safe medication practices (including medication storage and disposal), identifying 
red flags that warrant further investigation (e.g., diversion, improper prescribing, drug-drug 


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interaction), and engaging in care coordination (Green et al., 2015). Regulations are in place that 
would allow a more direct intervention of pharmacists in the management of OUD medications as 
part of a treatment team (Bluml, 2005; CMS, 2016a; Giberson et al., 2011). A physicianpharmacist 
collaborative buprenorphine maintenance practice piloted at the same clinical setting with the help 
of a medical assistant has suggested that patient care can be improved by providing a treatment 
continuum (DiPaula & Menachery, 2015). Benefits included enhanced communication, reduced 
physician burden, enhanced monitoring for diversion, and reduced cost (DiPaula & Menachery, 
2015). When patients initiate OBBT for OUD, they are expected to refill their buprenorphine 
medications approximately monthly and may receive medication use counseling at the pharmacy. 
The regular frequency with which patients visit the pharmacy to obtain buprenorphine refills offers 
an opportunity to evaluate pharmacy-based OUD care, including pharmacist-operated medication 
management under the supervision of a physician.  
  
Figure 1. The conceptual model of physician-pharmacist collaboration in 
the management of patients with opioid use disorder  
 
  
  
 
2.2.1  
Overview of Study Design   
Study design:  
For the purpose of evaluating the feasibility of and obtaining operational information to guide a 
future multi-site RCT of pharmacy-based OUD care, we will implement a non-randomized 
prospective study design that will take place over a period of approximately 16-19 months. The 
overarching goal of the study is to explore the feasibility of the pilot physician-pharmacist 
 
Patient OUD treatment initiation : office - 
based buprenorphine treatment (OBBT)  
clinicians initiate OBBT and prescribe  
buprenorphine. 
Continuation of OUD care via health  
promotion practice: pharmacists dispense  
medications, monitor Rx use and other risks  
( e.g., via urine drug testing), and conduct  
interventions or referrals.  
Outcome evaluation  
: 
OBBT provider’s views 
Pharmacist’s views 
Patient self - reports 
Clinical outcomes  
Coordinated  
care between  
OBBT  
physicians  
( prescribers) &  
pharmacists  
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collaborative OUD care model, as well as OUD treatment outcomes and safety measures. In this 
study, pharmacists are defined broadly as community pharmacists. The intent to include a range 
of treatment settings and choosing community pharmacists versus a smaller subset of clinical 
pharmacists is related to generalizability. In particular, the model of collaboration is designed to 
follow general guidelines and be applicable to the participation of pharmacists in other states 
across the U.S.   
The community pharmacist and the local pharmacy store are ubiquitous, similar to the mailman 
and post office. The identification of community retail pharmacists and pharmacies to be involved 
with buprenorphine treatment management guarantees a basic level of generalizability to the 
design and potential significance to feasibility data gathered in this pilot study.  
Study sites:  
Approximately 3-4 outpatient or ambulatory clinical sites will be included in this pilot study in order 
to explore the feasibility of implementing the interventional model in different clinical environments 
(e.g., academic, community-based, primary care). Each clinical site may include up to 4 
buprenorphine physicians. A pharmacy typically includes 2 or 3 pharmacists, and buprenorphine 
physicians often have established working relationships with certain pharmacies. To reflect the 
real-world situation, up to 4 buprenorphine physicians at one site will collaborate with up to 3 
pharmacists at a pharmacy in the management of patients with OUD.   
Study Population and Sample Size:  
1. Taking into account study attrition or dropout (Marcovitz et al., 2016; Soyka et al., 2008), 
approximately up to 140 adults aged 18 or older with DSM-5 OUD (defined by DSM-5 
OUD Checklist) who are stabilized on buprenorphine may be consented in this study over 
a period of approximately 6-7 months at 3-4 buprenorphine clinic sites in order for 70 
participants to be enrolled in the maintenance phase.  
2. Approximately 6-12 (3-4 sites) OBBT physicians: Each study physician may enroll 10 or 
more patients over a period of 6-7 months to meet the goal for enrolling up to 70 
participants (i.e., defined as meeting the study eligibility and enrolling into the maintenance 
phase). Each OBBT practice requires at least 2 OBBT physicians to participate in the 
study to reflect the real-life situation.   
3. Approximately 6-12 pharmacists (up to 3 community pharmacists at a pharmacy).  
Study Intervention/Pharmacy OUD care:  
An Operational Care Agreement (see SOP for OCA in the MOP) is used to specify the pharmacist-
provided patient care services that will be supervised by buprenorphine physicians.   
  
  
Table 1: Estimated Study Duration  
Phase  
  
Total  
Duration  
(Months)  
Location  
Task  
1 
M  
2 
M  
3 
M  
4 
M  
5 
M  
6 
M  
7 
M  
8 
M  
9 
M  
10 
M  
11 
M  
12 
M  
13 
M  
14 
M  
15 
M  
16 
M  
17 
M  
18  
M  
19  
M  
Pharmacist 
coaching  
  
  
3-6 M  
Pharmacy  
Buprenorphine 
treatment 
education and 
training  
X  
X  
X  
X  
X  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  


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 OBBT  
stabilization  
  
  
6-7 M  
OBBT  
Clinic  
Intake/Baseline:  
OBBT  
 Stabilization  
  
  
  
X  
X  
X  
X  
X  
X  
X  
  
  
  
  
  
  
  
  
  
Pharmacy  
OUD care  
  
  
13 M  
Pharmacy  
Maintenance 
and monthly 
follow-up  
  
  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
  
  
  
  
  
  
  
  
  
   
Pharmacy OUD Maintenance Care Phase  
 
  
  
  
  
EHR data 
collection & 
analysis  
16 M  
N/A  
(Medical  
Records)  
Compare 
outcomes with  
matched patients, 
if data available  
  
  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
Note: These study phases will overlap. Participants will be consented and enrolled on a rolling basis. Eligible 
participants may be consented as early as the beginning of the stabilization phase, upon the suggestion of 
the treating buprenorphine physician. Consented participants will not start pharmacy OUD management 
care until the stabilization phase ends, when they will be enrolled into the maintenance phase of the study. 
Pharmacists must complete the Pharmacist Coaching Training Phase before participating in the Pharmacy 
OUD Maintenance Care Phase.  
Study duration:  
Each paired study site will start study recruitment on a rolling basis, contingent on the timing of 
completing site initiation requirements. The estimated total study duration will be approximately 
16-19 months. Given the variation across study sites in completing study training and participant 
enrollment, the duration of study duration will vary by study site. The study will consist of four 
overlapping phases:  
1. Pharmacist Coaching Phase: It may take 3-6 months for all pharmacists and physicians 
to complete the coaching phase as specified by the SOP for Pharmacist Coaching in the 
MOP (3-6 months per pharmacist).  
2. Consent and Enrollment Phase: Patients with OUD who are considered clinically 
stabilized and in OUD treatment for no more than 12 months since the start of the 
current OUD treatment episode will be recruited and consented. Participants will be 
consented in the study during their stabilization visits and enrolled in the maintenance 
phase at the end of their stabilization visits. Enrollment will be completed on a rolling 
basis. It may take 6-7 months for all participants to be consented and enrolled.   
3. Pharmacy OUD Care Phase: This phase includes 6 monthly visits at the pharmacy. It 
will take about 13 months for all participants to complete this phase (6 months per 
participant).  
4. EHR Data Collection and Analysis Phase: This phase involves the comparison of 
Buprenorphine Visit Checklist outcomes between study participants and matched 
nonpharmacy treated patients using medical record data, if available. Data from this 
phase will be utilized as part of the exploratory analyses.   
Each participant will be asked to participate in this study for approximately 28-78 weeks. This 
range accounts for differences in the timing of study enrollment and individual differences in each 
participant’s buprenorphine treatment schedule (e.g., within 12 months since the start of the 
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Rationale for study duration:   
1. Pharmacist Coaching Phase: The coaching phase will include sufficient time for 
individual education and training, test taking, and coaching meetings (at least 1-2 per 
month). Based on the coaching plan, it is estimated that each pharmacist may complete 
coaching within 3-6 months.   
2. Consent and Enrollment Phase (to be completed during the OBBT care stabilization 
period): Based on the time allotted for consent and enrollment, it is estimated that each 
study site may recruit about 4-6 participants per month, or approximately 2-3 participants 
per buprenorphine prescribing physician per month. Potential participants will be 
prescreened and consented (i.e., sign the informed consent form) before the end of the 
stabilization period. The buprenorphine stabilization phase may take around 2-4 months 
per patient. However, the duration can vary depending on individual clinical conditions, 
with some patients needing more clinical monitoring by the buprenorphine physician 
and/or a longer time to be considered clinically stabilized. Thus, participant recruitment 
and consent may start before the stabilization phase is completed, and it will include 
patients receiving buprenorphine treatment for no more than 12 months for the current 
OUD treatment episode. The stabilization visit (Intake/Baseline) at the buprenorphine 
treatment clinic will be included among the study visits to establish treatment continuity 
with the subsequent pharmacist visits, as the participant is enrolled into the maintenance 
phase of the study.  
3. Pharmacy OUD Care Phase (Maintenance): Following buprenorphine induction and 
stabilization, maintenance visits will occur for 6 months, as this length of time is 
considered to be an adequate observation period to detect changes in treatment 
outcome among patients receiving OBBT for OUD (Mattick et al., 2014; Potter et al., 
2013; Soyka et al., 2008; Fiellin et al., 2006; Schottenfeld et al., 2005). From the 
buprenorphine physician standpoint, the proposed observation time seems adequate to 
explore the ability of a pharmacist to manage and comply with a range of clinical 
scenarios and potential challenges offered by office-based buprenorphine treatment.  
 
2.3  
Outcome Assessments  
One of the primary goals of the study is to monitor and reduce opioid and other drug use, as well 
as to explore the possibility of doing so with the help of the pharmacist. Outcome assessments 
will be conducted at each monthly visit throughout the maintenance phase of the study. Where 
applicable, assessments will be completed during the screening/baseline phase (following 
consent) to establish a baseline. Assessments will focus mainly on the feasibility and treatment 
outcome measures, which include the following:  
Primary:  
• 
Rate of recruitment among patients with OUD, defined as the number of participants 
recruited (i.e., signed the informed consent form) per month and by site. The average 
monthly rate of participants entering the maintenance phase among potential participants 
who were consented will also be calculated. We will also evaluate the number of potential 
participants pre-screened and the reasons for pre-screen failure and screen failure.  
• 
Treatment retention: proportion of scheduled visits completed for Visit 2 through Visit 7.  
• 
Opioid and other substance use: measured via urine drug screen and self-report (Timeline 
Followback).  


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• 
Medication compliance: measured by film count/dose reconciliation at each visit (proportion 
of expected buprenorphine use in relation to actual use).  
Secondary:  
• 
Treatment fidelity: adherence of physician and pharmacist to the Buprenorphine Visit 
Checklist using the Buprenorphine Visit Monitor form.  
• 
Indicators of satisfaction with treatment delivery measured by participants, pharmacists, 
and physicians using the Treatment Satisfaction Survey.  
• 
Participant safety measures over time: fatal and non-fatal substance-related overdoses and 
substance-related emergency department (ED) visits or hospitalizations, measured by self-
report.  
• 
Pharmacist’s use of the Prescription Drug Monitoring Program (PDMP) and 
communications with the physician(s) to address PDMP reports at each visit, measured via 
self-report.  
Preliminary/exploratory:   
• 
Pharmacist’s use of the EHR and PDMP to capture and monitor treatment outcome 
measures. Binary outcomes will be identified at each visit for measures from the 
Buprenorphine Visit Checklist that can be captured by or are missing from EHR, and their 
overlay with measures explored by the PDMP will be identified in a similar binary fashion. 
This outcome will only be assessed if EHR data are available.   
• 
Use of the EHR to compare treatment outcome measures. A comparison of  
Buprenorphine Visit Checklist outcomes may be performed between study participants and 
matched non-pharmacy treated patients, if EHR data are available.   
Depending on the access to the EHR, the EHR-related data elements may be collected by medical 
record abstraction.  
Safety Reporting: For the purposes of this protocol, the collection and reporting of safety events 
will be limited to those collected on the Safety Event Response Checklist (see Section 10.5), 
including overdoses and death of any participant who provided informed consent. This includes 
any substance use-related ED visits and hospitalizations. The Safety Event Response Checklist 
will be available to report any safety events that occur during the course of the study.   
 
2.4  
Analyses  
Because this is a non-randomized pilot study with a small sample size, descriptive analyses will 
be conducted to describe distributions of primary, secondary, and exploratory outcome measures. 
Random effects models will be considered and used to assess outcomes that are measured 
repeatedly throughout the maintenance phase.  
3.0  STUDY FLOWCHART  
  


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4.0  INTRODUCTION AND SIGNIFICANCE  
 
4.1  
Prescription (Rx) Opioid and Heroin Overdose Epidemic  
Rx drug misuse and addiction is an epidemic, and Rx drug overdose (mainly opioids) is a leading 
cause of accidental death in the United States (CDC, 2012; Volkow et al., 2014). The opioid 
overdose epidemic has been escalating continuously for over a decade (Straus et al., 2013; Rudd 
et al., 2016). Rx opioid misuse is linked with a surge of heroin use and serious heroin use 
problems (Pollini et al., 2011; Compton et al., 2016). Between 2010 and 2013, the rate of 
heroininvolved deaths almost tripled; non-Hispanic whites and adults aged 18-44 had the highest 
opioidinvolved death rate (Hedegaard et al., 2015). Most people who die from Rx opioid/heroin 


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overdose have been found to be adults 25-64 years old, non-Hispanic whites, or men; moreover, 
the mortality rate among women in recent years has increased rapidly to approach the rate among 
men (CDC, 2013a, 2015). Likewise, there has been an increase in opioid-involved treatment 
admissions to EDs and SUD treatment facilities (Crane, 2015; SAMHSA, 2015).  
The rise in rates of opioid overdose deaths is related to a parallel increase in the availability of Rx 
and illicit opioids (including heroin), as well as the prescribing practices of some physicians 
(Paulozzi et al., 2012; Rudd et al., 2016). Physicians are a leading source of Rx opioids for highrisk 
opioid users (CDC, 2012). Nonmedical opioid users, characterized by frequent use of nonmedical 
opioids, have been found to be likely to obtain opioids from a physician’s prescription or from a 
drug dealer (Jones et al., 2014). About 20% of the patients who were prescribed opioids have 
been prescribed high doses by either one or more physicians, and these patients were at a much 
higher risk for opioid-related overdoses (CDC, 2012). Prior data also suggested that about 25–
66% of individuals who died of Rx drug overdoses used opioids prescribed to someone else (CDC, 
2012). Opioid diversion or sharing is among the contributors to the opioid overdose epidemic 
(Paulozzi, 2012). Other clinical factors that may increase the likelihood of opioid overdoses 
include: medical conditions (especially chronic pain), use of high daily doses of opioids, history of 
mental health or psychiatric problems, substance misuse or SUD, co-use of opioids and 
benzodiazepines/sedatives, co-use of opioids and alcohol, and obesity (Gudin et al., 2013; 
McHugh et al., 2015; Paulozzi, 2012).  
Pharmacist-provided interventions:  
Pharmacists’ unique responsibilities and expertise in dispensing medications, conducting 
medication management or counseling (especially for chronic conditions), as well as their 
increased interest in participating in efforts aimed at reducing Rx opioid overdose deaths provide 
strong foundations to include pharmacists in addiction research and OUD interventions (APhA, 
2014). Pharmacists dispense Rx medications (e.g., opioids, naloxone) and have regular contact 
with patients at risk for opioid overdose. They are especially well-positioned to counsel patients 
and caregivers about opioid safety and provide naloxone rescue kits to the community.  
One key priority for combating the epidemic of opioid overdoses and addiction is to improve the 
access to medication-assisted treatment (MAT), especially OBBT, for people with OUD (Jones et 
al., 2015; Volkow et al., 2014). In 2015, an estimated 2 million Americans had prescription OUD 
in the past year, and about 0.6 million Americans had heroin use disorder in the past year 
(CBHSQ, 2016). Among persons with OUD in the past year, approximately 82% had prescription 
OUD only, 10% had heroin use disorder only, and 8% had both prescription OUD and heroin use 
disorder. Of persons with past-year OUD (prescription opioid or heroin use disorder), only about 
26% received any type of alcohol or substance use treatment services in the past year, and only 
19% received opioid-specific treatment (Wu et al., 2016). The low rate of service use for OUD is 
pervasive across all racial/ethnical groups; furthermore, this underutilization is the most marked 
amongst the uninsured, members of minority groups, and persons with prescription OUD only 
(i.e., without concurrent heroin use disorder) (Wu et al., 2016).  
One major barrier to expanding Medication-Assisted Treatment (MAT) for OUD is related to the 
limited number of buprenorphine providers who are available and willing to treat OUD with MAT 
(Jones et al., 2015). Non-metropolitan or rural areas have relatively high rates of opioid overdose 
deaths, but residents in these areas face additional barriers to receiving OUD treatment due to a 
greater shortage of mental health and/or SUD providers (CDC, 2012; Quest et al., 2012; 
Rosenblatt et al., 2015). There is a pressing need to identify collaborative care models that can 
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and to ensure that these models are applicable to remote areas where the access to 
buprenorphine-waivered physicians is limited. The main objective of the proposed 
physicianpharmacist collaborative care model is to address the significant barrier in the shortage 
of OBBT providers in the rural or remote areas by increasing pharmacists’ skills in managing 
patients with OUD. Because this is a new area of addiction research, a pilot study that is focused 
on exploring the feasibility of study recruitment and other study operations is considered 
appropriate.   
OUD is a chronic disorder that is often complicated by comorbidities (Wu et al., 2011a, 2011b). 
Adults with either prescription opioid or heroin use disorder tend to have an onset of OUD in their 
early 20s and experience more than one disorder episode, from which it may take up to 6-10 
years to recover (Wu et al., 2011a, 2011b). The monitoring requirements for buprenorphine 
treatment (which encompass an extended period of OUD treatment), unique medication 
properties, and risk for diversion justify a significant role for pharmacist intervention. Pharmacists 
are well-versed in preventative care, patient counseling, and medication education to improve 
medication adherence and patient safety. Clinical trials have found that pharmacist interventions 
or pharmacist-provided patient care can improve chronic disease management and patient 
outcomes (e.g., medication adherence, patient knowledge, quality of life or general health status), 
and such pharmacist interventions appear to work best when pharmacists work collaboratively 
with primary care providers (Chisholm-Burns et al., 2010; O’Malley, 2011; Tsuyuki et al., 2002).   
In light of increased concerns for primary care physician shortage, physician-pharmacist 
collaborative care models are considered an important solution for meeting patients’ primary care 
service needs and mitigating potential adverse effects due to physician shortage (Smith et al., 
2013). In the U.S., the supply of pharmacists is growing progressively (HHS, 2008). The total 
active pharmacist supply is projected to grow from 226,000 in 2004 to 305,000 by 2020 and 
368,000 by 2030. The number of full-time-equivalent pharmacists is projected to grow from 
191,200 in 2004 to 260,000 by 2020 and 319,000 by 2030 (HHS, 2008). Conversely, the U.S. is 
facing an increased level of primary care physician shortage. The demand for physicians has 
continued to grow faster than supply, leading to a projected shortfall of between 46,100 and 
90,400 physicians (12,500 to 31,100 of which are primary care physicians) by 2025 (AAMC, 
2015).  
When pharmacists are part of a healthcare team, they can reduce the physician burden by 
supporting a patient-centered care approach, lowering the cost but not the quality of care (CPNP, 
2016). Pharmacists’ patient care process and strategies may include: applying evidence-based 
practices, collecting and assessing subjective and objective information about the patient to 
develop and implement an individualized plan, monitoring and evaluating the effectiveness of the 
care plan, and modifying the plan in collaboration with other health care professionals and the 
patient as needed (JCPP 2014; ASHP 2014). Putting a pharmacist on a healthcare team can 
reduce adverse drug reactions and lower costs (CDC, 2013b). If patients can go to a pharmacist 
for day-to-day medication-related management of their non-urgent conditions, physicians can 
spend more time seeing patients that really need their expertise (CDC, 2013b; Smith et al., 2013).  
One codified approach to meet the goals of improving patient outcomes and reducing primary 
care physician burden is with a Collaborative Practice Agreement (CPA) between pharmacists 
and other health care physicians (CDC, 2013b). The CPA is a formal agreement in which a 
licensed physician makes a diagnosis, supervises patient care, and refers patients to a pharmacist 
under a protocol that allows the pharmacist to perform specific patient care functions (CDC, 
2013b). Under the conditions of this agreement, the pharmacists’ patient care services and tasks 
can be specified by the following terms (CDC, 2013b):  


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• 
Medication Therapy Management (MTM): MTM is a distinct service or group of services 
that optimizes therapeutic outcomes for individual patients (Bluml, 2005). MTM includes 
five core elements: medication therapy review, personal medication record, 
medicationrelated action plan, intervention and/or referral, and documentation and 
follow-up.   
• 
Collaborative Drug Therapy Management (CDTM): CDTM is a collaborative practice 
agreement between one or more providers and pharmacists in which qualified 
pharmacists working within the context of a defined protocol are permitted to assume 
professional responsibility for performing patient assessments, counseling, and referrals; 
ordering laboratory tests; administering medication; and selecting, initiating, monitoring, 
continuing, and adjusting medication regimens.   
In most states the law explicitly authorizes CPAs; in the majority of cases, it allows the pharmacist 
to provide MTM and CDTM, including, but not limited to, those providing direct contact with the 
prescribing physician (CDC, 2013b). The earlier Asheville Projects of pharmacist interventions in 
a collaborative healthcare team for diabetes, hypertension, and asthma care management in 
North Carolina demonstrated the feasibility and success of implementing pharmacist-provided 
care in improving clinical outcomes and lowering costs of care (Bunting et al., 2006, 2008; Cranor 
et al., 2003; Fera et al., 2009). Asheville Projects’ success has inspired the development of similar 
efforts (e.g., MTM, CDTM) by the American Pharmacists Association (APhA) and others (Smith, 
2009). The Asheville Projects’ model showed significant savings on overall health spending and 
improved patient health (e.g., a significant reduction in the number of sick days) (CDC, 2013b).  
Guided by the CPA, pharmacy health promotion practices, and OBBT guidelines, this pilot study 
will explore the feasibility of a physician and pharmacist collaborative care model that is defined 
by an Operational Care Agreement (OCA) between OBBT physicians and community pharmacies 
(APhA, 2014; Bluml, 2005; CMS, 2016a; Giberson et al., 2011; Green et al., 2015; Kampman and 
Jarvis, 2015). State-specific requirements of a CPA can limit the generalizability of the proposed 
study to other states. In addition, the national epidemic of opioid overdoses suggests the need for 
developing a feasible collaborative care model that can be applicable and acceptable to the 
general community pharmacists in order to increase its adoption and subsequent implementation. 
Thus, this pilot study seeks to explore the feasibility of a collaborative care model defined by an 
Operational Care Agreement that incorporates evidence-based OUD management care into the 
regular scope of community pharmacy practices, which fit into what pharmacists are doing or are 
prepared to do. An Operational Care Agreement between one or more buprenorphine physicians 
and pharmacists is developed to operationalize tasks and responsibilities in the management of 
patients with OUD for this pilot study (APhA, 2014; Bluml, 2005; CMS, 2016a; Green et al., 2015; 
Kampman and Jarvis, 2015).  
Involvement of pharmacists with OUD treatment:   
Recent federal opioid initiatives and the Comprehensive Addiction and Recovery Act of 2016 
provide a framework to promote pharmacists’ expanded roles in providing patient care activities 
to prevent opioid overdoses and improving OUD treatment (such as expanding access to 
naloxone and allowing partial fills for Schedule II controlled substances). The growing importance 
of pharmacists’ roles for OUD management is confirmed in the 2016 guideline document ‘Opioid 
Use Disorders: Interventions for Community Pharmacists’ (CPNP, 2016), which indicates a 
stepby-step process for managing safe and appropriate access to opioids while protecting the 
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The clinical importance of pharmacist support in OUD treatment management has been explored 
in the literature. In France, community pharmacies routinely supervise buprenorphine dosing. In 
addition to being supportive of primary care physicians in prescribing buprenorphine, this 
supervision has been found as useful as urine monitoring of drug use in preventing 
diversion/misuse (Fatseas and Auriacombe, 2007). Opportunities for pharmacy involvement have 
received preliminary evaluation in the United States. A survey of 179 pharmacies found that 77% 
were willing to participate in dispensing buprenorphine (Lofwall et al., 2010). Some reasons for 
limited interest from pharmacies included not stocking buprenorphine, being too busy, or having 
insufficient staff, which highlight the importance of a concerted effort held by a healthcare team. 
One study has suggested that close collaboration between pharmacists and physicians 
contributes to a reduction in the physician’s visit time and buprenorphine treatment cost (DiPaula 
and Menachery, 2015). A similar physician and pharmacist coordinated care model was utilized 
in the management of a methadone program in primary care with comparable positive results 
(Merril et al., 2005). These available but limited studies on OUD care support the proposed pilot 
study of a collaborative OBBT-physician and pharmacist OUD care model.   
Taken together and given the high prevalence of untreated OUD and the relatively low number of 
available OBBT providers, there is a critical need to develop coordinated care models that can 
mitigate the shortage of OBBT providers by improving buprenorphine-waivered physicians’ 
efficiency in managing OUD treatment and follow-up care (e.g., increasing the number of the 
patients with OUD treated by an OBBT provider). Community pharmacists’ expertise in 
pharmacotherapy management and monitoring, medication education, and care coordination can 
assist with OUD care management, which may contribute to the efficient delivery of OUD care 
(APhA, 2014; DiPaula and Menachery, 2015).  
 
4.2  
Significance to the Field and Sustainability  
To help combat the opioid epidemic, the U.S. Department of Health and Human Services (HHS) 
released a new rule in 2016 to allow qualified physicians to increase the total number of patients 
with OUD that they can treat with buprenorphine from 100 to 275 (Federal Register, 2016). The 
U.S. House of Representatives (2016) approved the Comprehensive Addiction and Recovery Act 
to promote a multi-faceted federal response to addressing the opioid epidemic, and which 
considers pharmacists key players of a healthcare team in curbing the opioid overdose epidemic 
(APhA, 2016a). Although the federal initiatives in supporting the expansion of OBBT are critical 
to improving OUD care (Stein et al., 2012), useful care models that can increase the efficiency of 
delivering the OBBT care to reach patients with OUD are needed to realize the stated goal.   
Pharmacists are the most accessible and convenient resources of healthcare professionals. Over 
60% of pharmacists reported that they could provide care for a minimum of 11 patients and up to 
100 patients per week (APhA, 2016b). Thus, the clinical significance of this pilot study is to explore 
a coordinated physician-pharmacist OBBT care model that can shift the work burden from OBBT 
physicians by enabling them to treat a higher number of patients with OUD while helping 
pharmacists develop OUD and SUD care skills and management. Because of the ubiquity of 
community pharmacies, such a coordinated physician-pharmacist care model could be further 
expanded and tested in future RCTs to determine the involvement of pharmacists with patient 
evaluation, buprenorphine induction, and delivery of OUD treatment in rural areas with reduced 
access to direct physician care to improve OUD treatment.  
As shown from the “landmark” Asheville Projects, the sustainability of the proposed pharmacy 
OUD care model will need to be evaluated from a value-based care program perspective (Bunting 
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health, better care, and lower costs (CMS, 2016b). This pilot test will focus on the feasibility and 
indicators of health and healthcare status. The results will be used to design a full RCT to evaluate 
full indicators of a value-based care model for informing sustainability and health policy. Although 
a cost analysis will not be implemented in the pilot study, it is appropriate for the future full RCT. 
The Centers for Medicare and Medicaid Services (CMS) and private insurance programs have 
supported the pharmacists’ MTM for qualified patients in an attempt to improve therapeutic 
outcomes, reduce the risk of adverse events, and lower cost (CMS, 2016a). Pharmacist 
collaborative care agreements have been implemented nationally and promoted by the Centers 
for Disease Control and Prevention (CDC, 2013b). Given that opioid overdose and addiction are 
among the most pressing public health crises in the nation, these multiple factors indicate the 
promise of sustainability.  
 
4.3  
Policy Support for Transforming Pharmacy Practices to Address OUD  
Pharmacists not only dispense opioids and other medications, but also can be involved in 
educating patients about safe medication practices and medication storage and disposal, 
identifying red flags of diversion or improper prescribing for further evaluation, and engaging in 
care coordination (Green et al., 2015). The American Pharmacists Association (APhA) has 
promoted efforts to expand the role of the pharmacist from a primary medication dispenser to a 
patient-centered care provider, which encourages pharmacists to use a team-based approach to 
engage patients in their pharmacy practice and optimize medication outcomes (APhA, 2014, 
2016b). One key focus of this expanded role is to increase training and education in prescription 
drug abuse and addiction for pharmacists, in order to facilitate the use of strategies or tools to 
address opioid addiction (APhA, 2014). Likewise, the American Association of Colleges of 
Pharmacy (AACP) announced that 54 colleges and schools of pharmacy have committed to 
joining the fight against prescription drug abuse by educating and training student pharmacists 
about lifesaving overdose interventions, including how to counsel patients and their family 
members on appropriate use of lifesaving medications (AACP, 2016).   
Furthermore, recent healthcare reforms (e.g., the Affordable Care Act) have shifted the landscape 
of healthcare delivery towards an integrated or coordinated model (e.g., medical homes, 
community-based care delivery models) by promoting the provision of the full spectrum care in 
order to improve the overall population health management. As a result, pharmacists have been 
progressively recognized as integrated members of team-based care delivery models, as they 
can provide some primary care services to meet the increased demands for primary care services. 
They can accomplish this by engaging in coordinated care across multiple settings to increase 
the efficiency in patient care and to mitigate the shortage of primary care providers (Smith et al., 
2013). Existing medical and OUD evidence suggests that the pharmacist can meet the challenges 
of managing buprenorphine treatment of OUD within the framework and specifications of a 
collaborative care agreement (APhA, 2014; CDC, 2013b; DiPaula and Menachery, 2015).  
Goal of this pilot study:  
Community pharmacists are an under-utilized resource for healthcare professionals in the OUD 
management efforts. A survey about pharmacists’ perceptions and attitudes toward dispensing 
buprenorphine to patients with OUD suggested that pharmacists expressed positive attitudes 
towards patients treated for OUD with buprenorphine (Raisch et al., 2005). The available research 
data provides the support to conduct a pilot study of the pharmacy-based coordinated OUD care 
model. The study goal is guided by the Pharmacists’ Patient Care Process Model (Figure 2) 
(JCPP, 2014). The overall findings from this pilot study will be used to guide NIDA CTN’s further 


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research designs, intervention components, and/or treatment approaches within pharmacy 
settings that are acceptable to pharmacists and feasible within pharmacy practices (JCPP, 2014).  
  
Figure 2. Pharmacists’ Patient Care Process Model  
• Collect  
The pharmacist collects subjective and objective 
information about the patient.  
• Assess  
The pharmacist assesses and analyzes the information in 
the context of the patient’s health goals.  
• Plan  
The pharmacist develops an individual patient-centered 
care plan.  
• Implement  
  The pharmacist implements the plan with other healthcare 
professionals and the patient.  
• 
Follow-up: Monitor and Evaluate  
The pharmacist monitors and evaluates the plan’s 
effectiveness and helps make modifications as needed.  
  
5.0  OBJECTIVES  
 
5.1  
Primary Objectives   
The overarching goal of this pharmacy OUD care pilot study is to explore the feasibility and 
acceptability of shifting the OBBT of OUD from physician to pharmacist care in order to inform the 
development of a future multi-site RCT. We will achieve this goal by pursuing four primary pilot 
study objectives. Specific measures of study objectives outcomes are defined in Section 8.0.   
1. Calculate the rate of recruitment among patients with OUD, defined as the number of 
participants recruited (i.e., signed the informed consent form) per month and by site. The 
average monthly rate of participants entering the maintenance phase among potential 
participants who were consented will also be calculated. The number of potential 
participants pre-screened and the reasons for pre-screen failure and screen failure will 
also be evaluated.  
2. Examine retention in treatment, as determined by the proportion of scheduled visits 
completed for Visit 2 through Visit 7.  
3. Examine prevalence of use of opioids/heroin and other substances, measured by the 
proportion of positive urine drug screens (UDS) at each visit and days of use of 


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opioids/heroin, and other substances as collected on Timeline Followback (TLFB) over 
the study duration.  
4. Determine medication compliance, measured by film count/dose reconciliation at each 
visit (proportion of expected buprenorphine use in relation to actual use).  
 
5.2  
Secondary Objectives   
The secondary objectives are to generate point estimates for:  
1. Treatment fidelity: adherence of physician and pharmacist to the Buprenorphine Visit 
Checklist (Section 10.4) as recorded on the Buprenorphine Visit Monitor form (Section 
10.6): proportion of visits showing 80% adherence or higher (Borrelli, 2011).  
2. Indicators of satisfaction with treatment delivery by participants measured using the 
Treatment Satisfaction Survey (adapted from Harland et al., 2005) at each visit:  
proportion of visits in which raters are satisfied (score of 4 on a Likert Scale of 1-5) or 
very satisfied (score of 5 on a Likert Scale of 1-5). Pharmacist and physician satisfaction 
with treatment delivery measured using the Treatment Satisfaction Survey on a monthly 
basis, and a proportion of physician and pharmacist monthly ratings of satisfied or very 
satisfied will be calculated.  
3. Participant safety, as measured by:   
a) Any fatal or non-fatal substance-related overdose measured by self-report.  
b) Any substance-related ED visit or hospitalization, measured by self-report.  
4. Pharmacist’s use of the PDMP and communications with physician to address PDMP 
reports including measures of multiple buprenorphine prescriptions, other class II and III 
medication prescriptions (e.g., communicate with physician to address PDMP reports and 
record it on the Buprenorphine Visit Checklist at each visit).  
 
5.3  
Preliminary/Exploratory Objectives   
1. Pharmacist’s use of the EHR to capture and monitor treatment outcome measures 
(monthly measures during the pharmacist OUD management phase). Binary outcomes 
will be identified at each visit for measures from the visit checklist, and their overlay with 
measures explored by the PDMP will be identified in a similar fashion. This outcome will 
only be assessed if EHR data are available.   
2. Use of the EHR to compare treatment outcome measures. A comparison of visit 
checklist outcomes may be performed between study participants and matched non-
pharmacy treated patients, if EHR data are available. Depending on the access to the 
EHR, these EHR data will be collected by medical record abstraction.  
  
 


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6.0  STUDY DESIGN  
 
6.1  
Overview of Study Design   
This pilot study is not designed to evaluate hypotheses. Given that the proposed study is a new 
area for the NIDA CTN and that it requires collaborative efforts among health professionals at 
multiple settings, the focus of this pilot study is to explore the feasibility and understand 
operational processes and potential challenges. Specifically, this pilot study is designed to explore 
the acceptability and feasibility of transferring OBBT of OUD from physician to pharmacist care 
and to inform the development of a future multi-site RCT that will compare physician-based and 
physician-pharmacist-collaborative OUD buprenorphine treatment. To maximize efficiency of 
research funding, we have selected design and measures to most effectively assess different 
aspects of the study. We have also considered the structure and organization of an OBBT 
physician office and of a community pharmacy in the real-world setting. We will track recruitment, 
reasons for pre-screen and screen failure, and request the feedback of study participants, 
buprenorphine physicians and pharmacists regarding satisfaction with treatment. Further, 
buprenorphine physicians and pharmacists will be asked to provide feedback on their satisfaction 
of the training/coaching process that will be utilized in the study. Because the study seeks to 
improve both the quality of OUD care and the involvement of pharmacists in OUD care, the OUD 
clinic care team and research staff will interact with community pharmacies based on an 
Operational Care Agreement.  
Although generalizability is not the main focus of the pilot study, we have incorporated key 
components to enhance the applicability and clinical utility of study results. First, we plan to 
include pharmacies that will collaborate with academic and non-academic sites. The diversity in 
setting is related to generalizability. Second, we will recruit “the general community pharmacists” 
to participate in this pilot study (i.e., any licensed pharmacist at an eligible site), and it will not be 
limited by a smaller subset of clinical pharmacists. In addition, our proposed ‘physician-pharmacist 
care agreement’ is designed to follow general clinical guidelines for community pharmacists that 
will allow community pharmacists to incorporate health care for patients receiving buprenorphine 
for opioid use disorder into their practice. This physician-pharmacist care agreement model will 
be applicable to pharmacists in other states across the country.   
We will track the problems encountered during the implementation of the study, including 
organizational readiness to deliver Medication-Assisted Treatment (MAT) services with feedback 
from physicians, pharmacists and participants, as well as operational feedback or comments from 
research staff members (e.g., issues discussed during regular project calls). A brief survey 
questionnaire will be developed to collect such information from physicians and pharmacists. We 
will discuss possible solutions and recommendations at the regular project meetings and 
summarize them in the final study report.  
Study setting:  
Approximately up to 4 clinical sites - including approximately up to 4 pharmacy sites - will be 
included in this pilot study in order to explore the feasibility and acceptability of the interventional 
model in different clinical environments (e.g., academic, community-based, primary care). Based 
on the practice considerations that 2 or more buprenorphine physicians often work together at a 
clinical site and that patients tend to have a regular pharmacy for refilling buprenorphine 
prescriptions, this pilot study will explore a collaborative care model between 2 or more 
buprenorphine physicians and pharmacists at a community pharmacy setting. In order to test the 
reproducibility and generalizability of the pilot study intervention in a future study, an Operational 


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Care Agreement (see SOP for OCA in the MOP) will be adopted to define and specify the 
pharmacist-provided patient care services that will be recognized by physicians, consistent with 
evidence-based OBBT of OUD.   
This pilot also will explore the use of the PDMP for OBBT care by physicians and pharmacists, 
and whether pharmacists have access to the EHR. Pilot data have shown the workflow, ease of 
use, and added technical value of presenting PDMP data in the EHR system by integrating the 
EHR and PDMP systems (Indiana, PDMP-INSPECT 2102). However, simultaneous use of the  
PDMP and EHR is typically limited to ED settings and has only been achieved through separate 
access to each system (i.e., the systems have not yet been successfully combined) 
(GreenwoodEricksen et al., 2016; SAMHSA, 2013).   
Design:  
This pilot study consists of a single-arm, 24-week (pharmacist OUD maintenance intervention), 
open-label, pilot study of pharmacist-provided buprenorphine maintenance treatment of OUD.   
Study participants and enrollment:  
Study participants will be adults aged ≥18 years with OUD who have completed buprenorphine 
induction at the study clinical sites. We will track the rate of participant recruitment (approximately 
up to 140 adults may be consented in order to enroll 70 participants into the study maintenance 
phase) and retention in treatment to estimate the duration of study recruitment and treatment 
required for a future multi-site RCT. Participants will be considered “recruited” once they have 
signed the informed consent form. The proposed sample size takes into account possible attrition 
during the early stage of the study, as prior studies suggest that approximately up to 50% of 
participants may drop out at some point during 6 months of treatment. Of note, approximately 
30% to 40% of the participants that drop out are usually lost to follow up in the induction-early 
stabilization phases of buprenorphine treatment (Marcovitz et al., 2016; Soyka et al., 2008). If the 
study timeline allows, additional participants will be recruited with the main intent to replace 
participants who discontinue from the study early (i.e., prior to Visit 2 or 3). Although all 
pharmacists are expected to complete the pharmacist training and coaching on buprenorphine 
treatment within 3-6 months, it is anticipated that pharmacists may complete this training after 34 
months. Thus, study recruitment may begin as early as the 3rd or 4th month. Pharmacists must 
successfully complete the buprenorphine treatment coaching phase before they can begin the 
pharmacist intervention.  
The study will recruit and consent patients with OUD that have been considered clinically 
stabilized and in the OUD treatment for no more than 12 months since the start of the current 
OUD treatment episode. During the stabilization phase, participants may be recruited into the 
study (i.e., complete the informed consent process and begin preliminary study assessments) 
before the last stabilization visit. The screening/intake and baseline assessments, together 
referred to as Visit 1 or the Intake/Baseline Visit, may be completed on more than one occasion 
within a short period of time, depending on the participant’s schedule. The Intake/Baseline Visit 
will include the stabilization visit at the OBBT physician’s office. Following completion of 
buprenorphine stabilization, participants will be transitioned to maintenance visits with the 
pharmacist. During this maintenance period, each participant will complete 6 monthly visits (i.e., 
every 4 weeks) at the pharmacy for buprenorphine management. Each of these 6 visits with the 
pharmacist will include the following procedures and assessments: collection of urine samples to 
confirm self-reported substance use/abstinence, medication compliance through recount and 
reconciliation, safety event assessment, psychosocial treatment engagement, and treatment 
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Primary outcomes:  
Primary outcomes of treatment participation retention at 24 weeks, opioid and other substance use, 
and medication compliance will be assessed at each visit.   
 
6.2  
Duration of Study and Visit Schedule   
Taking into account study attrition or dropout, approximately up to 70 adults stablized on 
buprenorphine may be consented and enrolled in the maintenance phase of the study over a 
period of approximately 6-7 months at 3-4 buprenorphine clinic sites. Each participant may be 
engaged in the overall study for approximately 28-40 weeks as follows:   
• 
Approximately 4-8 weeks: pre-screening, consent, and screening (beginning as early as 
the first stabilization visit), including the time for buprenorphine stabilization. It is possible 
that this period may last up to 16 weeks. Once all study eligbility criteria are confirmed, 
the participant may proceed to enrollment into the maintenance phase of the study.   
• 
24 weeks (6 visits total): maintenance treatment with monthly study visits.   
Buprenorphine physicians and community pharmacists will be involved with the study for an 
additional 3-6 months of education, training, and coaching (see Table 1). This coaching/training 
phase will be completed prior to enrolling the first study participant.   
 
6.3  
The Rationale for Study Duration  
(24-week pharmacy OUD intervention and timing of pharmacist treatment initiation)  
Study time periods have been developed to facilitate the participation of otherwise busy 
professionals and reproduce ‘real world’ clinical conditions. The coaching phase is designed to 
include sufficient time for individual education and training, test taking, and coaching meetings (at 
least 1-2 per month). Based on the time allotted for consent and enrollment, it is estimated that 
each study site may recruit about 4-6 participants per month, or approximately 2-3 participants 
per buprenorphine prescribing physician per month. The buprenorphine stabilization phase may 
take 2-4 months. However, the duration can vary depending on the individual clinical conditions, 
with some patients needing more clinical monitoring by the buprenorphine physician, and/or more 
time to be considered clinically stabilized. Thus, participant recruitment and consent may start 
before the stabilization phase is completed, and it will include patients receiving buprenorphine 
treatment for no more than 12 months for the current OUD treatment episode. Depending on the 
participant’s schedule, baseline assessments may be completed over multiple visits to the OBBT 
clinic. The stabilization visit at the buprenorphine treatment clinic (Intake/Baseline) will be included 
among the study visits to establish treatment continuity with the subsequent pharmacist visits. 
The main purpose of this pilot study is to assess the feasibility and acceptability of shifting the 
OBBT of OUD from physician to pharmacist in order to inform the development of a future multisite 
trial. We have, therefore, opted to study the phase of buprenorphine maintenance and test the 
aptitude of the pharmacist in managing treatment once the patient is considered clinically 
stabilized. A length of 24 weeks for the pharmacy OUD intervention allows sufficient time for 
detecting significant changes in outcomes as suggested in the literature (Mattick et al., 2014; 
Potter et al., 2013; Soyka et al., 2008; Fiellin et al., 2006; Schottenfeld et al., 2005) and confirmed 
by clinical experience.  


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7.0  STUDY POPULATION  
Taking into account study attrition or dropout (Marcovitz et al., 2016; Soyka et al., 2008), 
approximately up to 70 adults stabilized on buprenorphine may be consented and enrolled in this 
study (i.e., defined as meeting the study eligibility and enrolling into the study maintenance phase) 
over a period of approximately 6-7 months at 3-4 buprenorphine clinic sites.  
 
7.1  
Inclusion Criteria  
Individuals participating in the pilot study must:  
  
1. 
Be adults aged 18 years or older.   
2. 
If female, use adequate birth control methods.   
3. 
Meet DSM-5 criteria for past-year OUD.  
4. 
Have completed buprenorphine induction for OUD.  
5. 
Have expressed the intention to receive maintenance (≥6 months) buprenorphine 
treatment.  
6. 
Be willing to receive pharmacist administered buprenorphine maintenance treatment.  
7. 
Be willing and able to provide written informed consent and HIPAA authorization.   
8. 
Be able to read and communicate in English.   
9. 
Be able to comply with buprenorphine treatment policies.  
 
7.2  
Exclusion Criteria  
Individuals will be excluded from the pilot study participation if they:   
1. Have a serious medical, psychiatric or substance use disorder that, in the opinion of the 
study physician, would make study participation hazardous to the participant, 
compromise study findings, or prevent the participant from completing the study.   
Examples Include:  
Disabling or terminal medical illness (e.g., heart failure, cirrhosis or end-stage liver 
disease, acute hepatitis or moderate to severe renal impairment) as assessed by 
medical history, review of systems, physical exam, and/or laboratory assessments; 
current severe, untreated or inadequately treated mental health disorder (e.g., active 
psychosis, uncontrolled manic-depressive illness) as assessed by mental health history 
and/or clinical interview; current severe benzodiazepine or other substance use requiring 
medical detoxification; suicidal or homicidal ideation requiring immediate attention.   


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2. Have known allergy or hypersensitivity to buprenorphine, naloxone, or other components 
of the buprenorphine/naloxone formulation.   
3. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) liver enzymes 
greater than 5 times the upper limit of normal on screening phlebotomy performed within 
60 days prior to the date of the Intake/Baseline Visit (Visit 1).   
4. Have chronic pain requiring ongoing pain management with opioid analgesics.   
5. Currently in jail, prison or any overnight facility as required by court of law or pending 
legal action that couldprevent participation in study activities (i.e., unable to complete 6 
months of pharmacy-based OUD management).   
6. Pregnant or breastfeeding at the time of screening.   
 
7.3  
Participant Recruitment  
Study participants will be recruited from participating buprenorphine ambulatory, outpatient or 
primary care clinics, which will serve as study sites. These outpatient offices/clinics typically offer 
a broad array of on-site case management, social work, and counseling support services to 
engage and retain OUD patients in care. Members of the OUD clinic care team will be informed 
about the pilot study and asked to refer potential participants who are interested in learning more 
about the study to clinic research staff for pre-screening. Specific recruitment procedures (e.g., 
local educational activities, community outreach, print and web- based advertisements, etc.) will 
vary by site accordingly to local needs and established procedures of buprenorphine patient 
enrollment in research.  
Each Site Principal Investigator (PI) or Investigator will be a buprenorphine-waivered physician 
with a population of patients active in treatment sufficient to reach the recruitment goals. Each 
Site PI will work with at least one additional buprenorphine provider. We anticipate excellent 
cooperation between these providers in approaching potential participants and having the ability 
to function as backups for one another during the study period.   
If a potential study participant is interested in learning more about the study, a study staff member 
will meet with the participant to discuss the study. Potential participants will have initiated 
buprenorphine treatment (i.e., completed the induction phase) and will be briefly instructed 
regarding the study. If the potential participant is interested in joining the study, the study staff 
member will commence the formal informed consent process. Potential participants will have to 
demonstrate an understanding of the study requirements as part of the consent process prior to 
providing written informed consent. Strict ethical guidelines regarding professional conduct and 
confidentiality will be enforced for all study staff.   
Recruiting participants in clinical settings poses many challenges to pre-screening and consenting 
potential participants, including the rapid pace of care, interruptions in clinical workflow, clinic 
productivity requirements, space limitations, and participants not feeling well enough to meet with 
research staff (Berkman et al., 2001; Falcon et al., 2011). To minimize the impact of these 
challenges, research staff will spend considerable time interacting with clinical staff, familiarizing 
themselves with clinic patient flow, and learning how to communicate and negotiate with clinic 
staff regarding the necessary space and time to meet with potential study participants. Site 
Investigators will help facilitate negotiation of space and time requirements and serve as a 
resource to research staff regarding clinic procedures. Staff and sites with experience and 
expertise in buprenorphine treatment of OUD and conducting research studies in outpatient clinic 
settings will be prioritized for site selection.   


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The study staff member conducting the Intake/Baseline Visit will negotiate the location of the visit 
as necessary to protect confidentiality and respect clinic patient flow. Each study site will be 
compensated for space use based on the number of study visits. If necessary, the potential 
participant will be given the option to participate in study screening and consent procedures in a 
nearby exam room or staff/patient lounge if it is unoccupied, or to reschedule the visit for another 
time. If a participant feels ill during the interview, research staff will stop and reschedule the visit. 
Although all attempts will be made to conduct the intake/baseline assessments over 1 or 2 visits, 
it is possible that they may be completed over multiple visits to the OBBT clinic, depending on the 
participant’s schedule.   
 
7.3.1  
Special Populations to Consider  
This study may consent and enroll persons involved in the criminal justice system who are 
receiving OBBT for OUD and who will be available to complete 6 months of pharmacy-based 
OUD management. Parolees who are persons living in the community and sentenced to 
community-supervised monitoring may be consented and enrolled. Parolees who are detained in 
a treatment center as a condition of parole will NOT be consented and enrolled. Probationers 
(individuals wearing monitoring devices) may also be consented and enrolled, depending on their 
level of involvement with the criminal justice system. The study will not recruit persons 
incarcerated/detained in a correctional facility, persons who are pending trial, or persons who 
otherwise meet the definition of a prisoner as delineated in 45 CFR 46.303(c). However, the study 
will not exclude parolees and probationers if the persons will be available to complete 6 months 
of pharmacy-based OUD management. Those participants who become incarcerated or 
otherwise meet CFR-defined prisoner criteria during the course of their involvement with this study 
will be withdrawn from study participation. Research staff will assess each participant’s prisoner 
status at each visit, prior to conducting any research-related procedures. If a participant becomes 
incarcerated or otherwise meets the 45 CFR 46 definition of a prisoner, all applicable guidelines 
will be followed, including any required reporting to the IRB or other institution.   
 
7.4  
Number of Sites  
Approximately 3-4 primary care, outpatient, or ambulatory clinics will serve as study sites, with 
two or more buprenorphine-waivered physicians per site. Each primary care, outpatient, or 
ambulatory clinic will be paired with a community pharmacy site, such that up to 3-4 community 
pharmacy sites, with up to 3 pharmacists per site, will participate in the study. Each physician will 
supervise the activities in the study of one or more community pharmacists.   
 
7.5  
Site Characteristics  
Buprenorphine treatment clinics will be selected on the basis of the following characteristics:  
• 
Provide buprenorphine treatment to OUD patients at a primary care, outpatient, or 
ambulatory care setting.  
• 
Have a sufficient number of potential participants to achieve study recruitment goals (i.e., 
the OBBT clinic is expected to have the capability (e.g., structure, personnel) to treat at 
least 10 new patients per month).  
• 
Have at least two buprenorphine-waived physicians in good standing with their State 
Medical Board and willing to stipulate an Operational Care Agreement and coach and 
supervise pharmacists in the use of buprenorphine for the management of OUD.  


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• 
Have prior experience in clinical data collection or have previously participated in 
research/clinical studies.  
• 
Offer addiction counseling services as part of usual care on-site, or be able to refer 
participants to such services offered at an affiliated or nearby location (not required but 
encouraged).  
• 
Have adequate and safe tele-communication tools (phone, fax, email) to share protected 
health information regarding participants with pharmacists.  
Pharmacy sites will be selected on the basis of the following characteristics:  
• 
Have at least 2 years of experience with storing and dispensing class II and III controlled 
substances.  
• 
Have direct experience with dispensing buprenorphine treatment for OUD.  
• 
Have Clinical Laboratory Improvement Amendment (CLIA) certificate of Waiver to perform 
lab tests (or be willing to obtain the CLIA certificate of Waiver before the study initiation.)  
• 
Have at least one pharmacist in good standing with their State Board and willing to stipulate 
an Operational Care Agreement and comply with training and study guidelines.  
• 
Have available private areas (e.g., small room or office) to conduct visits with study 
participants.  
• 
Have adequate and safe tele-communication tools (phone, fax, email) to share protected 
health information regarding participants with buprenorphine physician(s).  
We will develop and use the site inventory/selection form (site survey) to collect this information 
from clinical and pharmacy sites in the geographical area identified for participation in the study. 
This form will briefly summarize the characteristics of the study and inquire on the characteristics 
of the site required for participation as reported above. In the case of the community pharmacies, 
we will also ask about reasons for participation and non-participation in the trial during discussions 
with potential study sites (e.g., lack of time, plethora of/insufficient staff, willingness/unwillingness 
to deal with substance users, concerns with losing business, intent to increase clientele, fear of 
not being up to the task, desire to show competency in the matter, etc.). We will use organizational 
readiness questions (to be completed by physicians, pharmacists, and clinic/pharmacy staff or 
managers) to explore participating sites’ barriers and/or facilitators to OUD treatment.  
 
7.6  
Rationale for Site Selection  
A pilot study is a requisite initial step in exploring a novel intervention or an innovative application 
of an existing intervention, which is often limited to testing the feasibility of the treatment at a 
single site (Leon et al., 2011). As the different components of treatment and the environment in 
which the treatment is delivered are particularly important in this case, we intend to assess the 
feasibility and generalizability of this model at different sites, including academic and community 
clinics. Sites that have an adequate number of new buprenorphine treated participants per month 
will be selected for participation.   
Depending on the number of study physicians at a study site, we will need to enroll approximately 
10-20 or more participants per site over 6-7 months of recruitment in order to meet the recruitment 
goal. We will track the reasons for pre-screen failure and the ratio of participants who have signed 
the informed consent form among those who have undergone the prescreening process (i.e., 
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were eligible on the pre-screen) to help project the expected recruitment in a subsequent multi-
site full-scale study.   
8.0  OUTCOME MEASURES  
 
8.1  
Primary Outcome Measures   
As this is a feasibility study, there are several outcomes of interest, all of which are important to 
evaluating the potentiality of a full-scale RCT and informing the power calculations and design of 
this subsequent RCT. There will be no formal hypothesis testing for these outcome measures, 
since only estimation is of interest.  
The primary outcome measures for this feasibility pilot study are:   
1. Rate of recruitment of participants into trial   
The recruitment rate will be assessed on a monthly basis until the enrollment target is 
reached. The recruitment rate is operationalized as the total number of participants 
consented in one month. The per-month proportion of consented participants reaching 
the the maintenance phase will also be calculated, as well as the per-month proportion 
of pre-screened participants that were consented. These rates will be used to estimate 
the speed at which a future multi-site RCT could consent, enroll, and randomize 
participants. Site-specific rates will also be computed to inform the design of the full-
scale trial.  
2. Retention in treatment  
Retention in treatment is defined as the proportion of scheduled visits completed (i.e., 
pharmacy OBBT maintenance phase visits) for Visit 2 through Visit 7. Not counting the 
Intake/Baseline Visit, the number of expected visits for all participants at the pharmacy is 
6, based on 1 visit per month for the 6 months of the pharmacy OBBT maintenance 
phase.   
3. Opioid and other substance use   
The prevalence of use of opioids/heroin, measured by the proportion of positive urine 
drug screens (UDS) at each visit and days of use of opioids/heroin as collected on 
Timeline Followback (TLFB) over the study duration will be examined.  
4. Medication compliance  
Buprenorphine will be provided in the form of buprenorphine-naloxone sublingual film 
(Suboxone®). Medication compliance will be measured by film count/dose reconciliation 
at each visit (i.e., film count). The proportion of expected buprenorphine use in relation 
to actual use will be calculated at each visit.  
 
8.2  
Secondary Outcome Measures  
There are also several secondary outcome measures. These outcomes will also be used to help 
explore whether and how to proceed with a future full-scale study.  
The secondary outcome measures for this pilot study are:  


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1. Treatment fidelity  
Treatment fidelity will be defined by adherence of physician and pharmacist to the 
Buprenorphine Visit Checklist (Section 10.4) using the Buprenorphine Visit Monitor form: 
proportion of visits showing 80% adherence or higher (Borrelli, 2011).   
2. Satisfaction of participants, physicians and pharmacists with OUD care   
Satisfaction with treatment delivery by participants will be measured using the Treatment 
Satisfaction Survey (adapted from Harland et al., 2005) at each visit. The proportion of 
visits in which participants are satisfied (score of 4 on a Likert Scale of 1-5) or very 
satisfied (score of 5 on a Likert Scale of 1-5) will be calculated. Pharmacist and 
physician satisfaction with treatment delivery will be measured using the Treatment 
Satisfaction Survey on a monthly basis, and a proportion of physician and pharmacist 
monthly ratings of satisfied or very satisfied will be calculated.  
3. Participant safety, as measured by:   
a) Any fatal or non-fatal substance-related overdose measured by self-report.  
b) Any substance-related ED visit or hospitalizationmeasured by self-report.   
4. Pharmacist’s use of the PDMP  
Pharmacist’s use of the PDMP and communications with physician to address PDMP 
reports, including measures of multiple buprenorphine prescriptions and other class II 
and III medication prescriptions, will be evaluated by self-report on the checklist at each 
visit.  
 
8.3  
Preliminary/exploratory Outcome Measures   
1. Pharmacist’s access to the EHR to capture and monitor treatment outcome 
measures   
Binary outcomes will be identified at each visit for measures from the Buprenorphine 
Visit Checklist, and their overlay with measures explored by the PDMP will be identified 
in a similar binary fashion. This outcome will only be assessed if EHR data are available.   
2. Use of the EHR to compare treatment outcome measures   
A comparison of visit checklist outcomes may be performed between study participants 
and matched non-pharmacy treated patients, if EHR data are available. Depending on 
the access to the EHR, such EHR data will be collected by medical record abstraction.  
9.0  STUDY PROCEDURES  
 
9.1  
Study Phases  
The pilot study will include 3 overlapping phases that are projected to take up to 16-19 months and 
reflect the fact that participants will be consented and enrolled on a rolling basis.   
  
Table 2: Timeline of study phases  
Phase  
Phase 1  
Phase 2  
Phase 3  
Location  
Pharmacy  
OBBT Clinic  
Pharmacy  


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Activity  
Pharmacist coaching, 
education  
Buprenorphine stabilization  
(pre-screening, consent, and 
screening)  
Buprenorphine maintenance  
Total 
Duration  
Up to 16-24 weeks (3-6 
months)  
Up to 16-20 weeks (6-7 
months)  
24 weeks (6 months) per 
participant;  
up 13 months for all participants  
to complete  
  
 
9.2  
Screening and Baseline Procedures  
 
9.2.1  
Informed Consent Procedures (OBBT Clinic)  
During the pre-screening phase, potential participants may be identified among patients with OUD 
receiving OBBT at the study sites. Patients will be either self-referred or referred by providers or 
other sources in the community. Patients who have completed OBBT induction and show interest 
in the pilot study will be approached by research staff before completion of the stabilization phase, 
and have explained to them the study procedures and the potential risks and benefits of 
participating in the trial. Staff will be available to answer questions about the consent form while 
participants are reviewing it. After signing the consent form, participants will be provided with a 
copy of the signed form to keep for their records. The process may take approximately 30 minutes. 
All participants who sign the Informed Consent Form will be added to the Master Enrollment Log. 
Following consent, participants will enter the screening phase of the study, which is comprised of 
the completion of screening and baseline assessments at Visit 1.  
Information regarding potential participants pre-screened and participants consented, as well as 
reasons for pre-screen and screen failure, will be collected. This information will be consolidated 
and developed into a web report.  
 
9.2.2  
HIPAA Authorization and Medical Record Release Form   
Study sites may be required by their institutions and/or the single IRB of Record to obtain 
authorization from participants for use of protected health information. Sites and/or a Lead Node 
representative will be responsible for communicating with the institution(s), IRB(s) or Privacy 
Board(s) and obtaining the appropriate approvals or waivers to be in regulatory compliance.   
Participants will complete Medical Record Release Forms throughout the study (as applicable), 
including at the time of Informed Consent and/or intake/baseline, to grant permission to study staff 
to review inpatient, outpatient, mental health, and substance use treatment medical records as 
needed.   
 
9.2.3  
Intake and Baseline Assessment (OBBT Clinic)  
The data collected from the intake/baseline assessments will be primarily utilized to determine 
each participant’s eligibility for continuation to the maintenance phase of the study. After the 
prescreening and consent process is complete (i.e., participant has signed the informed consent 
form), study staff will prepare a new research data record for the participant and administer the 
intake/baseline assessments. Because participants may be consented (i.e., sign the informed 
consent form) at any time during the stabilization visits, some participants may complete all intake 
and baseline assessments on the same day, while others may complete these assessments over 
the course of multiple visits (conducted within a short period of time). All efforts will be made to 


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conduct the intake/baseline assessments over 1 or 2 visits; however, in rare cases it is possible 
that it will take more than 2 visits to complete these assessments, depending on the participant’s 
schedule. The intake/baseline assessments will focus on collecting inclusion and exclusion 
criteria, demographics and other information related to recruitment (e.g., locator form, pregnancy 
and birth control assessment for women of childbearing potential). The baseline assessments, 
detailed in Section 10.0, will capture the participant’s clinical presentation and treatment history, 
as well as measures of efficacy and safety (see Study Assessment Timetable (Table 3)). In 
total, the intake/baseline assessments will take approximately 45-60 minutes to complete.   
Information on the reasons for screen failure (i.e., reasons the participant did not reach the 
maintenance phase) willl be collected and summarized in a web report.  
 
9.2.4  
Randomization  
This pilot study is not a randomized trial and thus will not utilize a randomization method.  
 
9.3  
Use of EHR Data  
The study team will obtain IRB approval to review and analyze available EHR data of matched 
non-study participants to collect biological and safety measures and for exploratory outcomes 
purposes, if the EHR data are available. Potential matching participants will be adults with OUD 
receiving buprenorphine treatment at the study sites who do not participate in this pilot study. 
They will be selected based on participant inclusion and exclusion criteria. Participants’ key 
clinical information will be obtained from the EHR data and compared with some key information 
from the Buprenorphine Visit Checklist. Investigators will request a waiver of both HIPAA 
authorization and informed consent from the IRB of Record to use this de-identified information 
for the analysis. Further, the pharmacists’ access to the EHR data will be explored by the 
Buprenorphine Visit Checklist. We expect some challenges regarding pharmacists’ access to the 
EHR data; therefore, pharmacists’ access to the EHR data are considered exploratory for the pilot 
study.  
Throughout the study and/or at the end of the study, research staff will obtain proper permission 
to review each participant’s medical record to abstract relevant medical information from all study 
visits, including the Intake/Baseline Visit. The research staff will conduct the medical record review 
with the EHR or paper records located at the practice. If a practice is not adopting EHR, paper 
records will be used to collect biological test results and safety information.   
  
  
 
9.4  
Study Interventions  
 
9.4.1  
Overview of Study Interventions  
Typically, the initiation phase of OBBT begins with a low dose of buprenorphine and is followed 
by increasing doses over several days to minimize the likelihood of precipitating opioid withdrawal. 
After initiation, buprenorphine may be taken once or twice daily. Once a stable dose of 
buprenorphine is established, a therapeutic dose can be maintained over a stable period of time 
(SAMHSA, 2004; Kampman and Jarvis 2015).   
This study will assign a pharmacist to manage the buprenorphine maintenance phase of the 
treatment (Figure 3: Transitional Treatment Model and Roles). In this pilot study model, the 
buprenorphine physician will be responsible for various aspects of patient treatment following 
induction, including:   


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• 
conducting or reviewing patient assessments (including but not limited to drug testing),   
• 
prescribing buprenorphine in accordance with Schedule III requirements,   
• 
managing buprenorphine stabilization,   
• 
record keeping that may be referenced for a DEA inspection, and   
• 
providing clinical guidance, coaching, and supervision to each pharmacist, who is in turn 
managing a portion of buprenorphine maintenance treatment.  
Figure 3: Transitional Treatment Model and Roles  
 
The research staff will assist with the study data collection and facilitate the communication 
between physician and multiple pharmacists, as well as between providers and LIs.   
Co-LI (Mannelli) will serve as a coaching and research/clinical supervisor, as well as a treatment 
fidelity monitor.  
9.4.2  
Pharmacist Coaching Timeline and Procedures (see SOP for 
Pharmacist Coaching in the MOP)  
The training phase will be completed within 3-6 months before the pilot clinical trial phase. This 
training phase will include pharmacist education and coaching regarding OBBT management, as 
well as study-specific protocol and assessment training. Pharmacist coaching for OBBT 
management will involve buprenorphine physicians, pharmacists, and Lead Investigators.  
Coaching model rationale:  
The approach that will be utilized in this study intends to provide standard, up-to-date knowledge 
that a physician who wants to be certified for buprenorphine would receive, including specific 
evaluations and passing grades. In addition, physicians and pharmacists are educated on aspects 
of the study relevant to their intervention and interactions.  
 
physician coaching: pharmacist education and training 
CONTENTS 
- Learning materials:  
- study SOPs, PCSSMAT modules 
- Buprenorphine waiver training 
- Visits and notes supervision 
physician: buprenorphine stabilization and supervision 
ROLE 
- Conducting or reviewing patient  
assessments,  
- Prescribing buprenorphine in  
accordance with Schedule III  
requirements,  
- Managing buprenorphine treatment,   
- Record keeping that may be referenced  
for a DEA inspection,  
- Providing clinical guidance, coaching,  
and direct supervision to the pharmacist,  
who is in turn managing a portion of  
buprenorphine maintenance treatment. 
- Assessing safety events   
pharmacist: maintenance visits 
ROLE 
- Medication reconciliation and patient  
education 
- Rating opioid withdrawal and craving 
- Collecting drug use self - report, toxicology  
samples 
- Monitoring PDMP 
- Medication dispensing 
- Monitoring compliance with psychosocial  
interventions 
- Monitoring comorbid psychiatric and medical  
conditions,  
- Monitoring family, social, financial, and legal  
issues 
- Monitoring safety events 


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Coaching model overview:   
Coaching meetings: Each pharmacist will complete between 8-10 coaching meetings 
(either in-person or web-based) with the supervising physician. Each meeting will be 
approximately 1-2 hours in duration (at least 1 hour).   
Coaching participants: Study physicians will have an active part and engage study 
pharmacists in this coaching model. In order to complete the coaching phase and proceed 
with the study, each pharmacist must pass the training tests where provided (i.e., based on 
the PCSS-MAT or equivalent materials) and participate in at least 80% (8 of 10) of the 
coaching sessions.   
Coaching and Study Materials: The Providers' Clinical Support System (PCSS) for 
Medication-Assisted Treatment (MAT) educational modules (encompassing 5 mandatory 
modules and 1 optional module) will be utilized throughout this study, including the following 
subjects: clinical evaluation of SUD, overdose, withdrawal, comorbid psychiatric disorders, 
and buprenorphine legislation/guidelines/biological testing (PCSS-MAT, 2016).  
The following OBBT-related coaching materials are expected to be completed within 3-6 months 
for all study pharmacists and physicians:   
• 
SOP for the Operational Care Agreement,  
• 
PCSS educational modules 1-2,  
• 
PCSS educational modules 3-4,  
• 
Educational module 5,  
• 
Buprenorphine waiver training and decisional trees.  
In addition, physicians and pharmacists are required to participate in protocol–specific 
presentations and meetings (e.g., study design, materials, forms reviewing, study MOP).  
Each pharmacist will be individually evaluated for satisfactory training completion, and 
pharmacists who are not considered ready at the end of the training (as operationalized in the 
MOP) will be required to receive additional individual training before their participation in the study 
begins.  
9.4.3  
SOP for the Management of Patients Receiving Pharmacy-Based 
OUD Management (Operational Care Agreement) (see MOP)  
The SOP for the Operational Care Agreement will address:  
• 
Visit components, biological testing: routine and extra testing, treatment monitoring and 
compliance (diagrams, forms);  
• 
Buprenorphine dose and dose changes criteria (associated decisional tree);  
• 
Treatment plan;  
• 
Special presentations;  
• 
Management of no-show participants, overdose prevention, withdrawal management, 
psychiatric or medical emergencies;  


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• 
Contacts with supervising physician, research staff, LIs; coaching as articulated in the 
treatment phase of the study.  
 
9.4.4  
Replicability of Training and Treatment Structure  
Intervention Fidelity (Evaluation of Treatment Integrity) and Quality Control   
Integrity Evaluation and Treatment Fidelity evaluation will measure the replicability of training. 
Elements of fidelity include a common training path for pharmacists and buprenorphine 
prescribing physicians, which offers standard knowledge, measurable treatment goals and results 
(e.g., passing scores). As structured, the training will be replicable and generate reproducible 
results. To address possible weaknesses of the training and treatment structure, the LIs will collect 
feedback from the physicians and pharmacists who participated in the pilot study at the end of the 
coaching phase and again after last study visit using the ad hoc Buprenorphine Education 
Feedback Questionnaire (see Section 10). This feedback will be used to improve the training 
phase and help to develop a ‘curriculum’ that will be utilized in a future randomized, multisite 
study. A progress note checklist (Buprenorphine Visit Checklist, Section 10) will be used by 
physicians and pharmacists so that treatment structure, fidelity, and replicability can be monitored. 
The use of the Buprenorphine Visit Checklist will facilitate supervision of treatment quality of the 
physicians’ and pharmacists’ care of patients. Quality control will also include LI 
supervision/resolution of clinical and research queries.   
Supervision of Pharmacists  
The buprenorphine certified physician will supervise 1 or more pharmacist(s) during the 
buprenorphine maintenance phase. Supervision will be exerted as follows:   
(a) Confirm the daily dose of buprenorphine at the end of each visit via email, telephone, 
computer teleconference (e.g., Skype), or other type of telecommunications;  
(b) Conduct regular clinical review meetings, in person or via remote communication, 
regarding all open clinical cases. These meetings will occur monthly or more frequently if 
physician, pharmacist, or LIs deem it necessary; and   
(c) Communicate with the pharmacist regarding specific patients. At any time, pharmacist or 
physician may request a contact regarding a specific patient. A research staff member 
will facilitate interactions and keep track of reason, characteristics, and frequency of the 
communications.  
Approximately twenty percent (20%) of each pharmacist’s progress notes, randomly selected, will 
be scored by the supervising physician using the Buprenorphine Visit Monitor form (Complete, 
Incomplete, or N/A for each section of the Buprenorphine Visit Checklist). A score of Incomplete 
in any section will be discussed between the pharmacist and physician as part of the supervision 
activity, and all discussions will be documented. If more than two Incomplete sections are 
identified per visit, this will determine a change of course and closer monitoring of visits/notes. If 
more than two insufficient visits (i.e., with more than 2 Incomplete sections) are identified per 
pharmacist, or by decision of LIs, additional training will be assigned.  
Supervision of Physicians and Pharmacists  
The Co-LI (Mannelli) has more than 25 years of clinical and research experience in the 
management of buprenorphine for OUD. For evaluation purposes, Co-LI (Mannelli) will randomly 
monitor pharmacist visits and score treatment fidelity based on scoring sheets, which will weigh 


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different aspects of treatment and therapeutic interaction. At least 1 visit will be performed per 
pharmacist, and the Co-LI will perform the supervision by using the Buprenorphine Visit Monitor 
Form (Section 10). The Co-LI will intervene in any unresolved issue between the physician and 
pharmacist when prompted by either physician or by a research staff member, particularly in 
cases of unanswered requests and low-scored or incomplete Buprenorphine Visit Checklists. The 
Co-LI will also participate in at least one regular clinical review meeting per physician/pharmacist.  
Tracking Implementation Problems and Readiness to Deliver Treatment  
We will collaborate with CTN DSC/CCC about the approach to track the problems encountered 
during the implementation of the study with feedback from physicians, pharmacists, participants, 
and help from a research staff member. We will discuss possible solutions and recommendations 
at regular project meetings and summarize them in the final study report. The resulting tracking 
list/document can be reported to the DSMB upon request.  
In addition, we will collaborate with CTN DSC/CCC to conduct two brief surveys of physicians and 
pharmacists, as well as staff/managers of participating sites, regarding organizational readiness 
in implementing MAT services (a first survey before the study initiation, a second survey after the 
completion of the study). The content of the survey will be framed to understand barriers and 
facilitators of implementing MAT at their facilities (e.g., administrative support, staffing, training, 
and organizational processes in place). Participants of the organizational readiness survey will be 
compensated via a $25 gift card for completion of each survey ($50 total).  
  
  
 
9.5  
Buprenorphine Stabilization and Maintenance Visits  
 
9.5.1  
Buprenorphine Stabilization Visits   
(OBBT clinic visits with buprenorphine physician; up to 16-20 weeks per participant)  
The stabilization phase has begun when a patient is experiencing no withdrawal symptoms, 
minimal or no side effects, and no longer has uncontrollable cravings for opioid agonists 
(SAMHSA, 2004; Kampman and Jarvis 2015). At this point, the physician should identify the 
lowest dose of buprenorphine at which the patient discontinues or markedly reduces the use of 
other opioids without experiencing withdrawal symptoms, significant side effects, or cravings. 
Reduction and elimination of opioid/heroin use (via self-report and negative urine toxicology) 
represent the key target goals of this phase. Participants will enter into a maintenance phase of 
treatment when a stable dose of buprenorphine is achieved and maintained for at least 3 weeks.  
During the stabilization phase, patients complete visits with the buprenorphine physician regularly 
(e.g.,  weekly, bi-weekly, or monthly), depending on their clinical status. A research staff member 
will be present at the OBBT clinic to help with research procedures and physicians’ tasks as 
needed. Physicians will complete the Buprenorphine Visit Checklist, and the research staff 
member will help with other research-specific assessments and forms, including UDS and TLFB 
collection. Following the last stabilization visit or after the patient is considered clinically stablized, 
the participant will be referred to pharmacist care for maintenance visits.   
A stabilization visit will take approximately up to 1 hour to complete and will consist of the following 
elements:  
Stabilization Visit Elements:  
1. Medication use and patient education.  


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2. Opioid withdrawal using the Clinical Opioid Withdrawal Scale (COWS) worksheet (Wesson 
and Ling, 2003) and opioid craving on a self-rated visual analogue scale of 0100 (McMillan 
and Gilmore-Thomas, 1996).   
3. Collection of substance use via urine toxicology samples and self-report using the TLFB.   
4. Monitoring the PDMP.   
5. Medication management.  
6. Compliance with psychosocial interventions via the Psychosocial Counseling Attendance 
form.  
7. Concomitant medications assessment.  
8. Psychiatric and medical problems, family, social, financial, and legal issues, using a 
modified version of the Problem List Form (NIDA, 1998).  
9. Safety events.  
10. Suicidality risk evaluation.   
11. Treatment plan evaluation (including medication dose adjustments, as needed).   
Data for the following components may be abstracted from the medical record, if available, if they 
occured during the current treatment episode’s stabilization phase:   
1. Physical exam, up to 6 months prior to consent.   
2. Vital sign assessment, up to 1 month prior to consent.   
3. Monitoring of the PDMP, up to 1 week prior to consent.  
4. Treatment plan, up to 1 month prior to consent.  
 
9.5.2  
Buprenorphine Maintenance Visits   
(Participant visits with pharmacist; 24 weeks per participant)  
When a stable buprenorphine dose is achieved (i.e., the same dose of buprenorphine is 
maintained for at least 3 weeks), patients enter into the maintenance phase of treatment. In 
accordance with clinical practice, maintenance visits will occur with the pharmacist at the 
pharmacy location at least monthly, and study-specific data will be collected at weeks 4, 8, 12, 
16, 20, and 24. Visits may also be conducted at shorter intervals, depending on participants’ 
clinical stability. If a participant relapses or destabilizes, he or she should be monitored more 
frequently. During the maintenance phase, less direct medication dose management and 
increased monitoring of problematic behavioral areas are usually needed (HRSA, 2016).  
In the management of buprenorphine maintenance, the pharmacist will be required to implement 
and expand a patient centered care approach already implemented in collaboration with other 
members of the health care team to optimize medication outcomes in the treatment of other 
medical conditions (CPNP, 2016). This process includes the following evidence-based practices: 
collect and assess subjective and objective information about the patient to develop and 
implement an individualized plan, monitor and evaluate the effectiveness of the care plan, and 


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modify the plan under supervision of physician and in collaboration with patient as needed (JCPP, 
2014; ASHP, 2014).  
Each maintenance visit will take approximately 30-45 minutes to complete and will consist of the 
following elements:  
Maintenance Visit Elements:   
1. Film count/dose reconciliation and patient education.  
2. Opioid withdrawal using the Clinical Opioid Withdrawal Scale (COWS) worksheet and opioid 
craving on a self-rated visual analogue scale of 0-100.   
3. Collection of substance use via urine toxicology samples and self-report using the TLFB.   
4. Monitoring the PDMP.   
5. Compliance with psychosocial interventions via the Psychosocial Counseling Attendance 
form.  
6. Concomitant medications assessment.  
7. Psychiatric and medical problems, family, social, financial, and legal issues, using a 
modified version of the Problem List Form.  
8. Safety events.  
9. Suicidality risk evaluation.   
10. Monitoring the EHR (optional: depending on the access to the EHR).  
11. Treatment plan evaluation by physician (including medication dose adjustments, as 
needed).   
12. Dispensing medication following the prescription of supervising physician.  
A research staff member will be present at the pharmacy to help with research procedures and 
pharmacists’ tasks as needed. Pharmacists will complete the Buprenorphine Visit Checklist, and 
the research staff member will help with other research-specific assessments and forms, including 
UDS and TLFB collection (Table 3).  
The pharmacist and supervising physician will sign the Operational Care Agreement. As specified 
in the MOP, scheduling of an earlier follow up visit (2-3 weeks) may be prompted by: poor 
compliance with medication, study visits, or counseling attendance, or worsening of opioid use 
(higher number of days of use than the previous month or positive toxicology following a negative 
sample).  
The results of evaluations will be discussed after the visit with the supervising physician who will 
release buprenorphine prescription contingent on the evaluation results, and the date of the next 
appointment will be confirmed with the patient. At the end of the 24-week pharmacist management 
period, the patient will return to the buprenorphine physician’s care.  


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9.5.3  
Early Termination Visit (at pharmacy)  
This visit will be completed at the pharmacy site for participants who discontinue study 
participation early (including those who stop buprenorphine treatment prematurely). Baseline 
clinical and safety measures will be repeated as detailed in Section 10.  
 
9.5.4  
Counseling-Psychosocial Intervention  
As mandated by guidelines, all providers must have the ability to refer buprenorphine-treated 
patients to behavioral treatment (SAMHSA, 2004). Despite these regulations, the optimal content 
of this behavioral treatment remains unknown for this patient population. To date, studies have 
not provided enough evidence to demonstrate a significant benefit of any one form of psychosocial 
intervention (such as the addition of a specific type of counseling or self-help group attendance to 
buprenorphine treatment), and different forms of behavioral treatment can coexist (Copenhaver 
et al., 2007; Dugosh et al., 2016). Thus, no specific counseling model will be suggested to 
participants. Counseling is not delivered as part of the study interventions and is conducted 
separately from the physician or pharmacist-managed buprenorphine visits, but the occurrence 
of the event at the study site or other site will be recorded at each visit. At the beginning of 
treatment, it is recommended that participants attend psychosocial counseling at least once per 
week. As treatment progresses, counseling frequency will be individualized based on each 
participant’s characteristics and needs, and may lessen in frequency over time.   
Each participant’s compliance with the psychosocial intervention will be assessed by the 
Psychosocial Counseling Attendance Form at each visit. The case report form will assess whether 
the participant’s counseling attendance matches what is recommended in the treatment plan. This 
will be accomplished by participants’ self-reports and may be confirmed by contacting or calling 
the participant’s designated family member/significant other (Psychosocial Counseling 
Attendance Form, Section 10).   
 
9.5.5  
Other Medications and Concurrent Treatments  
This study will not restrict the use of concomitant prescribed medications, with the exception of 
opioids. Concurrent medical and psychiatric treatments will be under direct control of the 
prescribing physician and will be assessed at each scheduled visit for their potential to interact 
with buprenorphine. Concurrent treatments will be recorded using the Concomitant Medications 
form and Non-Drug Therapy Log.   
 
9.5.6  
Handling of Missed Visits and Substance Use   
Given that opioid agonist substitution therapy primarily targets illicit opioid use, and that complete 
and continuous abstinence from substances requires some time to be achieved, it is possible that 
opioid or other substance use may present a significant safety concern in the management of 
participants receiving the buprenorphine therapy.   
• 
If the participant misses a scheduled visit, no additional buprenorphine prescription will 
be given, and one alternative visit will be scheduled as a make-up visit.   
• 
If opioid use is reported or suspected at any time during treatment, the participant will be 
contacted to perform at least one random urine drug use test prior to the next scheduled 
visit if the treating physician deems it appropriate.   


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• 
If the participant misses three consecutive visits (e.g., the first monthly visit, the following 
early substitution visit, and the second monthly visit), he/she will be discontinued from 
study and contacted by pharmacist/research staff to complete the Early Termination 
Visit and be referred back to the buprenorphine physician.   
• 
The same provision will be adopted when as many as six visits in total need to be 
rescheduled, or in the case of three consecutive or five non-consecutive positive 
opioid/heroin urine drug tests.   
• 
Any non-prescribed use of benzodiazepines that is detected will prompt analogue 
measures to those adopted for opioid use. The abuse of other substances or alcohol is 
strongly discouraged as part of the treatment plan and will be discussed with the 
participant, reviewed with the supervising physician and Co-LI (Mannelli) if needed, and 
reported in the visit progress note.   
• 
Missed visits will be documented using the Missed Visit CRF. Under the consideration 
of Lead Investigator(s), phone interviews may be used to collect study assessments for 
missed visits.  
 
9.6  
Participant Discontinuation  
All participants will be followed for the duration of the study (24 weeks for pharmacy OUD 
maintenance) unless they withdraw consent, stop the study medication, die, or the investigator or 
sponsor decides to discontinue their enrollment for any reason. In addition to what is described in 
Section 9.5.6 (discontinuation based on missed visits and/or illicit substance use), reasons for the 
investigator or sponsor to terminate a participant from the study may include, but are not limited 
to: study participation becoming unsafe, the participant becoming a threat to self or others, lack 
of funding, or DSMB early termination of the study for safety reasons. Of note, participants who 
discontinue study medication for any reason will be discontinued from the study. If a participant is 
discontinued from the study, an Early Termination Visit and End of Medication form should be 
completed as soon as possible following participant discontinuation to assess the participant’s 
safety.  
 
9.7  
Blinding  
This study will not utilize a blinding method.  
 
9.8  
Participant Reimbursement  
Participants will be compensated for their time and transportation to study visits. Participants will 
be paid $50 for the Intake/Baseline Visit (i.e., for completing assessments for this visit) and $50 
for the last study visit (either Visit 7 or the Early Termination Visit). Participants will be paid $40 
for attending each of the other visits (Visits 2, 3, 4, 5 and 6). If the participant completes all study 
visits, total reimbursement will be $300. No reimbursement will be provided for extra visits.  


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10.0 STUDY ASSESSMENTS  
The primary focus of the pilot clinical trial is to explore and assess needs and capability to support 
CTN’s new efforts in engaging pharmacists and connecting pharmacists with primary care and 
ambulatory providers (e.g., team-based coordinated care model) in OUD-related intervention 
trials. Study assessments will focus on the feasibility (e.g., recruitment, implementation of the 
intervention), OUD treatment outcomes, and safety measures.  
  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suicidal Risk (SUR) 
 
P4 Screener (P4S) 
 
Patient Health Questionnaire (PHQ 
- 9 )  
Medical History 
 
PhenX Core Tier 1 measures  
-  
Quality of Life and  
Tobacco Us 
e History 
 
Substance Abuse and Addiction PhenX Core Tier  
1 
2 
and  
 
Timeline Follow 
b 
ack (TLFB) 
 
Urine Drug Screen (UDS) 
 
DSM 
- 
5 
OUD Checklist 
 
Research Tasks: Clinical Assessments 
 
Missed Visit  
 
Protocol Deviations 
 
Study Completion 
 
End of  
Medication 
 
Form 
 
Buprenorphine Log 
 
Treatm 
ent Satisfaction Survey 
1  
Demographics 
 
Locator Form 
 
Inclusion/Exclusion Checklist 
 
Master Enrollment Log 
 
Medical Release Form 
 
Informed Consent/HIPAA 
 
Prisoner S 
tatus Assessment 
 
Research Tasks: General Assessments  
 
Assessment/Activity 
 
Location 
 
Study visit numbe 
r  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Training/ 
 
coaching 
 
Pharmacy/ 
 
OBBT clinic 
 
 
 
x  
x  
x  
x  
x  
x  
x  
x  
 
 
 
 
 
x  
x  
x  
x  
x  
x  
x  
x  
Screening and 
 
Stabilization  Visit 
 
OBBT clinic 
 
( 
) 
Intake/Baseline 
 
Visit 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
 
 
 
 
 
 
 
x  
Screening and 
 
Stabilization  Visit 
 
Pharmacy 
 
( 
) 
Intake/Baseline 
 
Visit 1B 
 
 
 
 
 
x  
 
x  
x  
 
 
 
 
 
x  
x  
 
x  
 
 
 
 
x  
Week 
 
1 - 
4  
Pharmacy 
 
(1 
) M  
Visit 2 
 
 
 
 
 
x  
 
x  
x  
 
 
 
 
 
x  
x  
 
x  
 
 
 
 
x  
Week 
 
5 - 
8  
Pharmacy 
 
(2 
) M  
Visit 3 
 
 
 
 
 
x  
 
x  
x  
 
 
 
 
 
x  
x  
 
x  
 
 
 
 
x  
Week 
 
9 - 
12  
Pharmacy 
 
(3 
) M  
Visit 4 
 
 
 
 
 
x  
 
x  
x  
 
 
 
 
 
x  
x  
 
x  
 
 
 
 
x  
Week 
 
13 
- 
16  
Pharmacy 
 
( 
) 
4 M 
 
Visit 5 
 
 
 
 
 
x  
 
x  
x  
 
 
 
 
 
x  
x  
 
x  
 
 
 
 
x  
Week 
 
17 
- 
20  
Pharmacy 
 
(5 
) M  
Visit 6 
 
CTN 
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- 
OUD 
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10.1 
 
Table 3:  
Study  
Assessment  
Timetable 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
 
x  
x  
 
 
 
 
 
 
 
 
x  
x  
x  
x  
 
x  
 
 
 
 
x  
Week 
 
21 
- 
24  
Pha 
rmacy 
 
(6 
) M  
Visit 7 
 
 
x  
x  
 
x  
 
x  
x  
 
 
 
x  
x  
x  
x  
 
x  
 
 
 
 
x  
 
Pharmacy 
 
 
 
Early  
Termination 
 
x  
x *  
 
 
 
 
 
x  
 
x  
x  
 
 
x  
 
 
x  
 
 
x  
x  
x   
As needed 
 
 
 
 


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39  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
40  
1 
Participants will c 
omplete the Treatment Satisfaction Survey 
 
after each visit.  
e the Treatment Satisfaction Survey once per month, beginning the month of  
the first  
ir paired site and ending the month of the last participant, last visit (LPLV) 
 
at their paired site 
.  
2 
ta may be abstracted from the medical record, if available, prior  
to consent.  
 
3 
A s 
erum pregnancy test will be completed  
aring potential at screening (up to7 days prior to Visit 1 
B 
) 
regnancy test will also be completed at the pharmacy  
at  
Visit 1 
B 
, before the participant is 
 
ensed the study medication. Subsequent u 
egnancy tests will be performed at Visits 2 
 
through 
 
(including  
7 
Early Termination 
 
Visit if  
a  
participant discontinues study  
participation early) 
 
and as needed 
.   
4 
norphine Education Feedback Ques 
nnaire will be completed at the  
site complete Visit 7 (or the Early Termination Visit, if not Vis 
it 7). 
 
* 
During treatment Visits 2 
- 
4S will be prompted by any suicidal  
7 
sychological problem section of the Problem List. 
 
Psychosocial Counseling Attendance Form 
 
Organizational Readiness 
 
Buprenorphine Education Feedback  
Questionnaire 
4  
Buprenorphine Visit 
 
Monitor 
 
Form 
 
Coaching Training Completion (Pharmacists) 
 
Recruitment Log 
 
Research Tasks: Treatment Com 
pliance and  
Feasibility 
 
Safety Event Response Checklist  
 
Birth Control Assessment 
 
Pregnancy 
3  
L 
iver Function 
 
Tests (LFTs) 
 
Research Tasks: Safety Assessments 
 
Clinical Opioid Withdrawal Scale (COWS) 
 
VAS Opioid Craving 
 
Buprenorphine Visit Checklist 
 
Clinical Tasks 
 
Non 
- 
Drug Therapy Log 
 
Concomitant Medications 
 
Problem List 
 
Vital Signs 
2 
Physical Exam 
2 
Assessment/Activity 
 
Location 
 
Study visit numbe 
r  
 
x  
x  
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training/ 
 
coaching 
 
Pharmacy/ 
 
OBBT clinic 
 
 
x  
 
 
 
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Screening and 
 
Stabilization  Visit 
 
OBBT clinic 
 
( 
) 
Intake/Baseline 
 
Visit 1 
 
 
 
 
 
 
 
 
 
x  
 
 
 
 
 
 
 
 
 
Screening and 
 
Stabilization  Visit 
 
Pharmacy 
 
( 
) 
Intake/Baseline 
 
Visit 1B 
 
x  
 
 
 
 
 
x  
x  
x  
 
x  
x  
x  
x  
 
x  
 
 
Week 
 
1 - 4  
Pharmacy 
 
(1 
) M  
Visit 2 
 
x  
 
 
 
 
 
x  
x  
x  
 
x  
x  
x  
x  
 
x  
 
 
Week 
 
5 - 8  
Pharmacy 
 
(2 
) M  
Visit 3 
 
x  
 
 
 
 
 
x  
x  
x  
 
x  
x  
x  
x  
 
x  
 
 
Week 
 
9 - 
12  
Pharmacy 
 
(3 
) M  
Visit 4 
 
x  
 
 
 
 
 
x  
x  
x  
 
x  
x  
x  
x  
 
x  
 
 
Week 
 
13 
- 
16  
Pharmacy 
 
( 
) 
4 M 
 
Visit 5 
 
x  
 
 
 
 
 
x  
x  
x  
 
x  
x  
x  
x  
 
x  
 
 
Week 
 
17 
- 
20  
Pharmacy 
 
(5 
) M  
Visit 6 
 


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x  
 
x  
 
 
 
x  
x  
x  
 
 
 
 
 
 
x  
x  
x  
 
 
 
 
 
x  
 
x  
 
 
Week 
 
21 
- 
24  
Pha 
rmacy 
 
(6 
) M  
Visit 7 
 
x  
 
x  
 
 
 
x  
x  
x  
 
x  
x  
x  
x  
 
x  
 
 
 
Pharmacy 
 
 
 
Early  
Termination 
 
 
 
 
x  
 
 
 
 
x  
x  
 
 
 
 
 
 
x  
 
As needed 
 
 
 
 


 
 
 
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10.2 Research Tasks: General Assessments  
Note: the visit numbers used in this section follow the order indicated in the Study Assessment 
Timetable.  
Inclusion/Exclusion Checklist  
This form will include each inclusion and exclusion criterion to document eligibility. Eligibility will 
be assessed continually, as appropriate. Only participants who continue to meet study eligibility 
criteria will be allowed to continue with the screening process and study intervention.   
Locator Form  
A locator form is used to obtain information to assist in finding participants during treatment and 
at follow-up. The information on this form will also be used to contact participants to remind them 
of upcoming study visits. This form collects the current address, email address, and phone 
numbers of the participant AND one or more family members/significant other, friends, or 
counselors designed by the participant to provide participant’s attendance of psychosocial 
interventions. In order to facilitate locating participants if direct contact efforts are unsuccessful, 
addresses, email adresses and phone numbers of at least one other person (e.g., family 
members, significant others, friends) who may know how to reach the participant are collected, 
as well as information such as social security number, driver’s license number and other 
information to aid in searches of public records. This information will be collected at screening, 
and will be updated at each visit as needed. No information from this form is used in data analyses 
nor is this information captured in the data capture system.  
Demographics  
The Substance Abuse and Addiction Collection of the PhenX Toolkit (http://www.phenxtoolkit.org) 
includes recommended measures that are being adopted across NIDA-funded research (NIDA, 
2012). The Demographics form will collect information about demographic characteristics of the 
participant, including sex, date of birth, ethnicity, race, education, employment pattern, and marital 
status.   
Treatment Satisfaction Survey  
Participants, pharmacists and buprenorphine physicians will be asked to rate their overall 
satisfaction with the quality of the treatment (modified from Harland et al., 2015). Participant 
satisfaction with treatment will be recorded on the Treatment Satisfaction Survey (based on a 
5point Likert scale: 0 = very dissatisfied, to 5 = very satisfied) that is completed by study 
participants at each study visit (1-7), including the Early Termination Visit (if participant 
discontinues study participation early). Pharmacists and physicians will also be asked to complete 
the Treatment Satisfaction Survey once per month, beginning the month of the first participant, 
first visit (FPFV; Visit 1) at their paired site and ending the month of the last participant, last visit 
(LPLV) at their paired site.   
End of Medication Form  
This form tracks the participant's status with regard to the study intervention/medication. It will be 
completed at the pharmacy at the Early Termination Visit (if the participant discontinues study 
participation early), or at Visit 7 (for participants who complete study participation). Phone 
interviews may be used to collect study assessments for participants who discontinue study 
participation early and are unable to return for Early Termination Visit during the specified time 
period.  


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Study Completion  
This form tracks the participant's status in the study. It will be completed at Visit 7 (for participants 
who complete the study) or at the Early Termination Visit (for participants who discontinue study 
participation early). For participants who do not complete a final visit, the Study Completion form 
will be completed once the Visit 7 visit window elapses. This form will be used in data analyses 
to address variables such as treatment retention and completion.   
Protocol Deviations  
Protocol Deviations will be assessed and documented throughout the study.  
10.3 Research Tasks: Clinical Assessments  
DSM-5 Opioid Use Disorder (OUD) Checklist   
The DSM-5 OUD Checklist is a semi-structured, interviewer-administered instrument that 
provides past-year diagnosis for opioid use disorder based on DSM-5 diagnostic criteria (APA, 
2013; Forman et al., 2004). The DSM-5 OUD Checklist will be completed at screening to 
determine eligibility.  
Urine Drug Screen (UDS)  
Urine drug screens will be collected at Intake/Baseline, at Visits 2 through 7, and/or as needed, 
based on clinical decision. If the participant discontinues study participation early, UDS will be 
collected at the Early Termination Visit. However, should the study participant have a medical 
condition (e.g., being on a catheter) that prevents or affects the proper collection of UDS and its 
temperature testing, UDS and its temperature testing may not be needed to define the validity of 
the test. For example, the catheter urine does not have to be subject to temperature testing.  
All urine specimens will be collected using FDA-approved one-step temperature-controlled urine 
drug test cups and all of the manufacturer's recommended procedures will be followed. The 
commercially available UDS system (Rapid Dip Drug Test,Opiate 2000 ng single strip, and BUP 
10 ng single strip) will test for the presence of the following drugs: opiates, oxycodone, 
barbiturates, benzodiazepines, cocaine, amphetamines, methamphetamines, marijuana, 
methadone, buprenorphine, phencyclidine, and ecstasy (MDMA). The phencyclidine results will 
not be entered into the data system or used for data analysis. UDS tests are temperature 
controlled to avoid tampering, and a further validity check is performed using a commercially 
available adulterant test strip. In the event that urine specimen tampering is suspected, either 
based on observation or adulterant test results, study staff should request a second urine sample 
and may observe the urine collection process according to clinic standard operating procedures.  
Urine is recognized as the prime matrix for drug test screening with well-established methods and 
testing protocols (Allen, 2011). Compared to oral fluid testing, urine drug screening is more 
sensitive, less expensive, and can detect drug use for several days prior to the date of testing, 
whereas oral fluid cannot (Allen, 2011). The presence of drug in saliva has been insufficiently 
tested to be able to offer reliable and scientifically reproducible results; further, the lack of 
concordance studies examining both urine and oral fluid drug levels and kinetics in the clinical 
setting is of some concern (Allen, 2011). In addition, instant saliva tests have produced 
inconsistent results compared with laboratory evaluation (Yacoubian and Wish, 2006), and cannot 
be reliably used for the purpose of evaluating and adjusting buprenorphine treatment based on 
the drug testing during the clinical visit.  


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In this study, urine drug screening results demonstrating ongoing opioid use or other substance 
use (e.g., cocaine) will be managed in a non-punitive manner. Results demonstrating 
opioidnegative tests will receive positive reinforcement. Unexpected urine drug screen results 
provide opportunities for counseling and brief intervention.   
Timeline Followback (TLFB)   
The Timeline Followback (TLFB), an instrument with high test-retest reliability and validity for the 
assessment of self-reported substance and alcohol use over a 30-day look-back period (Sobell 
and Sobell, 1992; Sobell and Sobell, 2000), will be utilized in this study. Participants will be asked 
to report daily substance and alcohol use since the previous TLFB assessment at the 
Intake/Baseline Visit and Visits 2 through 7. If the participant discontinues study participation 
early, TLFB will be collected at the Early Termination Visit.   
Substance Abuse and Addiction: PhenX Core Tier 1-2  
The PhenX Toolkit provides researchers with well-established and low-burden measures suitable 
for human subject research (NIDA, 2012; Pan et al., 2012). We will use the measures from the 
Substance Abuse and Addiction PhenX Core Tier 1 to collect information regarding substance 
use including age of onset, past 30-day quantity and frequency, lifetime use for alcohol, tobacco 
and other substances; quality of life; and HIV Risk and Status. We will also assess annual family 
income. The assessments will be completed at Intake/Baseline. The “Quality of Life” and 
“Tobacco Use History” measures will be also be repeated at visits 2, 3, 4, 5, 6, and 7 (or the Early 
Termination Visit if the participant discontinues study participation early).   
Medical and Psychiatric History and Status – Medical History (MHX), Patient Health 
Questionnaire (PHQ-9), P4 Screener (P4S), and Suicidal Risk form (SUR)  
The MHX, PHQ-9, and P4S case report forms will assess information about medical and 
psychiatric history, as well as past and present health conditions, to help determine eligibility and 
to provide baseline information. The MHX gathers medical and behavioral history exploring 
current symptoms, including psychiatric treatments and medications, and will be collected during 
screening only.   
The PHQ-9 (Spitzer et al., 1999), a validated, self-administered version of the PRIME-MD, 
contains the mood (PHQ-9) module as covered in the original PRIME-MD. It will be administered 
at Intake/Baseline and repeated at the Early Termination Visit if the participant discontinues study 
participation early. Endorsements of suicidality on the PHQ-9 (i.e., if the participant answers Q9 
(“Thoughts that you would be better off dead, or of hurting yourself in some way”) as “Several 
days”, “More than half the days” or “Nearly every day”) will be addressed locally at each site and 
will trigger the completion of the Suicidal Risk form.  
The P4 Screener (Dube et al., 2010) is a brief measure (approximately 5 minutes used for 
assessing potential suicide risk in primary care. The participant will answer 4 questions regarding 
past attempts, a plan, probability of completing suicide, and preventive factors at screening to 
exclude active suicidal ideation at Intake/Baseline. If the participant answers “Yes” to Question 2 
of this screener, “Have you thought about how you might actually hurt yourself?”, study staff will 
ask the participant additional clarifying questions to assess suicidality. During treatment Visits 27, 
any suicidal ideation investigated and/or reported in the psychological problem section of the 
Problem List (see below) will prompt the administration of the P4S. If the participant discontinues 
study participation early, the P4S Screener will be completed at the Early Termination Visit. The 
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by qualified healthcare individual(s) according to the site’s specific SOPs or existing procedures 
or policy at the site to address such risk. This evaluation will take place immediately following the 
outcome analysis of the results and prior to the participant leaving the study site. Medical or 
psychiatric history information collected before study participation may be used with the 
participant’s permission. Information from this form may be used in data analyses.   
Physical Exam   
The study clinician will complete a physical examination and review of systems at screening to 
ensure that there are no medical concerns regarding participation and to gather baseline 
information regarding the participant's physical health. Alternatively, physical exam data may be 
abstracted from medical records, when available, if conducted within 6 months prior to the date 
of informed consent. Research staff will record the information on the case report form.  
Vital Signs   
Study personnel will collect vital signs information (blood pressure, pulse, temperature, height, 
and weight) at screening to inform overall medical fitness for participation (in combination with 
data from the physical exam). Alternatively, vital sign data may be abstracted from medical 
records, when available, if conducted within 1 month prior to the date of informed consent.   
Problem List  
This form has been in use at community treatment programs (NIDA, 1998) and explores 7 
problematic areas in open-ended fashion, including Drugs/Alcohol, Employment/Support, Family, 
Recreational/Social Psychological, Legal, and Medical. It will be used at the Intake/Baseline Visit 
and at Visits 2 through 7 (or the Early Termination Visit if the participant discontinues study 
participation early). Initially, information regarding the previous year will be collected, then 
changes from the previous visit will be recorded.  
Concomitant Medications & Non-Drug Therapy Log  
Concomitant medications will be collected on the Concomitant Medications form at the 
Intake/Baseline Visit (Visit 1). Concomitant medications will be reviewed at every subsequent 
study visit (including Visit 7 or the Early Termination Visit if the participant discontinues study 
participation early), and changes will be documented on the Buprenorphine Visit Checklist. If at 
any point it is indicated that the participant has a need for ongoing opioid analgesic treatment, he 
or she will be excluded/withdrawn in accordance with study eligibility criteria. Non-drug therapies 
will be assessed and documented at Intake/Baseline and at each study visit after that, including 
Visit 7 (or the Early Termination Visit if the participant discontinues study participation early). The 
study medical clinician may also exclude any participant taking medications or receiving non-drug 
therapies that could interact adversely with the study drug at his/her clinical discretion.  
10.4 Clinical Tasks  
Buprenorphine Visit Checklist  
The purpose of this document is to provide the buprenorphine prescribing physician with a clinical 
instrument for coaching, supervising, and monitoring the activities of pharmacists while the 
pharmacists are involved with patient evaluation and buprenorphine treatment dispensing. In 
order to fully understand and utilize the checklist, physicians will be asked to become familiar with 
the instrument and its application. Both the buprenorphine prescribing physician (during the 
stabilization phase) and the pharmacist (during the maintenance phase) will be asked to adopt 
the Buprenorphine Visit Checklist and follow a consistent grid of interventions, including the main 


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evaluation and management actions listed in Section 9.5. The results of this effort will be captured 
for the Intake/Baseline Visit 1/1B and subsequent Visits 2 through 7 (or Early Termination Visit if 
the participant discontinues study participation early). Different aspects of treatment compliance, 
fidelity and replicability are associated with and justify the use of this checklist.  
Visual Analog Craving Scale (VAS)   
Participants' craving for opioids will be documented on a visual analog scale (VAS) that ranges 
from 0 (no craving) to 100 (most intense craving possible) (McMillan, Gilmore-Thomas, 1996). 
Participants will be specifically instructed to indicate the overall intensity of craving experienced. 
This scale will be completed at the following visits: Intake/Baseline and Visits 2, 3, 4, 5, 6, and 7. 
If the participant discontinues study participation early, the scale will be completed at the Early 
Termination Visit. Results from this scale are part of the clinical information the physician will 
receive and utilize to adjust the buprenorphine treatment as outlined in the study protocol.   
Clinical Opioid Withdrawal Scale (COWS)  
The presence of withdrawal discomfort will be documented using the COWS (Wesson and Ling, 
2003), an 11-item, interviewer-administered questionnaire designed to provide a description of 
directly observed signs and symptoms of opiate withdrawal (e.g., sweating, runny nose). This 
scale will be completed at each visit (i.e., Intake/Baseline and Visits 2 through 7). If the participant 
discontinues study participation early, this scale will be completed at the Early Termination Visit. 
Results from this scale are part of the clinical information the physician will receive and utilize to 
adjust the buprenorphine treatment as outlined in the study protocol.   
10.5 Research Tasks: Safety Assessments  
Laboratory tests  
Trained staff will be responsible for collecting and processing biologic specimens. Local 
laboratories at participating sites will be used to conduct laboratory tests. Laboratories 
must participate in the Clinical Laboratory Improvement Act of 1998 (CLIA) (or provide equivalent 
evidence of laboratory certification). Laboratories will provide reference ranges and proof of 
laboratory certification prior to study initiation and as needed throughout the study.   
Safety labs: Liver function tests (LFTs, consisting of AST and ALT) will be performed to help 
determine eligibility at screening. Receipt and review of laboratory test results is necessary before 
confirming eligibility and beginning the study intervention. Results of laboratory tests conducted 
within 60 days prior to the Intake/Baseline Visit (Visit 1) (e.g., collected as part of routine care 
before the induction admission) will be acceptable. Throughout the study, LFTs may be collected 
as needed for participant safety, per the discretion of the study physician.   
Pregnancy and Birth Control Assessment   
This form will document the administration of pregnancy tests, test results, childbearing potential, 
and female participants' self-reports of an acceptable method of birth control. The Pregnancy and 
Birth Control Assessment, will be collected during screening (Visit 1) to determine eligibility, as 
well as at Visits 2 through 7.   
For females of childbearing potential: a blood pregnancy test will be performed at Visit 1 (or up to 
7 days prior to Visit 1B) to confirm participant eligibility. A confirmatory urine pregnancy test will 
also be completed at the pharmacy following Visit 1, immediately before the participant is 
dispensed the first dose of study medication. Following initiation of the study intervention. 
subsequent urine pregnancy tests will be performed at Visits 2 through 7 and as needed 


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throughout the study. If the participant discontinues study participation early, the birth control 
assessment and urine pregnancy test will be completed at the Early Termination Visit.   
A positive pregnancy test following initiation of the study intervention will result in the cessation of 
study medication and a referral back to the buprenorphine physician. The site staff will follow the 
participant until an outcome of the pregnancy is known and reported.  
Safety Events  
As buprenorphine is an approved drug being prescribed in accordance with the approved usage, 
there would be no need to capture AEs per se, as the likely AEs are already known. However, in 
terms of compliance, informing dosing, side effects or monitoring those aspects, a solicited 
collection of information is relevant. To aid the collection of safety events, a tool in the form of a 
Safety Event Response Checklist [SERC-75] with solicited symptom information, yes/no 
responses, and level of severity (mild, moderate, severe) will be developed for addition to the 
MOP. The checklist will be used by research staff to obtain self-reported information from each 
participant at the monthly pharmacist visit, which will then be captured electronically in the 
database. The MOP will specify the process of reporting safety events that may require 
interventions (such as dosing, side effects, etc.) to participants’ physicians and pharmacists, as 
well as to the Lead Investigators. In this way, open-ended questions that are left up to the 
determination of the Pharmacists/research staff are avoided and staff members remain within 
their scope by eliminating the expectation that they will be assessing physical symptoms of a 
participant. The completion of the checklist will be documented in the progress note for each visit 
so that the physician is able to review along with the other information provided by the pharmacist 
from the visit prior to writing the participant’s prescription.  
For the purposes of this protocol, the following safety events will be collected and reported to 
inform dosing as well as assist with monitoring of medication compliance: possible side effects of 
the medication: headache, nausea, vomiting, constipation, insomnia, excessive sweating, 
increased sensitivity in the mouth, burning sensation in the mouth, sores in the mouth, pain, 
swelling, and overdoses. In addition, we will collect all ER visits, hospitalizations, and death of 
any participant who provided written informed consent.   
Following informed consent, the protocol-specified safety events will be solicited and recorded at 
each study visit (including the Early Termination Visit if the participant discontinues study 
participation early), according to the outlined procedures. If a reportable safety event suggests 
medical or psychological deterioration, it will be brought to the attention of the study clinician for 
further evaluation. The safety event will be medically managed, reported, and followed in 
accordance with applicable regulatory requirements. The participant may need to return to the 
clinician’s office for extra visits in order to adequately manage an identified safety event.   
Hospitalizations  
Hospitalization for any medical and/or psychiatric reason will be reported accordingly on the 
Safety Event Response Checklist [SERC-75]. All hospitalizations will be assessed by self-report 
at visits 1 through 7 (or Early Termination Visit if the participant discontinues study participation 
early).  
Overdoses  
Non-fatal overdoses since the last visit will be captured via self-report using the Safety Event 
Response Checklist at each visit following consent (including the Intake/Baseline Visit) through 
Visit 7 (or the Early Termination Visit if the participant discontinues study participation early). 


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Overdose events are sentinel events that are less likely to be prone to recall bias than other 
events.   
Data on fatal overdoses may be collected via medical chart record review, if EHR data is available, 
at Visit 7 (or the Early Termination Visit if the participant discontinues study participation early). This 
will be supplemented with information from contact with persons listed on the participant's locator 
form when participants are lost to follow-up throughout the study. Fatal overdoses will be captured 
on the Safety Event Response Checklist [SERC-75].   
Death  
All deaths, regardless of cause, will be captured for this study. These events will be identified 
through the participants’ locator information, or when possible through state medical examiner 
records, National Death Index, and/or review of medical records. Deaths will be reported using 
the Safety Event Response Checklist [SERC-75].   
10.6 Research Tasks: Treatment Compliance and Feasibility  
Recruitment Log  
Drawing on the information captured in the Master Enrollment Log, as well as by reviewing the 
signed consent forms, the Recruitment Log will collect data on the number of potential participants 
who have been pre-screened for participation in the study and the number of participants who 
signed the informed consent form. This data will be used monthly to calculate the recruitment 
rates for each study site during the 6-7 month enrollment phase. Data from this log will be used 
to project the number of participants and inform the duration of enrollment (i.e., recruitment rate) 
for a future multi-site clinical trial.  
Coaching Training Completion (Pharmacists)  
This form will capture the successful completion of training by each single pharmacist and will be 
completed by the end of the coaching phase. Pharmacists will not be able to see study 
participants unless they have participated in the expected training and have passed the tests as 
required.  
Buprenorphine Visit Monitor Form  
The Buprenorphine Visit Monitor Form adopts a Complete, Incomplete, or N/A scoring system for 
each section of the Buprenorphine Visit Checklist. A specific task is defined in each section of the 
checklist: Complete will be defined a completed task, Incomplete will be assigned if the task was 
not completed or was missing, and N/A defines tasks that are Not Applicable. An Incomplete 
score in any section will be discussed between the pharmacist and physician as part of the 
supervision activity. If more than two Incomplete sections are identified per visit, this will determine 
a change of course and closer monitoring of visits/notes. If more than two insufficient visits (i.e., 
with more than 2 Incomplete sections) are identified per pharmacist, or by decision of the LIs, 
additional training will be assigned. Pharmacist monitoring by physician will be performed during 
the maintenance phase. Twenty percent (20%) of each pharmacist’s progress notes (i.e., the 
Buprenorphine Visit Checklist), randomly selected, will be scored by the supervising physician 
using the Buprenorphine Visit Monitor form. Further, random monitoring by the Co-LI (Mannelli) 
of physician, pharmacist and pharmacist-physician interaction will be performed at each site using 
the Buprenorphine Visit Monitor form. One or more visits per physician and pharmacist 
respectively will be monitored in this fashion. The Co-LI will also participate in at least one regular 
clinical review meeting per physician/pharmacist.  


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Buprenorphine Education Feedback Questionnaire  
We will collect the opinions of pharmacists and buprenorphine physicians about the clarity and 
utility of the coaching materials, as well as any lack of useful information from the training. The 
questionnaire will consist of specific questions on each training module to be rated on a 5-point 
Likert Scale of satisfaction, and will be filled out at the end of the coaching phase and once all 
participants at each site complete Visit 7 (or the Early Termination Visit, if not Visit 7). The results 
will be used to structure the coaching education material for a subsequent multi-site clinical trial.  
Psychosocial Counseling Attendance Form  
Participants’ psychosocial counseling attendance will be assessed at each visit (Intake/Baseline 
Visit and maintenance Visits 2 through 7 (or the Early Termination Visit if the participant 
discontinues study participation early)). It serves the purpose of monitoring and reporting whether 
counseling attendance matches what is recommended in the treatment plan at each visit. This 
will be accomplished through participants’ self reports, which may be confirmed by communication 
with the participant’s counselor/therapist or family/significant other. The physician or pharmacist 
will also assess the participant’s attendance of self-help group or other counseling encounters by 
confirming with their sponsor/significant other. This information will be documented on the 
Psychosocial Counseling Attendance Form and summarized on the Buprenorphine Visit  
Checklist.  
Process Measures  
The pilot study seeks to evaluate the acceptability and feasibility of having pharmacists administer 
office-based buprenorphine therapy under the supervision of buprenorphine physicians and 
improve safe access to evidence-based treatment. Patient and physician or pharmacist attitudes, 
assessed in the pilot study, influence and ultimately determine adoption of new treatment 
modalities (Rieckmann, Daley et al., 2007). The patient, physician or pharmacist, and 
organizational attitudes are key inputs to adoption of new evidence-based approaches in 
healthcare settings (Damschrodern et al., 2009). In the case of this pilot study, the quality of 
transfer of the OBBT treatment to a pharmacy environment is crucial and will be adopted as a 
process measure. Further, we will collaborate with CTN DSC/CCC to conduct two brief surveys 
of physicians and pharmacists, as well as staff/managers, of participating sites regarding 
organizational readiness in implementing MAT services (a first survey before the study initiation, 
a second survey after the completion of the study). Prior to agreeing to complete the survey, 
survey participants will be asked to read an IRB-approved information sheet that outlines the 
purpose of the survey and the procedures involved. Survey participants who proceed with the 
survey after reading the information sheet are considered to have provided informed consent for 
the survey. The content of the survey will be framed to understand barriers and facilitators of 
implementing MAT at their facilities (e.g., administrative support, staffing, training, and 
organizational processes in place). Participants of the Organizational Readiness Survey will be 
compensated $25 for completion of each survey ($50 total).  
The pilot study will assess treatment satisfaction using the Treatment Satisfaction Survey (1-5). 
Comparing treatment satisfaction between participants, pharmacists and physicians will inform 
the link between treatment process and outcomes.  
  


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11.0 STUDY TREATMENTS  
11.1 Study Medication  
 
11.1.1  
Study Medication Management  
Each research site, including pharmacies, is required to observe local, state, and federal 
regulations regarding receipt, custody, dispensing, and disposition of all study medications. Each 
site will maintain an adequate supply of unexpired study medications on site.  
Upon receipt of the study medication, the investigator, pharmacist, or authorized designee at each 
site is responsible for taking inventory of the study drug. A record of this inventory must be kept 
and usage must be documented. Any unused or expired study drug shall be accounted for.  
During the stabilization phase, buprenorphine prescribing clinicians are instructed to provide the 
study medication as follows: Give total daily dose administered on the previous day. Add an 
additional 2 to 4 mg as needed (up to 16 mg) based on severity of withdrawal symptoms (e.g., 
add 2 mg for mild withdrawal or 4 mg for moderate-severe withdrawal as rated by COWS). Criteria 
for dose increase: Increased opioid craving or withdrawal since last observation. Target Dose will 
be the dose that results in the optimal relief of objective and subjective opioid withdrawal 
symptoms and cravings. The expected dose is 16 mg daily, though lower doses such as 8 mg 
per day may be sufficient and higher doses such as 24 mg may be required. Maximum suggested 
daily dose is 24 mg (HRSA, 2016).   
During the maintenance phase, dose is maintained stable unless recent opioid use and/or increased 
withdrawal and craving from previous visit suggest adjustment by the study physician.  
 
11.1.2  
Medication (Drug) Accountability Records  
Appropriately qualified and trained study personnel will maintain accurate and current accounting 
of all study medication by utilizing drug accountability records which are made available for review 
by study monitors and other appropriate research personnel.  
 Accurate drug accountability records:  
• 
Demonstrate that the study drug was dispensed according to standard clinical practice;  
• 
Document receipt of the study medication, date, lot #, expiration date, quantity and dosage;  
• 
Account for unopened, un-dispensed, unused, returned, wasted or broken medication;  
• 
Dosing logs should record participant ID #, date dispensed, drug name, lot # and amount 
dispensed;  
• 
Temperature logs should show a daily record of medication storage temperature.  
 
11.1.3  
Dispensing of Study Medication  
All study medications shall be prepared and dispensed by a pharmacist or licensed medical 
practitioner appropriately trained and authorized to dispense study medications per local 
regulations.   
  
  


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11.1.4  
Study Medication Storage  
The medication will be stored at the pharmacy where maintenance visits are conducted at 25°C 
(77°F), with excursions permitted between 15-30°C (59-86°F). Study medication will be stored in 
compliance with the Package Insert and all federal, state, and local laws and institutional policy, 
including the regulations observed with other class III medications dispensed at the pharmacy. 
Study medication is stored in a secured location, separate from any commercial stock, under the 
conditions specified by the package insert.   
 
11.1.5  
Used/Unused Medication  
Study medication returned by a participant may not be re-issued for use. Unused study medication 
is returned and logged into a perpetual inventory of study medication returned. Damaged, 
returned, expired or unused study medication is accounted for by the NIDA contract monitor and 
sent to the central distributor or a reverse distributor for destruction.   
 
11.1.6  
Lost Medication  
No replacement of study medications is permitted. Exceptions may be made on a case-by-case 
basis at the request of the site study physician with LI(s) agreement and will be considered a 
study deviation.  
 
11.1.7  
Medication Packaging  
Buprenorphine/naloxone sublingual film will be provided at no cost for participants after enrollment 
and supplied individually for both the 4mg and 8mg films.   
Each package has the study drug information. Lot number, medication expiration date, and 
storage conditions, as well as manufacturer and distributor information, will be included on the kit 
labels as supplied by the manufacturer.   
 
11.1.8  
Provisions for Access to Treatment after Study  
Prior to the conclusion of the 24-week treatment phase, the research team will make efforts to 
arrange for continued treatment with buprenorphine as locally appropriate. In most cases, 
participants will be returned to the care of referring study physician who will continue to prescribe 
buprenorphine. Where this is not possible (due to insurance or availability of treatment resources, 
etc.), alternative treatment referrals (e.g., other buprenorphine physicians, methadone 
maintenance, intensive outpatient psychosocial aftercare) will be made as appropriate.  
  
12.0 CONCOMITANT THERAPY  
12.1 General Considerations  
Past research has demonstrated that the metabolism of buprenorphine is mediated by the 
cytochrome P450 pathway, as it inhibits the activity of both CYP2D6 and CYP3A4 (Picard et al., 
2005). Further, in vitro studies employing human liver microsomes have demonstrated that the 
major metabolite of buprenorphine, norbuprenorphine, moderately inhibits the activity of CYP2D6 
(Picard et al., 2005). Despite these findings, the relatively low plasma concentrations of 
buprenorphine and norbuprenorphine that results from therapeutic dosing are not expected to 
raise a concern for significant drug-drug interactions. However, the concomitant use of 


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buprenorphine with CYP3A4 inhibitors (e.g., azole antifungals such as ketoconazole, macrolide 
antibiotics such as erythromycin, and HIV protease inhibitors) should be monitored, and may 
require dose-reduction of one or both agents. The interaction of buprenorphine with CYP3A4 
inducers has not been studied; therefore, it is recommended that patients receiving buprenorphine 
be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, 
phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. Buprenorphine 
treatment induction (performed before study screening) and therapy management during the trial 
are anticipated to greatly decrease the risk of precipitating opioid withdrawal.  
12.2 Prohibited Medications   
As described in the eligibility criteria, participants will be excluded from the study if there is a need 
for ongoing opioid analgesic treatment at any point during the study (including screening/baseline 
or following re-assessment during the trial). The study medical clinician may also exclude any 
participant taking medications that could interact adversely with the study drug at his/her clinical 
discretion.  
12.3 Medications Allowed During the Study  
Participants will be instructed to contact the pharmacist and supervising clinician if they plan on 
taking any concomitant medications (including prescription, over-the-counter, and herbal 
supplements) during the course of the study. At intake/baseline (Visit 1), all medications will be 
captured on the Concomitant Medications form. Changes to conconmitant medications will be 
recorded on the Buprenorphione Visit Checklist.   
 
12.3.1  
Ancillary Medications  
No ancillary medications use is expected.  
 
12.3.2  
Rescue Medications  
In the event a participant experiences opioid withdrawal during the study, this may be managed 
by adjusting the dose of buprenorphine. In case of prolonged discomfort, with or without 
concomitant opioid abuse reported by the managing pharmacist, a decision may be made by the 
supervising physician (in concert with the LIs) to discontinue the participant from the study. 
Discontinued participants will be asked to complete an Early Termination Visit. These participants 
will then be returned to physician care and/ or referred to local methadone treatment programs 
(see MOP for the management of patients receiving pharmacy-based OUD care (SOP for OCA)).  
  
13.0 STATISTICAL ANALYSIS  
13.1 General Design   
 
13.1.1  
Study Hypothesis   
This is a feasibility study, and as such there are no a priori hypotheses. The main objective is to 
understand the feasibility regarding the study design features and operational procedures in order 
to inform the design of a full scale clinical trial (e.g., whether participants can be recruited in a 
timely fashion, whether the collaboration between OBBT physician and pharmacist can ensure 
standard buprenorphine maintenance care).  


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13.1.2  
Primary and Secondary Outcomes (Endpoints)   
As noted in Section 8.1, the main objective of this pilot study is to assess the feasibility of a full scale 
trial thus the primary outcome measures are as follows:  
• 
Recruitment rate  
• 
Retention in treatment  
• 
Substance use (self-report and urine drug testing)  
• 
Medication compliance  
The secondary outcomes are also itemized in Section 8.2.  
 
13.1.3  
Recruitment   
Based on the feedback from the local buprenorphine practice, it is anticipated that the clinical 
sites will each be able to recruit a sufficient number of participants who are stabilized on 
buprenorphine during the screening and baseline period to enroll 20-30 into the maintenance 
phase. The main objective of this feasibility study is to assess the recruitment rate, so there will 
be no specific targeted recruitment rate for assessing clinical site performance. Whatever 
recruitment rate is observed will inform the results of this feasibility study. Note that it is possible 
for a consented participant to drop out or be lost to follow-up prior to initiating the maintenance 
phase of their buprenorphine treatment. The recruitment rate will be calculated using all 
participants consented, however the number of participants who enroll into the maintenance 
phase of the study will also be tracked closely versus the number of potential participants that 
were consented. Additional details on participant recruitment are given in Section 7.3.  
 
13.1.4  
Randomization and Factors for Stratification   
This is not a randomized study, as the treatment arm is the same for all clinical sites.  
13.2 Rationale for Sample Size and Statistical Power   
 
13.2.1  
General Approach  
As CTN-0075 is a feasibility study, there will be no hypothesis testing and thus performing sample 
size and/or power calculations are inappropriate. Instead, it is important to evaluate the precision 
with which primary outcome measures can be estimated. Particularly, we focus on the width of 
confidence intervals for the following: (1) the marginal odds of a scheduled visit being attended 
(retention in treatment), (2) the number of days of self-reported opioid use in the 30 days prior to 
the six month follow-up visit (opioid use), and (3) proportion of participants with an opiate-positive 
UDS at the six month follow-up visit (opioid use).   
 
13.2.2  
Projected Number of Study Sites   
The Lead Node and the NIDA CCTN have determined that it is only possible fiscally and timelinewise 
to utilize approximately 3-4 study sites for the CTN-0075 feasibility pilot study.  


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13.2.3  
Projected Number of Participants per Study Site  
Depending on the number of study physicians at a study site, each study site may enroll up to 
2030 participants who are stabilized on buprenorphine into the maintenance phase. However, 
this is an outcome of the study and will not be considered when assessing performance of a study 
site during this pilot study.  
 
13.2.4  
Confidence Interval Estimation for Retention in Treatment  
The retention in treatment outcome measure is defined as an indicator of whether each of the six 
scheduled visits during the six month follow-up phase for each participant. Thus, there are two 
layers of correlation: visits within participants, and participants within site. To estimate the 
precision of the probability that any given follow-up was attended, we used simulations. Appendix 
C describes the approach to simulating the data for this outcome measure. For each simulated 
dataset, proc GLIMMIX (SAS 9.4) was used to model the log-odds of visit attendance and 
calculate the 95% confidence interval for the corresponding probability. Example code:  
proc glimmix data=simul; class 
site patid;  
model x(event=’1’) = / dist=binary link=logit solution; 
random intercept / subject=site; random intercept / 
subject=patid(site); estimate "intercept" intercept 1 / 
ilink cl; run;  
  
Generalized estimating equations (Liang and Zeger, 1986) were also considered for the method 
of analysis, however the coverage probabilities were low and thus that approach is not reported 
here. Several other approaches (e.g., bootstrap, MCMC) were also considered but suffered from 
poor coverage as well and thus were dropped from consideration.  
The key parameters necessary for this set of simulations are (notation defined in Appendix C):  
μ = P(visit attended)  
γ = independence parameter for visits within a participant α / β = relative 
contribution of study site effect to participant effect on μ   
As summarized in Figure 4, the confidence interval width decreases as the visits within a 
participant become increasingly independent (“abg(3)” = γ → 1). Further, the confidence interval 
width also decreases as the ratio of the site effect to the participant decreases (i.e., “rat” = α / β 
→ 0).  


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Figure 4. Simulation Results for Precision in the Retention in 
Treatment Outcome Measure  
13.2.5  
Confidence Interval Estimation for Opioid Use (self-report and 
UDS-based)  
For the UDS-based opioid use outcome, data were simulated in a similar fashion to that for the 
retention in treatment except there is only one visit per participant (the six month follow-up visit). 
It is anticipated that the proportion of participants attending the final six month follow-up visit who 
will have an opioid-positive UDS ranges from 20-30% (Cunningham et al., 2013). Figure 5 
provides a graphical summary of the simulation results.  


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Figure 5. Simulation Results for Precision in the UDS-based Opioid Use 
Outcome Measure  
The opioid use outcome measure based on self-report is the total number of days of opioid use, 
from TLFB, during the last 30 prior to the six month follow-up visit. The data for the precision 
simulations were also generated in a manner similar to that for the retention in treatment outcome.  
In this instance, each day in the evaluation period is considered a “visit”, thus the “abg3” = γ 
parameter captures the relationship between days of self-reported use within a participant. As 
with the previous simulations, the closer γ is to 0, the greater the degree of correlation of days of 
use within a participant. Figure 6 summarizes the results of these precision simulations when the 
daily opioid use rates varies from 20-40% (Cunningham et al., 2013, Rosenthal et al., 2016).  


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Figure 6. Simulation Results for Precision in the TLFB-based Opioid 
Use Outcome Measure  
13.3 Statistical Methods for Primary and Secondary Outcomes  
For the primary outcomes, estimates and 95% confidence intervals will be constructed as 
described below. As there is only one arm in this pilot feasibility study, no statistical testing will be 
performed. Descriptive statistics, including measures of spread, will be reported. The remainder 
of this section provides basic information regarding the primary outcome measures. A separate 
Statistical Analysis Plan will be developed that provides additional details regarding the statistical 
methods for both the primary and secondary outcomes.  
 
13.3.1  
Recruitment Rate  
The recruitment rate will be estimated as the number of participants consented per month during 
the enrollment period. We will also calculate the number of participants reaching the maintenance 
phase on a per-month basis. These rates will also be calculated by site.   
 
13.3.2  
Retention in Treatment  
For a particular participant, this outcome measure is captured by a vector of length six, denoted 
by r (r1, … r6), where each element of the vector is an indicator of whether the participant attended 


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the ith visit (i=1, ..., 6) during the maintenance phase. This is outcome measure involves 
hierarchical clustering as follows: visits within participant, and participants within study site. Given 
the target effective sample size (e.g., study completers) of 45 participants, asymptotic confidence 
intervals will be constructed. Based on the poor coverage findings from the simulation studies 
presented in Section 13.2, a random effects model will be used to construct these intervals while 
adjusting for the two levels of clustering.  
 
13.3.3  
Substance Use  
Primary interest lies in opioid (licit and illicit) and heroin use. Both biological assessment of use, 
as well as self-reported use will be considered. For biological assessment, urine drug testing will 
be used for all substances . While we will focus on the six month follow-up visit, as has been done 
in other studies, we will also estimate substance use over all six visits during the maintenance 
phase. For self-reported use, the main outcome measure of interest is quantified as the number 
of days of use of opioids/heroin in the 30 days prior to the six month follow-up visit. In addition, 
we will also examine daily use rates and evaluate patterns over time. Similar to the analyses 
described in Section 13.2.2, a random effects model will be used to construct the 95% confidence 
intervals while adjusting for the two levels of clustering.  
 
13.3.4  
Medication Compliance  
The operational definition of this outcome measure is the proportion of expected buprenorphine 
use in relation to actual use. The expected dose will be based on the number of milligrams 
expected based on the dispensed dose during the maintenance phase. The expected dose will 
accommodate adjustments to dosing made during the maintenance phase. The Statistical 
Analysis Plan will describe how compliance is calculated for early study terminations.  
13.4 Significance Testing   
Significance testing will not be conducted in this pilot study of feasibility. Section 13.3 describes the 
statistics and analytic approaches that will be used to summarize the data.  
13.5 Interim Analysis  
No interim analyses for efficacy or futility are planned for this study. Safety and data quality reports 
will be prepared for the Data and Safety Monitoring Board, and they may request interim analyses 
at any time during the trial.   
13.6 Exploratory Analysis   
Given the small sample size and the limited scope of this trial, every effort will be made to minimize 
any post hoc exploration of the data entered into Advantage eClinical.  
  
  
13.7 Missing Data and Dropouts   
For simplicity in this small pilot study, all missing data will be handled as follows for the four primary 
outcome measures:  
1. Recruitment rate – no missing data  
2. Retention in treatment – no missing data  


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3. Substance use  
a. Any day with missing self-reported substance use during the last 30 days of the 24 week 
follow-up period will be imputed as non-abstinent  
b. A missing UDS at the six month follow-up visit, for any reason, will be imputed positive  
4. Medication compliance – no missing data  
Should there be a substantial amount of missing data for the substance use outcomes, a 
sensitivity analysis may be implemented to see how the estimated outcome measures are 
impacted by deviations from the imputation schemes specified above.  
13.8 Demographic and Baseline Characteristics   
Baseline demographic and clinical variables will be summarized for participants enrolled in the 
maintenance phase. Descriptive summaries of the distribution of continuous baseline variables 
will be presented with percentiles (median, 25th and 75th percentiles), and with mean and 
standard deviation. Categorical variables will be summarized in terms of frequencies and 
percentages. The NIH requires subgroup analyses by gender, race and ethnicity (NIH, 2016). 
Given the scope of this study, all primary outcome measures will be summarized by these three 
factors but there will be no testing for differences across the demographic groups.   
13.9 Safety Analysis   
All protocol-defined safety events reported on the SERC-75 will be coded for body system and 
preferred term using MedDRA codes (per The Medical Dictionary for Regulatory Activities). Safety 
events on the SERC-75 will be summarized by frequency in the screening phase and 
maintenance phase. Listings of emergency department visits, hospitalizations, overdoses, and 
deaths will include system organ class (SOC) and preferred term (PT). Suicide risk from the P4 
Screener will be assessed and presented in a listing.  
14.0 REGULATORY COMPLIANCE AND SAFETY  
14.1 Regulatory Compliance  
This study will comply with all applicable rules and regulations. These include requirements of 
having received federal funding and the HIPAA requirements for data.  
14.2 Statement of Compliance  
This trial will be conducted in compliance with the appropriate protocol, current Good Clinical 
Practice (GCP), the principles of the Declaration of Helsinki, and all other applicable regulatory 
requirements. Participating sites must obtain written approval of the study protocol, consent form, 
other supporting documents, and any advertising for participant recruitment from the Institutional 
Review Board (IRB) of Record in order to participate in the study. Prior to study initiation, the 
protocol and the informed consent document(s) will be reviewed and approved by an appropriate 
Ethics Review Committee (ERC) or IRB. Any amendments to the protocol or consent materials 
must be approved before they are implemented. Annual progress reports and local Serious 
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14.3 Institutional Review Board Approval  
Prior to initiating the study, the Lead Node will obtain written IRB approval to conduct the study 
from a single IRB. Further, each site investigator will be required to set up a written IRB Reliance 
(Authorization) Agreement to name the single IRB as the IRB of Record for the study. The reliance 
agreement will also contain information about how communication between the participating site 
and the single IRB will take place. Should changes to the study protocol become necessary, 
protocol amendments will be submitted in writing by the Lead Node for IRB approval from the 
single IRB prior to implementation. In addition, the IRB will approve all consent forms, recruitment 
materials, and any materials given to the participant. Annual reports and progress reports will be 
submitted to the IRB annually or at a frequency requested by the IRB so that continuous study 
approval is maintained without lapse. Lead Investigators (LIs) will be responsible for maintaining 
in their research files copies of all performance site(s) current IRB/IEC approval notice(s), 
IRBapproved consent document(s), including approval for all protocol modifications. These 
materials must be received by LIs prior to the initiation of research activities at a given site, and 
must be available at any time for audit.  
14.4 Informed Consent  
The informed consent process is a means of providing study information to each prospective 
participant and allows for an informed decision about participation in the study. The informed 
consent form will include all of the required elements of informed consent. The study informed 
consent (and any updates made to the consent form throughout the trial) will be approved by the 
IRB prior to use. A copy of the IRB-approved consent, along with the IRB study approval, must 
be sent to the Clinical Coordinating Center (CCC) and the Lead Node (LN) (as needed) prior to 
the site initiation visit and with each subsequent consent revision. Every study participant is 
required to sign a valid, IRB-approved current version of the study informed consent form prior to 
the initiation of any study related procedures. The site must maintain the original signed informed 
consent for every participant in a locked, secure location that is in compliance with the IRB and 
any applicable institutional policies and that is accessible to the study monitors. Every study 
participant should be given a copy of the signed consent form.  
Prior to informed consent, research staff will explain the study to the potential participant and 
provide a copy of the consent to read. If the participant is interested in participating in the study, 
a staff member will review each section of the informed consent form in detail and answer any 
questions the participant may pose. The participant will consent by signing and dating the consent 
document. The person obtaining consent and a witness, if required by the IRB, will also sign and 
date the consent document. It is strongly recommended that another research staff member 
review the consent after it is signed to ensure that the consent is properly executed and complete. 
Staff members delegated by the PI to obtain informed consent must be listed on the Site Staff 
Delegation of Responsibilities and Signature Log and must be approved by the IRB, if required. 
All persons obtaining consent must have completed appropriate training.  
The informed consent form must be updated or revised whenever important new safety 
information is available, or whenever the protocol is amended in a way that may affect 
participants’ participation in the trial. A copy of the informed consent will be given to a prospective 
participant to review during the consent process and to keep for reference. The participant will be 
informed that their participation is voluntary and they may withdraw from the study at any time, 
for any reason without penalty. Individuals who refuse to participate or who withdraw from the 
study will be treated without prejudice. Study sites will be responsible for maintaining signed 
consent forms as source documents for quality assurance review and regulatory compliance.  


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14.5 Confidentiality  
Confidentiality will be maintained in accordance with all applicable federal regulations and/or 
state/Commonwealth law and regulations. By signing the protocol signature page, the investigator 
affirms that information furnished to the investigator by NIDA will be maintained in confidence and 
such information will be divulged to the IRB, Ethical Review Committee, or similar expert 
committee; affiliated institution; and employees only under an appropriate understanding of 
confidentiality with such board or committee, affiliated institution and employees. The lead 
investigator will obtain a federal Certificate of Confidentiality (CoC), protecting participants against 
disclosure of sensitive information (e.g., substance use), and will distribute it to all sites when 
received. If applicable, the NIH office that issues the CoC will be advised of changes in the CoC 
application information. Participating sites will be notified if CoC revision is necessary. Participant 
records will be held confidential by the use of study codes for identifying participants on CRFs, 
secure storage of any documents that have participant identifiers, and secure computing 
procedures for entering and transferring electronic data.   
There is the potential risk of loss of confidentiality. Every effort will be made to keep participants’ 
information confidential; however, this cannot be guaranteed.  
 
14.5.1  
Health Insurance Portability and Accountability Act (HIPAA)  
Study sites may be required by their institutions to obtain authorization from participants for use 
of protected health information. Sites will be responsible for communicating with their IRBs or 
Privacy Boards and obtaining the appropriate approvals or waivers to be in regulatory compliance. 
Releases of participant identifying information that are permitted by the HIPAA regulations, but 
which are prohibited by other applicable federal regulations and/or state/Commonwealth law and 
regulation, are prohibited.  
14.6 Investigator Assurances  
Each research site must file (or have previously filed) a Federal Wide Assurance (FWA) with the 
HHS Office for Human Research Protection setting forth the commitment of the organization to 
establish appropriate policies and procedures for the protection of human research subjects, with 
documentation sent to NIDA or its designee. Research covered by these regulations cannot proceed 
in any manner prior to NIDA receipt of certification that the research has been reviewed and 
approved by the IRB provided for in the assurance (45 CFR 46.103(b) and (f)). Prior to initiating the 
study, the Principal Investigator at each study site will sign a protocol signature page, providing 
assurances that the study will be performed according to the standards stipulated therein.  
 
14.6.1  
Financial Disclosure  
All investigators will comply with the requirements of 42 CFR Part 50, Subpart F to ensure that 
the design, conduct, and reporting of the research will not be biased by any conflicting financial 
interest. Everyone with decision-making responsibilities regarding the protocol will confirm to the 
sponsor annually that they have met their institutional financial disclosure requirements.  
 
14.6.2  
DEA Registration  
All DEA requirements must be met, including registration, inspection if required, and certification, 
as applicable. Additionally, dispensing any controlled substance requires a DEA registration 
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Buprenorphine physicians and pharmacists will operate with their own buprenorphine DEA 
numbers.  
14.7 Clinical Monitoring  
Investigators will host periodic visits by NIDA contract monitors who will examine whether study 
procedures are conducted appropriately and that study data are generated, documented and 
reported in compliance with the protocol, GCP, and applicable regulations. These monitors will 
audit, at mutually agreed upon times, regulatory documents, case report forms (CRFs), informed 
consent forms and corresponding source documents for each participant. Monitors will have the 
opportunity and ability to review any study-associated document or file.  
NIDA-contracted monitors will assess whether submitted data are accurate and in agreement with 
source documentation and will also review regulatory/essential documents such as 
correspondence with the IRB. Areas of particular concern will be participant informed consent 
forms, protocol adherence, reported safety events and corresponding assessments, and Principal 
Investigator oversight and involvement in the trial. Reports will be prepared following the visit and 
forwarded to the site Principal Investigator, the Lead Investigator and NIDA CCTN.  
Qualified node personnel and NIDA CCTN CCC staff will provide site management for each site 
during the trial. Node and CCC staff will audit source documentation, including informed consent 
forms and HIPAA forms. This will take place as specified by the local protocol team, node PI or 
lead team, and will occur as often as needed, and is feasible, to help prevent, detect, and correct 
problems at the study sites. Node and CCC personnel will verify that study procedures are 
properly followed and that site personnel are trained and able to conduct the protocol 
appropriately. If the node personnel or CCC’s review of study documentation indicates that 
additional training of site study personnel is needed, node and/or CCC personnel will undertake 
or arrange for that training. Details regarding monitoring are found in the study monitoring plan.  
14.8 Inclusion of Women and Minorities  
The study sites should aim and take steps to enroll a diverse study population. If difficulty is 
encountered in recruiting an adequate number of women and/or minorities, the difficulties 
involved in recruitment will be discussed in national conference calls and/or face-to-face 
meetings, encouraging such strategies as linkages with medical sites and/or treatment programs 
that serve a large number of women and/or minorities, advertising in newspapers or radio stations 
with a high female/minority readership/listening audience, etc.  
Female-Specific Risks  
Being a part of this study while pregnant may expose the unborn child to significant risks, some 
of which may be currently unforeseeable. Therefore, pregnant women will be excluded from the 
study. Women of childbearing potential will have a serum pregnancy test completed during 
screening (using 1 teaspoon of blood drawn from a vein by needle-stick). The pregnancy test 
must yield a negative result before the participant can continue in the study. If sexually active, 
women who consent to the study and are of childbearing potential must agree to use appropriate 
contraceptive measures while participating in the study. Medically acceptable contraceptives 
include: (1) surgical sterilization (hysterectomy or bilateral oophorectomy, NOT tubal 
litigation/cauterization or vasectomy of male partner), (2) approved hormonal contraceptives 
(such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom 
or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive 
measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable 


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methods for routine use. In addition to the confirmatory urine pregnancy test conducted at the 
pharmacy following Visit 1, immediately prior to dispensation of the first dose of study medication, 
urine pregnancy tests will be performed at study visits 2 through 7. Women are asked to inform 
the study pharmacist and physician immediately if they become pregnant during this study or 
have unprotected sex.  
14.9 Regulatory Files  
The regulatory files should contain all required regulatory documents, study-specific documents, 
and all important communications. Regulatory files will be checked at each participating site for 
regulatory document compliance prior to study initiation, throughout the study, as well as at study 
closure.  
14.10 Records Retention and Requirements  
Research records for all study participants (e.g., case report forms, source documents, signed 
consent forms, and regulatory files) are to be maintained by the investigator in a secure location 
for a minimum of 3 years after the study is completed and closed. These records are also to be 
maintained in compliance with IRB, state and federal requirements, whichever is longest. The 
sponsor and Lead Investigator must be notified in writing and acknowledgment must be received 
by the site prior to the destruction or relocation of research records.  
14.11 Reporting to Sponsor  
The site Principal Investigator agrees to submit accurate, complete, legible and timely reports to 
the Sponsor, as required. These include, but are not limited to, reports of any changes that 
significantly affect the conduct or outcome of the trial or increase risk to study participants. Safey 
event reporting will occur as previously described. At the completion of the trial, the Lead 
Investigator will provide a final report to the Sponsor.  
14.12 Audits  
The Sponsor has an obligation to ensure that this trial is conducted according to good research 
practice guidelines and may perform quality assurance audits for protocol compliance. The Lead 
Investigator and authorized staff from the Mid Southern Node; the National Institute on Drug 
Abuse Clinical Trials Network (NIDA CTN, the study sponsor); NIDA’s contracted agents, 
monitors or auditors; and other agencies such as HHS, the Office for Human Research Protection 
(OHRP) and the Institutional Review Board may inspect research records for verification of data, 
compliance with federal guidelines on human participant research, and to assess participant 
safety.  
14.13 Study Documentation  
Study documentation includes all case report forms, workbooks, source documents, monitoring 
logs and appointment schedules, sponsor-investigator correspondence, signed protocol and 
amendments, Ethics Review Committee or Institutional Review Committee correspondence and 
approved consent form and signed participant consent forms.  
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Whenever possible, the original recording of an observation should be retained as the source 


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document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document.  
14.14 Protocol Deviations  
Any departure from procedures and requirements outlined in the protocol will be classified as 
either a major or minor protocol deviation. The difference between a major and minor protocol 
deviation has to do with the seriousness of the event and the corrective action required. A minor 
protocol deviation is considered an action (or inaction) that by itself is not likely to affect the 
scientific soundness of the investigation or seriously affect the safety, rights, or welfare of a study 
participant. Major protocol deviations are departures that may compromise the participant safety, 
participant rights, inclusion/exclusion criteria or the integrity of study data and could be cause for 
corrective actions if not rectified or prevented from re-occurrence. Sites will be responsible for 
developing corrective action plans for both major and minor deviations as appropriate. Those 
corrective action plans may be reviewed/approved by the Lead Node and the CCC with overall 
approval by the IRB. All protocol deviations will be monitored at each site for (1) significance, (2) 
frequency, and (3) impact on the study objectives, to ensure that site performance does not 
compromise the integrity of the trial.   
All protocol deviations will be recorded in the Electronic Data Capture (EDC) system via the 
Protocol Deviation CRF. The CCC, DSC and the Lead Investigator must be contacted 
immediately if an unqualified or ineligible participant is consented and enrolled into the study.  
Additionally, each site is responsible for reviewing the IRB’s definition of a protocol deviation or 
violation and understanding which events need to be reported. Sites must recognize that the CTN 
and IRB definition of a reportable event may differ and act accordingly in following all reporting 
requirements for both entities.  
  
  
14.15 Safety Monitoring  
 
14.15.1  Safety Events   
All protocol-defined safety events (medical and/or psychiatric) occurring during the course of the 
study will be assessed, documented, and reported. Safety events occurring during the course of 
the clinical trial will be collected, documented, and reported by the Principal Investigator or 
subinvestigators according to the specific instructions detailed in this section of the protocol. 
Appropriately qualified and trained personnel will elicit participant reporting of safety events at 
each study visit designated to collect safety events (i.e., the first visit following informed consent 
and at every study visit thereafter).   
A study medical clinician (MD, DO, PA, or NP) will review or provide consultation for each safety 
event as necessary. The study medical clinician and site Principal Investigator (if different) will 
also make decisions to exclude, refer, or withdraw participants as required. The study staff will be 
trained to monitor for and report safety events.   
 
14.15.2  Reportable Safety Events  
For the purposes of this protocol, the following safety events will be collected and reported: 
headache, nausea, vomiting, constipation, insomnia, excessive sweating, increased sensitivity in 
the mouth, burning sensation in the mouth, sores in the mouth, pain, swelling, overdoses, ED 
visits, hospitalizations, and death of any participant who provides informed consent in this study.   


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The local site is responsible for the reporting of safety events to their local IRB and/or the IRB of 
Record per applicable IRB guidelines.  
 
14.15.3  Medical Monitor and Safety Monitor  
Under the supervision of the NIDA-assigned Medical Monitor, the study Safety Monitor will be 
responsible for overseeing safety and for evaluating all safety events. The Safety Monitor will 
review all reported safety events on a regular basis. The Medical Monitor will review events 
regularly and will be available at all times for consultation. Where further information is needed, 
the Safety Monitor will discuss the event with the site. It is the responsibility of the site Principal 
Investigator to provide this information to the Safety Monitor. It is also the site Principal 
Investigators’ responsibility to inform the IRB per IRB guidelines.  
The Medical Monitor will independently review the safety data, present it to the DSMB for periodic 
review, and provide PIs a Safety Letter when necessary for submission to the IRB for regulatory 
compliance. The Medical Monitor will determine which safety events require expedited reporting 
to NIDA, the DSMB, pharmaceutical/distributors, and regulatory authorities. This will include 
events that are serious, related, and unexpected (SUSAR).  
 
14.15.4  Data and Safety Monitoring Board (DSMB)  
This study will utilize the CTN DSMB to oversee ongoing trial progress and examine accumulating 
data to assure protection of participants’ safety while the study’s scientific goals are being met. 
The purpose of this board is to determine whether risks emerge during the conduct of the trial that 
make continuation unethical. This process is intended to assure the IRBs, the sponsor, and 
investigators that participants are provided with an accurate and ongoing risk evaluation when 
participating in CTN research trials. It will determine whether there is support for continuation of 
the trial, evidence that study procedures should be changed, or if the trial should be halted, for 
reasons relating to the safety of the study participants, the efficacy of the treatment under study, 
or inadequate trial performance (e.g., poor recruitment). Safety monitoring begins with the initial 
review of the protocol during the study development process. The CTN DSMB is responsible for 
conducting periodic reviews of accumulating safety and efficacy data. The DSMB will meet at 
least annually. Recommendations from these reviews will be distributed to site investigators and 
submitted to the IRB.  
 
14.15.5  Known Potential Toxicities of Study Drug  
Refer to package insert in Appendix B.  
14.15.6 Potential Events Related to the Underlying Clinical Condition and/or 
Study Populations  
Each of the participating research sites have established practices for managing medical and 
psychiatric emergencies, and the study staff will continue to utilize these procedures. Participants 
at each research site will be referred for medical care in the event of possible clinical deterioration 
or other problems, and for implementing appropriate courses of action.   


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14.15.7  Additional Study-Specific Risks  
Buprenorphine Side Effects  
Side effects commonly observed with the administration of BUP-NX sublingual (under the tongue) 
film include sore mouth, partial loss of sensation of touch, headache, nausea, vomiting, 
constipation, signs and symptoms of withdrawal, insomnia, pain, and swelling of the limbs. The 
long-term side effects of BUP-NX are unknown at the present time.  
It is also possible that a patient may have a hypersensitivity or allergic reaction to BUP-NX. The 
most common signs and symptoms of having an allergic reaction include rashes, hives, and 
itching. More serious, but less common occurrences include those related to anaphylactic shock 
such as difficulty breathing. To minimize the risk of hypersensitivity or allergic reaction, the study 
doctor will ask each participant if he or she has taken buprenorphine/naloxone prior to entering 
the study to see if he or she has had a previous allergic reaction or increased sensitivity to the 
medication or any of its components.  
BUP-NX itself causes physical dependence and can result in withdrawal symptoms when BUPNX 
is stopped. BUP-NX can also cause drowsiness and breathing that is slow and shallow.  
A number of deaths have been reported in people who abuse BUP-NX in combination with 
benzodiazepines, such as Valium or sleeping pills. Combining BUP-NX with alcohol or other drugs 
may be hazardous. Patients must not drink alcohol-containing beverages or take other drugs 
including benzodiazepines, like Valium or sleeping pills, or narcotic pain relievers, while using 
BUP-NX. Patients who are receiving benzodiazepine treatment by another physician will only be 
able to participate in the study if his or her doctor monitors their prescriptions during the study.  
Patients should not inject (“shoot-up”) BUP-NX. Injecting BUP-NX may cause serious withdrawal 
symptoms such as pain, cramps, vomiting, diarrhea, anxiety, sleep problems, and cravings.  
BUP-NX may also impair mental or physical abilities involved in such activities as driving or 
operating machinery. Patients are advised not to engage in such activities for at least 6 hours 
after taking the first dose of BUP-NX. The researchers will be happy to discuss alternative 
methods of transportation with patients, such as getting a ride from a family member or friend, or 
taking a taxi or bus.  
Risks of Buprenorphine Misuse  
As buprenorphine is a partial opioid agonist medication, missing one or more doses during 
treatment could result in opioid withdrawal. Use of full opioid agents (e.g., heroin or prescription 
opioid medications) during treatment may result in lack of effects or trigger opioid withdrawal 
discomfort. Administering a large amount of exogenous opioids to overcome such symptoms 
could result in potentially life-threatening opioid intoxication and overdose. Use of sedative 
substances (e.g., alcohol and benzodiazepines) in addition to buprenorphine could lead to 
excessive sedation and respiratory depression. Patients are advised to discuss these risks with 
the study pharmacist and doctor if they so choose.  
Risks of Drawing Blood   
Risks associated with drawing blood from the arm include momentary discomfort and/or bruising. 
Infection, excess bleeding, clotting, or fainting are also possible, although unlikely.  


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Drug Interactions  
For the participant’s safety, participants must tell the study pharmacist, doctor, and staff about all 
of the prescribed medical foods and drugs, herbal products, over-the-counter (OTC) drugs, 
vitamins, natural remedies, and alcohol that he or she is taking before starting the study. 
Participants must also tell the study pharmacist, doctor, and staff before starting to take any of 
these products while enrolled in the study.  
Other Risks   
Some of the questions the researchers will ask participants as part of this study may make 
participants feel uncomfortable. Participants may decline to answer any of the questions and 
participants may take a break at any time during the study visits. Participants may stop their 
participation in this study at any time.  
There may be risks, discomforts, drug interactions or side effects that are not yet known.  
  
15.0 DATA MANAGEMENT AND PROCEDURES  
15.1 Design and Development  
This protocol will utilize a centralized Data and Statistics Center (DSC). The DSC will be 
responsible for the development of the case report forms (CRFs), development and validation of 
the clinical study database, ensuring data integrity, and training site and participating node staff 
on applicable data management procedures. A web-based distributed data entry model will be 
implemented. This electronic data capture system (Advantage eClinical) will be developed to 
ensure that guidelines and regulations surrounding the use of computerized systems used in 
clinical trials are upheld. The remainder of this section provides an overview of the data 
management plan associated with this protocol.  
15.2 Site Responsibilities  
The data management responsibilities of each site will be specified by the Lead Node and the DSC.  
15.3 Data Center Responsibilities  
The DSC will 1) develop and apply data management procedures to ensure the collection of 
accurate and good-quality data, 2) provide final Case Report Forms (CRFs) and electronic CRFs 
(eCRFs) for the collection of all data required by the study, 3) develop data dictionaries for each 
CRF that will comprehensively define each data element, 4) prepare instructions for the use of 
Advantage eClinical and for the completion of CRFs, 5) conduct ongoing data validation and 
cleaning activities on study data collected from all study sites, and 6) perform data validation and 
cleaning activities prior to any interim analyses and prior to the final study database lock.   
15.4 Data Acquisition and Entry  
Data will be collected at the study sites on source documents and entered by the site into eCRFs 
in Advantage eClinical, or will be collected via direct entry into the eCRF. In the event that 
Advantage eClinical is not available, the DSC will provide the sites with paper CRF source 
documents and completion instructions. Data will be entered into Advantage eClinical in 
accordance with the instructions provided during protocol-specific training and guidelines 


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established by the DSC. Data entry into the eCRFs shall be performed by authorized individuals. 
Selected eCRFs may also require the investigator’s electronic signature.  
The Principal Investigator at each site is responsible for maintaining accurate, complete and upto-
date research records. In addition, the investigator is responsible for ensuring the timely 
completion of eCRFs for each research participant.   
15.5 Data Editing  
Data will be entered into the DSC automated data acquisition and management system 
(Advantage eClinical). eCRFs will be monitored for completeness and accuracy throughout the 
study. Dynamic reports listing missing values and forms are available to sites at all times in 
Advantage eClinical. These reports will be monitored regularly by the DSC. In addition, the DSC 
will identify inconsistencies within eCRFs and between eCRFs and post data clarification requests 
or queries in Advantage eClinical on a scheduled basis. Sites will resolve data inconsistencies 
and errors by entering all corrections and changes directly into Advantage eClinical.  
The CCC will conduct regular on-site and remote visits, during which audits comparing source 
documents to the data entered on the eCRF will be performed. Any discrepancies identified 
between the source document and the eCRF will be corrected by the site.  
Trial progress and data status reports, which provide information on recruitment, availability of 
primary outcome, treatment exposure, regulatory status, and data quality, will be generated daily 
and posted to a secure website. These reports are available to the site, the corresponding node, 
the lead node, the coordinating centers, and NIDA to monitor study progress overall and at each 
individual participating site.  
15.6 Data Transfer/Lock  
At the conclusion of data collection for the study, the DSC will perform final cleaning activities and 
will “lock” the study database from further modification. The final analysis datasets will be 
transferred to the Lead Investigator and to NIDA, as requested, for storage and archiving.  
15.7 Data Training  
The training plan for site staff includes provisions for training on assessments, eCRF completion 
guidelines, data management procedures, and the use of Advantage eClinical.   
15.8 Data Quality Assurance  
To address the issue of data entry quality, the DSC will follow a standard data monitoring plan. 
An acceptable quality level prior to study lock or closeout will be established as a part of the data 
management plan. Data quality summaries will be made available during the course of the 
protocol.  
16.0 TRAINING REQUIREMENTS  
The study staff will be trained as specified in the study Training Plan. Required training will include 
Human Subjects Protection (HSP) and Good Clinical Practice (GCP), as well as protocol-specific 
training as needed (e.g., assessments, study interventions, fidelity to protocol, safety procedures, 
data management and collection, and other research procedures). Attention will be given to 
provide the study clinic staff physicians and pharmacists training in management of OUD, 


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buprenorphine induction and maintenance, and to familiarize study personnel with study 
procedures. Support mechanisms are identified (e.g., who to contact for aid, questions, 
resources), as well as re-training procedures. All study staff will also be required to complete any 
training requirements per their study site and IRB requirements.  
Training in study-specific assessments will be provided as specified in a comprehensive training 
plan that will be developed by the Lead Node, the CCC, and the DSC. All non-intervention training 
is expected to be delivered via conference call, webinar and self-study. Research staff (and all 
other study personnel) will receive HSP and GCP training through the web-based system 
currently in use. The CTN-0075 Training Plan will provide a detailed description of training, 
supervision, and fidelity monitoring procedures.  
 


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17.0 PUBLICATIONS AND OTHER RIGHTS  
Per NIH policy, the results of the proposed trial are to be made available to the research 
community and to the public at large. The planning, preparation, and submission of publications 
will follow the policies of the Publications Committee of the CTN.  
 


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18.0 SIGNATURES  
  
SPONSOR – CCTN SCIENTIFIC OFFICER OR DESIGNEE  
  
  
  
  
  
       
  
  
  
  
 
 
Printed Name  
  
Signature  
  
Date  
  
ACKNOWLEDGEMENT BY INVESTIGATOR:  
  
• 
I am in receipt of version 7.0 of the protocol and agree to conduct this clinical study in accordance 
with the design and provisions specified therein.  
• 
I agree to follow the protocol as written except in cases where necessary to protect the safety, rights, 
or welfare of a participant, an alteration is required, and the sponsor and IRB have been notified prior 
to the action.  
• 
I will ensure that the requirements relating to obtaining informed consent and institutional review board 
(IRB) review and approval in 45 CFR 46 are met.  
• 
I agree to personally conduct or supervise this investigation at this site and to ensure that all site staff 
assisting in the conduct of this study are adequately and appropriately trained to implement this 
version of the protocol and that they are qualified to meet the responsibilities to which they have been 
assigned.  
• 
I agree to comply with all the applicable federal, state, and local regulations regarding the obligations 
of clinical investigators as required by the Department of Health and Human Services (HHS), the 
state, and the IRB.  
  
SITE’S PRINCIPAL INVESTIGATOR  
       
  
  
  
  
 
 
Printed Name  
  
Signature  
  
Date  
  
 
Site Name   
  
       
 
 
Node Affiliation   
  
       
 
  
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20.0 APPENDIX A: Data and Safety Monitoring Plan   
20.1 Brief Study Overview  
The primary goal of the CTN-0075 study is to determine the acceptability and feasibility of shifting 
the outpatient buprenorphine based treatment (OBBT) of OUD from physician to pharmacist care. 
Secondary objectives are to generate point estimates for treatment fidelity and satisfaction, 
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20.2 Oversight of Clinical Responsibilities  
A. Site Principal Investigator  
Each participating site’s Principal Investigator (PI) is responsible for study oversight, including 
ensuring human research subject protection by designating appropriately qualified, trained 
research staff and medical clinicians to assess, report, and monitor safety events.   
All protocol-defined reportable safety events occurring during the course of the clinical trial will be 
collected, documented, and reported by the investigator or sub-investigators according to the 
protocol.   
The occurrence of safety events will be assessed at each visit during the study.    
Reportable safety events are required to be entered into the data system within 48 hoursof the 
site staff becoming aware of the event by completing the checklist. Deaths are required to be 
entered into the data system within 24 hours of the site's knowledge of the event.   
B. CCC Medical Monitor  
The NIDA CTN Clinical Coordinating Center’s (CCC) Medical Monitor or designee is responsible 
for reviewing all safety events reported. Where further information is needed the Medical Monitor 
or designee will discuss the event with the site staff. All safety events are reviewed on a regular 
basis to observe trends or unusual events.  
Voluntary Regulatory Reporting in non-IND Trials:  
For non-IND trials, if an event meets expedited reporting criteria (serious, related and unexpected) 
the CCC Medical Monitor or designee will voluntarily report to FDA/Regulatory Authorities using 
the MedWatch Form 3500 or similar.   
C. Data and Safety Monitoring Board (DSMB)  
The NIDA CTN DSMB affiliated with this trial will be responsible for conducting periodic reviews 
of accumulating safety, trial performance, and outcome data. Reports will be generated and 
presented for Data and Safety Monitoring Board (DSMB) meetings. The DSMB will receive listings 
of safety events and summary reports of all deaths at a frequency requested by the DSMB, but 
at least annually. Furthermore, the DSMB will be informed of expedited reports of safety events. 
The DSMB will make recommendations to NIDA CCTN as to whether there is sufficient support 
for continuation of the trial, evidence that study procedures should be changed, or evidence that 
the trial (or a specific site) should be halted for reasons relating to safety of the study participants 
or inadequate trial performance (e.g., poor recruitment).  
Following each DSMB meeting, the NIDA CCTN will communicate the outcomes of the meeting, 
based on DSMB recommendations, in writing to the study Lead Investigator. This communication 
summarizing study safety information will be submitted to participating IRBs.  
D. Quality Assurance (QA) Monitoring  
The monitoring of the study sites will be conducted on a regular basis by the NIDA CTN CCC. 
Investigators will host periodic visits for the NIDA CTN CCC monitors. The purpose of these visits 
is to assess compliance with GCP requirements and to document the integrity of the trial progress. 
Areas of particular concern will be the review of inclusion/exclusion criteria, participant Informed 
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documents, participant records, study drug accountability, and Principal Investigator supervision 
and involvement in the trial. The monitors will interact with the site staff to identify issues and 
retrain the site as needed to enhance research quality.  
Site Visit Reports will be prepared by the NIDA CCC monitors following each site visit. These reports 
will be sent to the site Principal Investigator, the study Lead Investigator and NIDA CCTN.  
E. Management of Risks to Participants Confidentiality  
Confidentiality of participant records will be secured by the use of study codes for identifying 
participants on CRFs, and secure storage of any documents that have participant identifiers on 
site, as well as secure computing procedures for entering and transferring electronic data. The 
documents or logs linking the study codes with the study participant on site will be kept locked 
separately from the study files and the medical records. No identifying information will be 
disclosed in reports, publications or presentations.  
Information Meeting Reporting Requirements  
The consent form will specifically state the types of information that are required for reporting and 
that the information will be reported as required. These include suspected or known sexual or 
physical abuse of a child or elders, or threatened violence to self and/or others.  
Participant Protection  
The site’s study clinician will evaluate all pertinent screening and baseline assessments prior to 
commencing the study intervention to ensure that the participant is eligible and safe to enter the 
study. Safety events and concomitant medications will be assessed and documented at each 
clinic visit. Individuals who experience a safety event that compromises safe participation in the 
study will be discontinued from further medication administration and provided referrals for other 
treatment or to specialized care. Study personnel will request that the participant complete an 
Early Termination Visit to assure safety and to document end-of-medication outcomes.  


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21.0 APPENDIX B: SUBOXONE® Package Insert  
  


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22.0 APPENDIX C: Simulation of Data for Precision Analyses  
To give some idea of the precision of the estimate of the probability of success, we performed a 
simulation with various scenarios. Each scenario had 10,000 iterations. The scenarios were 
defined by the following parameters:  


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1. 𝜇𝜇= the probability of a positive response at a given time, for a given patient, in a given 
site. That is, we assumed that this probability would be constant across all study sites, 
patients, and times.  
2. (𝛼𝛼, 𝛽𝛽, 𝛾𝛾), where all terms are positive and 𝛼𝛼 + 𝛽𝛽 + 𝛾𝛾 = 1. These parameters, which 
control the correlation structure of the outcomes, have the following intuitive explanations:  
a. 𝛾𝛾 is the “independence” parameter. The closer 𝛾𝛾 is to 1, the more independent all 
the outcomes are from each other.  
b. 𝛼𝛼 is the “site importance” parameter. For a given 𝛾𝛾, the larger 𝛼𝛼 is, the bigger the 
influence of the study site (in comparison to the influence of the patient), upon the 
correlation between observations.  
c. 𝛽𝛽 is the “patient importance” parameter. For a given 𝛾𝛾, the larger 𝛽𝛽 is, the bigger 
the influence of the patient (in comparison to the influence of the study site), upon the 
correlation between observations.  
We assume that all the observations of a given patient have a compound-symmetric correlation 
structure. From the point of view of estimating the probability of success, this is a more pessimistic 
assumption than assuming the observations of a given patient have an AR(1) or other time series 
correlation structure. So we assume that the precision results of our simulation will be 
conservative with respect to real life data.  
We explored the effect of the simulation parameters on the width of the 95% confidence interval of 
the probability of success.   
For each iteration of the simulation:  
1. Flip S independent coins, one for each of the S study sites, and also SP independent coins, 
one for each of the P patients at each site, and also TSP coins, one for each of the T time 
points for each patient at each site. All these coins have P(heads) = 𝜇𝜇.  Name the study site 
outcomes 𝑍𝑍1, … , 𝑍𝑍𝑆𝑆, the patient outcomes 𝑍𝑍11, … , 𝑍𝑍𝑃𝑃𝑆𝑆, and the time outcomes 𝑍𝑍111, 
… 𝑍𝑍𝑇𝑇𝑃𝑃𝑆𝑆.  Each 𝑍𝑍 will be 1 or 0, depending on whether the corresponding coin-flip was 
Heads or Tails, and is a latent random variable in the simulation.  
2. For each time t for patient p at study site s, calculate 𝜃𝜃𝑡𝑡𝑡𝑡𝑡𝑡 = 𝛼𝛼𝑍𝑍𝑡𝑡 + 𝛽𝛽𝑍𝑍𝑡𝑡𝑡𝑡 + 𝛾𝛾𝑍𝑍𝑡𝑡𝑡𝑡𝑡𝑡. 
The 𝜃𝜃′s are also latent random variables.  
3. For each patient p at study site s, time t, calculate his observed (i.e., non-latent)  
outcome 𝑋𝑋𝑡𝑡𝑡𝑡𝑡𝑡 by flipping an independent coin with P(heads) = 𝜃𝜃𝑡𝑡𝑡𝑡𝑡𝑡. Each 𝑋𝑋 will be 1 or 
0, depending on whether the corresponding coin flip was either Heads or Tails.  
It is shown below that 𝐸𝐸(𝑋𝑋𝑇𝑇𝑃𝑃𝑆𝑆) = 𝜇𝜇, 𝑉𝑉(𝑋𝑋𝑇𝑇𝑃𝑃𝑆𝑆) = 𝜇𝜇(1 − 𝜇𝜇), and the X’s have the following 
correlation structure:  
0 
if 𝑆𝑆 ≠ 𝑆𝑆′ 
 
corr(𝑋𝑋𝑇𝑇𝑃𝑃𝑆𝑆, 𝑋𝑋𝑇𝑇′𝑃𝑃′𝑆𝑆′) = 𝛼𝛼2𝛼𝛼+2𝛽𝛽2if 𝑆𝑆 if= 𝑆𝑆𝑆𝑆=′, 𝑃𝑃𝑆𝑆=′ and 𝑃𝑃′,and𝑃𝑃 ≠ 
𝑇𝑇𝑃𝑃≠′ 𝑇𝑇′  


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1 
if 𝑆𝑆 = 𝑆𝑆′, 𝑃𝑃 = 𝑃𝑃′, and 𝑇𝑇 = 
𝑇𝑇′ The algebra to demonstrate these moments follows.  
Theorem – Let 𝐸𝐸 𝜃𝜃𝜏𝜏 = 𝜇𝜇𝜇𝜇 
𝜃𝜃𝜏𝜏 = 𝜎𝜎𝜎𝜎𝜃𝜃𝜃𝜃2,𝜏𝜏 
𝜎𝜎𝜎𝜎𝜃𝜃𝜏𝜏2,𝜏𝜏, 𝑋𝑋~Bernoulli(𝜃𝜃), and 
𝑌𝑌~Bernoulli(𝜏𝜏). Note that 𝑋𝑋 , 𝑉𝑉   
and 𝑌𝑌 are independent, conditional on 𝜃𝜃, 𝜏𝜏.  Then:  
1. 𝐸𝐸(𝑋𝑋) = 𝐸𝐸(𝑌𝑌) = 𝜇𝜇  
2. 𝑉𝑉(𝑋𝑋) = 𝑉𝑉(𝑌𝑌) = 𝜇𝜇(1 − 𝜇𝜇)  
3. 𝑐𝑐𝑐𝑐𝑐𝑐(𝑋𝑋, 𝑌𝑌) = 𝜎𝜎𝜃𝜃,𝜏𝜏  
  
Proof: (1) follows using conditional expected values. (2) follows because X and Y are (0,1) random 
variables for which (1) is true. (3) follows using the law of total covariance, i.e.:  
𝑐𝑐𝑐𝑐𝑐𝑐(𝑋𝑋, 𝑌𝑌) = 𝐸𝐸𝜃𝜃,𝜏𝜏[𝑐𝑐𝑐𝑐𝑐𝑐(𝑋𝑋, 𝑌𝑌|𝜃𝜃, 𝜏𝜏)] + 
𝑐𝑐𝑐𝑐𝑐𝑐𝜃𝜃,𝜏𝜏[𝐸𝐸(𝑋𝑋|𝜃𝜃), 𝐸𝐸(𝑌𝑌|𝜏𝜏)]  
= 0 + 𝑐𝑐𝑐𝑐𝑐𝑐(𝜃𝜃, 𝜏𝜏) = 𝜎𝜎𝜃𝜃,𝜏𝜏  
Now, let   
𝜃𝜃 = ∑𝛼𝛼𝑖𝑖𝑍𝑍𝑖𝑖  
𝜏𝜏 = ∑𝛽𝛽𝑖𝑖𝑍𝑍𝑖𝑖  
where ∑𝛼𝛼𝑖𝑖 = ∑𝛽𝛽𝑖𝑖 = 1, all (𝛼𝛼, 𝛽𝛽) are non-negative, and each 𝑍𝑍𝑖𝑖~Bernoulli(𝜇𝜇). Note that 𝜃𝜃 
and 𝜏𝜏 meet the conditions of the Theorem. This means that 𝐸𝐸(𝑋𝑋) = 𝐸𝐸(𝑌𝑌) = 𝜇𝜇, 𝑉𝑉(𝑋𝑋) = 
𝑉𝑉(𝑌𝑌) = 𝜇𝜇(1 − 𝜇𝜇), and:  
𝑐𝑐𝑐𝑐𝑐𝑐(𝑋𝑋, 𝑌𝑌) = 𝑐𝑐𝑐𝑐𝑐𝑐(𝜃𝜃, 𝜏𝜏) = 𝜇𝜇(1 − 𝜇𝜇)∑𝛼𝛼𝑖𝑖𝛽𝛽𝑖𝑖  
from which 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐(𝑋𝑋, 𝑌𝑌) = ∑𝛼𝛼𝑖𝑖𝛽𝛽𝑖𝑖.    
The statement above about corr(𝑋𝑋𝑇𝑇𝑃𝑃𝑆𝑆, 𝑋𝑋𝑇𝑇′𝑃𝑃′𝑆𝑆′) follows on choosing 𝛼𝛼, 𝛽𝛽, 𝛾𝛾, 𝜇𝜇, and the Z’s 
as given in the description of the simulation.