Validation of a Community Pharmacy-Based Prescription Drug Monitoring Program Risk Screening Tool
Conditions: Opioid Abuse, Prescription Drug Abuse (Not Dependent)
Sponsor: University of Utah

Study Protocol  
CTN-0093: Validation of a Community Pharmacy-Based Prescription Drug Monitoring Program 
Risk Screening Tool  
NCT039369 
Document Date: May 25, 2021 

 
 
 
 
 
 
NIDA CTN Protocol 0093 
 
VALIDATION OF A 
COMMUNITY PHARMACY-BASED 
PRESCRIPTION DRUG MONITORING 
PROGRAM RISK SCREENING TOOL 
(PHARMSCREEN)  
 
 
 
Lead Investigator (LI): Gerald Cochran, PhD  
 
Co-LI: Theresa Winhusen, PhD 
 
 
 
Funded by: National Institute on Drug Abuse (NIDA) 
May 25, 2021 
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Lead Investigator (LI): 
  
 
Gerald Cochran, PhD 
 
  
 
Greater Intermountain Node 
 
  
 
University of Utah 
 
Co-LI: 
  
 
Theresa Winhusen, PhD  
 
 
  
 
Ohio Valley Node 
 
  
 
University of Cincinnati  
 
Co-Investigator 
  
 
Jennifer Brown, PhD 
 
  
 
Ohio Valley Node 
 
  
 
University of Cincinnati 
 
Co-Investigator 
  
 
Margie Snyder, PharmD, MPH, FCCP 
 
  
 
Ohio Valley Node 
 
  
 
Purdue University  
 
 
Project Manager 
  
 
Irene Ewing  
 
 
  
 
Ohio Valley Node 
 
  
 
University of Cincinnati 
 
CCTN Scientific Officer:   
 
Udi Ghitza, PhD 
 
  
 
National Institute on Drug Abuse 
 
 

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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ............................................................................................ 5 
 
STUDY SYNOPSIS ......................................................................................................... 6 
 
STUDY OBJECTIVES ....................................................................................................... 6 
 
STUDY DESIGN .............................................................................................................. 6 
 
STUDY POPULATION ...................................................................................................... 6 
 
ASSESSMENTS .............................................................................................................. 6 
 
ANALYSES ..................................................................................................................... 7 
 
STUDY SCHEMA ............................................................................................................ 8 
 
BACKGROUND AND RATIONALE ................................................................................ 9 
 
BACKGROUND ............................................................................................................... 9 
 
RATIONALE...................................................................................................................10 
 
SIGNIFICANCE TO THE FIELD ..........................................................................................10 
 
OBJECTIVES.................................................................................................................11 
 
PRIMARY OBJECTIVE ....................................................................................................11 
 
SECONDARY OBJECTIVE ................................................................................................11 
 
STUDY DESIGN ............................................................................................................12 
 
OVERVIEW OF STUDY DESIGN .......................................................................................12 
 
DURATION OF STUDY AND VISIT SCHEDULE ....................................................................12 
 
RECRUITMENT SITES AND PARTICIPANT SELECTION........................................................12 
 Site Selection ..........................................................................................................12 
 Participant Selection ................................................................................................13 
 
STUDY ASSESSMENTS ...............................................................................................14 
 
OVERVIEW OF ASSESSMENTS ........................................................................................14 
 
PRIMARY MEASURES OF INTEREST ................................................................................14 
 NS metric ................................................................................................................14 
 WHO ASSIST ..........................................................................................................14 
 TAPS Tool ...............................................................................................................15 
 
OTHER STUDY MEASURES ............................................................................................15 
 Prescription Opioid Misuse Index ............................................................................15 
 Overdose Experiences, Self and Witnessed—Drug .................................................15 
 Brief Pain Inventory .................................................................................................15 
 Short Form-12 .........................................................................................................15 
 Patient Health Questionnaire ...................................................................................15 
 
SAFETY MEASURES ......................................................................................................16 
 
OTHER MEASURES .......................................................................................................16 
 Recruitment/Screening Assessments ......................................................................16 
 Self-screening assessment......................................................................................16 
 Additional PDMP Data .............................................................................................16 

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STUDY PROCEDURES .................................................................................................17 
 
OVERVIEW OF PROCEDURES .........................................................................................17 
 
PARTICIPANT RECRUITMENT AND CONSENT ...................................................................17 
 
SCREENING ..................................................................................................................18 
 
PREMATURE WITHDRAWAL OF PARTICIPANTS .................................................................18 
 
STUDY HALTING RULES ................................................................................................18 
 
FOLLOW-UP .................................................................................................................18 
 
PARTICIPANT REIMBURSEMENT .....................................................................................18 
 
STATISTICAL DESIGN AND ANALYSES .....................................................................19 
 
GENERAL DESIGN .........................................................................................................19 
 Study Hypotheses ...................................................................................................19 
 
RATIONALE FOR SAMPLE SIZE AND STATISTICAL POWER .................................................19 
 Projected Number of Sites .......................................................................................19 
 Projected Number of Participants per Site ...............................................................19 
 
STATISTICAL METHODS FOR PRIMARY AND SECONDARY OUTCOMES ...............................20 
 
SIGNIFICANCE TESTING .................................................................................................20 
 
MISSING DATA AND DROPOUTS .....................................................................................20 
 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..........................................................20 
 REGULATORY COMPLIANCE, REPORTING AND MONITORING ..............................21 
 REGULATORY COMPLIANCE ...........................................................................................21 
 STATEMENT OF COMPLIANCE ........................................................................................21 
 INFORMED CONSENT ....................................................................................................21 
 QUALITY ASSURANCE MONITORING ...............................................................................22 
 PARTICIPANT AND DATA CONFIDENTIALITY .....................................................................22 
 FINANCIAL DISCLOSURE/CONFLICT OF INTEREST ............................................................23 
 PERFORMANCE MONITORING ........................................................................................23 
 INCLUSION OF WOMEN AND MINORITIES .........................................................................23 
 PRISONER CERTIFICATION ............................................................................................24 
 
REGULATORY FILES ..................................................................................................24 
 
RECORDS RETENTION AND REQUIREMENTS ................................................................24 
 
REPORTING TO SPONSOR ..........................................................................................24 
 
AUDITS .....................................................................................................................24 
 
STUDY DOCUMENTATION ...........................................................................................24 
 
PROTOCOL DEVIATIONS ............................................................................................25 
 
SAFETY MONITORING ................................................................................................25 
 Data and Safety Monitoring Board (DSMB) ..........................................................25 
 
TRAINING ..................................................................................................................25 
 DATA MANAGEMENT ..................................................................................................26 
 DESIGN AND DEVELOPMENT ..........................................................................................26 
 SITE RESPONSIBILITIES .................................................................................................26 
 DATA CENTER RESPONSIBILITIES ..................................................................................26 
 DATA COLLECTION .......................................................................................................26 

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 DATA MERGE ...............................................................................................................26 
 DATA ACQUISITION AND ENTRY .....................................................................................27 
 DATA TRANSFER/LOCK .................................................................................................27 
 DATA TRAINING ............................................................................................................27 
 DATA QUALITY ASSURANCE ..........................................................................................27 
 PUBLICATIONS AND OTHER RIGHTS ........................................................................28 
 PROTOCOL SIGNATURE PAGE ..................................................................................29 
 REFERENCES ...............................................................................................................30 
 APPENDIX: DATA AND SAFETY MONITORING PLAN ...............................................34 
 
 
 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Full Name 
AUC 
Area under the curve 
BPI 
Brief Pain Inventory 
CTN 
Clinical Trials Network 
LI 
Lead Investigator 
NS Metric 
Narcotic Score Metric 
OVN 
Ohio Valley Node 
OUD 
Opioid use disorder 
OESW-D 
Overdose Experiences, Self and Witnessed-Drug 
PHQ-2 
Patient Health Questionnaire-2 
PDMP 
Prescription Drug Monitoring Program 
POMI 
Prescription Opioid Misuse Index 
POUD 
Prescription opioid use disorder  
ROC 
Receiver operating characteristic 
SF-12 
Short Form-12 
TAPS 
Tobacco, Alcohol, Prescription medication and other  Substances 
WHO ASSIST 
World Health Organization Alcohol, Smoking, and Substance Involvement 
Screening Test 
 

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 STUDY SYNOPSIS  
 Study Objectives  
Using opioid therapy to treat pain effectively, while minimizing potential adverse consequences, 
is an important goal. Appriss Health has developed the “Narcotic Score,” referred to as the “NS 
metric” hereafter, which uses Prescription Drug Monitoring Program (PDMP) data on opioid and 
sedative prescriptions and aberrant drug behavior (e.g., multiple providers, pharmacies, etc.) to 
compute a score quantifying the extent of the patient’s risk for opioid-related adverse events in 
relation to all prescription opioid users. The association between the NS metric and other 
indicators of opioid use or risk has not been evaluated, and hence, the degree to which this metric 
is a useful clinical screening tool is unknown. In addition to the NS metric, the Tobacco, Alcohol, 
Prescription medication and other Substances (TAPS) tool is rapidly becoming recognized as a 
high-quality substance use screening measure for outpatient health care settings. Given the 
somewhat limited opioid-using sample in the TAPS tool validation study (≤5% for prescription 
opioids; <4% for heroin1), the current study provides the opportunity to (1) to better assess the 
validity of the TAPS Tool as it would be used in clinical practice in community pharmacy settings 
(including rural locations), and (2) to provide more clinically useful information for the use of the 
TAPS Tool by community pharmacists. The present study has two objectives: 
1) Evaluate the concurrent validity of the NS metric as a clinical measure of high risk opioid 
use and establish clinically useful risk-level thresholds relative to the widely validated gold 
standard of the World Health Organization Alcohol, Smoking, and Substance Involvement 
Screening Test (WHO ASSIST).2  
 
2) Collect TAPS tool data in a large sample of individuals filling opioid pain medications to 
facilitate further validation of this instrument with the WHO ASSIST.  
 Study Design  
This study is a one group, cross-sectional, health assessment study. Participants who enroll in 
the study will complete on-line surveys of opioid utilization and risk, overdose history, substance 
use, mental health, and physical health at a single time point. Appriss Health will provide NS 
metric scores for all participants. These data will also be used to 1) validate and to identify clinical 
cut-off values for the NS metric and 2) to further validate the TAPS tool.  
 Study Population  
Approximately 1,523 patients will be recruited from approximately 15 community Kroger 
community pharmacies. Trained pharmacy staff will inform potentially eligible participants, or 
individuals receiving at least one prescription(s) for potentially eligible participants, of the survey 
opportunity. Interested patients will complete an encrypted electronic “interest survey,” which will 
trigger REDCap to email the patient a link to a secure web-portal containing e-consent (i.e., an 
electronic information sheet that is submitted by participants indicating their consent to participate 
in the study) and self-screening assessment forms. Following submission of the e-consent and 
successful qualification on the self-screening assessment, the health survey will be made 
available to participants for completion. The REDCap audio features will be enabled to allow 
participants with any reading difficult to request specific items be read out loud.   
 Assessments 
The key assessments are: 1) The NS metric, obtained from Appriss Health, which is a continuous 
indicator on a 000-999 scale (higher scores indicate increased risk for adverse opioid-related 

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outcomes);3,4   2) The WHO ASSIST; and (3) the TAPS Tool. The WHO ASSIST and TAPS Tool 
will be completed by participants through a secure REDCap-hosted web portal. Other 
assessments to be captured via self-report through the secure REDCap-hosted web portal 
include: 1) opioid medication misuse assessed with the Prescription Opioid Misuse Index (POMI);5 
2) pain severity assessed by the Brief Pain Inventory (BPI);6 3) general health status measured 
with a 1-item subscale from the Short Form (SF)-12;7 4) depression assessed with the Patient 
Health Questionnaire (PHQ)-2;8 and 5) overdose frequency history assessed using the Overdose 
Experiences, Self and Witnessed (OESW-D)—Drug instrument.9  
 Analyses 
A series of a priori analyses will be conducted to evaluate the validity of the NS metric relative to 
the widely validated gold standard WHO ASSIST and to identify cutoff thresholds. A priori 
analyses will involve conducting Receiver Operating Curve Analyses (ROC; i.e., sensitivity and 
specificity, area under the curve [AUC]) to identify clinical cutoff values for the NS metric and low, 
moderate, and high WHO ASSIST scores. We will also conduct correlational, regression, and 
Cohen’s Kappa statistical analyses to evaluate the relationship between the NS metric and the 
WHO ASSIST.   
 
We will also conduct exploratory correlational and regression, and Cohen’s Kappa statistical 
analyses to validate the relationship between the NS metric and measures of opioid medication 
misuse as well as history of opioid overdose. Exploratory ROC, correlational, regression, and 
Cohen’s Kappa statistical analyses between the WHO ASSIST and the TAPS Tool will also be 
conducted.  

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 STUDY SCHEMA  
 
 
• 
Adult patients at participating Kroger Pharmacies in Ohio and Indiana 
will be approached while picking up qualifying opioid medications 
• 
Pharmacy staff shares details of study 
• 
Persons picking up medications for others will receive a study flyer with 
instructions on how the opioid recipient may remotely complete the 
interest form 
 
▼ 
 
• 
Patient inputs contact information into REDCap interest form 
• 
Patient receives email link to e-consent and self-screening assessment 
 
▼ 
 
• 
Upon successfully qualifying on the self-screening assessment and 
completing the e-consent, the health assessment survey is made 
available to the participant 
 
▼ 
 
• 
Participant completes survey, which includes: 
 
1. WHO ASSIST 
2. POMI 
3. TAPS Tool 
4. OESW-D  
5. PHQ-2 
6. SF-12 (general health subscale) 
7. BPI 
8. Demographics 
 
▼ 
 
• 
Ohio Valley Node (OVN) staff verifies the participant has not previously 
completed the survey and, if verified, sends participant $50  
 
▼ 
 
• 
Data are checked for completeness, stored in HIPAA compliant 
environment, and merged regularly with NS metric 
• 
Final merged dataset with NS scores and health assessments are 
shared with OVN and University of Utah 
• 
Data are analyzed and results are reported 
 
 

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 BACKGROUND AND RATIONALE 
 Background  
The US opioid epidemic continues to have serious public health ramifications. In 2017, nearly 
11.1 million individuals in the US reported misuse of opioid pain-relievers in the past year,10 with 
approximately 36% obtaining opioid medications for misuse through filling medications from a 
prescriber.10 A robust literature in the last decade has documented a clear trajectory for individuals 
who begin with opioid medication misuse transitioning to heroin use.11-22 In 2017, over 650,000 
individuals in the US reported past-year heroin use.10 Fatal overdose deaths involving prescription 
opioids, heroin, and synthetic opioids has continued to increase across the US—continuing to 
increase in 35 states from 2013-2017.23 Given these persistent trends for adverse opioid-related 
outcomes in populations across the US, it is critical to work to identify those who are at risk, deliver 
appropriate care that will help prevent progression to more severe opioid-related outcomes, and 
provide referral and treatment resources to those who suffer from opioid use disorder (OUD). 
Therefore, it is necessary to expand the continuum of care to health care settings that previously 
may have been underutilized.  
One underutilized resource for addressing the current opioid epidemic is community pharmacies. 
In the US, 93% of individuals live within 5 miles24 of the >60,000 community pharmacies that 
employ >170,000 pharmacists.25 National data show that >40% of community pharmacies have 
private counseling rooms where pharmacists can discretely and confidentially provide care.26 
Pharmacists are ranked among the top 2 most trusted professionals in the US,27 with research 
showing patients are willing to receive behavioral health information from these professionals.28  
Previous research among pharmacists has further provided support for possible identification and 
intervention by community pharmacists for opioid misuse among patients.  Results of a survey in 
2 states (N=739) about opioid medication misuse and possible screening and intervening found 
that most pharmacists (90%) wanted to help patients who misuse opioid pain medications but 
reported needing training (81%) and tools (80%) to effectively do so.29,30  Furthermore, results 
from 333 patients (response=71.2%) screened in 4 community pharmacies receiving opioid 
medications found opioid medication misuse among 15% of patients.31 Among those with misuse, 
98% had ≥1 comorbid health condition known to increase risk for misuse or overdose, including 
depression, posttraumatic stress, risky alcohol use, and poor health and pain exceeding US 
norms. Patients in this sample were agreeable to pharmacists screening their opioid medication 
use (70.9%) and discussing medication use if pharmacists had a concern (82.1%; with no 
differences between misusing and non-misusing respondents, p>.05).32,33 Given this important 
foundation for the expansion of the role of community pharmacy to address the opioid epidemic, 
it is critical to identify opportunities to better equip these health care professionals with tools to 
identify patients who are at risk for opioid-related adverse events.   
The most important clinical tool pharmacists have available to identify possible misuse of opioid 
medications is prescription drug monitoring programs (PDMP),34-41 which capture patient-level 
prescription dispensing information to inform monitoring, dispensing decisions, and possible 
intervention.35,36,38,41 These tools are available in all US states (Missouri relies on a county-
administered program) and have the potential to enable pharmacists to identify patients at-risk for 
opioid-related adverse events, such as addiction and overdose. Appriss Health is the largest 
PDMP platform vendor in the US, providing PDMP services statewide in 42 states, with 
approximately 1 million users. The Appriss platform facilitates PDMP data sharing in 44 states 
and captures 8 million monthly transactions. PDMP programs, such as the Appriss platform, have 
demonstrated clear results for reducing opioid prescribing.35-41 PDMP effectiveness has not been 
clear on substance use outcomes,38 including rates of overdose.42-44 PDMP output data are limited 

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in clinical utility, do not provide decision support, and thus users must act on “best judgment” to 
provide patient care and referrals with a limited evidence base. Appriss Health has developed an 
opioid risk measure, the NS metric, which could support community pharmacists’ decision-making 
regarding interventions for opioid risk. However, the validity of the NS metric has not been 
evaluated. 
 Rationale 
In light of the continued escalation of the opioid epidemic nationally, combined with the promising 
opportunities afforded by the further inclusion of community pharmacy settings for engaging 
patients with opioid-related risk, it is important to evaluate whether current PDMP risk metrics 
correlate with clinically validated opioid risk tools and if clinically meaningful risk cutoffs exist for 
PDMP risk metrics. The present study will accomplish two important objectives. 
 
First, the NS metric has not been empirically validated with standardized opioid risk tools. This 
formative research project will leverage public/private partnerships among the OVN, University of 
Cincinnati, University of Utah, Purdue University, Appriss Health, and Kroger Pharmacies to 
validate and identify risk thresholds for the NS metrics through comparison with the widely 
validated gold standard WHO ASSIST. Successfully completing this objective is the first important 
step in understanding the validity of current PDMP metrics and establishing clinically meaningful 
risk tools for opioids, which would allow community pharmacists to accurately and rapidly triage 
patient opioid risk. These results will provide foundational data that will allow our team to continue 
this line of research and further collaborate with Appriss Health to identify and test a PDMP-based, 
opioid-focused, decision support tool for community pharmacies.  
 
The second objective of this study is to further validate the TAPS tool. Mentioned previously, the 
TAPS tool is rapidly becoming recognized as a high-quality substance use screening measure for 
outpatient health care settings. 1  The recent validation study for this tool, conducted with primary 
care patients, showed high levels of sensitivity and specificity for tobacco and heavy alcohol use 
(>0.79), and adequate sensitivity and specificity for illicit and prescription drug use (>0.63).1 Given 
the somewhat limited opioid using sample in the validation study (≤5% for prescription opioids; 
<4% for heroin1), the current study provides the opportunity (1) to better assess the validity of the 
TAPS Tool as it would be used in clinical practice in community pharmacy settings (including rural 
locations), and (2) to provide more clinically useful information for the use of TAPS Tool by 
community pharmacists. 
 Significance to the Field 
 
The first study objective builds on previous research from our team that has focused on 
understanding the needs and opportunities available for identification of, and intervention for, 
problematic 
opioid 
use 
among 
community 
pharmacy 
patients 
prescribed 
opioid 
medications.29,30,45-47 The results of this project stand to meet several important needs of 
community pharmacy to increase their involvement in the identification of patients at-risk for 
opioid-related adverse events, such as addiction and overdose. Specifically, if the first objective 
is achieved, the results from this study would enable rapid identification of opioid-related risk 
utilizing data from a widely-available PDMP platform vendor (Appriss Health). 
 
The second study objective also builds on previous research from CTN investigators1,48 and 
stands to extend the knowledge base in the field regarding the utility of the TAPS Tool as a 
universal substance use screening instrument for outpatient clinical care settings. 

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  OBJECTIVES  
 Primary Objective  
The primary objective of this project is to validate and identify low, moderate, and high risk 
thresholds for the NS metric through comparison to the widely validated gold-standard WHO 
ASSIST measure for opioid use risk in adult community pharmacy patients dispensed opioid 
medication therapies.  
 Secondary objective 
The secondary objective of this study is to collect data to further validate the TAPS Tool. This 
measure will be compared to the WHO ASSIST in a novel sample of adult outpatients from 
community pharmacies with active opioid medication prescriptions.  

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 STUDY DESIGN  
 Overview of Study Design  
We will implement a one-time, cross-sectional, self-administered, health survey among eligible 
adult patients dispensed opioid medications from 15 participating Kroger pharmacies in Ohio and 
Indiana. This design will accomplish the purpose of the study given that it will allow for recruitment 
of a sample of patients with sufficient power to identify and validate clinical threshold values for 
the NS Metric. Patients recruited will complete a series of validated measures to assess opioid 
use and risk behaviors, substance use, and physical and mental health.  
Study survey data will be merged on a regular basis with the NS metric by Appriss Health and 
shared with OVN and University of Utah investigators for assessment of data quality and to 
conduct statistical analyses. See section 11.9 for an overview of Data Quality Assurance. Appriss 
Health will deterministically match and merge the survey data with the NS metric using patient 
contact information (e.g., name, address, phone number) as well as information regarding the 
location of the pharmacy and time/dates for when the study interest form was completed and 
submitted into REDCap.  
 Duration of Study and Visit Schedule 
Enrollment is expected to take place over a period of approximately 6-8 months. Enrolled 
participants will complete surveys at a single time point, which will take approximately 35-40 
minutes to complete. 
 Recruitment Sites and Participant Selection 
 Site Selection 
Participating University sites for this project include, the: University of Cincinnati, University of 
Utah, and Purdue University. Recruitment sites for the study include approximately 12 Kroger 
Pharmacies in Ohio and approximately 3 rural Kroger Pharmacies in Indiana. The rural Indiana 
pharmacy locations will be identified as rural by meeting at least one of the definitions of rural 
using the “Am I Rural” online tool (https://www.ruralhealthinfo.org/am-i-rural).  
6.3.1.1 Recruitment Site Characteristics 
Study site characteristics reflect the need to recruit community pharmacy patients receiving opioid 
medications in urban and rural settings in order increase the generalizability of the study results. 
For study feasibility, it was determined that each recruitment site also needed to be a Kroger 
pharmacy in the state of Ohio or rural Indiana that filled an adequate number of patients’ opioid 
prescriptions. The Kroger Pharmacy chain was selected as the partner for this project based on 
4 primary reasons: 
 
1. Sites selected will dispense and average of ≥300 patients’ opioid prescriptions within a 
6-month period, resulting in a patient pool of approximately ≥4,500 potential participants; 
 
2. Kroger and Appriss Health have a long history of collaboration, and therefore partnering 
on this project will be familiar to both companies. Kroger also has a long history of 
collaboration with University of Cincinnati and Purdue University.  
 
3. Kroger is the 5th largest pharmacy chain in the US, and thus represents a possible 
scalable service setting if the primary objective of the current study is successful.  
 

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4. Kroger corporate offices are located in Cincinnati, Ohio. Thus, working with company 
leadership and staff training will be facilitated by proximity to the OVN investigative 
teams at the University of Cincinnati and Purdue University Indianapolis campuses.  
 
In addition to the above points, the study investigative team will work closely with Kroger 
Pharmacy to select pharmacy locations within ethnically and racially diverse populations to 
promote the recruitment of a diverse study sample.   
 Participant Selection 
This study will enroll approximately 1,523 patients who will complete a web-based health survey.  
 
6.3.2.1 
Inclusion Criteria 
Potential participants must: 
1. be dispensed ≥1 opioid medication (including tramadol) by a participating Kroger 
Pharmacy; 
 
2. be ≥18 years of age according to Kroger Pharmacy data and self-report 
 
6.3.2.2 
Exclusion Criteria 
Potential participants must not self-report: 
1. solely filling buprenorphine or buprenorphine combination products i.e., patients 
receiving OUD treatment with no other opioid medication use; 
 
2. currently receiving treatment for cancer; 
 
3. having previously completed the survey (this will be re-verified by OVN staff by 
examining identifying information following health assessment submission); 
 
4. having current involvement with the criminal justice system that has, or could, lead to 
incarceration 
Mentioned above, we will enable REDCap audio features to allow participants with any reading 
difficult to request specific items be read out loud.   

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  STUDY ASSESSMENTS  
 Overview of Assessments 
The selection of assessments was based on the validity of the assessments, costs of data 
collection in terms of participant time and staff time and training, and feasibility of 
completion.   
 Primary Measures of Interest  
Unlike a clinical trial evaluating the impact of an intervention, the present study is a validation 
study, and thus, does not include traditional outcome measures. 
 NS metric 
The NS metric is a continuous indicator on a 000-999 scale, with the last digit representing 
number of active opioid prescriptions (those with ≥9 prescriptions coded as 9) and the first two 
numbers representing a composite risk score. Higher scores indicate increased risk for adverse 
opioid-related outcomes (e.g., overdose). The first two digits of the score are based on 
deterministic calculations3,4 and use well-known indicators associated with opioid-related 
adverse events.49-52 These calculations are produced through the following steps: 
1) For a given patient, raw indicators of five risk factors are extracted from PDMP data: (a) 
morphine milligram equivalents (MME) dispensed, (b) lorazepam milligram equivalents 
(LME) dispensed, (c) overlapping prescription days, (d) number of prescribers, and (e) 
numbers of pharmacies. 
2) Each raw indicator is converted to a scaled value between 0 and 99 (based on percentiles 
from a large PDMP reference population), for four time periods: (a) past 2 months, (b) past 
6 months, (c) past 12 months, and (d) past 24 months. Therefore, each patient is assigned 
20 scaled percentile values. These scaled values weigh the contribution of recent values 
more heavily than values further in the past; for example, having 6 unique prescribers over 
the past 2 months has a greater scaled percentile score (i.e., 85) than having 6 unique 
prescribers over the past 2 years (i.e., 30). 
3) Scaled values for each of the five indicators are averaged across their four respective time 
periods.  
4) A weighted sum of the five averaged values is calculated: MME is given a weight of 3; 
overlapping medication days is given a weight of 2; and LME, number of prescribers, 
number of pharmacies are each given a weight of 1. This sum is divided by 8 to produce a 
weighted average, yielding a two-digit composite risk score; these are the first two digits of 
the NS metric.  
5) The total number of active opioid prescriptions is appended to the two-digit composite risk 
score, to form the final three-digit NS metric. 
 WHO ASSIST 
The WHO ASSIST will be used as the gold standard to which the NS metric will be compared. 
The WHO ASSIST was constructed in a large-scale multi-country study, which demonstrated 
criterion, construct, concurrent, discriminant validity.2 This assessment contains between 8-74 
Likert scale items, depending on the number of substances endorsed by study participants, and 
will require 5-15 minutes to complete. The WHO ASSIST asks about use of the following 

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substances in the past 3 months and lifetime: tobacco, alcohol, cannabis, cocaine, 
amphetamine, inhalants, sedatives, hallucinogens, opioids, and other drugs. 
In addition to the WHO ASSIST, we will capture 2 additional opioid items from an adapted WHO 
ASSIST, developed by McNeely, et al.53 In this adapted version, opioid items specifically inquire 
about use of prescription opioids and heroin. These items have been tested in an audio assisted 
computerized format and have demonstrated reliability.53 These items will not be used in our a 
priori assessment of the NS score and the WHO ASSIST.  
 TAPS Tool 
Substance use will also be captured using TAPS 1/2 tool, which has demonstrated concurrent 
validity. 1 This assessment contains between 5-14 items regarding a respondent’s substance 
use in the last 3 and 12 months. It specifically addresses use of tobacco and alcohol as well as 
illicit and prescription drug misuse. This assessment will require 5-15 minutes to complete. This 
measure will be captured to provide additional information regarding its psychometric properties 
compared to the WHO ASSIST. 
 Other Study Measures  
Additional measures of opioid misuse, overdose, health, and mental health will also be collected 
in order to describe the participant population, adjust analytical models, and perform exploratory 
analyses.  
 Prescription Opioid Misuse Index 
Opioid medication misuse will be captured using the Prescription Opioid Misuse Index, which 
has demonstrated criterion validity.5 This measure contains 6 yes/no items about an individual’s 
current use of opioid medications and covers domains such as early refills, taking more than 
prescribed, doctor shopping, and using the medication to cope with problems. This assessment 
will require 5 minutes or less to compete.  
 Overdose Experiences, Self and Witnessed—Drug 
Overdose frequency history will be assessed using the overdose frequency item from the 
criterion-valid Overdose Experiences, Self and Witnessed—Drug instrument.9 This single item 
asks respondents how many times in their lifetime they have experienced a drug overdose. This 
assessment will require 1 minute or less to compete. 
 Brief Pain Inventory 
Pain severity will be assessed using the Brief Pain Inventory (BPI), a well-validated, reliable 
instrument that consists of a 4-item pain Intensity subscale and a 7-item pain interference 
subscale.6 This BPI will require 5 minutes or less to compete. 
 Short Form-12 
General health status will be measured using a 1-item subscale from the construct-valid Short 
Form-12.7 This Likert scale item asks respondents to rate their general health from excellent to 
poor. This assessment will require 1 minute or less to compete. 
 Patient Health Questionnaire 
Depression will be captured using the criterion-valid  Patient Health Questionnaire-2.8 This 2-
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every day’) their interest or pleasure in doing things and feeling of being down or depressed in 
the last two weeks. This assessment will require 1 minute or less to compete. 
 Safety Measures  
This study will not involve the use of any clinical intervention or medications. The only expected 
risk to participants is a loss of confidentiality, which will be minimized by utilizing an encrypted 
REDCap platform. Any breach of confidentiality will be reported on a protocol deviation form. 
Data security will also be ensured for transferring data files to and from Appriss Health by 
utilizing a HIPAA compliant, encrypted, and secure data storage cloud site.   
 Other Measures 
 Recruitment/Screening Assessments 
Recruitment – Kroger Pharmacy staff will aid in tracking which patients have been provided with 
information about the study and how that information was shared.   
 
Interest form – Participants interested in learning more about the study will complete an electronic 
“interest form” in which they provide their contact information as well as basic demographic 
characteristics (e.g., age, sex, race/ethnicity). Kroger pharmacy staff will be available to answer 
participant questions regarding the interest form. If completing the interest form remotely, study 
staff’s contact information will be available for potential participants to call for assistance.  
 
 Self-screening assessment 
Following e-consent, participants will complete a self-screening assessment, which will include 
questions about opioid medication prescriptions (including Kroger Pharmacy at which the 
qualifying prescription was filled), whether they are being treated for cancer, have involvement 
with the criminal justice system, and whether they have participated in the study previously. 
Study staff’s contact information will be shared on the e-consent form, self-screening 
assessment, and the health survey. They will be available to answer any questions the 
participant may have.  
 Additional PDMP Data 
Appriss Health may also provide, in addition to the NS metric, other related data that possibly 
will be informative for the objectives of this study. Examples of these other data elements could 
include non-opioid medication information, prescribing information, and/or dispensing 
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 STUDY PROCEDURES  
 Overview of Procedures 
Table 1 provides an overview of the participant procedures and assessments. 
 
Table 1. Overview of Assessments and Procedures 
Form 
Done by 
Before 
screening 
Screening/ 
Eligibility 
Assessment 
Recruitment Tracking 
Pharmacy 
x 
 
 
Interest form 
Participant 
 
x 
 
E-consent 
Participant 
 
x 
 
Self-screening 
Participant 
 
x 
 
 
Assessment domain: Opioid Use 
Narcotic Score (NS metric) 
Appriss 
 
 
x 
WHO ASSIST: opioid items2 
Participant 
 
 
x 
Who ASSIST: adapted opioid Items53 
Participant 
 
 
x 
TAPS 1 / 2 Tool: Prescription drug and 
prescription opioid items1 
Participant 
 
 
x 
TAPS 1 / 2 Tool: Illicit drug and heroin 
items1 
Participant 
 
 
x 
Prescription Opioid Misuse Index5 
Participant 
 
 
x 
Overdose Experiences, Self and 
Witnessed—Drug 
(OESWD) 9 
Participant 
 
 
x 
 
Assessment domain: Substance Use 
WHO ASSIST: Non-opioid drug use 
items2 
Participant 
 
 
x 
TAPS 1 / 2 Tool: Non-opioid items1 
Participant 
 
 
x 
 
Assessment domain: Mental Health 
Patient Health Questionnaire-28 
Participant 
 
 
x 
 
Assessment domain: Physical Health 
Short Form-12: General health 
subscale7 
Participant 
 
 
x 
Brief Pain Inventory6 
Participant 
 
 
x 
 
Assessment domain: Demographics 
PhenX demographics: age, education, 
gender, race, ethnicity, insurance, 
employment, marital status 
Participant 
 
 
x 
 Participant Recruitment and Consent  
A convenience sample of adult patients being dispensed opioid prescriptions (including tramadol 
and not solely receiving buprenorphine or buprenorphine combination products) at any of the 
participating Kroger Pharmacy locations will be recruited. Recognizing the busy nature of the 
Kroger Pharmacy environment, we have intentionally designed the recruitment process to require 
minimal pharmacy staff involvement, requiring staff to only assess the patients’ ages and 
prescription information to target potentially eligible participants. Trained Kroger Pharmacy staff 
will inform potentially eligible participants of the survey opportunity. Interested patients will be 
handed a study flyer and an electronic device (e.g., tablet, etc.) with an electronic “interest survey.” 
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who choose not to initially share contact information. The flyer will only be targeted to those who 
the pharmacy staff believes are eligible for the study. The flyer will direct interested individuals to 
a secure web-version of the interest survey. Interested patients will complete the encrypted 
electronic “interest survey,” which will trigger REDCap to email the patient a link to a secure web-
portal containing the e-consent (i.e., an electronic informed consent information sheet that is 
submitted by participants indicating their consent to participate in the study).  
 
The IRB will be asked to waive the written informed consent requirement because this is a minimal 
risk study. This study, which includes participants completing on-line self-assessments, could not 
be practicably carried out if written consent were required. The IRB-approved e-consent 
information sheet will include a description of all significant elements of the study: what 
participation entails; risks and benefits of study procedures; alternatives to participation in the 
study; confidentiality; $50 payment for participation information; a statement that participation is 
voluntary and that the participant may withdraw at any time; and information about whom to 
contact with questions. The e-consent form will also indicate that the decision to participate will in 
no way influence other aspects of the participant’s treatment, and participants’ data will not be 
shared with their clinicians.  
  
 Screening  
Following submission of the e-consent, the participant will complete the screening self-
assessment, and if qualified, the participant will be given access to the health survey. 
 Premature Withdrawal of Participants  
All participants are allowed to withdraw consent at any stage of the study. In addition, 
the Ll, or designee, can remove the participant from the study when there is evidence that 
the study might be harmful to the participant. 
 Study Halting Rules 
Given that this study is low risk and does not provide a clinical intervention of any type, it is not 
anticipated that study will be halted at any time. However, if for an unforeseen reason the study 
is prematurely terminated or temporarily suspended, the LI, or designee, will promptly inform the 
respective IRB and sponsor and provide the reason(s) for the termination or temporary 
suspension. If the study is suspended, the investigative team will work with the appropriate parties 
to resolve the existing issue in order to reinitiate the study. 
 Follow-Up  
Participants who complete the e-consent and are eligible for the study but do not complete the 
health survey within 3 business days will be contacted by study staff and encouraged to 
complete the survey.  
 Participant Reimbursement  
Following submission of the completed survey and research staff verifying data are complete with 
valid answers (valid indicated by response patterns with no or minimal missing values) and are 
not a duplicate participant submission, participants will be provided with a $50 prepaid debit card. 
Partial compensation will not be provided to those who partially complete the survey. Mailing 
address information for participant compensation will be collected during the survey process.  
 
   
 

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 STATISTICAL DESIGN AND ANALYSES  
 General Design 
This study seeks to evaluate the concurrent validity of the NS metric as a clinical measure of 
opioid risk and establish clinically useful risk-level thresholds relative to the WHO ASSIST. This 
study also seeks to collect data on the TAPS tool in a large sample of individuals filling opioid 
medications in order to further validate this instrument in a novel outpatient setting, community 
pharmacy. 
 Study Hypotheses  
Similar to the “The TAPS Tool: Screen and Brief Assessment Tool Validation  Study, CTN-
0059”, this study will not test any intervention or hypothesis.54 This study will focus on the level 
of agreement between the NS metric and participants' responses to opioid risk assessment 
questions. The goal of the project is to validate and identify risk cutoffs between the NS metric 
and the WHO ASSIST. As such, the study is a measurement validation project and so has no 
primary outcome variables.54 See CTN 0093 Statistical Analysis Plan for details.  
 
In addition to analyses involving the NS metric, we will examine the association of the TAPS 
Tool with the WHO ASSIST risk categories. See CTN 0093 Statistical Analysis Plan for details.  
 Rationale for Sample Size and Statistical Power  
 Projected Number of Sites  
This study will involve 15 participating Kroger Pharmacies. Sites will include 12 Kroger 
Pharmacies in Ohio and 3 rural Kroger Pharmacies in Indiana.  
 Projected Number of Participants per Site 
Survey sample size power estimates are based on the allocation ratio of the national rate of 
prescription opioid use disorder (POUD) among those prescribed opioid medications in the last 
year (2.1%,55 i.e. 46.6/1). Thus, the sample is powered to the least prevalent but most severe 
condition among potential patients. We calculated an array of sample sizes powered to achieve 
≥80% power (α=0.05) and 0.70 (“fair”) Area Under the Curve value, 56,57 using a conservative null 
hypothesis assumption of 0.5 for discrimination power (Table 2).58 Therefore, to ensure the 
maximum power for the study, we will target recruitment to 1,523 total patients.  
 
Table 2. Power Analyses (AUC=0.70, Discrimination Power=0.5) 
Power 
N 
0.80 
618 
0.85 
714 
0.90 
809 
0.95 
1,047 
0.98 
1,523 
 
Each Kroger pharmacy site will be responsible for approaching approximately 207 patients 
(~3,105 collectively). Of these, we anticipate 70% will be interested and agree to share their 
contact information.31 Of these, based on our current research among this population 
(NCT03149718), we anticipate 70% will actually provide e-consent and complete the survey. 
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survey. We will calculate the survey response rate based on the number of potential participants 
who submit contact information compared to the survey completion rate.  
 Statistical Methods for Primary and Secondary Outcomes  
A series of a priori analyses will be conducted to evaluate the validity of the NS metric relative to 
the widely validated gold standard WHO ASSIST and to identify cutoff thresholds. A priori 
analyses will involve conducting Receiver Operating Curve Analyses (ROC; i.e., sensitivity and 
specificity, area under the curve [AUC]) to identify clinical cutoff values for the NS metric and 
low, moderate, and high WHO ASSIST scores. We will also conduct correlational, regression, 
and Cohen’s Kappa statistical analyses to evaluate the relationship between the NS metric and 
the WHO ASSIST.   
 
We will also conduct exploratory correlational, regression, and Cohen’s Kappa statistical 
analyses to validate the relationship between the NS metric and measures of opioid medication 
misuse as well as history of opioid overdose. Exploratory ROC, correlational, regression, and 
Cohen’s Kappa statistical analyses between the WHO ASSIST and the TAPS Tool will also be 
conducted. Considerations in determining the statistical approach can be found in the CTN-
0093 Statistical Analysis Plan. 
 Significance Testing  
The analyses will be conducted using a two-sided test with a type I error rate of 5%. 
 Missing Data and Dropouts  
This study does not include follow-up assessments, and all study assessments will be 
completed during the electronic health assessment survey. Missing data and dropouts are 
expected to be relatively minimal. Nonetheless, the analysis will determine the extent of 
missing data for all study variables and explore differences in missing data by age, gender, 
and race/ethnicity. The completer population, defined as participants who complete opioid 
outcome score contributing items on the WHO ASSIST and TAPS tool, will be used for the 
main analysis. Completers also must have NS metric scores. Multiple imputation will be 
conducted for missing covariates, but missing key outcome data will not be imputed. See CTN 
0093 Statistical Analysis Plan for details. 
 Demographic and Baseline Characteristics  
Baseline demographic and clinical variables will be summarized for enrolled participants. 
Descriptive summaries of the distribution of continuous baseline variables will be presented, 
with measures of central tendency. Categorical variables will be summarized in terms of 
frequencies and percentages. In addition, analyses will be conducted on the primary and 
exploratory aims for male and female gender subgroups. See CTN-0093 Statistical Analysis 
Plan. 
 
 
 

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REGULATORY COMPLIANCE, REPORTING AND 
MONITORING 
 Regulatory Compliance  
This study will be conducted in full conformity with the ethical principles outlined in the 
Declaration of Helsinki, the Regulations for the Protection of Human Subjects codified in the 
International Council for Harmonization Good Clinical Practice (GCP) Guidelines, and all other 
applicable regulatory requirements. Written approval for the study protocol, e-consent form, 
other supporting documents, and any advertising for participant recruitment will be provided to 
the participating University sites and Kroger recruitment sites by the Institutional Review Board 
(IRB) of record prior to participation in the study. Any amendments to the protocol or e-consent 
materials must be approved by the IRB of record before they are implemented. Unanticipated 
problems involving risk to study participants will be promptly reported to and reviewed by the 
IRB of record, according to its usual procedures. Annual progress reports will be submitted to 
the IRB, according to its usual procedures.  
 
This study will be registered and updated as needed in ClinicalTrials.gov. 
 Statement of Compliance  
This study will be conducted in accordance with the current version of the protocol, in full 
conformity with the ethical principles outlined in the Declaration of Helsinki, the Regulations for 
the Protection of Human Subjects codified in the International Council for Harmonization Good 
Clinical Practice (GCP) Guidelines, and all other applicable regulatory requirements. Institutional 
Review Board Approval  
 
Per NOT-OD-16-094, the University of Cincinnati IRB (UC IRB) will be the IRB of record for the 
protocol and will provide study oversight in accordance with 45 CFR 46.  Participating institutions 
have agreed to rely the University of Cincinnati and have entered into reliance/authorization 
agreements for Protocol CTN 0093. The University of Cincinnati will follow written procedures for 
reporting its findings and actions to appropriate officials at each participating institution, see Single 
Site IRB (sIRB) Plan.  
 
Prior to initiating the study, university site investigators will obtain written IRB approval to conduct 
the study at their respective site, see sIRB Plan. If changes to the study protocol become 
necessary, protocol amendments will be submitted in writing by the investigators for IRB approval 
prior to implementation. In addition, IRBs will approve the e-consent form, recruitment materials, 
and any materials given to the participant, and any changes made to these documents throughout 
study implementation. For changes to the e-consent form, a decision will be made regarding 
whether previously enrolled participants need to be re-enrolled. IRB continuing review will be 
performed annually, or at a greater frequency contingent upon the complexity and risk of the 
study. Each site principal investigator is responsible for maintaining copies of all current IRB 
approval notices, IRB-approved e-consent documents, and approval for all protocol modifications. 
These materials must be received by the investigator prior to the initiation of research activities at 
the site, and must be available at any time for audit. 
 Informed Consent  
The consent process is a means of providing study information to each prospective participant 
and provides an opportunity for an informed decision about participation in the study. Because 
this study is minimal risk, involving on-line completion of a survey at one time point, an altered 

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consent process will be utilized. Specifically, participants will access an IRB-approved electronic 
informed consent information sheet (i.e., e-consent) and indicate their consent to participate by 
selecting “continue” at the end of the sheet. The e-consent information sheet 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 study. The rights and welfare 
of the participants will be communicated by emphasizing that the quality of their medical care or 
pharmacy services will not be adversely affected if they decline to participate in this study. 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.  
 Quality Assurance Monitoring  
In accordance with federal regulations, the study sponsor is responsible for ensuring proper 
monitoring of an investigation and ensuring that the investigation is conducted in accordance with 
the protocol. Qualified local monitors will oversee participating University sites to ensure they are 
operating within the confines of the protocol and in accordance with GCP. Monitoring includes, 
but is not limited to, protocol compliance, documentation auditing, and reporting safety events. 
Non-conformity with protocol and federal regulations can be reported as a protocol deviation and 
submitted to the study sponsor and study IRB for further review. Reports will be prepared following 
monitoring reviews and forwarded to the investigative team and NIDA CCTN. If the monitor’s 
review indicates that additional training of site study personnel is needed, QA personnel will 
undertake or arrange for that training. Monitoring will occur not more than quarterly and not less 
than annually. Details of QA and data monitoring are found in the study QA Monitoring Plan. 
 Participant and Data 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/Privacy Board, 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.  
 
To further protect the privacy of study participants, the lead investigator will obtain a federal 
Certificate of Confidentiality (CoC) from NIH, which protects identifiable research information from 
forced disclosure and will distribute it to all sites when received. This protects participants against 
disclosure of sensitive information (e.g., drug use). The CoC allows the investigator and others 
who have access to research records to permanently refuse to disclose identifying information on 
research participation in any civil, criminal, administrative, legislative, or other proceeding, 
whether at the federal, state, or local level, excepting certain circumstances. 
 
By protecting researchers and institutions from being compelled to disclose information that would 
identify research participants, CoCs help achieve the research objectives and promote 
participation in studies by helping assure confidentiality and privacy to participants. 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 electronic case report forms (eCRF), secure 
storage of any encrypted documents that have participant identifiers, and secure computing 
procedures for entering and transferring electronic data.  
 

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 Financial Disclosure/Conflict of Interest  
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. 
 Performance Monitoring 
OVN and University of Utah leadership will develop a Performance Monitoring Plan. This plan 
will detail, according to the study timeline, progress the study will make to accomplish its goals. 
The plan will include the development of performance metrics and will likewise detail procedures 
and guidance for underperforming recruitment sites. Performance metrics will be assessed in 
regularly scheduled study meetings (not to occur more than weekly and less than monthly). For 
these meetings, a performance summary report will be made available to the research team. By 
pharmacy site, the report will include information such as: 
 Number of initiated vs. completed interest surveys  
 Number of completed interest surveys vs. expected by study timeline 
 Number of initiated vs. completed e-consent forms 
 Number of competed e-consent forms vs. expected by study timeline 
 Number of initiated vs. completed self-screening forms 
 Number completed self-screening forms vs. expected by study timeline  
 Description of reasons potential participants are screened as ineligible 
 Number of initiated vs. completed health assessment surveys 
 Number of completed health assessment surveys vs. expected by study timeline 
Based on the team’s regular comparison of these metrics by pharmacy recruitment site, low 
performing sites will be identified. Procedures for improvement of low performing sites will 
include actions such as: 
 Discussion of the site’s performance with Kroger Corporate, Regional, and local 
management.  
 Performing on-site visits to discuss performance issues, identify barriers, and make 
plans to increase performance. 
 Discussion and planning with research staff regarding outreach to participants with 
initiated and uncompleted forms.  
 Identification of possible additional Kroger pharmacy sites for outreach advertisement 
 Inclusion of Women and Minorities  
The study sites should aim and take steps to enroll a diverse study population. Noted in section 
2.3 of the study appendix, based on our previous research on this topic, we anticipate 57% of our 
sample will be female, and 43% will be male. Assessments captured (i.e., TAPS Tool alcohol 
subscale) are specified for male vs. female respondents. We also anticipate our study sample will 
approximate the racial/ethnic distributions of the local areas in which the recruitment stores 
operate. 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 and plans to correct these difficulties will be put into place.  
 
 
 

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 Prisoner Certification 
As per 45 CFR 46 Subpart C, there are additional protections pertaining to prisoners as study 
participants. A prisoner is defined as any individual involuntarily confined or detained in a penal 
institution. The term is intended to encompass individuals sentenced to such an institution under 
a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment 
procedures which provide alternatives to criminal prosecution or incarceration in a penal 
institution, and individuals detained pending arraignment, trial, or sentencing. This study will not 
recruit individuals meeting this definition. 
 Regulatory Files  
Essential documents are those documents which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced. These documents serve to demonstrate 
the compliance of the investigator, sponsor, and monitor with the standards of Good Clinical 
Practice and with all applicable regulatory requirements. The regulatory files should contain all 
required regulatory documents, study-specific documents, and all important communications. 
Regulatory files will be checked at each participating University site for regulatory document 
compliance prior to study initiation, throughout the study according to regularly agreed upon 
schedule (not more than quarterly and less than annually), as well as at study closure by local 
research staff and quality monitors, see section 10.4.  
 Records Retention and Requirements  
Research records for all study participants are to be maintained by the participating University 
site 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 participating University site prior to the deletion or 
relocation of research records. 
 Reporting to Sponsor 
The investigative team agrees to submit accurate, complete, legible and timely reports to the 
Sponsor, as instructed by the sponsor. These include, but are not limited to, reports of any 
changes that significantly affect the conduct or outcome of the study or increase risk to study 
participants. Safety reporting will occur as previously described. At the completion of the study, 
the Lead Investigator will provide a final report to the Sponsor. 
 Audits  
The Sponsor has an obligation to ensure that this study is conducted according to good research 
practice guidelines and may perform quality assurance audits for protocol compliance. The LI and 
authorized staff from the participating research institutions; the National Institute on Drug Abuse 
Clinical Trials Network (NIDA CTN, the study sponsor); and other agencies such as the 
Department of Health and Human Services (HHS), the Office for Human Research Protection 
(OHRP), and the Institutional Review Board of record may inspect research records for verification 
of data, compliance with federal guidelines on human participant research, and to assess 
participant safety. 
 Study Documentation  
Each participating University site will maintain appropriate study documentation (including 
research records) for this study, in compliance with ICH E6 and regulatory and institutional 

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requirements for the protection of confidentiality of participants. Study documentation includes 
sponsor-investigator correspondence, signed protocol and amendments, Ethics Review 
Committee or Institutional Review Board correspondence, and approved e-consent document. As 
part of participating in a NIDA-sponsored study, each site will permit authorized representatives 
from NIDA and regulatory agencies to examine (and when permitted by law, to copy) records for 
the purposes of quality assurance reviews, audits, and evaluation of the study safety, progress, 
and data validity.  
 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 within a 
reasonable period of time following their discovery. Those corrective action plans may be 
reviewed/approved by the Lead Node with overall approval by the IRB of record. 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 study.  
All protocol deviations will be recorded in a REDCap form developed for this project.  
 
Additionally, each site is responsible for reviewing the IRB of record’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. 
 Safety Monitoring  
 
Data and Safety Monitoring Board (DSMB)  
This study is not an intervention trial and will not require a Data and Safety Monitoring Board. 
The Lead Investigator along with the Co-Lead Investigator and sub-investigators are 
responsible for adhering to the Data and Safety Monitoring Plan.  
 Training 
The CTN-0093 study staff will be trained as specified in the study Training Plan. Training will 
include Human Subjects Protection (HSP) and Good Clinical Practice (GCP) as well as protocol-
specific training on assessments, study procedures, data management, quality assurance, etc.  
 

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DATA MANAGEMENT  
 Design and Development  
The OVN and University of Utah will be responsible for development of eCRFs, development and 
validation of the study database, ensuring data integrity, and training site and participating 
research staff on applicable data management procedures. The remainder of this section provides 
an overview of the Data Management Plan associated with this protocol.  
 Site Responsibilities  
The data management responsibilities of each individual site will be specified by the OVN and 
University of Utah and outlined in the Data Management Plan. Given the fact that data in this 
study are entered remotely by study participants following contact with the pharmacy recruitment 
sites, limited responsibilities are designated to these sites. However, one important note regarding 
the Data Management Plan is that it will include procedures, for example, regarding how Kroger 
staff will capture: if patients were informed about the study and how they were informed about the 
study. The Plan will also discuss, for example, how these data will be shared on a scheduled 
basis with OVN and the University of Utah for assessing sampling bias.  
 Data Center Responsibilities  
The OVN and University of Utah will collaborate to 1) develop a Data Management Plan and will 
conduct data management activities in accordance with that plan, 2) provide guidance for eCRFs 
for the collection of all data required by the study, 3) develop data dictionaries for each eCRF that 
will comprehensively define each data element, 4) conduct ongoing data monitoring activities on 
study data from all participating sites, 5) conduct any preliminary analysis data cleaning activities 
as needed, and 6) conduct final study data cleaning. 
 Data Collection  
The data collection process consists of direct data entry at the recruitment pharmacies and/or by 
participants into the REDCap forms and surveys. Data entry into REDCap should be completed 
according to the instructions provided and project specific training. Assessments programmed in 
REDCap will use validation rules, integrity checks, and hard stops as needed to ensure that data 
are as complete and accurate as possible. For instance, validity checks will employ skip logic to 
ensure certain item sets are not available to respondents once initial responses are given (e.g., 
alcohol consumption questions will not be available to those who report they do not drink). 
Regarding completeness of responses, all survey response sets will require every item to be 
answered in order to complete the survey. However, to preserve participants’ rights to not respond 
to any item they wish, the response set will include an option that will allow the participant to 
indicate they wish to not respond to the item. This process will ensure survey data completion 
with minimal missing values. Furthermore, given that data are entered directly into the REDCap 
survey by participants without requiring interviewing or data transcription by research staff, we 
anticipate a high level of validity and accuracy (absence of data entry errors) in this project.  
 Data Merge 
Data collected in the health survey from study participants will be regularly merged with NS 
metric data from Appriss Health. OVN and University of Utah staff will securely share participant 
contact information, dispensing pharmacy, and demographic information with Appriss who will 
deterministically link NS metric data. Linked data will be returned from Appriss to the OVN and 
the University of Utah.  

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 Data Acquisition and Entry 
Completed forms and electronic data will be entered into REDCap in accordance with the 
instructions provided by the OVN and University of Utah. Only authorized individuals shall have 
access to eCRFs. 
 Data Transfer/Lock  
Data will be transmitted by the OVN and the University of Utah to the NIDA central data repository 
as requested by NIDA. The OVN and University of Utah will conduct final data quality assurance 
checks and “lock” the study database from further modification. The final analysis dataset will be 
returned to NIDA, as requested, for storage and archive. We will comply with the following policy 
regarding the preparation and transfer of the study data: 
 
“Data from CTN trials are posted 18 months after the final database lock or after 
the primary manuscript is published, whichever comes first. All of the data are de-
identified, and only raw data (i.e., no analysis datasets or derived variables) are 
provided. Data documentation, consisting of all annotated case report forms 
(CRFs), the data dictionary, and de-identification notes, is provided to users to 
assist in data interpretation. Protocol documentation, including a brief study 
description, the study protocol, and a link to the primary manuscript, is also 
provided, and users are encouraged to consult these documents for insight 
regarding proper interpretation of the data.” 
 Data Training  
The Training Plan for research staff includes provisions for training on assessments, eCRF 
completion guidelines, data management procedures, and the use of REDCap. 
 Data Quality Assurance  
To address the issue of data entry quality, the OVN and University of Utah will follow a Data 
Management Plan. Data quality summaries will be made available during the course of the 
protocol, and acceptable quality level prior to study lock or closeout will be established as a part 
of the Data Management Plan. Data quality will be assessed in regularly scheduled study 
meetings (not to occur more than weekly and less than monthly). For these meetings, a data 
quality summary report will be made available to the research team. By pharmacy site, the report 
will include information, such as:  
 
 Number of interest forms with missing data 
 Description of missing data on the interest form 
 Number of health assessment surveys with missing data 
 Description of missing data on health assessment surveys 
 Number of surveys linked to the NS metric 
 Description of surveys/participants with unlinked surveys 

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PUBLICATIONS AND OTHER RIGHTS  
Per NIH policy, the results of the proposed study 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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PROTOCOL SIGNATURE PAGE  
SPONSOR’S REPRESENTATIVE (CCTN SCIENTIFIC OFFICER OR DESIGNEE) 
 
 
 
 
 
      
 
 
 
 
Printed Name 
 
Signature 
 
Date 
ACKNOWLEDGEMENT BY INVESTIGATOR: 
• 
I am in receipt of version 2.0 of the protocol and agree to conduct this 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 e-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 (DHHS), the state, and the IRB. 
 
UNIVERSITY SITE’S PRINCIPAL INVESTIGATOR 
      
 
 
 
 
Printed Name 
 
Signature 
 
Date 
 
University Name  
 
      
Node Affiliation  
 
 
 
 
 
 

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Analgesics by a State Prescription Drug Monitoring Program: An Observational Study 
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Paulozzi LJ, Kilbourne EM, Desai HA. Prescription Drug Monitoring Programs and Death 
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Patrick SW, Fry CE, Jones TF, Buntin MB. Implementation Of Prescription Drug 
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Nam YH, Shea DG, Shi Y, Moran JR. State prescription drug monitoring programs and 
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medication misuse in community pharmacy. Research in Social and Administrative 
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Cochran G, Field C, Karp J, et al. A community pharmacy intervention for opioid 
medication misuse: A pilot randomized clinical trial. Journal of the American Pharmacists 
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TAPS Tool compared to the WHO ASSIST. Journal of substance abuse treatment. 
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possible and probable opioid misuse among recipients of chronic opioid therapy in 
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Cochran G, Lo-Ciganic WH, Gellad WF, et al. Prescription Opioid Quality Measures 
Applied Among Pennsylvania Medicaid Enrollees. Journal of managed care & specialty 
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Landis JR, Koch GG. The measurement of observer agreement for categorical data. 
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61. 
Rough K, Huybrechts KF, Hernandez-Diaz S, Desai RJ, Patorno E, Bateman BT. Using 
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63. 
Smith TC, Smith B, Jacobson IG, Corbeil TE, Ryan MAK. Reliability of Standard Health 
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Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of 
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Patient Health Questionnaire. JAMA. 1999;282(18):1737-1744. 
  

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APPENDIX: DATA AND SAFETY MONITORING PLAN  
Data and Safety Monitoring Plan  
1.0 
BRIEF STUDY OVERVIEW 
Using opioid therapy to treat pain effectively, while minimizing potential adverse consequences, 
is an important goal. Appriss Health has developed the NS metric, which uses PDMP data on 
opioid and benzodiazepine prescriptions and aberrant drug behavior (e.g., multiple providers, 
pharmacies, etc.) to compute a score quantifying the extent of the patient’s opioid risk in relation 
to all prescription opioid users. The association between the NS metric and other indicators of 
opioid-related risk has not been evaluated, and hence, the degree to which this metric is a 
useful screening tool is unknown.  
 
The primary objective of this one group, cross-sectional, validation study is to evaluate the 
concurrent validity of the NS metric as a clinical measure of opioid utilization risk and establish 
clinically useful risk level thresholds relative to the World Health Organization Alcohol, Smoking, 
and Substance Involvement Screening Test (WHO ASSIST). A secondary objective of the study 
is to collect validity data on the Tobacco, Alcohol, Prescription medication and other Substances 
(TAPS) tool in a large sample of individuals filling opioid pain medications.  
 
Participant Inclusion Criteria  
Potential participants must: 
1. be dispensed ≥1 opioid medication (including tramadol) by a participating Kroger 
Pharmacy; 
 
2. be ≥18 years of age according to Kroger Pharmacy data and self-report 
 
Participant Exclusion Criteria  
Potential participants must not self-report: 
1. not solely filling buprenorphine or buprenorphine combination products i.e., patients 
receiving OUD treatment with no other opioid medication use; 
 
2. currently receiving treatment for cancer; 
 
3. having previously completed the survey (this will be re-verified by OVN staff by 
examining identifying information following health assessment submission); 
 
4. having current involvement with the criminal justice system that has, or could, lead to 
incarceration 
Sample Size 
This study will recruit approximately 1,523 participants.  
2.0 
STUDY MANAGEMENT 
1. List of participating enrolling clinics or data collection centers: All potential participants will be 
Kroger community pharmacy patients dispensed opioid medications.  
2. Project timetable: This study will take approximately 24 months to complete. Data collection 
will require 6-8 months and data analysis will require approximately 3-6 months. 

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3. Target population distribution: As noted above, based on our previous research, we anticipate 
57% of participants will be women (n=868). In terms of racial distribution, we anticipate the 
population will generally reflect that of the states where participants are recruited. The 
following estimates assume an even distribution of participant recruitment across study sites. 
For Ohio, we anticipate 82.2% (n=1002) will be white, 12.9% (n=157) black or African 
American, 2.3% (n=28) Asian, and 2.3% (n=28) from two or more races. Of these, we 
anticipate 3.8% (n=46) will be Hispanic or Latino. For Indiana, we anticipate 83.9% (n=256) 
will be white, 9.3% (n=28) black or African American, 2.1% Asian (n=6), and 2.3% from two 
or more races (n=7). Of these, we anticipate 6.7% (n=20) will be Hispanic or Latino. 
3.0 
DATA MANAGEMENT AND ANALYSIS  
1. Data acquisition and transmission: Information for study participants will be obtained from two 
sources. The first source will be from self-reported responses on REDCap forms, including 
contact information, demographics, and health information. The second source will be Appriss 
Health, who will provide the NS metric for all patients enrolled in the study. All research staff 
will be trained in Good Clinical Practice (GCP) guidelines. In addition, demographic 
information about all patients informed about the study will be obtained from the participating 
Kroger pharmacies. Only research staff members directly involved with the study will have 
access to identifying information for the participants. 
 
2. Data entry methods: Demographic and clinical data for study participants will be managed in 
REDCap, a software toolset and workflow methodology for collection and management of 
clinical research data developed by Vanderbilt University, in collaboration with institutional 
partners including the University of Cincinnati Academic Health Center. Only the necessary 
study personnel will have access to the database. 
 
3. A priori statistical analysis plan: Our a priori analyses to identify clinical cutoff values will 
involve assessing the ability of the NS metric to discriminate between low, moderate, and 
high-risk opioid use from the WHO ASSIST via receiver operating curve characteristic (ROC) 
analyses. Area under the ROC curve (AUC) values will be used to determine the accuracy of 
discrimination threshold levels, and we will identify sensitivity and specificity values balancing 
low false positive and low false negative rates to determine the NS metric thresholds that 
classify the specified use thresholds from these opioid measures. Cohen’s Kappa Coefficients 
59,60 will be used to evaluate agreement between the identified thresholds and WHO ASSIST 
risk groups. We will further establish the concurrent validity of the NS metric corresponding to 
the WHO ASSIST using: Spearman’s rho correlation analyses and logistic regression models. 
61-64  Statistical significance values (p<0.05) and magnitudes of correlation and agreement will 
be used to assess association between indicators. Detailed specifications of study variables 
and a priori and exploratory analytical procedures are described in the CTN-0093 SAP.  
4.0 
OVERSIGHT OF CLINICAL RESPONSIBILITIES 
A. Lead Investigator 
The Lead Investigator, with assistance from the Co-Lead Investigator and investigative team, is 
responsible for study oversight, including ensuring human research subject protection. This study 
will not use any clinical interventions and there are no expected adverse events during the single 
on-line completion of the surveys. The only expected risk to participants is a loss of confidentiality, 
which will be minimized by utilizing an encrypted REDCap platform. Any breach of confidentiality 
will be reported on a protocol deviation form.  

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B. Data and Safety Monitoring Board (DSMB) 
This study is not an intervention trial and will not require a Data and Safety Monitoring Board. 
The Lead Investigator along with the Co-Lead Investigator and sub-investigators are 
responsible for adhering to the Data and Safety Monitoring Plan. 
C. Quality Assurance (QA) Monitoring 
Study monitoring will be conducted on a regular basis using local QA monitors. QA monitors will 
assess compliance with the protocol, GCP requirements, and other applicable regulatory 
requirements, as well as document the integrity of the study progress. Areas of particular concern 
will be protocol adherence, IRB reviews and approvals, and regulatory documents. The monitors 
will interact with the participating University site staff to identify issues and re-train the site as 
needed to enhance research quality. QA Reports will be prepared by the monitors following each 
site visit.  These reports will be sent to the investigative team and NIDA CCTN. The investigative 
site will provide direct access to all study related sites (e.g., research office), source 
data/documentation, and reports for the purpose of monitoring and auditing by local Node 
monitors, as well as inspection by local and regulatory authorities. See protocol sections 10.4, 
10.10, 10.11, and 10.13. 
D. Management of Risks to Participants 
Confidentiality 
Confidentiality of participant records will be ensured by encryption and secure storage of any 
documents that have participant identifiers as well as secure computing procedures for entering 
and transferring electronic data. No identifying information will be disclosed in reports, 
publications, or presentations. 
Information That Meets Reporting Requirements 
The e-consent document will specify 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. 
Pregnancy 
As there is no medication intervention, pregnancy will not be excluded within the context of this 
study. 
5.0 STUDY SAFETY 
Risks: 
Breach of confidentiality: As with any study, there is a potential risk of loss of confidentiality. To 
maintain participant confidentiality, study records and data will be stored in compliance with the 
International Conference on Harmonization (ICH) guidelines. Participant-reported data will be 
collected through REDCap, which is HIPAA-compliant and 21 CFR Part 11- ready for audit trails 
for tracking data manipulation and exports. Emails or text messages between researchers and 
participants, used in recruitment efforts, will be deleted after information exchange. We will train 
all study-related personnel to follow HIPAA regulations for research to ensure confidentiality of all 
data and that the rights of the patients are protected. All data will reside on password-protected 
encrypted computers, with only the investigators and key members of the research team having 
access. A variety of other measures will be taken to protect confidentiality, including: We will 1) 

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assign a unique ID number to each patient, instead of patient names and 2) restrict access to the 
key linking names and ID numbers to key staff and the PI at each site. Participants will be told 
that agents of the IRB and QA monitors will be allowed to inspect research records related to this 
study, if requested.  
Emotional Discomfort: The participants may experience some emotional discomfort from 
answering sensitive and/or personal questions. There is the possibility that the participant will feel 
bored. The patient’s ability to respond to study assessments in the privacy of his/her own home 
should help in reducing potential emotional discomfort.  
Benefits:  
Participants may not experience a benefit from participating in this study. Potential benefits 
include the chance to contribute to a scientific investigation which may benefit other patients like 
themselves in the future. The risk/benefit ratio is favorable and conduct of the research well 
justified. 
6.0 REGULATORY ISSUES 
Reporting of safety concerns to the IRB ad NIDA: The only expected risk to participants is a loss 
of confidentiality, which will be minimized by utilizing an encrypted REDCap platform. All breaches 
of confidentiality will be reported to and reviewed by study leadership in regularly scheduled 
meetings (not to occur more than weekly and less than monthly).  
Reporting of IRB action to NIDA: All communications with and actions of the IRB will be kept in a 
regulatory binder specific for this study. Any protocol changes, amendments, or deviations will be 
submitted to the IRBs and NIDA and the IRB’s actions will then be reported to NIDA. Any other 
IRB actions will be submitted to NIDA. 
Report of changes or amendments to the protocol: All changes and amendments to the protocol 
will be submitted to the IRBs and NIDA. Only after IRB and NIDA approvals are granted will the 
changes and amendments be implemented.  
Stopping rules: Individual study participants will be informed of their right to discontinue study 
participation at any time during the study. The PI may discontinue a participant from the study if 
deemed clinically appropriate. NIDA has the right to discontinue the investigation at any time. 
          
Disclosure of conflict of interest: The investigators have no conflicts of interest.  
7.0 
DATA MANAGEMENT PROCEDURES 
This protocol will utilize a centralized REDCap data capture program. This electronic data capture 
system (REDCap) will be developed in collaboration by OVN an and University of Utah teams to 
ensure that guidelines and regulations surrounding the use of computerized systems in clinical 
studies are upheld. Assessments programmed in REDCap will use validation rules, integrity 
checks, and hard stops as needed to ensure that data are as complete and accurate as possible. 
See Protocol section 11.4 for additional details.  
8.0 
DATA AND STATISTICS RESPONSIBILITIES OF THE OVN and UNIVERSITY OF 
UTAH 
The OVN and the University Utah will: 1) develop and apply data management procedures to 
ensure the collection of accurate and good-quality data, 2) eCRFs for the collection of all data 

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required by the study, 3) develop data dictionaries for each eCRF that will comprehensively define 
each data element, 4) prepare instructions for the use of REDCap and for the completion of 
eCRFs, 5) conduct ongoing monitoring activities on study data collected from all participating 
sites, and 6) perform data cleaning activities prior to the final study database lock. 
9.0 
DATA COLLECTION AND ENTRY 
Data will be entered by pharmacy staff and participants into eCRFs through REDCap. Data will 
be entered into REDCap in accordance with the instructions provided during protocol-specific 
training and guidelines established by the OVN and the University of Utah. Data entry into the 
eCRFs is performed by authorized individuals. Mentioned above, assessments programmed in 
REDCap will use validation rules, integrity checks, and hard stops as needed to ensure that data 
are as complete and accurate as possible. The investigator at the participating University site is 
responsible for maintaining accurate, complete and up-to-date research records. See Protocol 
sections 10.4 and 11.9 that provides overviews of Data Quality Assurance and Quality Assurance 
Monitoring. 
10.0 DATA MONITORING, CLEANING, AND EDITING 
eCRFs will be monitored for completeness and accuracy throughout the study. Dynamic reports 
listing missing values and forms are available in REDCap. These reports will be monitored 
regularly by the OVN and the University of Utah. See Protocol section 11.9 that provides an 
overview of Data Quality Assurance. 
Study progress and data status reports, which provide information on recruitment, availability of 
primary outcome, regulatory status, and data quality, will be generated regularly and shared with 
project research leadership and staff. 
11.0 
DATABASE LOCK AND TRANSFER 
At the conclusion of data collection for the study, the OVN and University of Utah will perform final 
data cleaning activities and will “lock” the study database from further modification. The final 
analysis dataset will be transferred to the Lead Investigator or designee. De-identified versions of 
these datasets will also be provided to the NIDA CCTN-designated parties for posting on 
Datashare, as well as storage and archiving. We will comply with the following policy regarding 
the preparation and transfer of the study data:  
“Data from CTN trials are posted 18 months after the final database lock or after 
the primary manuscript is published, whichever comes first. All of the data are de-
identified, and only raw data (i.e., no analysis datasets or derived variables) are 
provided. Data documentation, consisting of all annotated case report forms 
(CRFs), the data dictionary, and de-identification notes, is provided to users to 
assist in data interpretation. Protocol documentation, including a brief study 
description, the study protocol, and a link to the primary manuscript, is also 
provided, and users are encouraged to consult these documents for insight 
regarding proper interpretation of the data.” 
 
 

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DSM PLAN ADMINISTRATION 
Responsibility for data and safety monitoring: the study Lead Investigators will be responsible for 
the safety monitoring of the study participants.  
Frequency of DSM reviews: The study protocol will be reviewed by the CCTN Protocol review 
Board before recruitment starts. Breaches of confidentiality will be reviewed by study leadership 
in regularly scheduled meetings for the duration of the study. DSM reports will be submitted to 
the IRBs and NIDA annually.  
Content of DSM report: The DSM report will include a brief description of the study and any 
changes made. Additionally, we will report baseline sociodemographic characteristics, including 
age, gender, and race of the subjects screened and randomized.  We will also report retention 
rates and the disposition for all study participants. Any quality assurance issues, regulatory 
issues, and breaches of confidentiality will be included in the report.