Determining the Feasibility and Acceptability of a Novel Stigma Resistance Text Message Intervention for People Who Use Drugs
Phase: NA
Conditions: Stigma, Social, Substance Use
Sponsor: University of North Carolina, Chapel Hill

CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
Determining the Feasibility and Acceptability of a Novel Stigma 
Resistance Text Message Intervention for People who Use Drugs 
NCT06281548 
February 19, 2024  
 

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Acceptability of a Novel Text Message 
Stigma Resistance Intervention for People 
who Use Drugs 
Principal Investigator 
Adams Sibley 
Sponsor 
National Institute on Drug Abuse 
Three White Flint North, 11601 Landsdown Street, North Bethesda, MD 20852 
 
Protocol Version 
19 February 2024 
 
 
 
 
Confidentiality Statement:  This document contains confidential information that must not be 
disclosed to anyone other than the sponsor, the investigator team, and members of the 
Institutional Research Board, unless authorized to do so. 
 
 
 

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Study Personnel 
Principal Investigator 
Adams Sibley, MPH 
The University of North Carolina at Chapel Hill 
Department of Health Behavior 
Email: asibley@live.unc.edu 
Faculty Advisor & Co-Investigator 
Vivian F. Go, PhD 
The University of North Carolina at Chapel Hill 
Department of Health Behavior 
Email: vgo@email.unc.edu 
Co-Investigator 
William C. Miller, MD, PHD 
The University of North Carolina at Chapel Hill 
Department of Epidemiology 
Email: bill_miller@unc.edu 
Co-Investigator 
Seth M. Noar, PhD 
The University of North Carolina at Chapel Hill 
School of Media & Journalism 
Email: noar@email.unc.edu 
Co-Investigator 
Kathryn E. Muessig 
The University of North Carolina at Chapel Hill 
Department of Health Behavior (Fixed Term) 
Email: kmuessig@fsu.edu 
Co-Investigator 
Nisha C. (Gottfredson) O’Shea, PhD 
The University of North Carolina at Chapel Hill 
Department of Health Behavior (Fixed Term) 
Email: ngottfredson@rti.org 
 
 
 

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SYNOPSIS 
Primary Objective 
We will use an iterative convergent mixed method design1 to develop and evaluate a stigma 
resistance text message intervention for PWUD. Text messaging is a scalable and cost-
effective modality for health behavior change with demonstrated acceptability and 
effectiveness in interventions with PWUD, a historically hard-to-reach group.2–8 Specifically, 
we aim to: 
Aim 1: Identify PWUD self-stigma subgroups and describe associated demographic, health, 
and drug use risk factors among rural PWUD in an eight-state multi-site cohort using latent 
class analysis.^ 
Aim 2: Identify a) stigma-related attitudes and beliefs that are salient to PWUD and amenable 
to change, and b) text message content and delivery preferences through iterative elicitation 
interviews with 20 rural Ohio PWUD.^ 
Aim 3: Tailored around findings from Aim 1 and Aim 2, develop an automated daily short 
message service (SMS) stigma resistance intervention.^ 
Aim 4: Evaluate feasibility, acceptability, and preliminary effectiveness of the SMS 
intervention to increase stigma resistance and reduce self-stigma. We will conduct a pilot trial 
of the intervention among 30 rural Ohio PWUD in active use and collect quantitative and 
qualitative data at baseline and four-week follow-up. 
Despite wide acknowledgement that stigma is a key barrier to harm reduction and treatment 
utilization, few studies have intervened on this construct among PWUD in active use. Results 
of our study will address the current research gap of stigma reduction interventions for 
PWUD. Our study will further inform whether text messaging is a feasible and acceptable 
modality for promoting preventive health behaviors in this population. 
^ This study protocol covers Aim 4 only. Aims 1-3 were approved and conducted under 
separate protocols (UNC IRB# 17-1887 & 18-2747). 
General Design Description 
This Phase 1 study is a single-group feasibility trial of a text message intervention to increase 
stigma resistance and reduce self-stigma among people who use drugs. All participants will 
be assigned to the intervention condition. The primary outcomes are changes in stigma 
resistance and self-stigma from baseline to 4-week follow-up using self-report. We will assess 
implementation and process outcomes to inform future intervention refinement. 
Primary Outcome Variables 
This social-behavioral intervention is theorized to change attitudes and beliefs in the short 
term. The primary attitudinal outcomes indicating preliminary effectiveness are stigma 
resistance and self-stigma. Improvements in stigma resistance are expected to give 
participants the cognitive and behavioral tools to challenge internalized stigma and resist 

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fearing enacted stigma,9,10 which will in turn improve secondary psychosocial outcomes for 
participants, such as self-esteem and hope.11–15 
Feasibility outcomes include implementation feasibility and user feasibility. Implementation 
feasibility outcomes include recruitment rate (% screened who are deemed eligible, % 
screened who proceed to consent and enrollment), retention rate (% enrolled who complete 
post-survey), time from recruitment initiation to sample saturation, and intervention 
engagement (message response rate and mean response time). User feasibility outcomes 
include phone access, phone plan challenges, and technological literacy during the 
intervention. 
Acceptability outcomes include the seven component constructs of the Theoretical 
Framework of Acceptability: affective attitude, burden, perceived effectiveness, ethicality, 
intervention coherence, opportunity costs, and self-efficacy.  
As this is a feasibility trial, long-term behavioral outcomes will not be measured. However, we 
expect that reductions in self-stigma from the intervention may attenuate the 'why try?' effect 
and have distal effects on behavioral outcomes like treatment- and harm reduction-seeking 
which, in turn, may reduce the risk of drug overdose.16–19 These outcomes could be assessed 
in future clinical trials if the pilot demonstrates feasibility, acceptability, and preliminary 
effectiveness. 
Number of Participants 
The proposed sample size is 30. As the primary goal is to assess feasibility and acceptability, 
not effectiveness, sample size is not based on anticipated effect sizes. Previous guidance 
has indicated our proposed sample size is an acceptable number for feasibility studies.20–22 
This sample size will allow us to estimate the retention rate to within a 95% confidence 
interval of +/- 12% (calculated assuming a retention rate of 85%). Although exploratory only, 
the sample size will further allow us to detect moderate effect sizes in the continuous 
outcomes (Cohen's d = 0.53) with 80% power (alpha = .05, two-tailed) using paired t-tests. 
Based on our prior work recruiting from the same population using identical eligibility criteria, 
we estimate that 40 prospective participants will need to be screened to achieve our sample 
size. 
Visit Schedule 
Baseline visit: All participants. In-person. Computer-assisted self-interview (CASI) survey, 
program orientation, enrollment. 
4-week follow-up visit: All participants. In-person. CASI survey. 
Telephone interview: Sub-sample of up to 12 participants. Via telephone. Completed within 2 
weeks of follow-up visit. 
 
 
 

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Table of Contents 
SYNOPSIS ................................................................................................................................ 4 
1. Statement of Compliance ....................................................................................................... 9 
2. Background ...........................................................................................................................10 
3. Rationale/Significance ...........................................................................................................12 
3.1 Problem Statement ..........................................................................................................12 
3.2 Purpose of Study/Potential Impact ...................................................................................13 
3.3 Potential Risks and Benefits ............................................................................................14 
3.3.1 Potential Risks ..........................................................................................................14 
3.3.2 Potential Benefits ......................................................................................................15 
4. Study Objectives ...................................................................................................................17 
4.1 Hypothesis .......................................................................................................................17 
4.2 Primary Objective ............................................................................................................17 
5. Study Design .........................................................................................................................18 
5.1 General Design Description .............................................................................................18 
5.2 Outcome Variables ..........................................................................................................18 
5.2.1 Primary Outcome Variables ......................................................................................18 
5.2.2 Secondary and Exploratory Outcome Variables ........................................................18 
6. Study Population ...................................................................................................................19 
6.1 Study Population .............................................................................................................19 
6.1.1 Number of Participants ..............................................................................................19 
6.1.2 Eligibility Criteria/Vulnerable Populations ..................................................................19 
7. Methods ................................................................................................................................21 
7.1 Intervention ......................................................................................................................21 
7.1.1 Description of Intervention .........................................................................................21 
7.1.2 Method of Assignment/Randomization ......................................................................21 
7.1.3 Selection of Instruments/Outcome Measures ............................................................21 
7.1.4 Intervention Administration ........................................................................................26 
7.1.5 Reaction Management ..............................................................................................27 
7.2 Study Procedures ............................................................................................................27 
7.2.1 Study Schedule .........................................................................................................27 
7.2.2 Informed Consent ......................................................................................................27 
7.2.3 Screening ..................................................................................................................28 

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7.2.4 Recruitment, Enrollment and Retention .....................................................................28 
7.2.5 Study Visits ...............................................................................................................29 
7.2.6 End of Study and Follow Up ......................................................................................30 
7.2.7 Removal of Subjects .................................................................................................30 
7.3 Statistical Method ............................................................................................................30 
7.3.1 Statistical Design .......................................................................................................30 
7.3.2 Sample Size Considerations .....................................................................................31 
7.3.3 Planned Analyses .....................................................................................................31 
7.3.3.1 Primary Analyses ...................................................................................................31 
7.3.4 Handling of Missing Data ..........................................................................................31 
8. Trial Administration ...............................................................................................................32 
8.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization ...................32 
8.2 Institutional Review Board (IRB) Review..........................................................................32 
8.3 Subject Privacy, Confidentiality & Data Management ......................................................32 
8.4 Data Collection ................................................................................................................33 
8.5 Data Quality Assurance ...................................................................................................33 
8.6 Access to Source .............................................................................................................34 
8.7 Data or Specimen Storage/Security .................................................................................34 
8.8 Retention of Records .......................................................................................................35 
8.9 Data Safety Monitoring Plan ............................................................................................35 
8.10 Study Modification .........................................................................................................37 
8.11 Study Discontinuation ....................................................................................................37 
8.12 Study Completion ..........................................................................................................37 
8.13 Conflict of Interest Management Plan ............................................................................37 
8.14 Funding Source .............................................................................................................37 
8.15 Publication Plan .............................................................................................................37 
9. References ...........................................................................................................................38 
 
 
 

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1. Statement of Compliance 
This study will be conducted as specified in the protocol and in accordance with the 
International Conference on Harmonisation Guidelines for Good Clinical Practice (ICH E6), the 
Code of Federal Regulations on the Protection of Human Subjects (45 CFR Part 46), and other 
applicable requirements (e.g., National Institutes of Health, National Institute on Drug Abuse).  
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the 
protocol and consent form must be obtained before any participant is enrolled. Any amendment 
to the protocol will require review and approval by the IRB before the changes are implemented 
in the study. In addition, all changes to the consent form will be IRB approved; a determination 
will be made regarding whether a new consent needs to be obtained from participants who 
provided consent, using a previously approved consent form. 
If required by the IRB, the master protocol document, informed consent form, recruitment 
materials, and all participant materials will be submitted to the Scientific Review Committee 
(SRC) prior to IRB review (research.unc.edu/clinical-trials/src).  
All personnel involved in the conduct of this study have completed human subjects protection 
training. 
 
Name of Investigator of Record: Adams Sibley 
Signature of Investigator of Record:  
Date: 12.08.2023 
 
 

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2. Background 
Substance use disorder (SUD) stigma is an important barrier to ending the opioid epidemic, yet 
research on this phenomenon is deficient. Nearly 850,000 Americans have died from overdose 
in the past two decades, and mortality reached an all-time high during the COVID-19 pandemic. 
SUDs are more highly stigmatized than other health conditions (e.g., HIV, mental illness). SUD 
stigma prevents uptake of treatment and harm reduction among people who use drugs (PWUD), 
contributing to needless morbidity (e.g., infectious disease) and mortality (e.g., overdose), and 
explains in part why only 6.5% of Americans with SUD received past year treatment. Though 
key federal agencies have identified stigma as a strategic priority in the epidemic, little is known 
about how to conceptualize and address SUD stigma compared with other health conditions. 
Strategies to address SUD self-stigma, in particular, are severely lacking. Self-stigma manifests 
in PWUD as internalized stereotypes and fear of experienced stigma, leading to the so-called 
'why try' phenomenon in which the stigmatized are disempowered from pursuing life goals. SUD 
self-stigma is associated with numerous psychosocial outcomes including depression, anxiety, 
diminished quality of life, maladaptive coping and leads to delays in treatment and harm 
reduction seeking and retention. To date, SUD interventions have overwhelmingly targeted 
public stigma such as treatment provider attitudes, while there is a remarkable dearth of 
evidence-based interventions for addressing self-stigma in PWUD. More research is needed to 
identify strategies that empower PWUD to resist and overcome stigma, especially given the 
promise of self-stigma interventions in conditions like HIV/AIDS and mental illness. 
Stigma resistance, a coping strategy that promotes resilience through empowerment and 
positive identity formation, is a promising approach to reducing self-stigma. Stigma resistance is 
associated with multiple psychosocial outcomes, including reductions in self-stigma and 
improvements in quality of life, self-efficacy, hope, help-seeking, and recovery. Stigma 
resistance includes both cognitive and behavioral strategies, such as catching and challenging 
stigmatizing thoughts, forming positive alternative identities, and empowering oneself through 
learning about substance use. These strategies align directly with techniques used in the 
HIV/AIDS and mental illness self-stigma intervention literature. Stigma resistance thus serves as 
an ideal conceptual framework and menu of strategies for self-stigma reduction interventions for 
PWUD. 
The proposed trial builds on the success of the Ohio Opioid Study (OHOP), a rural opioid 
intervention study (Miller, W.C., Go, V.F., mPIs; UNC IRB #s 20-0660, 17-1887). Qualitative and 
quantitative findings from OHOP indicated that there is a high level of self-stigma among PWUD 
residing in southern Ohio. These findings have been corroborated in the PI's dissertation 
research to date (aims 1 and 2, approved under the above IRB #s), in which PWUD elaborated 
on their experiences with stigma and provided feedback on the proposed intervention. 
Participants in qualitative aim 2 (n=22) expressed strong need and enthusiasm for the 
intervention. 
Text messaging is a scalable and cost-effective modality for health behavior change with 
demonstrated acceptability and effectiveness in interventions with PWUD, a historically hard-to-
reach group. Building on our six years of research experience with PWUD in southern Ohio, we 
will pilot and evaluate a stigma resistance automated text message intervention for PWUD.  

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3. Rationale/Significance 
3.1 Problem Statement 
The United States is experiencing a drug overdose epidemic that shows no signs of abating. In 
the past two decades, 841,000 Americans have died from overdose, of which over 500,000 
involved opioids.23,24 Urgency to address the epidemic reached new heights during the COVID-
19 pandemic;25 an estimated 93,398 people died from overdose in 2020, a record number that 
eclipsed the previous 12-month total by nearly 30%.23 Appalachia, where our study is situated, 
continues to be disproportionately burdened by the opioid epidemic.26–31 
Substance use disorder (SUD) self-stigma is a barrier to treatment and harm reduction 
utilization. Among highly stigmatized health conditions, SUD stigma is particularly striking: the 
general public sees PWUD as significantly more blameworthy and dangerous than people with 
mental illness, and drug-related stigma is higher than HIV stigma among individuals with both 
conditions.32–34 SUD stigma is associated not only with increased drug use and overdose,35–37 
but with many indicators of healthy functioning and recovery, including depression, social 
isolation, suboptimal healthcare, social and familial rejection, and employment discrimination.38–
42 Self-stigma (self-devaluation and fear of enacted stigma) mediates the relationship between 
perceived public stigma and poor health outcomes10,12–16: Feelings of unworthiness and fear of 
discrimination create what Corrigan et al. call the 'why try' effect, a sense of futility that 
diminishes health-promoting behaviors among stigmatized individuals.43 Self-stigma has been 
reported in multiple studies as a primary barrier to treatment or harm reduction seeking among 
PWUD, both in rural settings and more broadly,17,26,27,44–51 and explains in part why only 6.5% of 
Americans with a SUD received treatment in the past year.52 
Strategies for addressing self-stigma in PWUD remain poorly understood, especially for PWUD 
in active use. Intervention researchers have largely ignored the opportunity to address self-
stigma, despite recent calls for its inclusion on the SUD stigma agenda.53 A 2011 meta-analysis 
of SUD stigma interventions found only one program that addressed self-stigma, with the 
majority focusing on public stigma (i.e., attitudes and actions of the general public). More recent 
systematic reviews have likewise been dominated by studies targeting treatment providers, 
medical students, and other potential stigmatizers.54–56 Among the few interventions we have 
identified intervening directly with PWUD, all studies targeted individuals already in treatment or 
recovery.10 Research is thus critically needed to develop and evaluate stigma reduction 
strategies for the 90% of Americans with SUDs not receiving treatment.52 By piloting a SUD 
stigma intervention with PWUD in active use, our study will characterize the feasibility, 
acceptability, and preliminary effectiveness of one such strategy that may buffer the effects of 
stigma on poor health among PWUD. Our study will offer lessons in implementation that will 
inform future intervention efforts in this population. 
Effective health communication modalities are needed to promote behavior change in PWUD. 
PWUD have been defined as hard-to-reach, and substance use researchers face challenges in 
recruitment and retention.2 Text messaging is one method that has been successfully used with 
PWUD and other hard-to-reach populations.3,4 In addition to its cost effectiveness, text 
messaging is an effective vehicle for behavior change across multiple health domains,5 
including substance use and mental health,57–61 and PWUD have deemed text messaging an 
acceptable way to receive health messaging and share sensitive information across multiple 

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intervention studies.6–8 Text message interventions with PWUD have demonstrated significant 
reductions in drug use, HIV risk behaviors, depression, and anxiety, and increases in recovery 
self-efficacy and medication adherence.62–67 In one trial, automated text messages actually 
outperformed peer supporter-delivered messages in reducing drug use and risk behaviors, 
indicating that the automated modality may in some cases be as effective as traditional 
therapeutic approaches.67 Our study will contribute to the growing literature on the acceptability 
and effectiveness of text message-based interventions for people who use drugs within the 
novel context of stigma reduction. Stigma reduction mHealth interventions have recently been 
piloted with people living with HIV and people at risk for suicide, lending promise to such an 
approach with PWUD.68–70 
Identifying low-burden, accessible, and scalable interventions is critical for reaching the majority 
of PWUD. Ultimately, our findings will add to the critically underdeveloped toolkit of SUD stigma 
reduction strategies — a toolkit that is essential to ending the overdose epidemic. 
3.2 Purpose of Study/Potential Impact 
Across three systematic reviews of substance use stigma interventions published since 2011, 
only three self-stigma interventions have been documented, including just one in the 21st 
century.54–56 We have since undertaken an updated systematic review focused on self-stigma 
interventions (manuscript in preparation) and identified 11 additional trials with evaluation 
data.71–81 Although these studies demonstrated some promising evidence of effectiveness (nine 
had significant improvements in at least one primary outcome), we note three prevailing gaps in 
the literature that require attention: 
1. Lack of empowerment approaches: Across 11 studies, 10 included psychoeducational 
and/or psychotherapeutic components (the 11th provided structural support services like 
care navigation). No study included an empowerment component. Corrigan and 
colleagues have called for a greater balance of interventions to restore self-esteem and 
promote empowerment among PWUD, noting that the 'self-worth agenda' is a necessary 
complement to public stigma reduction efforts in the overdose epidemic,82–84 while 
researchers have also called for more strength-based approaches to addressing 
stigma.85 
2. Lack of programs for PWUD in active use: Participants in eight of the studies were 
enrolled in inpatient or intensive outpatient treatment programs for substance use; only 
three recruited PWUD in active use. Given 6.5% of Americans with SUD received 
treatment in the past year, strategies are needed to serve the majority of PWUD not 
currently engaged in care.52 
3. Lack of self-help approaches: PWUD have been described as a hard-to-reach 
population, with documented challenges in recruitment, engagement, and retention in 
interventions.2 All 11 interventions involved face-to-face contact, and eight included a 
group component. However, structural (e.g., transportation) and intrapersonal (e.g., fear 
of disclosure) barriers may preclude many PWUD with self-stigma from participating in 
such programs.86 Self-help interventions, which allow participants to absorb knowledge 
at their own pace through websites, apps, or print materials, have demonstrated 
effectiveness for mental health self-stigma.86 One such recent pilot used automated text 
messaging to improve mental wellness using anti-stigma messages and simulated peer 

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support.87 Such an approach may be appropriate for PWUD, who have deemed text 
messaging an acceptable modality for receiving health messaging and for participating 
in research studies.3,4,6–8 
To address these gaps, and to build the evidence base of substance use self-stigma reduction 
strategies, we propose to pilot and evaluate feasibility and acceptability of a novel text 
message-based intervention with PWUD living in rural Appalachian Ohio. 
3.3 Potential Risks and Benefits 
3.3.1 Potential Risks 
Emotional distress. A small risk of psychological distress (e.g., embarrassment, upset) is posed 
by study questions concerning stigma. Participants may find answering questions about these 
issues upsetting; participants will be reminded at the beginning of the pre- and post-surveys that 
they may decline to answer any questions at any time without any repercussions. Survey 
administrators will be trained to recognize the signs of distress and how to respond 
appropriately, including expressing empathy and offering to pause or end the survey with no 
repercussions to the participant. In our experience using similar data collection methods in the 
past with people who use drugs, the likelihood and seriousness of this risk is minimal, and we 
will strive to create a safe and comfortable environment for all study participants. 
A secondary source of psychological risk is during administration of the intervention. Though the 
text message content is positive and affirming, mention of stigma may distress some 
participants. During the intervention orientation, participants will be provided a list of external 
counseling and support resources they can access if they feel distressed. These resources will 
also be shared in a text message during the intervention, along with a text message that the 
messaging exchange will not be monitored and participants should reach out to the suggested 
resources if they feel distressed.  
Consequences of breach of confidentiality. There is always the possibility of a breach of 
confidentiality when conducting research. A primary ethical concern of this study is that 
participation may reveal that participants are engaging in stigmatized behaviors like illicit drug 
use. Inadvertent disclosure of such information collected during the interviews may subject 
persons to discrimination and potential social harm. To help minimize the risk of these 
disclosures, staff will take necessary precautions to keep participant information and 
participation private. Participant names will not be stored with the survey data. Files - audio, 
paper, and electronic - will not have any identifying information, and study participants will be 
tracked through a unique participant study ID#. Interview transcription will be completed in-
house by trained study staff. All research data will be stored on a secure, password-protected 
server at UNC-Chapel Hill, to which only study staff will have access. No participants will be 
identified in any report or publication that comes from the study. 
We will take every available step to minimize the risk of identifying/linking data being 
subpoenaed, stolen, or inadvertently released. First, we have a Certificate of Confidentiality 
from the NIH. Second, all research staff members are required to complete ethical clearance 
certification regarding protection of human's subjects through UNC-Chapel Hill. Third, the study 
will safeguard against the risk of the linking information being stolen by keeping such 
information in a locked Excel file stored on a secure server at UNC to which only essential study 

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personnel who have completed CITI certification for human subjects' research ethics training 
(http://citiprogram.org) will have access. 
A secondary risk to confidentiality is that the automated text messages, if viewed by an 
unintended recipient, may suggest that the participant engages in illicit drug use. There are two 
scenarios where a breach of confidentiality may occur. The first scenario is during the delivery 
of messages, e.g., they could be intercepted by a third party. However, messages are delivered 
using Twilio, a service that uses end-to-end encryption and follows industry-standard security 
measures, certified under ISO/IEC 27001 with additional attestations to ISO/IEC 27017 and 
ISO/IEC 27018. The risk of breach of confidentiality in this scenario is extremely low. The 
second scenario is during receipt of the messages. For example, a person other than the 
participant may read the messages and deduce that they use illicit drugs. To protect against this 
risk, during orientation, participants will be trained to secure their phones (i.e., password-
protecting or fingerprint-protecting) and instructed not to share their phone with anyone for 
whom unintentional disclosure is a concern. In our formative qualitative research, participants 
expressed no concerns about inadvertent disclosure in the intervention, so the risk in this 
second scenario is likely low.  
Steps taken to ensure that potential participants do not feel coerced to enter or remain in the 
study. Research staff recruiting participants will follow a standardized script to ensure that all 
ethical issues are adhered to and that study protocols are followed. Research staff reviewing 
consent with all participants will be trained to probe for comprehension. All written and oral 
communications about the study will emphasize that this study is completely voluntary and will 
not impact status or position in any organization or setting (including entitlement to services at 
the harm reduction program serving as our recruitment setting), and that they can drop out of 
the research at any time without jeopardizing their status or position. Participants will further be 
reminded that declining to participate or dropping out early will have no bearing on their ability to 
participate in future research studies at UNC-Chapel Hill or other institutions.  
3.3.2 Potential Benefits 
Benefits to society. The main benefit of the proposed study to society is the development of a 
potentially feasible and acceptable text messaging intervention for people who use drugs. The 
knowledge gained from the study has the potential to fill a critical research gap on acceptable 
self-stigma reduction techniques and messages in this population. While stigma is 
acknowledged by experts as a critical barrier to treatment access and utilization, and ultimately 
a key to ending the opioid epidemic, there are few evidence-based stigma reduction 
interventions for people who use drugs, and to our knowledge, no self-help interventions that 
have undergone rigorous evaluation. Our study will further inform whether text messaging is a 
feasible and acceptable modality for promoting preventive health behaviors in this population. 
Findings may inform local, state, and national efforts to reduce stigma and encourage service 
engagement among people who use drugs. 
Benefits to participants. The purpose of this study is to determine the feasibility and acceptability 
of the intervention. However, the intervention is designed to improve psychosocial health 
outcomes, including reducing self-stigma and improving stigma resistance. The intervention's 
messages, which are based in evidence-based psychotherapeutic and psychoeducational 
principles, may improve participant's knowledge about stigma, beliefs about overcoming stigma, 

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and stigma-related coping skills. The intervention is novel, so it is unclear how likely these 
benefits are; however, automated therapeutic text messaging interventions have been shown to 
improve mental health outcomes in the short term. Further, participants in the formative 
qualitative aim of this study (n=22) expressed strong enthusiasm for the intervention and its 
content, citing a dire lack of social-emotional support for people who use drugs.  
 
 
 

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4. Study Objectives 
4.1 Hypothesis 
As a feasibility study, there is no formal hypothesis testing. Outcomes related to feasibility, 
acceptability, and preliminary effectiveness will be presented descriptively.  
4.2 Primary Objective 
We will use an iterative convergent mixed method design1 to develop and evaluate a stigma 
resistance text message intervention for PWUD. Text messaging is a scalable and cost-effective 
modality for health behavior change with demonstrated acceptability and effectiveness in 
interventions with PWUD, a historically hard-to-reach group.2–8 Specifically, we aim to: 
Aim 1: Identify PWUD self-stigma subgroups and describe associated demographic, health, and 
drug use risk factors among rural PWUD in an eight-state multi-site cohort using latent class 
analysis.^ 
Aim 2: Identify a) stigma-related attitudes and beliefs that are salient to PWUD and amenable to 
change, and b) text message content and delivery preferences through iterative elicitation 
interviews with 20 rural Ohio PWUD.^ 
Aim 3: Tailored around findings from Aim 1 and Aim 2, develop an automated daily short 
message service (SMS) stigma resistance intervention.^ 
Aim 4: Evaluate feasibility, acceptability, and preliminary effectiveness of the SMS intervention 
to increase stigma resistance and reduce self-stigma. We will conduct a pilot trial of the 
intervention among 30 rural Ohio PWUD in active use and collect quantitative and qualitative 
data at baseline and four-week follow-up. 
Despite wide acknowledgement that stigma is a key barrier to harm reduction and treatment 
utilization, few studies have intervened on this construct among PWUD in active use. Results of 
our study will address the current research gap of stigma reduction interventions for PWUD. Our 
study will further inform whether text messaging is a feasible and acceptable modality for 
promoting preventive health behaviors in this population. 
^ This study protocol covers Aim 4 only. Aims 1-3 were approved and conducted under 
separate protocols (UNC IRB# 17-1887 & 18-2747). 
 

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5. Study Design 
5.1 General Design Description 
This Phase 1 study is a single-group feasibility trial of a text message intervention to increase 
stigma resistance and reduce self-stigma among people who use drugs. All participants will be 
assigned to the intervention condition. The primary outcomes are changes in stigma resistance 
and self-stigma from baseline to 4-week follow-up using self-report. We will assess 
implementation and process outcomes to inform future intervention refinement. 
5.2 Outcome Variables 
5.2.1 Primary Outcome Variables 
This social-behavioral intervention is theorized to change attitudes and beliefs in the short term. 
The primary attitudinal outcomes indicating preliminary effectiveness are stigma resistance 
and self-stigma. Improvements in stigma resistance are expected to give participants the 
cognitive and behavioral tools to challenge internalized stigma and resist fearing enacted 
stigma.9,10 Stigma resistance will be measured using the Stigma Resistance Scale.88 Self-stigma 
will be measured using the Substance Abuse Self-Stigma Scale.10  
Feasibility outcomes include implementation feasibility and user feasibility. Implementation 
feasibility outcomes include recruitment rate (% screened who are deemed eligible, % screened 
who proceed to consent and enrollment), retention rate (% enrolled who complete post-survey), 
time from recruitment initiation to sample saturation, and intervention engagement (message 
response rate and mean response time). User feasibility outcomes include phone access, 
phone plan challenges, and technological literacy during the intervention. 
Acceptability outcomes include the seven component constructs of the Theoretical Framework 
of Acceptability: affective attitude, burden, perceived effectiveness, ethicality, intervention 
coherence, opportunity costs, and self-efficacy.  
As this is a feasibility trial, long-term behavioral outcomes will not be measured. However, we 
expect that reductions in self-stigma from the intervention may attenuate the 'why try?' effect 
and have distal effects on behavioral outcomes like treatment- and harm reduction-seeking 
which, in turn, may reduce the risk of drug overdose.17–19,33 These outcomes could be assessed 
in future clinical trials if the pilot demonstrates feasibility, acceptability, and preliminary 
effectiveness. 
5.2.2 Secondary and Exploratory Outcome Variables 
The intervention is theorized to affect the following secondary psychosocial outcomes for 
participants: self-esteem and hope.11–15 Self-esteem is measured with the Rosenberg Self-
Esteem Scale.89 Hope is measured with the Adult Dispositional Hope Scale.90 
We will also explore the following categorical demographic characteristics in subgroup analyses 
of the effectiveness outcomes: age, race, gender, educational attainment, drug of choice. 
 
 
 

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6. Study Population 
6.1 Study Population 
Study participants are people who use drugs (PWUD), an appropriate population for receiving 
stigma reduction interventions. PWUD are disposed to high levels of substance use stigma, 
which, compared with other health stigmas, is particularly strong (Luoma, 2011).49 For instance, 
the general public considers PWUD to be significantly more dangerous and blameworthy than 
people with mental illness, and substance use-related stigma is higher than HIV-related stigma 
in people with both conditions.32–34,91 
Participants will be recruited from Scioto County, Ohio, a rural county designated distressed by 
the Appalachian Regional Commission with regard to economic status.92 Southern Ohio has 
long been a hotspot in the opioid epidemic, with overdose and infectious disease rates 
outpacing the rest of the state and nation since the turn of the century.93,94 Portsmouth, the 
county seat of Scioto and largest town in the region, has often been portrayed in the media as 
an archetype of the epidemic and was featured prominently in the book Dreamland: The True 
Tale of America's Opiate Epidemic.95–97 Portsmouth also has a strong treatment and harm 
reduction infrastructure, with multiple inpatient and outpatient clinics, an established syringe 
service program (SSP), and at least 37 providers waivered to prescribe buprenorphine.98,99 
Given the study team's research experience and established relationships in the region, along 
with the salience of stigma described by PWUD in formative aims of this study, Scioto County 
serves as an ideal recruitment site for this study. 
6.1.1 Number of Participants 
The proposed sample size is 30. As the primary goal is to assess feasibility and acceptability, 
not effectiveness, sample size is not based on anticipated effect sizes. Previous guidance has 
indicated our proposed sample size is an acceptable number for feasibility studies.20–22 This 
sample size will allow us to estimate the retention rate to within a 95% confidence interval of +/- 
12% (calculated assuming a retention rate of 85%). Although exploratory only, the sample size 
will further allow us to detect moderate effect sizes in the continuous outcomes (Cohen's d = 
0.53) with 80% power (alpha = .05, two-tailed) using paired t-tests. 
Based on our prior work recruiting from the same population using identical eligibility criteria, we 
estimate that 40 prospective participants will need to be screened to achieve our sample size. 
6.1.2 Eligibility Criteria/Vulnerable Populations 
Inclusion criteria: 
1. Ages 18 and older at enrollment 
2. Residing in Scioto County, Ohio at time of enrollment 
3. Able to speak and read English 
4. Reliable daily access to smartphone with a data plan capable of sending and receiving SMS 
text messages during the intervention period (4 weeks) 
5. Self-reported past 30-day use of illicit opioids (e.g., heroin, fentanyl), prescription opioids not 
as prescribed (e.g., oxycodone, buprenorphine), methamphetamine, or cocaine. 
6. Willing to provide informed consent 

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Exclusion criteria: 
1. Unable to be consented due to cognitive impairment 
2. Planning to move out of the study area during the study period 
3. Unwilling or unable to comply with protocol requirements 
4. Currently incarcerated in a correctional facility 
No participants will be excluded on the basis of race, gender, or ethnicity. 
 
 

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7. Methods 
7.1 Intervention 
7.1.1 Description of Intervention 
Project RESTART (Resisting STigma And Revaluating your Thoughts) is a theory-informed, 4-
week automated text message intervention to address self-stigma in people who use drugs. The 
intervention delivers two daily messages to participants for four weeks (56 messages total). 
Messages are designed to address the four components of the personal level of Stigma 
Resistance Theory: Not believing stigma/catching and challenging stigmatizing thoughts; 
empowering oneself through learning about substance use and one's own recovery; maintaining 
one's recovery and proving stigma wrong; and developing a meaningful identity and purpose 
apart from one's substance use. The preliminary library of messages was developed by the 
study team, who have expertise in stigma (Go, Sibley), substance use (Go, Miller, Sibley), 
health communications (Noar, Sibley), and mHealth (Gottfredson-O'Shea, Muessig, Noar). To 
ensure all messages are informed by communication and behavioral health theory and 
accurately map onto the stigma resistance domains, the team created a message development 
matrix, which was adapted from steps 1 and 2 of Intervention Mapping, an evidence-based 
protocol for designing interventions. Messages were then pilot tested (IRB #17-1887) with 
people who use drugs and revised based on their feedback. Message content is informed by 
evidence-based psychotherapeutic approaches (e.g., Acceptance and Commitment Therapy) 
and health communication theory (e.g., Elaboration Likelihood Model). 
At the baseline visit, participants complete a Computer-Assisted Self-Interview (CASI) survey, 
are oriented to Project RESTART, and are enrolled to receive text messages to their personal 
cell phone. Participants then receive two daily automated text messages (morning and evening) 
which provide psychoeducation about substance use and stigma, advice for coping with stigma, 
and suggestions for how to set personal goals and build self-esteem. After the 4-week 
intervention period ends, participants return for their follow-up visit where they will complete a 
follow-up CASI survey. A subset of participants (n=12) will complete a follow-up telephone 
interview to provide detailed feedback on the acceptability of the program.  
7.1.2 Method of Assignment/Randomization 
This is a single-group, pre-post design. All participants will be allocated to the intervention group 
and receive the same library of automated text messages.  
7.1.3 Selection of Instruments/Outcome Measures 
Preliminary Effectiveness Outcome Measures 
Preliminary effectiveness outcome measures were selected based on construct validity to the 
outcomes and internal consistency reliability. 
Construct 
Measure 
Example Question 

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Stigma resistance 
Stigma Resistance Scale 
(Firmin, Lysaker, et al., 2017) 
20 items, Likert-type, α=.93 
"I challenge negative thoughts 
that I may have about myself 
related to my substance use." 
Self-stigma 
Substance Abuse Self-Stigma 
Scale (Luoma et al., 2013) 
40 items, Likert-type, α=.86 
"I feel inferior to people who 
have never had a problem 
with substances." 
Hope 
Adult Dispositional Hope 
Scale (Snyder et al., 1991) 
12 items, Likert-type, α=.77-
.84 
"Even when others get 
discouraged, I know I can find 
a way to solve the problem." 
Self-esteem 
Rosenberg Self-Esteem Scale 
(Rosenberg, 1965) 
10 items, Likert-type, α=.77 
"I feel I do not have much to 
be proud of." 
Covariates 
Age, race, gender, 
educational attainment, drug 
of choice (all categorical 
N/A 
 
Implementation Feasibility Measures 
Measures indicating feasibility of implementation include recruitment rate (% screened who are 
deemed eligible, % screened who proceed to consent and enrollment), retention rate (% 
enrolled who complete post-survey), time from recruitment initiation to sample saturation, and 
intervention engagement (message response rate and mean response time). 
User Acceptability and Feasibility Measures 
User acceptability and feasibility will be measured at post-test only. Items were developed using 
the Theoretical Framework of Acceptability (TFA). The TFA was developed in light of poor 
guidance and inconsistent definitions in the literature on assessing acceptability in healthcare 
interventions (Sekhon et al., 2017). Questions address the TFA's seven component constructs 
of acceptability: affective attitude, burden, perceived effectiveness, ethicality, intervention 
coherence, opportunity costs, and self-efficacy.100,101 
User Feasibility and Acceptability Measures 
Sub-domain 
Question 
Response Options 
Notes 
Feasibility 

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User 
Before the start of this 
program, how often did 
you send or receive 
text messages? 
a. Every day b. A few 
times a week c. A few 
times a month d. Less 
than once a month e. 
Never 
From Lian et al., 
2022102 
Before the start of this 
program, how 
comfortable were you 
with sending or 
receiving text 
messages? Please 
select the statement 
that best applies to you. 
a. Not comfortable at all 
b. Not comfortable c. 
Neutral d. Comfortable 
e. Very comfortable 
From Lian et al., 2022 
Between the start of the 
program and now, did 
you experience any 
challenges or changes 
with your phone (e.g., 
lost, broken) that 
prevented you from 
receiving or reading 
text messages? 
a. Yes b. No c. Unsure 
From Lian et al., 2022 
Between the start of the 
program and now, did 
you experience any 
challenges or changes 
with your phone 
number or phone plan 
(e.g., changed number, 
ran out of minutes) that 
prevented you from 
receiving or reading 
text messages? 
a. Yes b. No c. Unsure 
From Lian et al., 2022 
What device did you 
use to receive text 
messages for this 
program? 
a. Basic cell phone 
(non-smartphone) b. 
Smartphone c. Tablet 
d. Program on 
computer or laptop e. 
Other: (please specify) 
From Lian et al., 2022 

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On average, when 
would you read the text 
message you received? 
a. As soon as you saw 
them b. Later that day 
c. Later that week d. 
More than one week 
later e. Never 
From Lian et al., 2022 
Acceptability 
Affective Attitude Overall, how much did 
you like or dislike the 
text message program? 
a. Strongly dislike b. 
Dislike c. Like d. 
Strongly like 
From Sekhon et al., 
2022 
Burden 
How much effort did it 
take to engage with the 
text message program? 
a. No effort at all b. A 
little effort c. A lot of 
effort d. Huge effort 
From Sekhon et al., 
2022 
It was easy to read and 
understand the text 
messages. 
a. Strongly agree b. 
Somewhat agree c. 
Somewhat disagree d. 
Strongly disagree 
From Lian et al., 2022 
I looked forward to 
receiving the messages 
each day. 
a. Strongly agree b. 
Somewhat agree c. 
Somewhat disagree d. 
Strongly disagree 
 
Ethicality 
I had concerns about 
the privacy of my 
information sent over 
text message. 
a. Strongly agree b. 
Somewhat agree c. 
Somewhat disagree d. 
Strongly disagree 
From Lian et al., 2022 
Intervention 
Coherence 
It is clear to me how the 
text message program 
can help me to deal 
with stigma. 
a. Strongly agree b. 
Somewhat agree c. 
Somewhat disagree d. 
Strongly disagree 
From Sekhon et al., 
2022 
Opportunity 
Costs 
Engaging with the text 
message program 
interfered with my other 
priorities. 
a. Strongly agree b. 
Somewhat agree c. 
Somewhat disagree d. 
Strongly disagree 
From Sekhon et al., 
2022 
How do you feel about 
the number of 
a. Way too few b. 
Somewhat too few c. 
 

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messages you received 
each day during the 
program (2 messages 
per day)? 
About right d. 
Somewhat too many e. 
Way too many 
How do you feel about 
the length of the 
program (4 weeks?) 
a. Way too short d. A 
little too short c. About 
right d. A little too long 
e. Way too long 
 
Perceived 
Effectiveness 
Overall, how helpful did 
you find the program? 
a. Very helpful b. 
Somewhat helpful c. 
Barely helpful d. Not at 
all helpful 
From Knutson et al., 
2021103 
I thought that the topics 
discussed in the 
messages were 
relevant to me. 
a. Strongly agree b. 
Somewhat agree c. 
Somewhat disagree d. 
Strongly disagree 
From Lian et al., 2022 
The messages I 
received were a useful 
way for me to learn 
about stigma. 
a. Strongly agree b. 
Somewhat agree c. 
Somewhat disagree d. 
Strongly disagree 
From Lian et al., 2022 
The messages I 
received were a useful 
way for me to learn to 
confront stigma. 
a. Strongly agree b. 
Somewhat agree c. 
Somewhat disagree d. 
Strongly disagree 
From Lian et al., 2022 
The messages I 
received made me feel 
better about myself. 
a. Strongly agree b. 
Somewhat agree c. 
Somewhat disagree d. 
Strongly disagree 
 
Self-Efficacy 
How confident did you 
feel about using the 
information in the text 
messages? 
a. Very unconfident b. 
Unconfident c. 
Confident d. Very 
confident 
From Sekhon et al., 
2022 
General 
Acceptability 
Overall, how 
acceptable was the text 
a. Completely 
unacceptable b. 
Unacceptable c. 
From Sekhon et al., 
2022 

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message program to 
you? 
Acceptable d. 
Completely acceptable 
How satisfied were you 
with participating in this 
study? 
a. Very satisfied b. 
Somewhat satisfied c. 
Barely satisfied d. Not 
at all satisfied 
From Knutson et al., 
2021 
How likely would you 
be to recommend this 
program to a 
friend/family member? 
a. Very likely b. 
Somewhat likely c. 
Barely likely d. Not at 
all likely 
From Knutson et al., 
2021 
Message Liking 
Please select three 
messages you liked the 
most. 
[TEXT MESSAGE 
LIBRARY] 
 
Please select three 
messages you disliked 
the most. 
[TEXT MESSAGE 
LIBRARY] 
 
Open-Ended 
What did you like about 
the text message 
program? 
 
 
What did you dislike 
bout the text message 
program? 
 
 
Any other comments 
about the program? 
 
 
 
Participants will also be asked to rate perceived message effectiveness during the intervention. 
Once per week (4 surveys total), participants will receive an anonymous Qualtrics link via text 
message to rate the previous week’s messages with the question “Think about the messages 
you received this week. How effective was each message at changing your feelings about 
stigma?” rated on a 5-point Likert-type scale from “Not at all effective” to “Extremely effective.” 
No identifying information will be collected in this weekly survey. 
7.1.4 Intervention Administration 
This automated text message intervention is self-administered, i.e., no interventionists will be 
engaged in implementation except to recite the orientation script during participants' baseline 
visit. 

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Text messages will be delivered via Twilio, a cloud-based communication platform for SMS. 
Twilio is a secure option for delivering and receiving text messages and has been used in 
multiple mHealth intervention studies. The messaging program will be developed in Python 
version 3.11.0, a programming language that is compatible with Twilio's application 
programming interface. Python scripts, message libraries, phone number database, and other 
files needed for automation will be stored in AWS Lambda, Amazon's secure serverless 
computer service for running code. The program will be triggered to run every 15 minutes with 
Amazon EventBridge Scheduler using cron expressions, ensuring that messages will be sent to 
participants' phones at their preferred times each day. 
7.1.5 Reaction Management 
Though the text message content is positive and affirming, mention of stigma may distress 
some participants. During the intervention orientation, participants will be provided a list of 
external counseling and support resources they can access if they feel distressed. These 
resources will also be shared in a text message during the intervention, along with a text 
message that the messaging exchange will not be monitored and participants should reach out 
to the suggested resources if they feel distressed.  
7.2 Study Procedures 
7.2.1 Study Schedule 
The study includes 3-4 visits for participants. 
1. Screening (pre-enrollment): Participants will be screened for eligibility pre-enrollment at the 
recruitment site or over the phone. Expected duration is 5 minutes. 
2. Baseline Visit (Day 0): Participants will provide informed consent, enroll in the intervention, 
complete baseline survey, and receive intervention orientation. Expected duration is 1-1.5 
hours. 
3. Follow-up Visit (Day 28-35): Within 1 week of the end of each participant's 4-week 
intervention enrollment period, participants will return for their follow-up visit and complete the 
follow-up survey. Expected duration is 1-1.5 hours. 
4. Telephone Follow-up Interview (Day 28-49): Within 2 weeks of the follow-up visits, selected 
participants (n=12) will complete a brief follow-up interview by telephone. Expected duration is 
30 minutes. 
Total duration of participation will vary depending on participants' availability for follow-up and 
can range from 28-49 days. 
 
7.2.2 Informed Consent 
Written voluntary informed consent will be obtained from each study participant. The consent 
procedures will be conducted with interested participants before any study activities are carried 
out. 
Participants who are eligible for the study will be approached by a study team member 
regarding the possibility of participating in the study. They will be reassured that their decision to 

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participate in the study or not will not affect their relationship with any program or organization, 
including but not limited to UNC-Chapel Hill and the SHRPS harm reduction program. If the 
participant is agreeable, the study coordinator will explain the study in-depth in plain language, 
including the possible risks and benefits to participating in the study. After reviewing the 
informed consent form, the study team member will reiterate that participation is voluntary and 
then provide time and opportunity for the participant to review the document again and ask any 
questions or share any concerns. Once all questions have been answered, potential participants 
will be told they have the opportunity to provide informed consent, decline to participate, or take 
additional time to consider participation (e.g. go home and return later). If they agree to 
participate, the study team member and participant will both sign and date the informed consent 
form. The participant will be offered a hard copy of the form to take home. 
Study staff performing consent procedures will be trained to probe for comprehension to ensure 
the participant understands the purpose and procedures of the study, their rights as a research 
participant, the voluntariness of the study, and the risks and benefits of participation.  
7.2.3 Screening 
Prospective participants expressing interest at the point of recruitment will be offered the 
opportunity to determine their eligibility to participate in the study via an oral screening process. 
These prospective participants may choose to a) screen on-the-spot in a private location, b) 
receive the study phone number to contact the study team for screening over the phone, or c) 
arrange a later time, date, and location to meet with study team to screen in-person. Study staff 
will use a standardized screening script to determine participant eligibility. 
As recruitment feasibility is a study outcome, all prospective participants will be logged, 
regardless of enrollment status. Participants who decline to participate or are determined 
ineligible will be logged with a non-identifying ID code (i.e., based on the date and order of 
recruitment) and the reason for ineligibility/non-participation. As the screening is oral only, no 
data will be recorded during the recruitment and screening process, and thus no data will need 
to be destroyed.  
7.2.4 Recruitment, Enrollment and Retention 
Recruitment. Participants will be recruited with the help of local organizations, including SHRPS, 
the area's harm reduction program, and word-of-mouth referral by study participants. SHRPS 
has served as a partner for recruitment in substance use studies conducted by our co-
investigators (Go and Miller) for the past 6 years. Prospective participants will be identified with 
the help of organization staff. Study staff will also distribute flyers with study contact information 
during program open hours. With approval of community-based organizations, participants may 
be recruited by distributing flyers to potential participants. Participants consenting to be re-
contacted in the formative portion of the study (IRB #17-1887) may also be re-contacted by 
phone to inform them of the study. 
If participants want to find out more about the study, we will ask the participant to move to a 
location where others cannot overhear their conversation. In-person discussions with potential 
participants will occur in private offices. If speaking to a potential participant over the phone, we 
will ask the individual to move to a location where others cannot overhear the 

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participant's telephone conversation. Prospective participants expressing interest will be 
screened for eligibility before scheduling baseline visits. 
Enrollment. Individuals will be asked to have their smartphone with them for the enrollment visit. 
To confirm an individual meets the smartphone eligibility criterion, study staff will confirm that 
the individual has a smartphone with a data plan at the visit. Individuals will then be screened to 
confirm eligibility at the start of the enrollment visit. 
Individuals meeting eligibility criteria will be guided through an informed consent process by 
research staff. Individuals will first be able to read or have read to them the informed consent 
sheet with the opportunity to have any questions answered by the interviewer. Prior to signing 
the consent document, staff will go through a brief comprehension check with the participant in 
order to ensure that the participant fully understands all study procedures. Informed consent will 
cover all procedures, potential risks, benefits and who to contact to report complaints. Study 
staff will confirm whether consent was obtained and the participant's enrollment status on a 
study case report form. 
After consent is obtained, participants will complete a computer-assisted self-interview (CASI) 
baseline survey hosted on Qualtrics, a secure HIPAA-compliant platform. Participants will then 
be given a brief oral orientation to the intervention.  
Participants will be considered enrolled upon meeting eligibility criteria, signing the consent 
form, completing the baseline CASI survey, and successfully enrolling in the text messaging 
program on their phones. 
Retention. We will collect multiple forms of participant contact information and study-related 
communication preferences (e.g. email, phone/text, social media handles) as part of study 
enrollment. Using a participant locator form at the baseline visit, participants will indicate which 
forms of contact they prefer if they cannot be reached on their primary phone. If the participant 
consents for a friend or family member to be contacted for follow-up, no details of the study will 
be shared, only that the participant is being contacted about a health study. 
Likelihood of recruitment success. There is a high likelihood that we will have access to the 
anticipated sample size (n=30). Our study team has successfully met recruitment quotas across 
several quantitative and qualitative research projects in southern Ohio over the past 6 years, 
including formative qualitative interviews for the current study (n=22), which were completed in 
3 weeks in October 2023. The primary recruitment site, SHRPS, is frequently utilized for harm 
reduction services by people who use drugs. In 2021, SHRPS had 2,199 unique visitors and 
12,111 interactions. The program is operated by the Portsmouth Health Department three days 
a week. The SSP has served as a recruitment site for more than four years in the parent study. 
SHRPS is well-situated for recruitment given the trust, safety, and legitimacy it has cultivated 
with the local PWUD community. 
7.2.5 Study Visits 
Baseline visit (1-1.5 hours) 
• 
Study staff completes informed consent process with participant 
• 
Participant completes CASI baseline survey 

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• 
Study staff reviews orientation script with participant 
• 
Participant completes participant locator form 
• 
Participant is enrolled to receive text message intervention 
Follow-up visit (1-1.5 hours) 
• 
Participant completes CASI follow-up survey 
Telephone interview (30 minutes) 
• 
Select participants (n=12) complete follow-up telephone interview 
7.2.6 End of Study and Follow Up 
Participation ends with the participant's final study visit (either the in-person follow-up visit or 
telephone survey, for selected participants). Study staff will complete a study 
discontinuation/completion case report form for each participant, regardless of disposition. The 
form will track the off-study date, off-study reason, and reason for discontinuation for those who 
left the intervention prematurely (e.g., lost to follow-up, left the study area early). 
7.2.7 Removal of Subjects 
Enrolled participants may withdraw from the study at any time for any reason upon request 
without penalty. A study discontinuation form will be completed as described in section 7.3.6.  
An investigator may withdraw a participant from the study for the following reasons: 
• 
If any clinical adverse event (AE), serious adverse event (SAE), or other medical 
condition or situation — related or unrelated to the study — develops after enrollment 
such that continued participation in the study would not be in the best interest of the 
participant. 
• 
If a patient presents a safety risk to the research staff. 
• 
If their participation in the study is disruptive to the study. 
 
7.3 Statistical Method 
7.3.1 Statistical Design 
The pilot trial features a single-group, pre-post quasi-experimental design. As this is a feasibility 
study, hypothesis testing on the main effectiveness outcomes is strictly exploratory. Analysis 
assumes a null hypothesis of no participant-level change in the outcome measures from 
baseline to follow-up. Inferential analysis will be conducted on all outcome measures described 
in 7.1.3. 
Basic descriptive statistics will be calculated for feasibility, acceptability, and outcome 
measures. We will present frequency tables for the categorical variables and means, standard 
deviations, and percentiles (25th, 50th, 75th) for the continuous variables. For outcome 

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measures, descriptive statistics will be calculated for baseline scores, follow-up scores, and 
change in scores. 
Inferential analysis will be conducted on participant-level change in outcome measures from pre 
to post using paired t-tests (or Wilcoxon signed-ran tests if response distributions are non-
normal). We will also examine differences in mean change scores across levels of each 
demographic variable using ANOVA. Significance levels for analyses will be set at α=0.05. We 
will use R version 4.3.0 for data cleaning, management, and analysis. 
7.3.2 Sample Size Considerations 
The proposed sample size is 30. As the primary goal is to assess feasibility and acceptability, 
not effectiveness, sample size is not based on anticipated effect sizes. Previous guidance has 
indicated our proposed sample size is an acceptable number for feasibility studies.20–22 This 
sample size will allow us to estimate the retention rate to within a 95% confidence interval of +/- 
12% (calculated assuming a retention rate of 85%). Although exploratory only, the sample size 
will further allow us to detect moderate effect sizes in the continuous outcomes (Cohen's d = 
0.53) with 80% power (alpha = .05, two-tailed) using paired t-tests. Power calculations were 
performed using G*Power 3.1.9.7. 
7.3.3 Planned Analyses 
7.3.3.1 Primary Analyses 
The primary outcomes (stigma resistance and self-stigma) and secondary outcomes (hope and 
self-esteem) will each be measured at baseline and follow-up for all participants. The 
effectiveness of the intervention will be measured as the mean change in participant-level 
outcome scores from pre to post given the null hypothesis of no change and a type I error rate 
of 0.05. We will use an intention-to-treat approach, including all participants with complete pre 
and post data in analysis regardless of adherence. 
Feasibility and acceptability will be characterized descriptively, as described in 7.4.1. 
Follow-up telephone interviews will be transcribed and computerized for analysis in the 
qualitative data analysis program Dedoose (v9.0). Transcripts will be coded and analyzed for 
emerging themes on intervention acceptability using the Braun & Clarke (2006) approach to 
reflexive thematic analysis (TA).104  
7.3.4 Handling of Missing Data 
To address missing data, we will review the frequency of missing and non-missing values for all 
variables at baseline and follow-up. We will conduct missing value analyses to determine 
whether persons with missing values are systematically different from those without missing 
values. If this assessment of the frequency of missing data suggests that bias may be 
introduced, we will employ multiple imputation to address the missing data. 
 
 

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8. Trial Administration 
8.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization 
Written voluntary informed consent will be obtained from each study participant. The consent 
procedures will be conducted with prospective participants before any study activities are 
carried out. 
The informed consent procedure follows the UNC-Chapel Hill required consent template 
including describing the purpose of the study, the procedures to be followed, and the risks and 
benefits of participation. The consent forms will use language that is sufficiently simple for lay 
persons to comprehend. 
Participants who are eligible for the study will be approached by a study team member 
regarding the possibility of participating in the study. They will be reassured that their decision to 
participate in the study or not will not affect their relationship with any program or organization, 
including but not limited to UNC-Chapel Hill and the SHRPS harm reduction program. If the 
participant is agreeable, the study coordinator will explain the study in-depth in plain language, 
including the possible risks and benefits to participating in the study. After reviewing the 
informed consent form, the study team member will reiterate that participation is voluntary and 
then provide time and opportunity for the participant to review the document again and ask any 
questions or share any concerns. Once all questions have been answered, prospective 
participants will be told they have the opportunity to provide informed consent, decline to 
participate, or take additional time to consider participation (e.g. go home and return later). If 
they agree to participate, the study team member and participant will both sign and date the 
informed consent form. The participant will be offered a hard copy of the form to take home. 
Study staff performing consent procedures will be trained to probe for comprehension to ensure 
the participant understands the purpose and procedures of the study, their rights as a research 
participant, the voluntariness of the study, and the risks and benefits of participation.  
8.2 Institutional Review Board (IRB) Review 
This protocol, the informed consent documents, and any subsequent modifications will be 
reviewed and approved by the UNC-Chapel Hill Institutional Review Board responsible for the 
oversight of the study. Annual IRB reporting and review is required for the duration of the study. 
8.3 Subject Privacy, Confidentiality & Data Management 
We will take the utmost caution to protect the confidentiality of participants' involvement in the 
study and all participant provided information/data throughout all research procedures and data 
management and analysis. Participants may be concerned about the security of their data, 
particularly since it is collected and stored electronically. Every effort will be made to ensure that 
study participants are protected from the risk of breach of confidentiality using a variety of steps 
to ensure participant data security across all sources.  
The results of the research will be disseminated but no participant names or other identifying 
information will be used in any dissemination materials (published or otherwise). 

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8.4 Data Collection 
Surveys will be completed by participants via Computer-Assisted Self-Interview (CASI) at the 
baseline follow-up study visits using Qualtrics. Participants will complete the survey in a private 
room. A trained study team member will be available to answer questions. Follow-up telephone 
interviews, conducted with a subsample of participants (n=12), will be completed within two 
weeks or the participant's follow-up study visit. Study data will be stored in a secure, password-
protected database on UNC-Chapel Hill servers. Survey and interview data will be uploaded to 
the database daily. 
Participant-related study information will be identified through a participant ID number (PID), 
derived from the participant's date of enrollment, on all participant case report forms, audio files, 
transcripts, and CASI files. Participant names or other personally identifying information will not 
be used on any study documents and will be redacted from interview transcripts. 
8.5 Data Quality Assurance 
The quality assurance (QA) plan will include the following components: 
• 
Develop standard operating procedures (SOPs) for important processes of the study, 
including those involving: 
o The data (including: contacting potential participants, data collection, data entry, 
data cleaning, data storage and transmission); 
▪ 
Systematic plan for data cleaning: Data management staff will be 
responsible for systematically cleaning the data on a regular basis, at 
least weekly, to prevent systematic problems with data collection from 
occurring. Discrepancies in data or missing data found during data 
cleaning will be investigated by the data manager by meeting with the 
survey administrator and data management team and referring to source 
documents, when applicable. 
o Modifications of a procedure that may change during the course of the study (due 
to reasons such as newly published data, guidelines, or changes in local policies 
or regulations, etc.). Revisions should be documented with the date of change 
and approved by the PI; all changes must be documented and communicated to 
the study staff. 
• 
Ensuring all study staff are trained on relevant SOPs (including the protocol they are 
carrying out and all data collection forms), before study initiation and annually thereafter 
with refresher trainings. 
• 
Ensuring all interviewers are extensively trained and will practice conducting study-
related interviews, for both qualitative and quantitative data collection. 
• 
Data management staff will produce data error reports on a weekly basis. The Data 
Manager will review data error reports weekly, and immediately bring any errors 
identified to the attention of appropriate staff for correction. Errors will be corrected within 
3 working days of identification. 

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• 
Data entry and transmission reports generated by the electronic data system, if 
applicable, will be reviewed by the data manager to assure that transmitted data was 
successfully entered into the database. Errors will be brought to the attention of the 
responsible person and corrected within 3 working days of identification. 
• 
New data staff members will have all records reviewed by the data manager during their 
first 1-2 months of employment or until their competency is determined to be at the level 
of other staff. If necessary, a more intense monitoring regimen is instituted according to 
the auditing results and needs of the new staff member. 
Quality assurance checks will be implemented throughout the data collection process to quickly 
identify and rectify potential problems. Survey instruments will employ skip patterns and built-in 
checks to minimize discrepant and unrealistic answers. Standard data cleaning procedures will 
be used prior to analyses, including outlier detection and graphical representation of the data. 
8.6 Access to Source 
The study PI and mentor will ensure the availability of all study-related records for audit by NIH, 
NIDA, and UNC IRB, including participant records, consent forms, case report forms, and 
supporting source documentation for the purpose of ensuring the protection of study 
participants, compliance with the protocol and regulatory policies, and accuracy and 
completeness of records. 
8.7 Data or Specimen Storage/Security 
All records will be identified by coded number only to maintain participant confidentiality. The 
data collected from individuals will be stored using a numerical system to identify each subject. 
Only the staff working on this study (Principal Investigator and Co-Investigators) will have 
access to the records and identities of the subjects. Any physical study-related information (e.g., 
informed consent forms) will be stored securely in locked filing cabinets with access limited to 
authorized study staff. All records that contain names or other personal identifiers, such as 
locator forms and informed consent forms, will be stored separately from study records 
identified by code number. Electronic study records, e.g., survey responses, interview 
transcripts, and case report forms, will be stored on a secure, password-protected university-
hosted server (Microsoft OneDrive/SharePoint). Only study staff approved by the UNC IRB will 
have access to the server.  
Qualtrics. Qualtrics will be used for study surveys. The UNC Information Security Office has 
approved Qualtrics for collection and storage of Private Health Information (PHI) and a Business 
Associates Agreement (BAA) is in place between UNC-Chapel Hill and Qualtrics. Qualtrics uses 
Transport Layer Security (TLS) encryption (also known as Hypertext Transfer Protocol Secure 
(HTTPS)) for all transmitted data. Survey data are protected with passwords and HTTPS 
referrer checking. The data is hosted by third party data centers that are Statement on 
Standards for Attestation Engagements (SSAE)-16 Service Organization Control (SOC) II 
certified. All data at rest are encrypted, and data on deprecated hard drives are destroyed by 
U.S. Department of Defense methods and delivered to a third-party data destruction service. 
Qualtrics deploys the general requirements set forth by many Federal Acts including the Federal 
Information Security Management Act (FISMA) of 2002. They meet or exceed the minimum 
requirements as outlined in Federal Information Processing Standards (FIPS) Publication 200. 

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Twilio. Twilio is a third-party vendor that will be used for transmitting intervention text messages 
to participants. Twilio uses end-to-end encryption and follows industry-standard security 
measures, certified under ISO/IEC 27001 with additional attestations to ISO/IEC 27017 and 
ISO/IEC 27018.  Twilio uses TLS 1.2 to encrypt data in transit between the customer application 
and Twilio over public networks. Databases housing customer data are encrypted at rest. Twilio 
is among the most commonly used softwares for transmission of text messages in mHealth 
intervention trials. 
8.8 Retention of Records 
We will permanently delete identifying information from the computer server 4 weeks after data 
collection ends, including participant contact information logs.  Only a completely de-identified 
copy of the dataset will remain on the server after this point. The de-identified copy of the 
dataset will be deleted five years after study data are published, as required by most journals. 
Interview audio files will be uploaded to the secure server within 24 hours of the interview then 
deleted from the recording device. The audio will be transcribed to text and stored on the server 
within one week, after which the audio file will be immediately and permanently deleted from the 
server. 
8.9 Data Safety Monitoring Plan 
Reporting of AEs and SAEs. Adverse incidents will be reported to the UNC Institutional Review 
Board and NIH project officers. Potential incidents may include protocol violations, security 
incidents, breach of confidentiality, or adverse psychological reactions to the intervention. 
In case of any adverse event, site study staff will record the incident in the adverse event 
tracking log and report the incident in writing via email to the PI and mentor within 24 hours of 
discovering the adverse event. Any adverse events or protocol violations will also be reported to 
the UNC IRB and NIH within 5-10 days (depending on severity and needed information 
collection) with follow-up reporting of any pending information, action, or follow-up. 
All SAEs will be reported by the PI to the IRB as soon as possible and reported to NIDA within 
24 hours of the event by email. A written follow-up must be received by NIDA within 72 hours of 
the event. The written follow-up will include the date of the event, what occurred, actions taken 
by project staff, planned follow-up (if any), whether the event appears to be related to the 
intervention or participation in the study, and whether the participant will continue in the study. 
All AE/SAE will also be included in the annual report to NIDA. 
Reporting of IRB Actions to NIDA. IRB actions will be reported by the PI to NIDA within 5 
working days. 
Reporting of Changes or Amendments to the Protocol. Changes or amendments to the protocol 
will be reported to NIDA within 5 working days. 
Process of AE/SAE Collection. Serious adverse events are based on the FDA definition and 
defined as those that result in death, are life-threatening, result in hospitalization or prolongation 
of existing hospitalization, a persistent or significant disability, a congenital abnormality or birth 
defect. Other injuries or medical events may be considered to be serious adverse events when, 
in the opinion of a physician, they may jeopardize the participant and may require medical or 

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surgical intervention to prevent one of the above outcomes. For the purposes of this study, 
substance abuse or dependency alone in the absence of other adverse impact will not be 
considered to be an adverse event. 
AE/SAE Follow-up Plan. Reports on AEs and SAEs wil be reviewed yearly by the PI, mentor, 
and co-investigators and included in annual reports to the IRB and NIDA. See Section 4.2 
above for details on AE/SAE reporting. 
Additionally, study staff will remind participants to report any physical or social harm to the study 
staff immediately, so that participants may receive counseling or other assistance. When 
necessary, referrals to a psychiatrist or physician will be made. 
Responsibility for Data and Safety Monitoring. The PI and mentor are ultimately responsible for 
data and safety monitoring. The QA processes above ensure that the PI and mentor will be 
aware of important study-related issues on a weekly basis. The PI will monitor all day-to-day 
study procedures. If an adverse event occurs, the PI will immediately report the event to the 
mentor, or in her absence, co-investigator Miller, mPI of the parent grant. 
We will establish a safety monitoring committee (SMC) comprising at least three people. The 
SMC will meet at the outset of the study in person then semi-annually by telephone or in person. 
The semi-annual SMC meeting will assess whether study objectives are being met and will 
ensure that benefit exceeds harm. The SMC will review the protocol, assessments, and consent 
forms prior to study initiation. The SMC will receive all reports of AEs at the same time that the 
AEs are forwarded to the UNC IRB. Severe AEs will trigger an immediate meeting of the SMC. 
Additional meetings of the SMC can be scheduled, as needed, to discuss and resolve AE 
issues. Members of the SMC will include at least one representative of local health 
departments, one substance use treatment professional, and one representative of the 
substance use research community. The SMC will submit minutes following every meeting to 
the UNC IRB. 
Staff Training. All study staff will be trained on confidentiality protection through the university's 
human subjects training modules prior to beginning their role on the study. The importance of 
protecting participant confidentiality and any confidentiality issues that arise will be discussed in 
staff meetings. Should such a violation occur, the study staff must report the event to the PI and 
mentor immediately after being notified. The study staff will provide the participant with social 
and emotional support. The study team will try to assist the participant in solving any problems 
related to loss of confidentiality. A staff member that breaks participant's confidentiality will be 
put on probation and re-trained on maintaining participant confidentiality.  If the same staff 
member violates a participant's confidentiality a second time, their employment on the study 
staff will be terminated. 
All study staff will be required to complete and maintain valid Human Subjects Research and 
Good Clinical Practice training certificates from CITI or an equivalent training program prior to 
working on any aspects of the study. 
In addition to reporting of any adverse events, yearly DSM review by the SMC will occur and 
reports will be sent to the PI, mentor, and co-investigators. 

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8.10 Study Modification 
Given the brief duration of the intervention, it is not expected that modifications to the protocol 
will be made during the study. Any modifications will be reported to the UNC-Chapel Hill IRB 
and NIDA program officer. Changes will not be implemented until approval is received from both 
parties. 
8.11 Study Discontinuation 
In consultation with NIDA and the UNC IRB, the trial may be stopped if unexpected issues arise 
suggesting that the intervention or research procedures are causing harm to participants. 
8.12 Study Completion 
The study completion date is the date of the last instance of data collection from a trial 
participant, i.e., the date of the last follow-up survey or exit interview, whichever comes last. The 
research team will notify the IRB of study completion within 30 days of this date. 
8.13 Conflict of Interest Management Plan 
UNC-Chapel Hill researchers are required to complete conflict of interest (COI) trainings and 
complete COI disclosures as listed personnel on IRB submissions. 
8.14 Funding Source 
This study is funded by the National Institute on Drug Abuse through a Ruth L. Kirschstein 
National Research Service Award (grant no.1F31DA058452-01, PI: Sibley). 
8.15 Publication Plan 
Per NIH policy ("Final Rule"), trial results must be published to ClinicalTrials.gov no later than 12 
months from the study completion date. The Final Rule requires that results information consist 
of tables of information summarizing: 1) participant flow information, 2) demographics and 
baseline characteristics of the enrolled participants, 3) primary and secondary outcomes, 
including results of any scientifically appropriate statistical tests, and 4) adverse events.  
Adverse event information consists of one table that summarizes all serious adverse events 
experienced by participants enrolled in the clinical trial, and a second table that summarizes 
other adverse events that exceed a frequency of 5 percent in any arm of the clinical trial. The 
Final Rule adds a third table for summarizing all-cause mortality, with the number and frequency 
of deaths due to any cause by arm. 
A summative manuscript detailing trial feasibility, acceptability, and preliminary effectiveness 
outcomes will be written and submitted to the peer-reviewed substance use or mHealth 
literatures. To standardize reporting, the manuscript will adapt the CONSORT 2010 extension to 
pilot and feasibility studies105 following guidelines for adaptation in non-randomized studies 
described by Lancaster & Thabane (2019).106 The intervention will be described using the 
TIDieR checklist and guide.107 The manuscript will be submitted to a peer-reviewed journal 
within 12 months of study completion.  
Findings will also be disseminated to the public during the principal investigator's dissertation 
defense, and a report summarizing primary results may be shared with stakeholders in the 
study community. 

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No participant names or other identifying information will be used in any dissemination materials 
(published or otherwise). 
 
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