Development of a Digital Therapeutic Targeting Anxiety Sensitivity to Reduce Posttraumatic Stress in Women Presenting for Emergency Care After Sexual Assault
Phase: NA
Conditions: Posttraumatic Stress Disorder, Sexual Assault, Pain
Sponsor: University of North Carolina, Chapel Hill

  
DEVELOPMENT OF A DIGITAL 
THERAPEUTIC TARGETING ANXIETY 
SENSITIVITY TO REDUCE PTS-CUD IN 
WOMEN PRESENTING FOR 
EMERGENCY CARE AFTER SEXUAL 
ASSAULT 
PROTOCOL NUMBER: 20-3494 
NATIONAL CLINICAL TRIAL (NCT) IDENTIFIED NUMBER: NCT05305235 
FUNDING SOURCE: MAYDAY FUND 
PRINCIPAL INVESTIGATOR: SAMUEL MCLEAN, MD 
VERSION NUMBER:  V2.8 
SUBMITTED: 27 NOVEMBER 2024 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION: 
VERSION 
DATE 
REVISION SUMMARY 
2.8 
20.24.11.27 
This version removed the blood sample collection, eSense, and trauma 
interviews during ED visit, which were not performed. 
 
We have also revised the aims of the study to assess feasibility, as opposed 
to efficacy, of the intervention. This change is reflected throughout the 
protocol.  

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TABLE OF CONTENTS 
1 
Abbreviations and Definitions of Terms .......................................................................................... 3 
2 
Protocol Summary ................................................................................................................................... 6 
2.1 
Synopsis ................................................................................................................................................ 6 
2.2 
Statement of Compliance ............................................................................................................... 7 
2.3 
Personnel .............................................................................................................................................. 7 
2.4 
Schema .................................................................................................................................................. 8 
2.5 
Schedule of Activities (SoA) .......................................................................................................... 8 
3 
Introduction ............................................................................................................................................... 10 
3.1 
Study Rationale ................................................................................................................................ 10 
3.1.1 
Sexual assault is common and results in high risk for cannabis use disorder 
(CUD).4–6 ........................................................................................................................................... 10 
3.1.2 
Posttraumatic stress (PTS) is common after sexual assault13,14 and heightens 
CUD risk.15,16 ................................................................................................................................... 10 
3.1.3 
Comorbid PTS-CUD is markedly impairing and difficult to treat.36 ............................. 10 
3.1.4 
Given the chronic and intractable nature of PTS-CUD, secondary prevention for 
CUD provided after sexual assault could reduce the public health burden of CUD.
 
10 
3.1.5 
Anxiety sensitivity (AS) is a risk factor for PTS and CUD. ............................................. 10 
3.1.6 
Biobehavioral model of the role of AS in PTS-CUD. ....................................................... 11 
3.1.7 
Measures of EDA would enable testing of this model. ................................................... 12 
3.1.8 
Brief CBT interventions are effective in reducing AS, PTS, and SUD. ..................... 12 
3.1.9 
Ecological momentary assessment (EMA) is an excellent approach to 
understanding PTS-CUD. ........................................................................................................... 12 
3.1.10 
This study employs current technologies towards trauma recovery. ........................ 12 
3.1.11 
This study addresses gaps in trauma recovery literature. ............................................. 13 
4 
Safety Monitoring and Management .............................................................................................. 13 
4.1 
Risk/Benefit Assessment .............................................................................................................. 13 
4.1.1 
Known Potential Risks ................................................................................................................. 13 
4.1.1.1 
Distress ........................................................................................................ 13 
4.1.1.2 
Loss of Privacy/Confidentiality ............................................................ 14 
4.1.1.3 
Side effects/Adverse Events ................................................................ 14 
4.1.1.4 
Bruising from Blood Draw .......... Error! Bookmark not defined. 
4.1.2 
Known Potential Benefits ............................................................................................................ 14 
4.1.2.1 
Benefits to Society ................................................................................... 14 
4.1.2.2 
Benefits to Individual Participants ..................................................... 14 
5 
Specific Aims ........................................................................................................................................... 14 
6 
Study Design ........................................................................................................................................... 16 
6.1 
Overall Design ................................................................................................................................... 16 
6.1.1 
Participants ....................................................................................................................................... 16 
6.1.2 
Procedure Overview ..................................................................................................................... 16 
6.1.3 
Emergency Department (ED) Visit .......................................................................................... 16 
6.1.4 
Study Confirmation ........................................................................................................................ 16 
6.1.5 
Mechanism Assessments ........................................................................................................... 16 
6.1.6 
Self-Report Assessments ........................................................................................................... 17 
6.1.7 
Experimental Conditions ............................................................................................................. 18 
6.1.7.1 
RISE Guide ................................................................................................. 18 
6.1.7.2 
Relaxation Control ................................................................................... 19 
6.2 
Scientific Rationale for Study Design ....................................................................................... 20 

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6.3 
End of Study Definition .................................................................................................................. 20 
6.4 
Study Population .............................................................................................................................. 21 
6.5 
Inclusion Criteria .............................................................................................................................. 21 
6.6 
Exclusion Criteria ............................................................................................................................. 21 
6.7 
Screen Failures ................................................................................................................................. 21 
6.8 
Strategies for Recruitment and Retention .............................................................................. 22 
6.8.1 
Data Coordinating Center ........................................................................................................... 22 
6.8.2 
Recruitment Sites .......................................................................................................................... 22 
6.8.2.1 
Austin SAFE ............................................................................................... 22 
6.8.2.2 
Tulsa Forensic Nursing Services ....................................................... 22 
6.8.3 
Recruitment Estimates ................................................................................................................. 22 
6.8.4 
Retention Plan ................................................................................................................................ 22 
7 
Study Intervention .................................................................................................................................. 25 
7.1 
Study Intervention(s) Administration ........................................................................................ 25 
7.1.1 
Study Intervention Description .................................................................................................. 25 
7.2 
Efforts to Minimize Bias ................................................................................................................. 25 
7.3 
Study Intervention Compliance .................................................................................................. 25 
8 
Intervention Discontinuation and Participant Withdrawal ....................................................... 26 
8.1 
Participant Discontinuation/Withdrawal from the Study .................................................... 26 
8.2 
Adverse Events and Serious Adverse Events ...................................................................... 26 
8.2.1 
Definition of Adverse Events (AE) ........................................................................................... 26 
8.2.2 
Definition of Serious Adverse Events (SAE) ....................................................................... 26 
8.2.3 
Classification of an Adverse Event ......................................................................................... 26 
8.2.3.1 
Severity of Event ...................................................................................... 26 
8.2.3.2 
Relationship to Study Intervention .................................................... 27 
8.2.3.3 
Expectedness ............................................................................................ 27 
8.2.4 
Time Period and Frequency for Event Assessment and Follow-Up .......................... 27 
8.2.5 
Adverse Event Reporting ............................................................................................................ 28 
9 
Statistical considerations .................................................................................................................... 29 
9.1 
Statistical Hypotheses .................................................................................................................... 29 
9.2 
Sample Size Rationale .................................................................................................................. 29 
9.2.1 
Hypothesis 1 (Acceptability) ........................................... Error! Bookmark not defined. 
9.2.2 
Hypothesis 2 (Initial Efficacy) ......................................... Error! Bookmark not defined. 
9.2.3 
Hypothesis 3 (Biobehavioral Mechanisms of PTS-CUD Prevention) ................ Error! 
Bookmark not defined. 
9.3 
Cohorts for Analyses ........................................................... Error! Bookmark not defined. 
9.4 
Statistical Analyses ......................................................................................................................... 29 
9.4.1 
Aim 1 (Usability, Acceptability, and Credibility) .................................................................. 29 
9.4.2 
Aim 2 (Initial Efficacy) ................................................................................................................... 29 
9.4.3 
Aim 3 (Biobehavioral mechanisms of PTS-CUD prevention) ....... Error! Bookmark 
not defined. 
9.4.4 
General Approach .............................................................. Error! Bookmark not defined. 
9.4.5 
Primary Outcome ................................................................ Error! Bookmark not defined. 
9.4.6 
Secondary outcome ........................................................... Error! Bookmark not defined. 
9.4.7 
Baseline Descriptive statistics .................................................................................................. 29 
9.4.8 
Planned Interim Analyses ................................................ Error! Bookmark not defined. 
9.4.9 
Sub-group Analyses .......................................................... Error! Bookmark not defined. 
9.4.10 
Sensitivity Analyses ........................................................... Error! Bookmark not defined. 
9.4.11 
Tabulation of Individual participant Data .............................................................................. 30 

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9.4.12 
Secondary Analyses .......................................................... Error! Bookmark not defined. 
10 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 30 
10.1.1 
Informed Consent Process ........................................................................................................ 30 
10.1.1.1 
Consent and Other Informational Documents Provided to 
participants ................................................................................................. 30 
10.1.1.2 
Consent Procedures and Documentation ...................................... 30 
10.1.2 
Study Discontinuation and Closure ........................................................................................ 31 
10.1.3 
Confidentiality and Privacy ......................................................................................................... 32 
10.1.3.1 
Certificate of Confidentiality ................................................................. 32 
10.1.4 
Future Use of Stored Specimens and Data ............. Error! Bookmark not defined. 
10.1.5 
Quality Assurance and Quality Control ................................................................................. 32 
10.1.6 
Data Handling and Record Keeping ....................................................................................... 33 
10.1.6.1 
Data Collection and Data Management Responsibilities ......... 33 
10.1.7 
Protocol Deviations ....................................................................................................................... 33 
10.1.8 
Conflict of Interest Policy ............................................................................................................ 34 
11 
Protocol Amendment History ............................................................................................................. 35 
12 
References ............................................................................................................................................... 38 
 
1 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse Event 
AR 
Autoregressive 
AS 
Anxiety Sensitivity 
AUDIT 
Alcohol Use Disorder Identification Test 
CBD 
Cannabinol 
CBM 
Cognitive Bias Modification 
CBT 
Cognitive Behavioral Therapy 
CEQ 
Credibility/Expectancy Questionnaire 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIDI-SC 
Composite International Diagnostic Interview Screening Scales 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CUD 
Cannabis Use Disorder 
DAST 
Drug Abuse Screening Test 
DCC 
Data Coordinating Center 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DSMB 
Data Safety Monitoring Board 
EBP 
Evidence-Based Practice 
ED 
Emergency Department 
EDA 
Electrodermal activity 
EMA 
Ecological Momentary Assessment 

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EMI 
Ecological Momentary Intervention 
FIML 
Full Information Maximum Likelihood 
FTND 
Fagerstrom Test of Nicotine Dependence 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HPA 
Hypothalamic-Pituitary-Axis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
MCQ 
Marijuana Cravings Questionnaire 
MMM 
Marijuana Motives Measure 
MPS 
Marijuana Problems Scale 
N 
Number (typically refers to subjects) 
NC TraCS 
North Carolina Translational and Clinical Sciences 
NSI 
New Safety Information 
PANAS 
Positive and Negative Affect Schedule 
PCL-5 
PTSD Checklist 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PTS 
Posttraumatic Stress 
PTSD 
Posttraumatic Stress Disorder 
QC 
Quality Control 
RA 
Research Associate 
RCT 
Randomized Control Trial 
REDCap 
Research Electronic Data Capture (database platform) 
RISE 
RCT for Innovating Stress-related eHealth 
SAE 
Serious Adverse Event 
SANE 
Sexual Assault Nurse Examiner 
SD 
Standard Deviation 
SE 
Standard Error 
SMS 
Short Message Service 
SNS 
Sympathetic Nervous System 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedures 
SSN 
Social Security Number 
SUD 
Substance Use Disorder 
TAAS 
Treatment Acceptability/Adherence Scale 
THC 
Tetrahydrocannabinol 
TUA 
Treatment Utilization and Acceptability 
UNC 
University of North Carolina 

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US 
United States 
WHS 
Women’s Health Study (observational study informing this RCT) 
 
 

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PROTOCOL SUMMARY 
2.1 
SYNOPSIS  
Title: 
Development of a Digital Therapeutic Targeting Anxiety Sensitivity to Reduce PTS-
CUD in Women Presenting for Emergency Care after Sexual Assault 
Study Description: 
The proposed research aims will test the hypotheses that a highly promising digital 
therapeutic targeting anxiety sensitivity (AS) will be acceptable to women sexual assault 
survivors, feasible to deliver, and that an RCT testing it will be feasible to recruit and 
retain participant for. If successful, this intervention (RISE Guide) could be provided at 
no cost to all women who present to US EDs for emergency care after sexual assault. 
 
Objectives and 
Associated 
Outcome 
Measures: 
 
Aim 1. Evaluate usability (TUA), acceptability (TAAS), and credibility (CEQ) of both 
interventions. 
• 
Treatment Acceptability/Adherence Scale (TAAS; 1 week) The TAAS is a 10-
item measure of treatment acceptability (e.g., I would recommend this 
treatment to a friend) and adherence (e.g., I would be able to finish [this 
treatment]) that participants rate on a 7-point Likert scale. 
• 
Credibility/Expectancy Questionnaire (CEQ; 1 week) 6-item measure of 
treatment credibility and expectancy of treatment to improve symptoms. Items 
are rated on 9-to-11-point Likert scales. 
• 
Treatment Utilization and Acceptability (TUA; 7 week) 6 items created for the 
current study on a 5-point Likert scale, such as How often did you log in? How 
interested were you? and 4 open-ended questions; e.g., What did you like 
about RISE Guide?; What did you not like? 
  
 
Aim 2. Assess feasibility of conducting a randomized controlled trial to test the RISE 
Guide intervention. 
• 
Recruitment. Final sample size recruited and number of participants 
recruited per month will be used to evaluate the feasibility of recruiting the 
target sample (goal recruitment=2-4 participants per month). 
• 
Retention. Final proportion of participants who completed all follow-ups (1 
week, 7-week, 6 months) will be used to evaluate feasibility of retaining the 
target sample (goal retention=75% or higher).  
• 
Adverse Events. We will examine whether adverse events occur throughout 
the study. 
• 
 
 
• 
 
Study Population: 
Women (natal and self-identifying) presenting for emergency care within 72 hours of 
sexual assault at one of our study sites (Section 6.8.1) may participate if they are English 
speakers, able to provide informed consent, have a smart phone with continuous 
service (1 year), and elevated AS (>17 on the ASI-3).2,3 
Target Sample 
Size 
In total, 150 eligible women will be enrolled. We anticipate that 37 of these 150 
enrollees (i.e., 25%) will drop out or have incomplete longitudinal data. 
Phase: 
2 
Description of 
Study 
Intervention: 
RISE Guide is a mobile health intervention that is designed to mitigate PTS-CUD among 
survivors of sexual assault by acting upon anxiety sensitivity. 
Study Duration: 
The study will begin in July 2021 and data collection will end in June 2026. 

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Participant 
Duration: 
12 months 
Data Coordinator 
Center (DCC) 
The University of North Carolina at Chapel Hill 
Study Sites 
Austin SAFE (Austin, TX) 
Tulsa Forensic Nurse Examiners (Tulsa, OK) 
Participant recruitment sites outside of UNC will sign reliance agreements with UNC’s 
IRB prior to launching the study locally. 
2.2 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with Good Clinical Practice (GCP) and federal regulations. 
The protocol, informed consent forms, recruitment materials, and all participant materials will be 
submitted to the UNC Institutional Review Board (IRB) for review and approval.  Approval of both the protocol 
and the 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 to the study.  In addition, all changes 
to the consent form will be IRB-approved; the IRB will determine whether previously consented participants will 
need to reconsent via a newly-approved consent form. 
2.3 
COLLABORATIVE STUDY SITES 
Institute for Trauma Recovery 
University of North Carolina at Chapel Hill 
100 Market Street, Suite 2 
Chapel Hill, NC 27516 
Contact Email: Samuel_McLean@med.unc.edu  
University of Nevada at Las Vegas 
4505 South Maryland Parkway, Mail Stop 5030 
Las Vegas, NV 89154 
Contact Email: Nicole.Short@unlv.edu 
2.4 
PERSONNEL 
Principal 
Investigator 
Samuel A. McLean, MD, MPH 
100 Market Street, Suite 2 
Chapel Hill, NC 27516 
(919) 843-5931 
Samuel_McLean@med.unc.edu 
 
Co-Investigator 
Nicole A. Short, PhD 
4505 South Maryland Parkway, Mail Stop 5030 
Las Vegas, NV 89154 
(702) 895-0606 
Nicole.Short@unlv.edu 
Coordinators 
Rachel Weese,  
4505 S Maryland Pkwy 
Las Vegas, NV 89154 
(775) 670-8905 
Rachel.weese@unlv.edu 
 

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Andrea Massa, PhD 
211B W. Cameron Avenue 
Chapel Hill, NC 27514 
(301) 908-7439 
Andrea_Massa@med.unc.edu 
Biostatistician 
Xinming An, PhD 
150 Dental Circle, Room 3617 
Chapel Hill, NC 27516 
(919) 966-5136 
Xinming_An@med.unc.edu 
2.5 
SCHEMA 
 
Figure 1 Study overview (See Figure 4 for detailed intervention timepoints) 
 
 
2.6 
SCHEDULE OF ACTIVITIES (SOA) 
Table 1. Study Activities by Time Point 
 
 
 
 
0 
1-
6 
7-21 
22-48 
49-
77 
110-138 
181-209 
365-393* 
Screening 
✓ 
 
 
 
 
 
 
 
Informed Consent 
✓ 
 
 
 
 
 
 
 
Self-Report 
Assessment 
✓ 
 
✓ 
 
✓ 
 
✓ 
✓ 
EMA 
 
✓ 
 
 
 
Randomization 
 
 
✓ 
 
 
 
 
 
Empatica Wearable 
 
 
✓ 
 
 
 
Intervention 
• 
Experimental: RISE 
Guide 
• 
Control: 
Breathe2Relax 
 
 
✓ 
 
 
 

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Contact information 
update 
✓ 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
* Self-report assessments and contact information updates are only conducted at the 12-month (365-393 day) 
timepoint for participants who consented to this study prior to the timepoint’s removal in version 2.4 of this 
protocol. 
Note. EMA = ecological momentary assessment. 
 

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3 
INTRODUCTION 
3.1 
STUDY RATIONALE  
3.1.1 
SEXUAL ASSAULT IS COMMON AND RESULTS IN HIGH RISK FOR CANNABIS USE 
DISORDER (CUD).4–6  
Approximately 683,000 women are sexually assaulted in the United States each year (more than one woman per 
minute).7 Sexual assault and other traumas are among the most potent risk factors for CUD, a public health 
problem affecting >14 million Americans during their lifetimes and contributing to the $200 billion annual cost of 
substance use disorders (SUDs) in the United States.8,9 CUD is often under-diagnosed and under-
treated,10,11 difficult to treat, and often chronic.12 Over half of those with CUD have survived a sexual assault, and 1 
in 5 sexual assault survivors report a SUD,4 underscoring the critical need for CUD preventions to reduce the 
public health burden of CUD in this population.  
3.1.2 
POSTTRAUMATIC STRESS (PTS) IS COMMON AFTER SEXUAL ASSAULT13,14 AND 
HEIGHTENS CUD RISK.15,16  
Sexual assault results in higher incidence of PTS than any other trauma14 (>50% of 706 women in our emergency 
care-based observational cohort study had clinically significant PTS at 1 year). Sexual assault survivors with PTS 
have 2-to-4 times higher risk of CUD compared to survivors without PTS,17,18 and 26 times the risk of SUD 
compared to women without assault history.7 Sexual assault survivors often use substances – such as cannabis –  
to cope with PTS5,19–22 (the “self-medication hypothesis”).23 Cannabis is often perceived as an anxiolytic,24 though it 
can have anxiogenic effects, depending on tetrahydrocannabinol (THC) and cannabinol (CBD) 
concentrations.25 Sexual assault survivors commonly use cannabis to cope with PTS,26–33 consistent with evidence 
that stress is a core motivator34 and antecedent of cannabis use.2,3,35 
3.1.3 
COMORBID PTS-CUD IS MARKEDLY IMPAIRING AND DIFFICULT TO TREAT.36  
Cannabis is often perceived as harmless37,38 or even helpful for PTS.24 Cannabis may provide subjective short-term 
relief, but, long-term, cannabis use leads to increased PTS39–41 and worse PTS treatment outcomes,42 and higher 
rates of depression,43 violence,40 suicidal behavior,44 and SUD.45Those with PTS-CUD have worse treatment 
outcomes than those with either PTS or CUD alone. Even after completing state-of-the-art treatments,46–48 half 
have residual clinically significant symptoms.17,48 The severity and chronicity of PTS-CUD underscores the 
importance of developing preventive interventions that could prevent or dampen the pathogenic processes leading 
to PTS-CUD development.   
3.1.4 
GIVEN THE CHRONIC AND INTRACTABLE NATURE OF PTS-CUD, SECONDARY 
PREVENTION FOR CUD PROVIDED AFTER SEXUAL ASSAULT COULD REDUCE THE 
PUBLIC HEALTH BURDEN OF CUD.  
One theory-driven and efficacious prevention approach is to identify mechanistic and transdiagnostic risk 
factors that can be targeted with cognitive behavioral therapy (CBT).49 Delivering such CBT interventions via 
smartphone has tremendous potential due to its scalability: a smartphone-based intervention could be offered at 
the time of ED care to the ~100,000 women presenting to US EDs6 after sexual assault annually. These women 
typically receive preventive interventions for pregnancy and sexually transmitted infections,50 but not for PTS or 
SUD, which are even more common sequelae.4,13 
3.1.5 
ANXIETY SENSITIVITY (AS) IS A RISK FACTOR FOR PTS AND CUD.  

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AS, or fear of anxious arousal, is a cognitive-affective risk factor that is trait-like but malleable via 
intervention.51,52 AS comprises three domains of fears about the consequences of anxious arousal: cognitive (e.g., 
uncontrollable thoughts indicate one is going “crazy”), physical (e.g., racing heart indicates a heart attack), 
and social (e.g., blushing will lead to negative evaluation from others).52 AS is a transdiagnostic risk factor, with 
cross-sectional,53 longitudinal,54 and prospective55–58 associations with PTS, including among sexual assault 
survivors.59 Our pilot data of 52 women presenting to the ED after sexual assault indicate that elevated 
AS prospectively predicts increased PTS, anxiety, and depression.60 AS is also associated with increased substance 
use,61–65 cravings,61,66–69 and SUD.70–72 These data are consistent with the self-medication hypothesis and with 
evidence that AS promotes substance use to cope with anxious arousal,73–76 including among women sexual 
assault survivors with PTS.68,77,78 AS is specifically associated with cannabis use,31,79 including increased 
use,80,81 maladaptive motives,82–84 barriers to cessation,64,85,86 and withdrawal,87 and may play a key role in mediating 
relations between PTS and SUD.88   
3.1.6 
BIOBEHAVIORAL MODEL OF THE ROLE OF AS IN PTS-CUD. 
 
Figure 2 Simplified heuristic model of role of AS in PTS-CUD. 
 As depicted in Figure 2, individuals with high AS are at risk for PTS after trauma.55,56,89,90 In addition to distress in 
response to trauma cues, individuals with PTS experience heightened/dysregulated stress reactivity, including 
increased sympathetic nervous system (SNS) activation91,92 measured via electrodermal activity (EDA).91,93 This 
heightened threat response continues at the neurobiological level, with dysregulated hypothalamic-pituitary-
axis (HPA) activity assessed via increased adrenocorticotropic hormone (ACTH)94 and 
cortisol secretion,95 continuing SNS activation. Interestingly, increased peritraumatic EDA response to trauma cues 
may also be a predictive biomarker of PTS development.96 Distress97 and SNS activation in response to trauma 
cues results in physiologic changes, such as increased heart rate, blood pressure and perspiration,1 which are 
aversive to those with high AS. AS is a common phenotype among individuals with PTS98 in which interoceptive 
sensations are interpreted as threatening (e.g., signs one is having a heart attack or “going crazy”), and to be 
avoided. These fears may motivate increased avoidance behaviors, such as using cannabis to cope with distress or 
dampen arousal.75 As noted above, consistent with this hypothesis, stress is often an antecedent and motivator of 
cannabis use,2,35 particularly among those with PTS.99,100 In turn, cannabis use is negatively reinforcing, providing 
rapid relief from distress,34 and likely leading to a cycle in which individuals continue cannabis use to cope, 
exacerbating PTS,41 further sensitizing stress responding,101 and increasing reliance on cannabis use to cope, 
increasing risk for PTS-CUD.102 In the long term, those with high AS report increased withdrawal symptoms during 

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cannabis cessation attempts,87 potentially motivating relapse and interfering with treatment.103,104 This model is 
particularly applicable to women, who are more likely to have affective comorbidities with CUD and use cannabis 
to cope with distress.105 Behaviorally, this model also likely applies to other substances that actually do or are 
expected to dampen arousal.65 
3.1.7 
MEASURES OF EDA WOULD ENABLE TESTING OF THIS MODEL. 
As noted above, EDA is a useful measure of SNS reactivity to trauma cues (e.g., trauma interviews91) and may be a 
biomarker of PTS development96 and treatment response.106 Consistent with the theoretical role of stress in 
cannabis use, a meta-analysis of craving paradigms found that increased EDA is linked with cravings in response to 
cannabis cues.107 In contrast with other psychophysiological assessments, EDA can be assessed portably, 
inexpensively, and feasibly in clinical settings, including EDs91. Importantly, as described below, unlike other 
biomarkers, EDA can also be assessed in the natural environment to assess physiological antecedents of substance 
use. 
3.1.8 
BRIEF CBT INTERVENTIONS ARE EFFECTIVE IN REDUCING AS, PTS, AND SUD.  
AS is malleable with brief, computerized CBT interventions.108,109 Existing evidence suggests AS interventions 
reduce chronic PTS and related symptoms (e.g., anxiety, depression) by up to 35%,110,111 including among sexual 
assault survivors. These interventions provide psychoeducation regarding the adaptive nature of stress, challenge 
distorted cognitions related to AS, and encourage interoceptive exposures to decrease AS. In >5 RCTs, these 
strategies targeting AS reduced PTS, anxiety, and depression.108,109,112–114 In addition, prior research indicates that 
such interventions are acceptable to recipients.115 Brief AS interventions also reduce opioid use,116 drinking,117–
119 and heroin cravings,120 improve smoking cessation outcomes120,121 and abstinence rates in SUD patients,122 and 
may prevent cannabis use.123,124 Despite these exciting data, no preventive studies targeting AS have been 
conducted in adults. The early aftermath of trauma may be an ideal time to initiate such interventions, as the early 
posttraumatic period is characterized by a high burden of PTS and is a key period of CUD development.125 
3.1.9 
ECOLOGICAL MOMENTARY ASSESSMENT (EMA) IS AN EXCELLENT APPROACH TO 
UNDERSTANDING PTS-CUD. 
EMA, the repeated sampling of current experiences in real time, in the natural environment,126 provides valid 
assessment of cannabis use not captured by retrospective questionnaires,127 as well as of dynamic factors that 
change over short periods of time such as PTS. EMAs can be performed in the context of traditional longitudinal 
assessments, allowing for measurement of both dynamic short-term and longer-term processes. Even more 
exciting, ecological momentary intervention (EMI) leverages data from EMA (e.g., symptom severity or profile) to 
provide personalized interventions in the moment (often via SMS). EMI boosts efficacy of CBT 
interventions,128 which may be critical for learning during the stressful acute post-trauma period. EMI is also useful 
for CUD interventions to target in-the-moment stress or cravings, reducing drinking,129 smoking,130 and cannabis 
use.131 
3.1.10 THIS STUDY EMPLOYS CURRENT TECHNOLOGIES TOWARDS TRAUMA RECOVERY. 
Previous work to prevent PTS-CUD after sexual assault has been promising, but limited by then-current 
technology (ED video), limited dissemination, and lack of mechanistic investigations of efficacy.132–134 This study will 
use techniques to maximize efficacy (Cognitive bias modification [CBM-I], EMI), investigate biobehavioral 
mechanisms of prevention, and our research network allows for a promising dissemination avenue.  
 

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3.1.11 THIS STUDY ADDRESSES GAPS IN TRAUMA RECOVERY LITERATURE. 
Biobehavioral mechanisms underlying targeting AS to prevent PTS-CUD have been neglected in prior research. 
Targeting AS likely reduces substance use and cravings in response to stress assessed via physiological indicators, 
but this has not been tested in the extant literature. This mechanistic work is critical to understanding how AS 
contributes to PTS-CUD and refine prevention strategies.135,136 EMAs complemented by wearables assessing 
EDA could reveal temporal associations and treatment mechanisms of targeting AS to reduce cannabis cravings/use 
in response to physiological reactivity to trauma cues. 
4 
SAFETY MONITORING AND MANAGEMENT 
4.1 
RISK/BENEFIT ASSESSMENT   
4.1.1 
KNOWN POTENTIAL RISKS  
4.1.1.1 
DISTRESS 
Participants may experience distress after revealing personal information during study activities, 
particularly when asked about mental health symptoms including PTS. Notably, among participants in the Women’s 
Health Study, 83-85% denied that participating in the study upset them more than expected. Regardless of levels of 
distress, the vast majority of participants felt that their contributions to the study were worth it (93-95%) despite 
any inconvenience they may have experienced. The researchers will remain vigilant in preventing and responding to 
participant distress by training site RAs to attend to and manage participant distress as needed and continually 
evaluating participants’ self-reported research experience, but do not expect substantial stress reactions to be 
common among participants. All research associates will have extensive prior experience working with sexual 
assault survivors and will receive training on human subjects protection prior to beginning work on the study. The 
research associate on call for the study will approach the potential participant independently at a time deemed 
appropriate by the care team. To decrease the risk of the participant continuing with an assessment despite the 
assessment being too emotionally difficult for them, participants are told that they may stop the study at any time, 
and that they will be paid the full amount for the assessment regardless of how many questions they answer or 
whether they decide to stop the assessment entirely. This practice was enacted during the Women’s Health Study 
(WHS), in which 85-94% of participants reported feeling that they could stop their assessments at any time and 74-
85% felt free to skip parts of the study. Research associates will be trained to alert Dr. Short (PI), a clinical 
psychologist, if they suspect that a participant is in distress. Dr. Short will assess the situation and take any 
necessary steps to ensure the participant’s safety, including supervising site RAs, calling the participants to debrief 
and manage acute distress, and suggesting referrals. Attending to participants’ distress in the moment during ED 
visits will also be possible in-person as all sites are emergency care facilities with trained providers, including site 
RAs, who can manage acute distress or make referrals to more intensive services as needed. All participant 
ecological momentary assessments and follow-up surveys are available via self-report questionnaire. The follow-up 
assessments never include details of or questions regarding the assault experience itself, decreasing risk of 
increased distress. This design increases privacy and anonymity and encourages candid participant feedback 
regarding study participation. The Lead Research Coordinator will pull and review data from self-report 
questionnaires (e.g., research experiences, qualitative data) every two weeks to determine whether any particular 
participant appears to be at high risk, in which case these participants will be called by the PI to assess distress 
levels and facilitate referrals, if appropriate. In our experience from WHS, however, this is rare, occurring in less 
than 1% of participants. Telephone interviews will only be performed if the survivors are unable to use the above 
method and wish to complete the follow-up assessment via telephone. We believe that this methodology balances 
our goals of providing as much anonymity as possible while adjusting for participants experiencing limitations in 
internet connectivity. 

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4.1.1.2 
LOSS OF PRIVACY/CONFIDENTIALITY 
Maintenance of privacy and confidentiality is of paramount importance for any study, and all possible 
strategies will be used to minimize any risk for breach of confidentiality, including intensive training of research staff 
in good clinical research practices, HIPAA, and the strategies listed in detail below.   
4.1.1.3 
SIDE EFFECTS/ADVERSE EVENTS 
Side effects and adverse events are expected to be rare in the delivery of these previously used and 
efficacious cognitive behavioral strategies to reduce PTS-CUD. However, they will be monitored and responded to 
appropriately as discussed in Section 8.2.  
4.1.2 
KNOWN POTENTIAL BENEFITS  
4.1.2.1 
BENEFITS TO SOCIETY 
This study will inform initial acceptability and efficacy of a brief, smartphone-based, cognitive behavioral 
intervention for women sexual assault survivors. Currently there is no standard preventative intervention for 
sexual assault survivors to mitigate the development of PTS and related symptoms such as CUD. This study will 
help us to understand whether it is feasible for women to receive a link to a smartphone-based intervention on 
their phone (representing an easily scalable intervention), whether and to what extent women engage with the 
intervention, as well as women's perceptions of acceptability of the intervention, and will provide an initial estimate 
of efficacy of the intervention in reducing AS, and, in turn, PTS and CUD. Developing early interventions to 
prevent chronic PTS-CUD among high-risk sexual assault survivors identified at the time of emergency care is 
important, because most survivors do not seek or receive further care after initial emergency department 
evaluation, and because once chronic PTS develops, it is difficult to treat and extremely costly. Of note, as we gain 
more knowledge with this population, we believe that we will also be able to include more of the women at high 
risk of PTS-CUD (e.g., adolescents, those living with assailants) beyond those eligible for the current study. 
4.1.2.2 
BENEFITS TO INDIVIDUAL PARTICIPANTS 
Participants may benefit from increased insight by providing self-report information via clinical outcome 
assessments, as well as during EMA and wrist wearables when they trigger stress measurements. Although not 
guaranteed, a potential direct benefit anticipated for participants receiving the active RISE Guide intervention is a 
decrease in AS, and, in turn, potentially PTS, SUD, depression, and anxiety. While this is not guaranteed, it is 
hypothesized to occur given the intervention is based on evidence-based cognitive behavioral principles and an 
intervention previously found to be efficacious. Further, we selected a relaxation control condition leveraging 
diaphragm breathing, as this practice can result in improvement in clinical symptoms such as PTS, though typically 
not a strongly as evidence-based practices (EBPs) such as CBT. However, regardless of condition, there is 
theoretical and empirical rationale to believe receiving one of these interventions would lead to better outcomes 
than receiving no preventive intervention at all. 
 
 
 
5 
SPECIFIC AIMS 

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• 
Hypothesis 1. Treatment acceptability (CEQ, TAAS) for RISE Guide is greater than or equal to treatment 
acceptability for a relaxation control, and similar to previously identified norms for the Credibility/Expectancy 
Questionnaire and the Treatment Adherence/Acceptability Scale. 
o 
Aim 1. Evaluate usability, acceptability (TAAS), and credibility (CEQ) of both interventions.  
• 
Aim 2. Assess feasibility of conducting a randomized controlled trial to test the RISE Guide intervention. 
o 
Recruitment. Final sample size recruited and number of participants recruited per month will be 
used to evaluate the feasibility of recruiting the target sample (goal recruitment=2-4 participants per 
month). 
o 
Retention. Final proportion of participants who completed all follow-ups (1 week, 7-week, 6 
months) will be used to evaluate feasibility of retaining the target sample (goal retention=75% or 
higher).  
o 
Adverse Events. We will examine whether adverse events occur throughout the study. 
 
 
 
 

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6 
STUDY DESIGN 
6.1 
OVERALL DESIGN 
6.1.1 
PARTICIPANTS 
Women (natal and self-identifying) presenting for emergency care within 72 hours of sexual assault to one 
of our sites (Section 6.8.1) and who meet eligibility criteria (Sections 6.5 and 6.6). As we are interested in incident 
substance use post-assault, women will not be required to be cannabis or other substance users at the time of 
assault. However, our pilot data suggest >50% of sexual assault survivors with high AS use cannabis, thus we 
expect our final sample will include high rates of CUD without this inclusion criterion. 
6.1.2 
PROCEDURE OVERVIEW 
Women presenting for emergency care within 72 hours of sexual assault will be enrolled. As in Dr. 
McLean’s recent large-scale observational study (UNC IRB 13-3193), women will be approached during their initial 
ED visit. In the 7 weeks after assault, women will complete EMAs to assess PTS, cannabis cravings and use, and 
wear a wrist wearable to assess EDA. Consistent with Dr. McLean’s observational study, women will complete 
self-report remote follow-up evaluations 1 week, 7 weeks and, 6 months after assault via online surveys 
(REDCap).137 
6.1.3 
EMERGENCY DEPARTMENT (ED) VISIT 
Providers will page the site research associate (RA), who will approach potentially eligible patients and 
describe the study. Alternatively, the providing Sexual Assault Nurse Examiner may be the site research associate. 
Interested and eligible participants will provide written informed consent and complete the assessments described 
below. Assault characteristics and past and prescribed medications will be abstracted from the medical record. 
EMAs will begin the day after the ED visit. 
6.1.4 
STUDY CONFIRMATION 
Women who complete their one-week follow-up survey will be randomized and sent a wrist wearable. 
The research coordinator will use REDCap, a secure survey platform, to randomize confirmed 
participants to the active or control condition. EMAs (for all participants), EMIs (for active participants) and RISE 
Guide (for active participants) will be delivered via Qualtrics, a smartphone-accessible, secure survey website that 
saves users’ progress and automatically sends SMS reminders on a predetermined schedule based on progress The 
research coordinator will email the participant instructions for bookmarking her personalized Qualtrics link to her 
phone, allowing it to appear as an icon (similar to an app) so the participant can click the link and return to it as 
desired. Qualtrics will automatically send EMAs/EMIs via SMS and provide access and SMS reminders to complete 
their assigned interventions. 
6.1.5 
MECHANISM ASSESSMENTS 
EMAs during the first 7 weeks after assault will assess PTS and cannabis cravings/use. EMAs 
will be distributed to participants via SMS a total of 4 times per day. Participants will be asked to complete > 2 
EMAs/day, as we have found providing additional opportunities to complete EMAs increases compliance rates. 
Three of the four EMAs will be signal contingent (i.e., occurring at random intervals throughout the day). The 
4th will be interval contingent, occurring at the end of the day and assessing 1) total cannabis use quantity for that 
day and 2) whether the participant engaged in any strenuous physical activity, and when the activity occurred (to 

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exclude these time periods from physiological data analysis). EMAs are delivered weeks 0-7 for the control, and 
weeks 0-1 for the active condition, who receive EMAs with EMIs weeks 1-7 
Figure 3 Empatica E4 wristband 
 
Participants who complete the 1-week survey will be randomized and receive a wrist wearable (Empatica 
E4, worn 6 weeks post-assault; Figure 3) via mail. This wearable continuously assesses physiologic measures (i.e., 
EDA), and allows users to press a button to mark occurrences. Participants will be asked to mark occurrences 
when they experience internal or external trauma reminders (e.g., intrusive memories or external cues). 
Participants will receive a brief introduction to the wrist wearable in the ED and further instructions at 1 week. 
Consistent with prior research,143 data will be analyzed in 40-min blocks (20 min pre- and post-event triggers) and 
compared to random 40-min blocks in which triggers did not occur. 
EDA will be assessed at 4 Hz from 2 wrist wearable sensors. Data (in MicroSiemens) will be analyzed 
using Ledalab,144 a validated software package. Processed and cleaned data will be output for every 500 ms in the 
40-min block. To quantify anxious reactivity, peak EDA will be identified from these data and subtracted from 
average EDA in the corresponding “baseline” interval. Wearable and EMA data will provide a naturalistic assessment of 
PTS and cannabis cravings/use, and whether the intervention impacts these variables. The E4 has been rated as 
acceptable and positive by substance users, from whom EDA data from the E4 has been successfully used to detect 
stress and cravings in the natural environment.143 
Self-report. The ASI-352 will be completed at ED visit, 1 and 7 weeks, and 6 months to measure AS. We 
expect that individuals will go from above the clinical cut-off of the ASI (17) to below. There is no specific 
expected magnitude in AS change, as this will depend on individuals’ initial levels of AS. It is expected that those in 
the control group may also have reductions in ASI, but to a lesser degree than those in the active group. The 
Marijuana Problems Scale (MPS) measures problems related to cannabis use (CUD symptoms). The Marijuana 
Motives Measure (MMM) includes a coping subscale to be used as an outcome measure. This measures using 
cannabis to cope with distress, which is a risk factor for CUD. The CIDI-SC measures the quantity/frequency of 
cannabis use regardless of whether or not this use is problematic, and is also a secondary outcome measure. 
Finally, the Marijuana Cravings Questionnaire (MCQ) measures state cravings to use cannabis. The total and 
emotionality subdomains (measuring cravings to use cannabis to cope with emotions) will be used as secondary 
outcomes. 
6.1.6 
SELF-REPORT ASSESSMENTS 
Clinical assessments (Table 2) will occur remotely via REDCap, a reliable and valid method of 
data collection.137 Treatment acceptability will be measured at 1 week via the Credibility/Expectance Questionnaire 
(CEQ),145 Treatment Acceptability/ Adherence Scale (TAAS),146 and 7 weeks with a study-
specific measure with open-ended questions. PTS, CUD and secondary outcomes will be assessed at 6 
months, allowing for temporal mediation tests.  Demographic information will be collected on the one-week 
survey.  Current medication use will be collected at one and seven weeks, and six months. 

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Table 2. Select Measures by Domain and Time Point 
Domain  
Measure  
ED  
EMA  
1-wk  
7-wk  
6-
mo  
12-
mo* 
Anxiety  
Patient-Reported Outcomes 
Measurement Information System 
(PROMIS) - Short Form 8a147 
 
 
X 
X 
X 
 
Pre-SA Anxiety 
Patient-Reported Outcomes 
Measurement Information System 
(PROMIS) - Short Form 8a147, 
Retrospective 
 
 
X 
 
 
 
Anxiety 
sensitivity  
Anxiety Sensitivity Index-3 (ASI-3)52 
X 
 
X 
X 
X 
 
Depression  
PROMIS - Short Form 8b147 
  
 
X 
X 
X 
 
Pre-SA 
Depression 
PROMIS - Short Form 8b147, 
Retrospective 
 
 
X 
 
 
 
Posttraumatic 
Stress  
PTSD Checklist (PCL-5)148, adapted for 
assault as index trauma and Ecological 
Momentary Assessment (EMA) when 
relevant 
X 
X 
X 
X 
X 
 
Stress Reactivity  
Empatica E4 (6 weeks post-
assault),  Positive and Negative Affect 
Schedule (PANAS)138  
X 
X 
 
 
 
 
Substance Use  
Composite International Diagnostic 
Interview Screening Scales (CIDI-
SC), daily use and quantity149 
 X 
X 
X 
X 
X 
 
Problematic 
Cannabis & 
Substance Use  
Cannabis: Marijuana Problems Scale 
(MPS),150 Marijuana Motives 
Measure (MMM),151 Marijuana Craving 
Questionnaire (MCQ)139; 
Other: Alcohol Use Disorder 
Identification Test (AUDIT)152, Drug 
Abuse Screening Test 
(DAST),153 Fagerstrom Test for Nicotine 
Dependence (FTND)154  
  
X 
X 
X 
X 
 
Treatment 
Credibility 
/ Acceptability  
Credibility/Expectancy 
Questionnaire (CEQ),145 Treatment 
Acceptability/Adherence Scale 
(TAAS),146 study specific measure of 
usability  
  
 
X 
X 
  
 
* Self-report assessments and contact information updates are only conducted at the 12-month (365-393 day) 
timepoint for participants who consented to this study prior to the timepoint’s removal in version 2.4 of this 
protocol. 
6.1.7 
3.5 MONTH CONTACT UPDATE 
At 3.5 months (~14 weeks), participants will be sent a request to either confirm or update their contact 
information via REDCap. Participants will be allowed from 12-16 weeks to complete this update. Those who do 
will be compensated $10 for their time. 
6.1.8 
EXPERIMENTAL CONDITIONS   
6.1.8.1 
RISE GUIDE 

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Figure 4 Overview of RISE Guide. 
The RISE (RCT for Innovating Stress-related eHealth) Guide is based on CAST, an AS intervention 
effective in reducing AS, PTS, depression, and anxiety 108–111 but tailored for recent assault survivors with PTS and 
for delivery by smartphone via Qualtrics. Psychoeducation and CBT principles are delivered in an interactive, 
audio-visual format discussing the stress response, “myth busting” cognitive distortions related to stress, 
and exposure to feared sensations (Figure 4). For example, common reactions after trauma (e.g., intrusive 
memories) and how these can be catastrophically misinterpreted (e.g., I am going crazy or losing control) are 
discussed while providing corrective information (i.e., intrusive memories are normal, and, while distressing, not 
dangerous) and coping strategies (e.g., recognize thoughts and let them pass rather than attempting to suppress 
them), including those related to substance use (e.g., anxiety may seem like it will never go away without substance 
use, but substance use actually maintains anxiety in the long run). Participants will then complete a 
validated cognitive bias modification for interpretation biases related to AS (CBM-I), as 
combining these approaches enhances AS treatment efficacy.114 Finally, intervention principles will be reinforced 
using EMI, in which surveys and personalized reminders are delivered (e.g., if a participant reports high re-
experiencing, she will be reminded this is normal and linked to review relevant material). Further, if substance 
cravings or use are reported, EMIs will deliver coping tools (e.g., reminder anxiety is temporary and substance use 
exacerbates it in the long run) to boost efficacy.155 RISE Guide is completed in approximately 45 
minutes over 2 weeks, with EMI in the initial 6 weeks post-assault. 
6.1.8.2 
RELAXATION CONTROL 
Breathe2Relax156 is a mobile application that instructs users on diaphragmatic breathing, a coping tool in 
which slow breathing through the diaphragm reduces anxiety.157,158 Participants in the control condition will 
download Breathe2Relax to their smartphones and receive SMS reminders to engage with the app. The control 
intervention is expected to reduce symptoms, but not as much as the CBT strategies taught in RISE Guide.159,160 

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6.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Overall, consistent with the ORBIT model of behavioral randomized controlled trials, the current study is 
considered to be Phase IIb. We have conducted an initial proof-of-concept, and now are at the stage of testing the 
feasibility of an RCT (termed a “pilot” RCT). The goal of the pilot RCT is to assess the feasibility of a further, 
larger efficacy trial (Phase III). Therefore, the design and outcomes are selected to be in line with a future, larger 
efficacy trial, but the current study will not test these outcomes. Instead, we will test whether the proposed RCT 
is feasible.  
 
The following design questions refer to the ultimate larger RCT for which this is a pilot trial: 
First, we selected a relatively narrow and homogeneous sample to maximize treatment effects. We will 
recruit those with high AS to ensure AS reduction is possible (in our pilot, nearly ¾ of women with high AS had 
clinically significant PTS in the 6 weeks post-assault), and exclude men as women are the vast majority (>90%) of 
survivors presenting to EDs.6,161 
Second, women presenting to the ED after sexual assault often have a history of assault and PTS-SUD. 
Thus, prevention may serve as intervention for some. However, new traumas often cause symptom 
exacerbation,125 preventive interventions may be even more effective among those with assault history,162 and AS 
interventions are effective for chronic symptoms.108,110,112 
Third, we selected an AS intervention vs. others (e.g., Resnick’s video,163 1-session Prolonged 
Exposure,7 Brief Behavioral Treatment for Insomnia164) because one transdiagnostic target (AS) can parsimoniously 
reduce symptoms of multiple disorders, level of engagement in out-of-session work does not impact AS treatment 
efficacy,165 and digital therapeutics targeting AS are efficacious, scalable, and feasible for ED dissemination. 
Fourth, we elected to initiate intervention 1 week after assault to allow between-group comparison of 
initial symptoms. 
Fifth, we chose an active control because 1) AS interventions are effective vs. active controls,108–110 2) 
other secondary CBT preventions are effective compared to RCs after sexual assault,166 and 3) ethically, this 
vulnerable group has a right to an intervention that provides some benefit.  
6.3 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if she has completed all phases of the study 
including the last survey shown in Section 2.6 Schedule of Activities (SoA). 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 

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6.4 
STUDY POPULATION 
This study recruits female sexual assault survivors only, a historically understudied and underserved 
population. Female sexual assault survivors who present to a participating SANE program site for a forensic exam 
kit within 72 hours of the assault will be approached regarding participating in the study. Women from all races 
and ethnicities will be eligible for enrollment. 
6.5 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Provision of signed and dated informed consent form 
• 
Stated willingness to comply with all study procedures and availability for the duration of the study 
• 
Women sexual assault survivors presenting for emergency care <72 hours post-assault at one of 
our study sites  
• 
Able to speak, read, and write English 
• 
18+ years of age 
• 
Able to provide informed consent 
• 
Have a smartphone with continuous service >1 year 
• 
Reports elevated AS (>17 on the ASI-3) 
6.6 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
• 
Inability to provide informed consent (e.g., serious injury preventing the ability to hear, speak, or see to 
consent and participate, or other causes [e.g., diagnosed cognitive deficits, diagnosed dementia, asleep at 
time of screening]) 
• 
Prisoner 
• 
Currently pregnant 
• 
Lives with assailant and plans to continue to do so 
• 
Admitted patient 
• 
No mailing address 
• 
Previously enrolled in this study 
• 
No SANE examination  
6.7 
SCREEN FAILURES 
Screen failures are defined as participants who do not meet eligibility criteria. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because their phone 
is not with them in-clinic may be rescreened within 1 week of assault. Rescreened participants will be assigned the 
same participant number as for the initial screening. EMA data scheduled to occur between initial and secondary 
screening will be considered missing and follow-up surveys will remain scheduled based on the initial screening 
date (e.g., a participant’s 7-week survey would take place 7 weeks after their initial screening).  

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6.8 
STRATEGIES FOR RECRUITMENT AND RETENTION 
6.8.1 
DATA COORDINATING CENTER 
The UNC Institute for Trauma Recovery will serve as the data coordinating center. UNC will send weekly 
email updates, and hold weekly site calls, annual in-person (or virtual if needed) conferences in Chapel Hill, NC, and 
quarterly teleconferences. These methods were used successfully in R01AR064700  
6.8.2 
RECRUITMENT SITES 
Recruitment will be conducted at the two below Better Tomorrow Network sites. Additional sites may 
be added throughout the study; these sites will cede to UNC’s Institutional Review Board (IRB), complete 
collaboration agreements with the UNC Institute for Trauma Recovery, receive a group-level training 
demonstrating proper enrollment procedures, complete one-on-one mock participant trainings (in which site 
research assistants “enroll” a member of the UNC research team in a non-production copy of the REDCap 
database), and receive a shipment of site start-up materials (a binder containing a current copy of the site standard 
operating procedures, a password-protected laptop or iPad and charger, and earbuds to distribute to participants). 
Site PIs will receive additional training entering patient screening results and managing site RA teams (further 
discussed in Section 10.1.6). 
We do not expect these sites to launch simultaneously, as the steps required to launch a site (as 
explained in the previous paragraph) will vary in duration across sites. 
6.8.2.1 
AUSTIN SAFE 
Site PI: Jenny Black 
 
jblack@safeaustin.org 
 
(512) 356-1530 
Site Address: 1515 Grove Boulevard 
 
 
Austin, TX 78741 
Projected enrollment (based on WHS recruitment): 70 women 
6.8.2.2 
TULSA FORENSIC NURSING SERVICES 
Site PI: Kathy Bell, RN, MS 
 
kbell@cityoftulsa.org 
 
(918) 596-7608 
Projected enrollment (based on WHS recruitment): 80 women 
6.8.3 
RECRUITMENT ESTIMATES 
All sites are emergency care providers for women sexual assault survivors and provide SANE services. In 
Dr. McLean’s prior sexual assault study, approximately 14 women per month were successfully recruited 
(10/month including only the sites at which we plan to launch this study), and 98% of these participants said they 
would be willing to participate in interventional studies.  
6.8.4 
RETENTION PLAN 

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For the prior sexual assault study, follow-up rates were >80% at all study time points (i.e., six-week, six-
month, one-year) over one year post-assault (Figure 5). 
Figure 5 Final follow-up rates for the Women's Health Study 
 
To achieve these successful follow-up rates, a number of strategies have been tested and will be utilized in 
the current study, including: collecting several different methods of contact (e.g., phone, email, address, emergency 
contact), ensuring participant contact early in the follow-up window, continuous tracking of retention rates and 
adding countermeasures if rates drop below 80%, using SMS to contact participants for follow-ups, and allowing 
participants to complete follow-ups remotely via an online, encrypted database or via phone if preferred. We have 
also devised a plan for possible retention challenges and countermeasures to be deployed for this study (Table 3). 
Table 3. Potential Retention Challenges and Strategies 
Potential Challenge 
Strategies to Address 
Reduced follow-up rate 
• 
Obtain multiple methods to contact. 
• 
Track follow-up rates for each follow-up method (i.e., treatment 
completion, standard questionnaire follow-ups, ecological momentary 
assessment, wearable wear) and implement countermeasures if rate is 
<80%. 
• 
Dedicate increased resources to achieving follow-up as patient nears 
end of window. 
• 
Confirm patient contact information at regular intervals. 
• 
Offer telephone follow-up. 
• 
Consider increasing compensation or adding bonuses for participation. 
Reduced treatment 
adherence 
• 
Ensure that participants’ feedback about the treatment during Phase I is 
implemented as needed. 
• 
Track adherence rates and execute follow-up countermeasures if rate 
is <80%. Contact participants via various modes of contact. 
• 
Offer opportunity to complete intervention all at once via their laptop 
or at a study site. 
Participants will also receive compensation for their time spent on and expertise provided to the current study as 
described in  
Table 4. These compensation rates are consistent with other studies of recent trauma survivors. 
Table 4. Participant Compensation by Activity 

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Initial 
One-
Week 
Time 
Intervention 
Completion 
Ecological 
Momentary 
Assessmen
t (EMA) 
Wristband 
Wear 
Seven-
Week 
3.5 
Month 
Contact 
Check 
Six-
Month 
Compensatio
n 
$40 
*Participant 
ineligible 
after 
screener 
earn $20 
$50 
Active: 
$15/module 
(3 modules, 
$50 for 
entire 
intervention 
completion) 
Control: 
$50 for 
intervention 
completion 
(no modules) 
$1/EMA 
$15 for 
meeting 
$1/day of 
wear 
$5/data upload 
$5 upon 
return 
($132 
maximum) 
$50 
 
 
 
 
$10 
$50 
 
Potential participants who are deemed ineligible after going through the initial screening process will be 
compensated with a one-time payment of $20.  
After 6 weeks of the wristband portion, if the participant does not return wristband after 3 attempts of contact, 
coordinator will reach out and notify participant that they will receive a bonus of $20 after they have mailed the 
wristband back. 
 
 
 

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7 
STUDY INTERVENTION 
7.1 
STUDY INTERVENTION(S) ADMINISTRATION 
7.1.1 
STUDY INTERVENTION DESCRIPTION 
Active Intervention. The RISE (RCT for Innovating Stress-related eHealth) Guide is based on CAST, 
an AS intervention effective in reducing AS, PTS, depression, and anxiety,108–111 but tailored for recent sexual 
assault survivors with PTS and for delivery by smartphone via Qualtrics. Psychoeducation and CBT principles 
are delivered in an interactive, audio-visual format discussing the stress response, “myth busting” cognitive 
distortions related to stress, and exposure to feared sensations (Figure 4). For example, common reactions after 
trauma (e.g., intrusive memories) and how these can be catastrophically misinterpreted (e.g., I am going crazy or 
losing control) are discussed while providing corrective information (i.e., intrusive memories are normal, and, 
while distressing, not dangerous) and coping strategies (e.g., recognize thoughts and let them pass rather than 
attempting to suppress them), including those related to substance use (e.g., anxiety may seem like it will never go 
away without substance use, but substance use actually maintains anxiety in the long run). Participants will then 
complete a validated cognitive bias modification for interpretation biases related to AS (CBM-I), as 
combining these approaches enhances AS treatment efficacy.114 Finally, intervention principles will be reinforced 
using EMI, in which surveys and personalized reminders are delivered (e.g., if a participant reports high re-
experiencing, she will be reminded this is normal and linked to review relevant material). Further, if substance 
cravings or use are reported, EMIs will deliver coping tools (e.g., reminder anxiety is temporary and substance use 
exacerbates it in the long run) to boost efficacy.155 RISE Guide is completed in ~45 minutes over 2 weeks, with 
EMI weeks 1-7 post-assault. 
Control Intervention. Breathe2Relax156 is a mobile application that instructs users on diaphragmatic 
breathing, a coping tool in which slow breathing through the diaphragm reduces anxiety.157,158 Participants in the 
control condition will download Breathe2Relax to their smart phones and receive SMS reminders to engage with 
the app. The control intervention is expected to reduce symptoms, but not as much as the CBT strategies taught 
in RISE Guide.159,160 
7.2 
EFFORTS TO MINIMIZE BIAS 
Randomization tables will be generated by the study Biostatistician and uploaded into the study REDCap 
database by the UNC Research Coordinator prior to launching data collection. Participants are randomized (1:1) 
to receive either the RISE Guide (experimental) condition or Breathe2Relax (control) condition after completing 
their 1-week survey. The list of assignments will be stored securely in REDCap. 
Participants will not be masked to their study conditions, as branding is visible in both RISE Guide and 
Breathe2Relax. Moreover, the UNC Research Coordinator will not be masked to condition, as they will be 
responsible for tracking RISE Guide progress and managing participant payments. The Principal Investigator, 
Biostatistician, Site Principal Investigators, Site Research Associates, and anyone involved in data analysis will 
remain masked to condition until data analysis is complete; masking will be maintained through reduced data 
viewing privileges in REDCap. 
7.3 
STUDY INTERVENTION COMPLIANCE 
The study database will track RISE Guide module progress and EMI/EMA completion in real time. 
Compliance is encouraged via reminders to engage with the intervention to participants and bonus compensation 
for timely module completion and significant EMI/EMA completion. Participants in both the experimental and 

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control conditions will complete the Treatment Acceptability/Adherence Scale (TAAS)146 during their 1-week and 
7-week follow-ups. 
8 
INTERVENTION DISCONTINUATION AND PARTICIPANT WITHDRAWAL 
8.1 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. The research team will 
ask participants to share their reason for leaving the study, though withdrawn participants may elect not to share 
their reason. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
1. Significant study intervention non-compliance  
2. If any clinical adverse event (AE) or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant 
3. If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded in the study 
database. Subjects who sign the informed consent form and are randomized, receive the study intervention, and 
subsequently withdraw, or are withdrawn from the study, will not be replaced. 
8.2 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.2.1 
DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.2.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of the 
investigator, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity, or substantial 
disruption of the ability to conduct normal life functions. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include expression of a suicidal or homicidal 
plan. 
8.2.3 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.3.1 
SEVERITY OF EVENT 
The following guidelines will be used to describe severity of AE: 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  

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• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, 
the term “severe” does not necessarily equate to “serious”. 
8.2.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her/their clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study product 
must always be suspect.  
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility that the 
study intervention caused the AE, or there is a temporal relationship between the study intervention and 
event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study 
intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study intervention caused 
the event, there is no temporal relationship between the study intervention and event onset, or an alternate 
etiology has been established. 
8.2.3.3 
EXPECTEDNESS  
Drs. Samuel McLean and Nicole Short will be responsible for determining whether an adverse event (AE) 
is expected or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event 
is not consistent with the risk information previously described for the study intervention. 
8.2.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care. 
All AEs not meeting the criteria for SAEs will be captured in the study REDCap database. Information to 
be collected includes event description, time of onset, clinician’s assessment of severity, relationship to RISE Guide 
(assessed only by Dr. Short), and time of resolution of the event. All AEs occurring while participating in the study 
must be documented appropriately regardless of relationship. All AEs will be followed to adequate resolution 
(assurance of immediate safety and provision of referral to care). 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, the study participant’s symptoms will be recorded as 
an adverse event if their: 
• 
anxiety severity doubles between assessments and falls above the cutoff for moderate anxiety 
(PROMIS Anxiety ≥ 17167), 
• 
depression severity doubles between assessments and falls above the cutoff for moderate 
depression, (PROMIS Depression ≥ 23167,168), 
• 
and/or PTS severity doubles between assessments and falls above the cutoff for probable PTSD 
(PCL-5 ≥ 31169). 

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Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Documentation of onset and duration of each episode will be maintained 
for AEs characterized as intermittent. 
The research coordinator will record all reportable events that they learn of with start dates occurring 
any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation. Events will be followed for outcome information until resolution or stabilization (assurance of 
immediate safety and provision of referral to care). 
8.2.5 
ADVERSE EVENT REPORTING  
Adverse events (AEs) will be tracked within the study’s REDCap database. Serious adverse events (SAEs) 
and AEs that are unexpected or possibly related to participation in the research study will be submitted to IRB as 
New Safety Information (NSI) within 7 calendar days of the event being brought to our attention. The report of 
AEs or SAEs will include whether they were expected or unexpected, the severity of the event, a brief narrative 
summary of the event, a determination of whether a causal relationship existed between the study procedures and 
the event, whether the informed consent or study procedures should be changed as a result of the event, and 
whether all enrolled participants should be notified of the event. 
 
 

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9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
• 
Hypothesis 1: Treatment acceptability for RISE Guide is greater than or equal to treatment acceptability 
for a relaxation control. 
• 
Hypothesis 2: A randomized controlled trial to test the RISE Guide intervention will be feasible.Sample 
Size Rationale 
A balanced, site-stratified randomization scheme (1:1) will be used. We ensured adequate power (.80, α
=.05) to test all hypotheses by ensuring power for the hypothesis in need of the greatest sample size (mediation 
effects of the intervention on clinical outcomes via changes in AS). Power analyses were conducted and sample 
sizes were chosen based on power as well as feasibility of this initial pilot study. 
 Statistical Analyses 
9.1.1 
AIM 1 (USABILITY, ACCEPTABILITY, AND CREDIBILITY) 
To examine usability, credibility, and acceptability of RISE Guide, mean credibility/acceptability scores will 
be compared to norms to ascertain treatment credibility/acceptability. 
Specifically, mean levels of the Credibility/Expectancy Questionnaire (CEQ)197 to assess credibility and the 
Treatment Acceptability/Adherence Scale (TAAS)211 will be examined to assess acceptability and adherence at 1 
week will be compared to published CBT interventions, with the hypothesis that CEQ and TAAS total scores will 
exceed 30 and 40, respectively. Utilization and acceptability will also be examined via response from the 6 week 
measure designed for the current study (including 6 items on a 5-point Likert scale, such as How often did you log 
in? How interested were you? and 4 open-ended questions; e.g., What did you like about RISE Guide?; What did you not 
like?). Descriptive statistics will be analyzed to determine if any specific area needs improvement. Then, open-
ended items will be evaluated by reading and noting important and common feedback, focusing on comments 
related to ease of use, comprehensibility, limitations, and suggestions for improvement. Scores will be compared to 
the Relaxation Control condition as well, but the primary Hypothesis is that mean scores will exceed the CEQ and 
TAAS cut-offs provided above. 
9.1.2 
AIM 2 (FEASIBILITY) 
To assess feasibility of conducting a randomized controlled trial to test the RISE Guide intervention. 
 
Recruitment. We will calculate the total number of participants recruited, and how many participants 
were recruited per month. The goal is that we will recruit 2-4 participants per month. 
 
Retention. We will calculate the total number of participants completing each time point, with the goal 
of 75%+ retention rates. 
 
Adverse Events. We will evaluate the total number of adverse events, including by condition. 
 will be used to assess whether RISE Guide attenuates associations between wrist wearable 
EDA reactivity to trauma cues (triggered on the E4 by participants) and EMA cannabis cravings/use. Hypothesis 3 
will be assessed when75 and 150 participants have completed the study. 
9.1.3 
BASELINE DESCRIPTIVE STATISTICS 

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We will use SPSS Version 25181 to analyze descriptive statistics and generate histograms. These will be 
reviewed and visually inspected for potential nonnormality and outliers. If needed, appropriate data 
transformations will be applied, or alternative data procedures (e.g., nonparametric, bootstrapping) will be used. 
Special attention will be paid to the distribution of cannabis use to determine if alternate analytic strategies are 
needed if rates are low.182 
9.1.4 
TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will be listed by measure and time point. 
 
10 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting the intervention.  The 
following materials are submitted with this protocol: 
• 
Adult consent form 
• 
HIPAA authorization form 
• 
Participant discharge flyer outlining study schedule and contact information for the study. 
Importantly, this flyer does not disclose anything about the assault. 
• 
Planned email and text communications 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Full study consent is obtained at the time of presentation for care. Each consent is obtained by traditional 
in-person consent or by electronic teleconsent (detailed below). A potential participant must provide consent to 
participate. The RA will explain the study and answer any questions from the potential participant, emphasizing the 
voluntary nature of the study and the ability for the participant to cease or withdraw their participation at any 
time. A signed copy of the consent form will be given to the participant. Consent will be obtained via REDCap, and 
it will be documented and timestamped in the study tracking database prior to the initial assessment.  
Teleconsent is used as a consent option, because it has been widely shown to be a safe and valid method 
of obtaining consent in medical settings,189,190 and because it addresses barriers that prevent critically needed 
research in settings where it is very difficult to consistently physically provide trained research staff at the time and 
place necessary for consent. (In this study, and more generally in research, teleconsent also addresses inequities 
created by the fact that research staff are more difficult to hire/provide in socioeconomically disadvantaged and/or 
rural areas). Teleconsent facilitates the consent process and provides the same opportunity to make an informed 
and voluntary decision as a traditional consent. Importantly, the teleconsent platform used in this study complies 
with Health Insurance Portability and Accountability Act (HIPAA) requirements by (1) encrypting all transmitted 
data, (2) not storing patient information, (3) keeping an audit trail of the consent process, and (4) signing a business 
associate’s agreement (BAA) with the user. 
Teleconsent is obtained in the following manner. The SANE nurse approaches the potential participant at 
the time of her SANE exam to assess her willingness to speak to an RA about participation in an ongoing study via 

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laptop or tablet. If the potential participant is willing, an individual at the local site will notify the on-call teleconsent 
RA with an estimate for when the participant will be ready to speak. Alternatively, if patient requests, the SANE 
may schedule an appointment time in a secure communication platform, within 24 hours, to meet directly with the 
teleconsent team to complete informed consent and the remainder of the enrollment process. 
Once ready, the SANE uses the study laptop or tablet to open Zoom and joins the teleconsent RA’s 
HIPAA-enabled Zoom meeting room. If the patient chooses to meet with RA within 24 hours, the RA will send 
the patient a Zoom meeting invite and join the meeting room at the scheduled time. The RA introduces 
her/him/themself via live two-way video communication and describes her/his/their role as a research associate in 
an ongoing study testing an app-based intervention to aid recovery after sexual assault. Just as in person, if the 
potential participant is willing, the RA reviews the study consent and requirements for participation in real-time, 
and uses the online database to screen the potential participant for study eligibility. If eligible, the teleconsent RA 
opens DocuSign – a secure eConsent platform – and sends the consent, HIPAA authorization, and social security 
number collection forms to the participant’s email inbox. Both the participant and the teleconsent RA will open 
and review the documents. Because both the RA and the participant will have the forms open, the participant can 
follow along on her screen while the RA explains each section. This allows teleconsent to be an interactive and 
engaging experience, similar to in-person consent, and facilitates a careful explanation and discussion of the 
consent document. 
After reviewing the consent documents on the laptop or tablet, if the potential participant is willing to 
participate, the RA and participant both electronically sign the consent through DocuSign and enter their time of 
signature (the date of signature is automatically piped in by DocuSign). DocuSign only allows the participant and RA 
to sign and timestamp their respective sections (i.e. the RA cannot mistakenly sign on behalf of the participant, and 
vice-versa), protecting the integrity of the consent process. 
Figure 6 Example of RA signature field. 
 
When the consent document is complete, DocuSign checks to ensure all data fields have been filled out. If 
required fields have not been completed, the document automatically scrolls to display the first missing field. When 
the document is completely filled out, a PDF file of the completed consent, HIPAA, and SSN documents is 
generated and emailed to the participant, and the RA saves a copy to the central, secure online study database. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
If participants in the active group exhibit, on average, clinically significant exacerbations in ASI scores 
(transition from scores <25 to ≥25), PCL-5 scores (12-point increase, scaled based on the 10-point cut-off used in 
PCL-IV191), or MPS scores (increase of 8 pts192), then the investigative team will review the findings to evaluate the 
safety of continuing with the trial. This study may be temporarily suspended or prematurely terminated if there is 
sufficient reasonable cause.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 

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promptly inform the Institutional Review Board (IRB) and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to the study activity 
schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, substantial, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the IRB. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators and their 
staff. This confidentiality is extended to cover testing of biological samples and genetic tests in addition to 
participants’ clinical information. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the Principle Investigator. 
All research activities will be conducted in as private a setting as possible. 
Representatives of the Institutional Review Board (IRB) and regulatory agencies may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) for the participants in this study. The clinical study site will permit access to such records. 
The study participant’s contact information and research data will be securely stored in the study’s 
REDCap database. At the end of the study, all records will continue to be kept in a secure location for 3 years 
prior to being destroyed. 
The study data entry and study management systems used by clinical sites and by UNC Institute for 
Trauma Recovery research staff will be secured and password protected. 
10.1.3.1 CERTIFICATE OF CONFIDENTIALITY 
To further protect the privacy of study participants, the research team already obtained a Certificate of 
Confidentiality (COC; CC-OD-20-266) for the ongoing pilot study of the proposed intervention. A COC for this 
RCT will be requested prior to enrolling participants. This certificate protects identifiable research information 
from forced disclosure. It allows the investigator and others who have access to research records to 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. By protecting researchers and institutions from being 
compelled to disclose information that would identify research participants, Certificates of Confidentiality help 
achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants. 
10.1.4 QUALITY ASSURANCE AND QUALITY CONTROL 

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Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion.  An individualized quality management plan will be developed to 
describe a site’s quality management. These plans will be reviewed and approved by the data coordinating center at 
UNC. 
The research coordinator will run quality control (QC) checks on the REDCap database each month. Any 
missing data or data anomalies will be communicated to the sites for clarification and resolution. 
10.1.5 DATA HANDLING AND RECORD KEEPING  
10.1.5.1 DATA COLLECTION AND DATA MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, and timeliness of the data 
reported. 
Study data (including adverse events (AEs), study assessment data, and digital copies of sexual assault 
medical records) will be entered into the study REDCap database, which includes password protection and 
internal quality checks (such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate). 
10.1.6 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol or International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) requirements. The noncompliance may be either on the part of 
the participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
These practices are consistent with the following sections of the ICH GCP Consensus Guideline193:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
Protocol deviations may be initially identified by a site research associate (RA), site principal investigator 
(PI), or UNC-based research coordinator. Site personnel are trained to report any deviations from the study 
protocol to both the UNC PI and Coordinator immediately following enrollment (the only timepoint at which site 
personnel and participants interact). The Coordinator maintains a digital Protocol Deviation Log, uploads Notes to 
File to the study REDCap database, and receives guidance from the PI regarding whether deviations constitute 
New Safety Information (NSI); the Coordinator reports NSI to UNC’s IRB within 7 calendar days of becoming 
aware of the deviation, per guidance from UNC’s Office of Human Research Ethics.194 
The reporting pathway for protocol deviations is illustrated in Figure 7: 

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Figure 7 Protocol deviation reporting pathway. 
10.1.7 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence is critical.  Therefore, any actual 
conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this 
trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial.  All team members will disclose Conflicts of Interests via the UNC Activities, Interests, and 
Relationships (AIR) Management System. 
 
 
UNC IRB 
Protocol Deviation 
Log 
All deviations 
NSI 
UNC PI and 
Coordinator 
All deviations 
Site RA or 
Site PI 

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11 PROTOCOL AMENDMENT HISTORY 
Version Date 
Description of Change  
Brief Rationale 
1.0 
04/13/2021 
(Initial submission) 
N/A 
1.1 
05/06/2021 
Described risk of bruising post- blood draw. 
Created table of abbreviations 
Per IRB stipulations 
 
Per scientific review 
requirements 
2.0 
07/02/2021 
Clarified that pre-assault depression and anxiety are 
collected retrospectively at 1 week. 
Clarified that re-screening does not shift study timeline. 
Clarified that primary outcome is CUD, not general 
SUD. 
Clarified plan to use FIML to address missing data. 
Clarified plan to compare AS between active and control 
participants. 
Revised definition of AE to require doubling of symptom 
severity and score within or above moderate range. 
Revised AE reporting guidelines to clarify that all only 
AEs possibly related to research participation will be 
reported as NSI. All SAEs will still be reported as NSI. 
Added Xinming An as biostatistical support. 
Created sub-headings within “Study Rationale”. 
Expanded Table of Contents to include 4 levels of 
headings. 
Expanded upon data monitoring plans to clarify that 
Lead Research Coordinator will review data every two 
weeks. 
Standardized font size and style throughout protocol. 
Rephrased “emergency care sites” to “study sites”. 
Added number of sites, site names, site PIs, estimated 
enrollments by site, site onboarding plans, and site 
protocol deviation reporting pathway. 
Detailed data coordinating center role. 
Clarified references to ICH GCP Consensus Guidelines. 
Justified use of multiple measures for similar constructs. 
Explained role of DNA and RNA analysis in study. 
Explained that reasons for study drop-out will be 
collected, given that participants are willing to share. 
Rephrased “Endpoints” to “Outcomes” throughout. 
Removed plans to modify RISE Guide during study. 
Expanded upon interim analysis plans and rationale. 
Per Scientific Review 
Committee feedback 

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Clarified criteria for stopping in the study based on 
interim analysis results. 
Corrected interim analysis timeline to take place when 
75 and 150 women complete study procedures. 
Clarified interim vs. safety monitoring. 
Clarified variables associated with specific constructs 
throughout protocol. 
Clarified that Aim 1 will assess active and control 
conditions. 
Organized outcomes by aim in Protocol Summary. 
Rephrased hypotheses to reference potential 
population-level impact and be testable. 
Changed heading “Sample Size Determination” to 
“Sample Size Rationale”. 
Changed heading “Populations for Analyses” to 
“Cohorts for Analyses”. 
Removed plans to test for demographic or clinical 
differences between control and active conditions, 
Added plans for sensitivity analyses. 
Rephrased “Exploratory Analyses” to “Secondary 
Analyses”. 
Stated that all hypotheses yielding high p-values will be 
reported as inconclusive. 
Stated that p-values will be reported to four decimal 
places without dichotomization. 
Removed references to statistical significance. 
Stated that all statistical estimates of population 
parameters will be tabulated along with corresponding 
CIs. 
Added “Target Sample Size” to Protocol Summary. 
Clarified plans to recruit 150 women. 
Incorporated full details of sample size rationale. 
Clarified that power analyses suggested, and did not 
reveal, target recruitment numbers. 
Expanded upon randomization process. 
Added funding source to title page. 
2.1 
09/01/2021 
Added Janhvi Rabadey as a Study Coordinator 
Added specific aim 2d: “Assess whether specific genetic 
variations predict RISE Guide treatment efficacy, as 
measured by AS (ASI-3) reductions 7 weeks post-
assault”. 
Clarified that the blood draw during the Initial wave is 
optional 
 

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2.2 
2021/12/14 
Added information regarding payments for participants 
during screener become ineligible. Table 4 updated to 
include one-time compensation of $20 for ineligible 
potentials after screener.  
 
2.3 
11/28/2022 
Removal of one year follow-up, providing payment for 
intervention completion, and collecting updated contact 
information at 3.5 months. 
Increase follow-up rates. 
2.4 
2022.11.28 
Due to logistical issues, the 1-year follow-up is being 
removed. Study participation will now end after the 6-
month follow-up. 
 
Participants will receive compensation for completing 
the RISE (active) intervention and the Breathe2Relax 
(control) intervention ($50 for each condition). 
 
At 3.5 months post-assault, we will collect updated 
contact information from participants. They will be 
compensated $10 for updating their information. 
 
2.5 
2023.12.13 
Updated PI to Samuel McLean. 
Dr. Nicole Short 
transitioned to a new role 
outside of UNC Chapel 
Hill. 
2.6 
2023.07.13 
Add the University of Nevada at Las Vegas as a 
collaborative study site. 
 
Update Nicole Short’s affiliation to the University of 
Nevada at Las Vegas 
Dr. Nicole Short 
transitioned to a new role 
outside of UNC Chapel 
Hill. 
2.7 
 
Specify NCT number. 
 
Update degree for Kristen Witkemper. 
 
Remove April Soward as personnel. 
 
Clarify that contact information updates are conducted 
at the baseline, 1-week, 6-week, and 6-month 
timepoints. 
 
Clarify that 1-year contact information updates and 
surveys are still being conducted with participants who 
consented prior to the Protocol 2.4 update. 
 
Specify mailing addresses for all study sites. 
 
Update mailing addresses for UNC-based personnel. 
 
 
 

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12 REFERENCES 
1.  
Goldstein DS. Stress-induced activation of the sympathetic nervous system. Baillieres Clin Endocrinol Metab. 
1987;1(2):253-278. doi:10.1016/S0950-351X(87)80063-0 
2.  
Buckner JD, Jeffries ER, Crosby RD, Zvolensky MJ, Cavanaugh CE, Wonderlich SA. The impact of PTSD 
clusters on cannabis use in a racially diverse trauma-exposed sample: An analysis from ecological 
momentary assessment. Am J Drug Alcohol Abuse. 2018;44(5):532-542. doi:10.1080/00952990.2018.1430149 
3.  
Sanjuan PM, Pearson MR, Poremba C, Amaro H de LA, Leeman L. An ecological momentary assessment 
study examining posttraumatic stress disorder symptoms, prenatal bonding, and substance use among 
pregnant women. Drug Alcohol Depend. 2019;195:33-39. doi:10.1016/j.drugalcdep.2018.11.019 
4.  
Dworkin ER. Risk for Mental Disorders Associated With Sexual Assault: A Meta-Analysis. Trauma Violence 
Abuse. 2020;21(5):1011-1028. doi:10.1177/1524838018813198 
5.  
Ullman SE, Relyea M, Peter-Hagene L, Vasquez AL. Trauma histories, substance use coping, PTSD, and 
problem substance use among sexual assault victims. Addict Behav. 2013;38(6):2219-2223. 
doi:10.1016/j.addbeh.2013.01.027 
6.  
Smith SG, Zhang X, Basile KC, et al. The National Intimate Partner and Sexual Violence Survey (NISVS): 2015 
Data Brief - Updated Release. Atlanta, GA: Centers for Disease Control and Prevention; 2018. 
https://www.cdc.gov/violenceprevention/pdf/2015data-brief508.pdf. Accessed October 10, 2019. 
7.  
Kilpatrick DG. The Mental Health Impact of Rape. National Crime Victims Center; 2000. 
8.  
Substance Abuse and Mental Health Services Administration. Results from the 2018 National Survey on 
Drug Use and Health. 2018. 
9.  
Hasin DS. US epidemiology of cannabis use and associated problems. Neuropsychopharmacology. 
2018;43(1):195-212. doi:10.1038/npp.2017.198 
10.  
Bujarski SJ, Feldner MT, Lewis SF, et al. Marijuana use among traumatic event-exposed adolescents: 
posttraumatic stress symptom frequency predicts coping motivations for use. Addict Behav. 2012;37(1):53-
59. doi:10.1016/j.addbeh.2011.08.009 
11.  
Bonn-Miller MO, Moos RH, Boden MT, Long WR, Kimerling R, Trafton JA. The impact of posttraumatic 
stress disorder on cannabis quit success. Am J Drug Alcohol Abuse. 2015;41(4):339-344. 
doi:10.3109/00952990.2015.1043209 
12.  
Dennis M, Scott CK. Managing addiction as a chronic condition. Addict Sci Clin Pract. 2007;4(1):45-55. 
13.  
Rothbaum BO, Foa EB, Riggs DS, Murdock T, Walsh W. A prospective examination of post-traumatic 
stress disorder in rape victims. J Trauma Stress. 1992;5(3):455-475. doi:10.1007/BF00977239 
14.  
Smith HL, Summers BJ, Dillon KH, Cougle JR. Is worst-event trauma type related to PTSD symptom 
presentation and associated features? J Anxiety Disord. 2016;38:55-61. doi:10.1016/j.janxdis.2016.01.007 
15.  
REED PL, ANTHONY JC, BRESLAU N. INCIDENCE OF DRUG PROBLEMS IN YOUNG ADULTS 
EXPOSED TO TRAUMA AND POSTTRAUMATIC STRESS DISORDER: DO EARLY LIFE EXPERIENCES 
AND PREDISPOSITIONS MATTER? ARCH GEN PSYCHIATRY. 2007;64(12):1435-1442. 
doi:10.1001/ARCHPSYC.64.12.1435 
16.  
CHILCOAT HD, BRESLAU N. INVESTIGATIONS OF CAUSAL PATHWAYS BETWEEN PTSD AND 
DRUG USE DISORDERS. ADDICTIVE BEHAVIORS. 1998;23(6):827-840. 
17.  
McCauley JL, Killeen T, Gros DF, Brady KT, Back SE. Posttraumatic stress disorder and co‐occurring 
substance use disorders: Advances in assessment and treatment. Clinical Psychology: Science and Practice. 
2012;19(3):283-304. 
18.  
Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National 
Comorbidity Survey. Arch Gen Psychiatry. 1995;52(12):1048-1060. 
doi:10.1001/archpsyc.1995.03950240066012 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
39 
19.  
Najdowski CJ, Ullman SE. Prospective effects of sexual victimization on PTSD and problem drinking. Addict 
Behav. 2009;34(11):965-968. doi:10.1016/j.addbeh.2009.05.004 
20.  
Ullman SE, Filipas HH, Townsend SM, Starzynski LL. Trauma exposure, posttraumatic stress disorder and 
problem drinking in sexual assault survivors. J Stud Alcohol. 2005;66(5):610-619. 
doi:10.15288/jsa.2005.66.610 
21.  
Austin AE, Short NA. Sexual violence, prescription opioid use and misuse, and the mediating role of 
depression and anxiety. Am J Prev Med. 
22.  
Ullman SE, Filipas HH, Townsend SM, Starzynski LL. Correlates of comorbid PTSD and drinking problems 
among sexual assault survivors. Addict Behav. 2006;31(1):128-132. doi:10.1016/j.addbeh.2005.04.002 
23.  
Flanagan JC, Korte KJ, Killeen TK, Back SE. Concurrent treatment of substance use and PTSD. Curr 
Psychiatry Rep. 2016;18(8):70. doi:10.1007/s11920-016-0709-y 
24.  
Bonn-Miller MO, Boden MT, Bucossi MM, Babson KA. Self-reported cannabis use characteristics, patterns 
and helpfulness among medical cannabis users. Am J Drug Alcohol Abuse. 2014;40(1):23-30. 
doi:10.3109/00952990.2013.821477 
25.  
Crippa JA, Zuardi AW, Martín‐Santos R, et al. Cannabis and anxiety: a critical review of the evidence. 
Human Psychopharmacology: Clinical and Experimental. 2009;24(7):515-523. 
26.  
Cougle JR, Bonn-Miller MO, Vujanovic AA, Zvolensky MJ, Hawkins KA. Posttraumatic stress disorder and 
cannabis use in a nationally representative sample. Psychol Addict Behav. 2011;25(3):554-558. 
doi:10.1037/a0023076 
27.  
Hayatbakhsh MR, Najman JM, Jamrozik K, Mamun AA, O’Callaghan MJ, Williams GM. Childhood sexual 
abuse and cannabis use in early adulthood: findings from an Australian birth cohort study. Arch Sex Behav. 
2009;38(1):135-142. doi:10.1007/s10508-007-9172-5 
28.  
Browne KC, Dolan M, Simpson TL, Fortney JC, Lehavot K. Regular past year cannabis use in women 
veterans and associations with sexual trauma. Addict Behav. 2018;84:144-150. 
doi:10.1016/j.addbeh.2018.04.007 
29.  
Fond G, Picot A, Bourbon A, et al. Prevalence and associated factors of cannabis consumption in medical 
students: the BOURBON nationwide study. Eur Arch Psychiatry Clin Neurosci. May 2020. 
doi:10.1007/s00406-020-01131-0 
30.  
Butterworth P, Slade T, Degenhardt L. Factors associated with the timing and onset of cannabis use and 
cannabis use disorder: Results from the 2007 A ustralian N ational S urvey of M ental H ealth and W ell‐
B eing. Drug and alcohol review. 2014;33(5):555-564. 
31.  
Bonn-Miller MO, Vujanovic AA, Boden MT, Gross JJ. Posttraumatic stress, difficulties in emotion 
regulation, and coping-oriented marijuana use. Cogn Behav Ther. 2011;40(1):34-44. 
doi:10.1080/16506073.2010.525253 
32.  
Dworkin ER, Kaysen D, Bedard-Gilligan M, Rhew IC, Lee CM. Daily-level associations between PTSD and 
cannabis use among young sexual minority women. Addict Behav. 2017;74:118-121. 
doi:10.1016/j.addbeh.2017.06.007 
33.  
Bonn‐Miller MO, Vujanovic AA, Feldner MT, Bernstein A, Zvolensky MJ. Posttraumatic stress symptom 
severity predicts marijuana use coping motives among traumatic event‐exposed marijuana users. Journal 
of Traumatic Stress: Official Publication of The International Society for Traumatic Stress Studies. 2007;20(4):577-
586. 
34.  
Hyman SM, Sinha R. Stress-related factors in cannabis use and misuse: implications for prevention and 
treatment. J Subst Abuse Treat. 2009;36(4):400-413. doi:10.1016/j.jsat.2008.08.005 
35.  
Buckner JD, Crosby RD, Silgado J, Wonderlich SA, Schmidt NB. Immediate antecedents of marijuana use: 
An analysis from ecological momentary assessment. Journal of behavior therapy and experimental psychiatry. 
2012;43(1):647-655. 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
40 
36.  
ROBERTS NP, ROBERTS PA, JONES N, BISSON JI. PSYCHOLOGICAL INTERVENTIONS FOR POST-
TRAUMATIC STRESS DISORDER AND COMORBID SUBSTANCE USE DISORDER: A SYSTEMATIC 
REVIEW AND META-ANALYSIS. CLIN PSYCHOL REV. 2015;38:25-38. doi:10.1016/J.CPR.2015.02.007 
37.  
Carliner H, Brown QL, Sarvet AL, Hasin DS. Cannabis use, attitudes, and legal status in the U.S.: A review. 
Prev Med. 2017;104:13-23. doi:10.1016/j.ypmed.2017.07.008 
38.  
D’Amico EJ, Tucker JS, Pedersen ER, Shih RA. Understanding rates of marijuana use and consequences 
among adolescents in a changing legal landscape. Curr Addict Rep. 2017;4(4):343-349. doi:10.1007/s40429-
017-0170-y 
39.  
Boden MT, Babson KA, Vujanovic AA, Short NA, Bonn-Miller MO. Posttraumatic stress disorder and 
cannabis use characteristics among military veterans with cannabis dependence. Am J Addict. 
2013;22(3):277-284. doi:10.1111/j.1521-0391.2012.12018.x 
40.  
Wilkinson ST, Stefanovics E, Rosenheck RA. Marijuana use is associated with worse outcomes in symptom 
severity and violent behavior in patients with PTSD. The Journal of clinical psychiatry. 2015;76(9):1174. 
41.  
Metrik J, Stevens AK, Gunn RL, Borsari B, Jackson KM. Cannabis use and posttraumatic stress disorder: 
prospective evidence from a longitudinal study of veterans. Psychol Med. June 2020:1-11. 
doi:10.1017/S003329172000197X 
42.  
Bedard-Gilligan M, Garcia N, Zoellner LA, Feeny NC. Alcohol, cannabis, and other drug use: Engagement 
and outcome in PTSD treatment. Psychol Addict Behav. 2018;32(3):277-288. doi:10.1037/adb0000355 
43.  
van Laar M, van Dorsselaer S, Monshouwer K, de Graaf R. Does cannabis use predict the first incidence of 
mood and anxiety disorders in the adult population? Addiction. 2007;102(8):1251-1260. doi:10.1111/j.1360-
0443.2007.01875.x 
44.  
Allan NP, Ashrafioun L, Kolnogorova K, Raines AM, Hoge CW, Stecker T. Interactive effects of PTSD and 
substance use on suicidal ideation and behavior in military personnel: Increased risk from marijuana use. 
Depress Anxiety. 2019;36(11):1072-1079. doi:10.1002/da.22954 
45.  
Blanco C, Hasin DS, Wall MM, et al. Cannabis use and risk of psychiatric disorders: prospective evidence 
from a US national longitudinal study. JAMA Psychiatry. 2016;73(4):388-395. 
doi:10.1001/jamapsychiatry.2015.3229 
46.  
Peirce JM, Schacht RL, Brooner RK. The Effects of Prolonged Exposure on Substance Use in Patients with 
Posttraumatic Stress Disorder and Substance Use Disorders. J Trauma Stress. June 2020. 
doi:10.1002/jts.22546 
47.  
Foa EB, Hembree E, Rothbaum BO. Prolonged exposure therapy for PTSD: Emotional processing of 
traumatic experiences therapist guide (Treatments that work) Oxford University Press. New York. 2007. 
48.  
Back SE, Killeen T, Badour CL, et al. Concurrent treatment of substance use disorders and PTSD using 
prolonged exposure: A randomized clinical trial in military veterans. Addict Behav. 2019;90:369-377. 
doi:10.1016/j.addbeh.2018.11.032 
49.  
Zvolensky MJ, Schmidt NB, Bernstein A, Keough ME. Risk-factor research and prevention programs for 
anxiety disorders: a translational research framework. Behav Res Ther. 2006;44(9):1219-1239. 
doi:10.1016/j.brat.2006.06.001 
50.  
Parekh V, Brown CB. Follow up of patients who have been recently sexually assaulted. Sexually transmitted 
infections. 2003;79(4):349-349. 
51.  
Reiss S, Peterson RA, Gursky DM, McNally RJ. Anxiety sensitivity, anxiety frequency and the prediction of 
fearfulness. Behavior Research and Therapy. 1986;24(1):1-8. 
52.  
Taylor S, Zvolensky MJ, Cox BJ, et al. Robust dimensions of anxiety sensitivity: development and initial 
validation of the Anxiety Sensitivity Index-3. Psychol Assess. 2007;19(2):176-188. doi:10.1037/1040-
3590.19.2.176 
53.  
Norr AM, Albanese BJ, Boffa JW, Short NA, Schmidt NB. The relationship between gender and PTSD 
symptoms: Anxiety sensitivity as a mechanism. Pers Individ Dif. 2016;90:210-213. 
doi:10.1016/j.paid.2015.11.014 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
41 
54.  
Marshall GN, Miles JNV, Stewart SH. Anxiety sensitivity and PTSD symptom severity are reciprocally 
related: evidence from a longitudinal study of physical trauma survivors. J Abnorm Psychol. 2010;119(1):143-
150. doi:10.1037/a0018009 
55.  
Boffa JW, Norr AM, Raines AM, Albanese BJ, Short NA, Schmidt NB. Anxiety sensitivity prospectively 
predicts posttraumatic stress symptoms following a campus shooting. Behav Ther. 2016;47(3):367-376. 
doi:10.1016/j.beth.2016.02.006 
56.  
Olatunji BO, Fan Q. Anxiety sensitivity and post-traumatic stress reactions: Evidence for intrusions and 
physiological arousal as mediating and moderating mechanisms. J Anxiety Disord. 2015;34:76-85. 
doi:10.1016/j.janxdis.2015.06.002 
57.  
Verreault N, Da Costa D, Marchand A, et al. PTSD following childbirth: a prospective study of incidence 
and risk factors in Canadian women. J Psychosom Res. 2012;73(4):257-263. 
doi:10.1016/j.jpsychores.2012.07.010 
58.  
Schmidt NB, Zvolensky MJ, Maner JK. Anxiety sensitivity: prospective prediction of panic attacks and Axis I 
pathology. J Psychiatr Res. 2006;40(8):691-699. doi:10.1016/j.jpsychires.2006.07.009 
59.  
Lang AJ, Kennedy CM, Stein MB. Anxiety sensitivity and PTSD among female victims of intimate partner 
violence. Depress Anxiety. 2002;16(2):77-83. doi:10.1002/da.10062 
60.  
Short NA, Lechner M, Bell K, et al. Anxiety sensitivity prospectively predicts increased acute 
posttraumatic stress and related symptoms after sexual assault. J Trauma Stress. 
61.  
Dixon LJ, Stevens EN, Viana AG. Anxiety sensitivity as a moderator of the relationship between trait 
anxiety and illicit substance use. Psychol Addict Behav. 2014;28(4):1284. 
62.  
Hearon BA, Calkins AW, Halperin DM, McHugh RK, Murray HW, Otto MW. Anxiety sensitivity and illicit 
sedative use among opiate-dependent women and men. Am J Drug Alcohol Abuse. 2011;37(1):43-47. 
doi:10.3109/00952990.2010.535581 
63.  
Bonn-Miller MO, Zvolensky MJ, Bernstein A. Marijuana use motives: Concurrent relations to frequency of 
past 30-day use and anxiety sensitivity among young adult marijuana smokers. Addictive behaviors. 
2007;32(1):49-62. 
64.  
Guillot CR, Blumenthal H, Zvolensky MJ, Schmidt NB. Anxiety sensitivity components in relation to 
alcohol and cannabis use, motives, and problems in treatment-seeking cigarette smokers. Addictive 
behaviors. 2018;82:166-173. 
65.  
DeMartini KS, Carey KB. The role of anxiety sensitivity and drinking motives in predicting alcohol use: A 
critical review. Clinical psychology review. 2011;31(1):169-177. 
66.  
Rogers AH, Kauffman BY, Bakhshaie J, McHugh RK, Ditre JW, Zvolensky MJ. Anxiety sensitivity and opioid 
misuse among opioid-using adults with chronic pain. Am J Drug Alcohol Abuse. 2019;45(5):470-478. 
doi:10.1080/00952990.2019.1569670 
67.  
McHugh RK, Votaw VR, Bogunovic O, Karakula SL, Griffin ML, Weiss RD. Anxiety sensitivity and 
nonmedical benzodiazepine use among adults with opioid use disorder. Addict Behav. 2017;65:283-288. 
doi:10.1016/j.addbeh.2016.08.020 
68.  
Stewart SH, Peterson JB, Pihl RO. Anxiety sensitivity and self-reported alcohol consumption rates in 
university women. J Anxiety Disord. 1995;9(4):283-292. 
69.  
McCaul ME, Hutton HE, Stephens MAC, Xu X, Wand GS. Anxiety, anxiety sensitivity, and perceived stress 
as predictors of recent drinking, alcohol craving, and social stress response in heavy drinkers. Alcohol Clin 
Exp Res. 2017;41(4):836-845. doi:10.1111/acer.13350 
70.  
DeHaas RA, Calamari JE, Bair JP, Martin ED. Anxiety sensitivity and drug or alcohol use in individuals with 
anxiety and substance use disorders. Addictive behaviors. 2001;26(6):787-801. 
71.  
Zvolensky MJ, Rogers AH, Shepherd JM, Vujanovic AA, Bakhshaie J. Anxiety sensitivity and opioid misuse 
and dependence among trauma-exposed adults with chronic pain. J Behav Med. 2020;43(2):174-184. 
doi:10.1007/s10865-020-00142-5 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
42 
72.  
Schmidt NB, Buckner JD, Keough ME. Anxiety sensitivity as a prospective predictor of alcohol use 
disorders. Behav Modif. 2007;31(2):202-219. 
73.  
Evatt DP, Kassel JD. Smoking, arousal, and affect: the role of anxiety sensitivity. J Anxiety Disord. 
2010;24(1):114-123. doi:10.1016/j.janxdis.2009.09.006 
74.  
Stewart SH, Karp J, Pihl RO, Peterson RA. Anxiety sensitivity and self-reported reasons for drug use. J 
Subst Abuse. 1997;9:223-240. doi:10.1016/S0899-3289(97)90018-3 
75.  
Stewart SH, Pihl RO. Effects of alcohol administration on psychophysiological and subjective-emotional 
responses to aversive stimulation in anxiety-sensitive women. Psychology of addictive behaviors. 1994;8(1):29. 
76.  
DeHaas RA, Calamari JE, Bair JP. Anxiety sensitivity and the situational antecedents to drug and alcohol 
use: An evaluation of anxiety patients with substance use disorders. Cognitive Therapy and Research. 
2002;26(3):335-353. 
77.  
Stewart SH, Zvolensky MJ, Eifert GH. Negative-reinforcement drinking motives mediate the relation 
between anxiety sensitivity and increased drinking behavior. Personality and Individual differences. 
2001;31(2):157-171. 
78.  
Berenz EC, Kevorkian S, Chowdhury N, Dick DM, Kendler KS, Amstadter AB. Posttraumatic stress 
disorder symptoms, anxiety sensitivity, and alcohol-use motives in college students with a history of 
interpersonal trauma. Psychol Addict Behav. 2016;30(7):755-763. doi:10.1037/adb0000193 
79.  
Chowdhury N, Kevorkian S, Sheerin CM, Zvolensky MJ, Berenz EC. Examination of the association among 
personality traits, anxiety sensitivity, and cannabis use motives in a community sample. J Psychopathol Behav 
Assess. 2016;38(3):373-380. doi:10.1007/s10862-015-9526-6 
80.  
Pang RD, Guillot CR, Zvolensky MJ, Bonn-Miller MO, Leventhal AM. Associations of anxiety sensitivity and 
emotional symptoms with the subjective effects of alcohol, cigarettes, and cannabis in adolescents. Addict 
Behav. 2017;73:192-198. doi:10.1016/j.addbeh.2017.05.016 
81.  
Buckner JD, Zvolensky MJ, Smits JAJ, et al. Anxiety sensitivity and marijuana use: an analysis from 
ecological momentary assessment. Depress Anxiety. 2011;28(5):420-426. doi:10.1002/da.20816 
82.  
Zvolensky MJ, Marshall EC, Johnson K, Hogan J, Bernstein A, Bonn-Miller MO. Relations between anxiety 
sensitivity, distress tolerance, and fear reactivity to bodily sensations to coping and conformity marijuana 
use motives among young adult marijuana users. Exp Clin Psychopharmacol. 2009;17(1):31-42. 
doi:10.1037/a0014961 
83.  
Farris SG, Metrik J, Bonn-Miller MO, Kahler CW, Zvolensky MJ. Anxiety sensitivity and distress 
intolerance as predictors of cannabis dependence symptoms, problems, and craving: the mediating role of 
coping motives. J Stud Alcohol Drugs. 2016;77(6):889-897. doi:10.15288/jsad.2016.77.889 
84.  
Mitchell H, Zvolensky MJ, Marshall EC, Bonn-Miller MO, Vujanovic AA. Incremental Validity of Coping-
oriented Marijuana Use Motives in the Prediction of Affect-based Psychological Vulnerability. J Psychopathol 
Behav Assess. 2007;29(4):277-288. doi:10.1007/s10862-007-9047-z 
85.  
Zvolensky MJ, Rogers AH, Manning K, et al. Anxiety sensitivity and cannabis use problems, perceived 
barriers for quitting, and fear of quitting. Psychiatry Res. 2018;263:115-120. 
doi:10.1016/j.psychres.2018.03.006 
86.  
Manning K, Garey L, Paulus DJ, et al. Typology of cannabis use among adults: A latent class approach to 
risk and protective factors. Addict Behav. 2019;92:6-13. doi:10.1016/j.addbeh.2018.12.008 
87.  
Bonn-Miller MO, Zvolensky MJ, Marshall EC, Bernstein A. Incremental validity of anxiety sensitivity in 
relation to marijuana withdrawal symptoms. Addict Behav. 2007;32(9):1843-1851. 
doi:10.1016/j.addbeh.2006.12.016 
88.  
Vujanovic AA, Farris SG, Bartlett BA, et al. Anxiety sensitivity in the association between posttraumatic 
stress and substance use disorders: A systematic review. Clin Psychol Rev. 2018;62:37-55. 
doi:10.1016/j.cpr.2018.05.003 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
43 
89.  
Short NA, Lechner M, McLean BS, et al. Health care utilization by women sexual assault survivors after 
emergency care: Results of a multisite prospective study. Depress Anxiety. October 2020. 
doi:10.1002/da.23102 
90.  
Keogh E, Ayers S, Francis H. Does Anxiety Sensitivity Predict Post-Traumatic Stress Symptoms Following 
Childbirth? A Preliminary Report. Cogn Behav Ther. 2002;31(4):145-155. doi:10.1080/165060702321138546 
91.  
Hinrichs R, Michopoulos V, Winters S, et al. Mobile assessment of heightened skin conductance in 
posttraumatic stress disorder. Depress Anxiety. 2017;34(6):502-507. doi:10.1002/da.22610 
92.  
Pineles SL, Suvak MK, Liverant GI, et al. Psychophysiologic reactivity, subjective distress, and their 
associations with PTSD diagnosis. J Abnorm Psychol. 2013;122(3):635-644. doi:10.1037/a0033942 
93.  
Wolfe J, Chrestman KR, Ouimette PC, Kaloupek D, Harley RM, Bucsela M. Trauma‐related 
psychophysiological reactivity in women exposed to war‐zone stress. J Clin Psychol. 2000;56(10):1371-
1379. 
94.  
de Kloet C, Vermetten E, Rademaker A, Geuze E, Westenberg HM. Neuroendocrine and immune 
responses to a cognitive stress challenge in veterans with and without PTSD. Eur J Psychotraumatol. 
2012;3(1):16206. 
95.  
Elzinga BM, Schmahl CG, Vermetten E, van Dyck R, Bremner JD. Higher cortisol levels following exposure 
to traumatic reminders in abuse-related PTSD. Neuropsychopharmacology. 2003;28(9):1656-1665. 
doi:10.1038/sj.npp.1300226 
96.  
Hinrichs R, van Rooij SJ, Michopoulos V, et al. Increased skin conductance response in the immediate 
aftermath of trauma predicts PTSD risk. Chronic Stress (Thousand Oaks). 2019;3. 
doi:10.1177/2470547019844441 
97.  
Vujanovic AA, Wardle MC, Bakhshaie J, et al. Distress tolerance: Associations with trauma and substance 
cue reactivity in low-income, inner-city adults with substance use disorders and posttraumatic stress. 
Psychol Addict Behav. 2018;32(3):264-276. doi:10.1037/adb0000362 
98.  
Taylor S. Anxiety sensitivity and its implications for understanding and treating PTSD. J Cogn Psychother. 
2003;17(2):179-186. doi:10.1891/jcop.17.2.179.57431 
99.  
Tull MT, Berghoff CR, Wheeless LE, Cohen RT, Gratz KL. PTSD symptom severity and emotion 
regulation strategy use during trauma cue exposure among patients with substance use disorders: 
associations with negative affect, craving, and cortisol reactivity. Behav Ther. 2018;49(1):57-70. 
doi:10.1016/j.beth.2017.05.005 
100.  
Tull MT, McDermott MJ, Gratz KL, Coffey SF, Lejuez CW. Cocaine-related attentional bias following 
trauma cue exposure among cocaine dependent in-patients with and without post-traumatic stress 
disorder. Addiction. 2011;106(10):1810-1818. doi:10.1111/j.1360-0443.2011.03508.x 
101.  
Becker HC. Influence of stress associated with chronic alcohol exposure on drinking. Neuropharmacology. 
2017;122:115-126. doi:10.1016/j.neuropharm.2017.04.028 
102.  
Cooper ML, Kuntsche E, Levitt A, Barber LL, Wolf S. Motivational models of substance use: A review of 
theory and research on motives for using alcohol, marijuana, and tobacco. 2016. 
103.  
Bakhshaie J, Kulesz PA, Garey L, et al. A prospective investigation of the synergistic effect of change in 
anxiety sensitivity and dysphoria on tobacco withdrawal. Journal of consulting and clinical psychology. 
2018;86(1):69. 
104.  
Zvolensky M, Bonn-Miller M, Bernstein A, Marshall E. Anxiety sensitivity and abstinence duration to 
smoking. J Mental Health. 2006;15(6):659-670. doi:10.1080/09638230600998888 
105.  
Khan SS, Secades-Villa R, Okuda M, et al. Gender differences in cannabis use disorders: results from the 
National Epidemiologic Survey of Alcohol and Related Conditions. Drug Alcohol Depend. 2013;130(1-3):101-
108. doi:10.1016/j.drugalcdep.2012.10.015 
106.  
Wangelin BC, Tuerk PW. Taking the pulse of prolonged exposure therapy: physiological reactivity to 
trauma imagery as an objective measure of treatment response. Depress Anxiety. 2015;32(12):927-934. 
doi:10.1002/da.22449 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
44 
107.  
Norberg MM, Kavanagh DJ, Olivier J, Lyras S. Craving cannabis: a meta-analysis of self-report and 
psychophysiological cue-reactivity studies. Addiction. 2016;111(11):1923-1934. doi:10.1111/add.13472 
108.  
Schmidt NB, Capron DW, Raines AM, Allan NP. Randomized clinical trial evaluating the efficacy of a brief 
intervention targeting anxiety sensitivity cognitive concerns. J Consult Clin Psychol. 2014;82(6):1023-1033. 
doi:10.1037/a0036651 
109.  
Schmidt NB, Norr AM, Allan NP, Raines AM, Capron DW. A randomized clinical trial targeting anxiety 
sensitivity for patients with suicidal ideation. J Consult Clin Psychol. 2017;85(6):596-610. 
doi:10.1037/ccp0000195 
110.  
Short NA, Boffa JW, Norr AM, Albanese BJ, Allan NP, Schmidt NB. Randomized Clinical Trial Investigating 
the Effects of an Anxiety Sensitivity Intervention on Posttraumatic Stress Symptoms: A Replication and 
Extension. J Trauma Stress. 2017. 
111.  
Short NA, Allan NP, Raines AM, Schmidt NB. The effects of an anxiety sensitivity intervention on insomnia 
symptoms. Sleep Med. 2015;16(1):152-159. 
112.  
Schmidt NB, Raines AM, Allan NP, et al. Brief interventions targeting interpersonal risk factors for suicide: 
A randomized clinical trial. 
113.  
Boffa JW, Schmidt NB. Prospective Reductions in Anxiety Sensitivity Cognitive Concerns Mitigate Analog 
Trauma Symptom Development. Behav Res Ther. 2019;113(39-47). 
114.  
Capron DW, Norr AM, Allan NP, Schmidt NB. Combined “top-down” and “bottom-up” intervention for 
anxiety sensitivity: Pilot randomized trial testing the additive effect of interpretation bias modification. J 
Psychiatr Res. 2017;85:75-82. doi:10.1016/j.jpsychires.2016.11.003 
115.  
Short NA, Fuller K, Norr AM, Schmidt NB. Acceptability of a brief computerized intervention targeting 
anxiety sensitivity. Cogn Behav Ther. 2017;46(3):250-264. doi:10.1080/16506073.2016.1232748 
116.  
Raines AM, Allan NP, McGrew SJ, et al. A computerized anxiety sensitivity intervention for opioid use 
disorders: A pilot investigation among veterans. Addict Behav. 2020;104:106285. 
doi:10.1016/j.addbeh.2019.106285 
117.  
Wolitzky-Taylor K, Krull J, Rawson R, Roy-Byrne P, Ries R, Craske MG. Randomized clinical trial 
evaluating the preliminary effectiveness of an integrated anxiety disorder treatment in substance use 
disorder specialty clinics. J Consult Clin Psychol. 2018;86(1):81-88. doi:10.1037/ccp0000276 
118.  
Paulus DJ, Gallagher MW, Raines AM, Schmidt NB, Zvolensky MJ. Intraindividual change in anxiety 
sensitivity and alcohol use severity 12-months following smoking cessation treatment. Behav Res Ther. 
2019;116:10-18. doi:10.1016/j.brat.2019.01.008 
119.  
Watt MC, Stewart SH, Lefaivre M-J, Uman LS. A brief cognitive-behavioral approach to reducing anxiety 
sensitivity decreases pain-related anxiety. Cogn Behav Ther. 2006;35(4):248-256. 
doi:10.1080/16506070600898553 
120.  
Tull MT, Schulzinger D, Schmidt NB, Zvolensky MJ, Lejuez CW. Development and initial examination of a 
brief intervention for heightened anxiety sensitivity among heroin users. Behavior Modification. 
2007;31(2):220-242. 
121.  
Zvolensky MJ, Garey L, Allan NP, et al. Effects of anxiety sensitivity reduction on smoking abstinence: An 
analysis from a panic prevention program. J Consult Clin Psychol. 2018;86(5):474-485. 
doi:10.1037/ccp0000288 
122.  
Worden BL, Davis E, Genova M, Tolin DF. Development of an anxiety sensitivity (AS) intervention for 
high-AS individuals in substance use disorders treatment. Cognitive Therapy and Research. 2015;39(3):343-
355. 
123.  
Mahu IT, Doucet C, O’Leary-Barrett M, Conrod PJ. Can cannabis use be prevented by targeting 
personality risk in schools? Twenty-four-month outcome of the adventure trial on cannabis use: a cluster-
randomized controlled trial. Addiction. 2015;110(10):1625-1633. doi:10.1111/add.12991 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
45 
124.  
Conrod PJ, Castellanos-Ryan N, Strang J. Brief, personality-targeted coping skills interventions and survival 
as a non-drug user over a 2-year period during adolescence. Arch Gen Psychiatry. 2010;67(1):85-93. 
doi:10.1001/archgenpsychiatry.2009.173 
125.  
Lijffijt M, Hu K, Swann AC. Stress modulates illness-course of substance use disorders: a translational 
review. Front Psychiatry. 2014;5:83. doi:10.3389/fpsyt.2014.00083 
126.  
Shiffman S, Stone AA, Hufford MR. Ecological momentary assessment. Annu Rev Clin Psychol. 2008;4:1-32. 
doi:10.1146/annurev.clinpsy.3.022806.091415 
127.  
Shiffman S. Ecological momentary assessment (EMA) in studies of substance use. Psychol Assess. 
2009;21(4):486-497. doi:10.1037/a0017074 
128.  
Heron KE, Smyth JM. Ecological momentary interventions: incorporating mobile technology into 
psychosocial and health behaviour treatments. Br J Health Psychol. 2010;15(Pt 1):1-39. 
doi:10.1348/135910709X466063 
129.  
Riordan BC, Conner TS, Flett JAM, Scarf D. A brief orientation week ecological momentary intervention 
to reduce university student alcohol consumption. J Stud Alcohol Drugs. 2015;76(4):525-529. 
doi:10.15288/jsad.2015.76.525 
130.  
Hébert ET, Stevens EM, Frank SG, et al. An ecological momentary intervention for smoking cessation: The 
associations of just-in-time, tailored messages with lapse risk factors. Addict Behav. 2018;78:30-35. 
doi:10.1016/j.addbeh.2017.10.026 
131.  
Shrier LA, Burke PJ, Kells M, et al. Pilot randomized trial of MOMENT, a motivational counseling-plus-
ecological momentary intervention to reduce marijuana use in youth. Mhealth. 2018;4:29. 
doi:10.21037/mhealth.2018.07.04 
132.  
Short NA, Morabito DM, Gilmore AK. Secondary Prevention for Posttraumatic Stress and Related 
Symptoms among Women who Experienced Recent Sexual Assault: A Systematic Review and Meta-
Analysis. Depress Anxiety. 
133.  
Resnick HS, Acierno R, Amstadter AB, Self-Brown S, Kilpatrick DG. An acute post-sexual assault 
intervention to prevent drug abuse: Updated findings. Addictive behaviors. 2007;32(10):2032-2045. 
134.  
Acierno R, Resnick HS, Flood A, Holmes M. An acute post-rape intervention to prevent substance use and 
abuse. Addict Behav. 2003;28(9):1701-1715. 
135.  
Kazdin AE. Understanding how and why psychotherapy leads to change. Psychother Res. 2009;19(4-5):418-
428. doi:10.1080/10503300802448899 
136.  
Insel TR, Gogtay N. National Institute of Mental Health clinical trials: new opportunities, new 
expectations. JAMA Psychiatry. 2014;71(7):745-746. doi:10.1001/jamapsychiatry.2014.426 
137.  
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture 
(REDCap)--a metadata-driven methodology and workflow process for providing translational research 
informatics support. J Biomed Inform. 2009;42(2):377-381. doi:10.1016/j.jbi.2008.08.010 
138.  
Watson D, Clark LA. The PANAS-X: Manual for the Positive and Negative Affect Schedule-Expanded Form. The 
University of Iowa: Ames; 1994. 
139.  
Heishman SJ, Evans RJ, Singleton EG, Levin KH, Copersino ML, Gorelick DA. Reliability and validity of a 
short form of the Marijuana Craving Questionnaire. Drug Alcohol Depend. 2009;102(1-3):35-40. 
doi:10.1016/j.drugalcdep.2008.12.010 
140.  
Mindfield Biosystems Inc. eSense system. Berlin, Germany 
141.  
Hinrichs R, Ressler K, McLean S, Jovanovic T. Increased Skin Conductance Response Hours After Trauma 
Predicts Post-Traumatic Mental Health Sequelae. Biol Psychiatry. 2020;87(9):S102-S103. 
142.  
Short NA, Schmidt NB. A multimethod examination of the effect of insomnia symptoms on anxious 
responding to a social stressor. Behav Ther. 2018;49(3):323-330. doi:10.1016/j.beth.2017.11.001 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
46 
143.  
Carreiro S, Chintha KK, Shrestha S, Chapman B, Smelson D, Indic P. Wearable sensor-based detection of 
stress and craving in patients during treatment for substance use disorder: A mixed methods pilot study. 
Drug Alcohol Depend. 2020;209:107929. doi:10.1016/j.drugalcdep.2020.107929 
144.  
Karenbach C. Ledalab-a software package for the analysis of phasic electrodermal activity. Allgemeine 
Psychologie, Institut für Psychologie, Freiburg, Germany, Tech Rep. 2005. 
145.  
Devilly GJ, Borkovec TD. Psychometric properties of the credibility/expectancy questionnaire. J Behav Ther 
Exp Psychiatry. 2000;31(2):73-86. doi:10.1016/S0005-7916(00)00012-4 
146.  
Milosevic I, Levy HC, Alcolado GM, Radomsky AS. The treatment acceptability/adherence scale: moving 
beyond the assessment of treatment effectiveness. Cogn Behav Ther. 2015;44(6):456-469. 
doi:10.1080/16506073.2015.1053407 
147.  
Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes Measurement Information System 
(PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-
2008. J Clin Epidemiol. 2010;63(11):1179-1194. doi:10.1016/j.jclinepi.2010.04.011 
148.  
Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL. The Posttraumatic Stress Disorder Checklist 
for DSM-5 (PCL-5): Development and Initial Psychometric Evaluation. J Trauma Stress. 2015;28(6):489-498. 
doi:10.1002/jts.22059 
149.  
Kessler RC, Calabrese JR, Farley PA, et al. Composite International Diagnostic Interview screening scales 
for DSM-IV anxiety and mood disorders. Psychol Med. 2013;43(8):1625-1637. 
doi:10.1017/S0033291712002334 
150.  
Stephens RS, Roffman RA, Curtin L. Comparison of extended versus brief treatments for marijuana use. J 
Consult Clin Psychol. 2000;68(5):898-908. 
151.  
Simons J, Correia CJ, Carey KB, Borsari BE. Validating a five-factor marijuana motives measure: Relations 
with use, problems, and alcohol motives. J Couns Psychol. 1998;45(3):265-273. doi:10.1037/0022-
0167.45.3.265 
152.  
Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the Alcohol Use Disorders 
Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful 
Alcohol Consumption--II. Addiction. 1993;88(6):791-804. doi:10.1111/j.1360-0443.1993.tb02093.x 
153.  
Skinner HA. The drug abuse screening test. Addict Behav. 1982;7(4):363-371. 
154.  
Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström Test for Nicotine 
Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict. 1991;86(9):1119-1127. 
doi:10.1111/j.1360-0443.1991.tb01879.x 
155.  
Newman MG, Przeworski A, Consoli AJ, Taylor CB. A randomized controlled trial of ecological 
momentary intervention plus brief group therapy for generalized anxiety disorder. Psychotherapy (Chic). 
2014;51(2):198-206. doi:10.1037/a0032519 
156.  
National Center for Telehealth & Technology. Breathe2Relax. Joint Base Lewis-McChord, WA, USA; 2016. 
157.  
Forbes EJ, Pekala RJ. Psychophysiological effects of several stress management techniques. Psychol Rep. 
1993;72(1):19-27. 
158.  
Jerath R, Crawford MW, Barnes VA, Harden K. Self-regulation of breathing as a primary treatment for 
anxiety. Appl Psychophysiol Biofeedback. 2015;40(2):107-115. doi:10.1007/s10484-015-9279-8 
159.  
Craske MG, Rowe M, Lewin M, Noriega‐Dimitri R. Interoceptive exposure versus breathing retraining 
within cognitive‐behavioural therapy for panic disorder with agoraphobia 1. British Journal of Clinical 
Psychology. 1997;36(1):85-99. 
160.  
Schmidt NB, Woolaway-Bickel K, Trakowski J, et al. Dismantling cognitive-behavioral treatment for panic 
disorder: questioning the utility of breathing retraining. J Consult Clin Psychol. 2000;68(3):417-424. 
doi:10.1037//0022-006x.68.3.417 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
47 
161.  
Saltzman LE, Basile KC, Mahendra RR, Steenkamp M, Ingram E, Ikeda R. National estimates of sexual 
violence treated in emergency departments. Ann Emerg Med. 2007;49(2):210-217. 
doi:10.1016/j.annemergmed.2006.10.015 
162.  
Resnick H, Acierno R, Waldrop AE, et al. Randomized controlled evaluation of an early intervention to 
prevent post-rape psychopathology. Behav Res Ther. 2007;45(10):2432-2447. doi:10.1016/j.brat.2007.05.002 
163.  
Resnick H, Acierno R, Kilpatrick DG, Holmes M. Description of an early intervention to prevent substance 
abuse and psychopathology in recent rape victims. Behav Modif. 2005;29(1):156-188. 
doi:10.1177/0145445504270883 
164.  
Short NA, Zvolensky MJ, Schmidt NB. A pilot randomized clinical trial of Brief Behavioral Treatment for 
Insomnia to reduce problematic cannabis use among trauma-exposed young adults. 
165.  
Keough ME, Schmidt NB. Refinement of a brief anxiety sensitivity reduction intervention. J Consult Clin 
Psychol. 2012;80(5):766-772. doi:10.1037/a0027961 
166.  
Gilmore AK, Walsh K, Frazier P, et al. Post-Sexual Assault Mental Health: A Randomized Clinical Trial of a 
Video-Based Intervention. J Interpers Violence. November 2019:886260519884674. 
doi:10.1177/0886260519884674 
167.  
Score Cut Points. https://www.healthmeasures.net/score-and-interpret/interpret-scores/promis/promis-
score-cut-points. Accessed May 25, 2021. 
168.  
PROMIS. Brief guide to the PROMIS© Depression instruments.; 2017. 
169.  
Weathers F, Litz B, Herman D, Huska J, Keane T. The PTSD checklist (PCL): Reliability, validity, and 
diagnostic utility. In: ; 1993. 
170.  
Treece EW, Treece Jr JW. Elements of research in nursing. Nursing2019. 1977;7(6):12-13. 
171.  
Connelly LM. Pilot studies. Medsurg Nursing. 2008;17(6):411. 
172.  
Zeltzer LK, Tsao JCI, Stelling C, Powers M, Levy S, Waterhouse M. A phase I study on the feasibility and 
acceptability of an acupuncture/hypnosis intervention for chronic pediatric pain. J Pain Symptom Manage. 
2002;24(4):437-446. doi:10.1016/s0885-3924(02)00506-7 
173.  
Garley A, Unwin J. A case series to pilot cognitive behaviour therapy for women with urinary 
incontinence. Br J Health Psychol. 2006;11(3):373-386. 
174.  
Dunn BD, Widnall E, Reed N, Owens C, Campbell J, Kuyken W. Bringing light into darkness: A multiple 
baseline mixed methods case series evaluation of Augmented Depression Therapy (ADepT). Behav Res 
Ther. 2019;120:103418. doi:10.1016/j.brat.2019.103418 
175.  
Barton S, Armstrong P, Freeston M, Twaddle V. Early intervention for adults at high risk of 
recurrent/chronic depression: Cognitive model and clinical case series. Behavioural and Cognitive 
Psychotherapy. 2008;36(3):263-282. 
176.  
Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: A flexible statistical power analysis program for the 
social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175-191. 
doi:10.3758/BF03193146 
177.  
Cohen J. Statistical power for the behavioural sciences. Hilsdale. NY: Lawrence Erlbaum. 1988. 
178.  
Fritz MS, Mackinnon DP. Required sample size to detect the mediated effect. Psychol Sci. 2007;18(3):233-
239. doi:10.1111/j.1467-9280.2007.01882.x 
179.  
Kleiman E. Power curves for multi-level studies. https://kleimanlab.org/resources/power-curves/. Published 
2020. 
180.  
McLean SA, Ressler K, Koenen KC, et al. The AURORA Study: a longitudinal, multimodal library of brain 
biology and function after traumatic stress exposure. Mol Psychiatry. 2020;25(2):283-296. 
doi:10.1038/s41380-019-0581-3 
181.  
IBM Corp. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp; 2017. 

RISE RCT Study 
Version 2.8 
Protocol 20-3494 
27 November 2024 
 
 
48 
182.  
Olsen MK, Schafer JL. A two-part random-effects model for semicontinuous longitudinal data. J Am Stat 
Assoc. 2001;96(454):730-745. 
183.  
Amrhein V, Greenland S, McShane B. Scientists rise up against statistical significance. Nature. 
2019;567(7748):305-307. doi:10.1038/d41586-019-00857-9 
184.  
Muthén LK, Muthén BO. Mplus User’s Guide. Los Angeles, CA 
185.  
Mazza GL, Enders CK, Ruehlman LS. Addressing Item-Level Missing Data: A Comparison of Proration and 
Full Information Maximum Likelihood Estimation. Multivariate Behav Res. 2015;50(5):504-519. 
doi:10.1080/00273171.2015.1068157 
186.  
Schwartz JE, Stone AA. Strategies for analyzing ecological momentary assessment data. Health Psychol. 
1998;17(1):6-16. doi:10.1037/0278-6133.17.1.6 
187.  
Black AC, Harel O, Matthews G. Techniques for analyzing intensive longitudinal data with missing values. 
2012. 
188.  
Stephens RS, Roffman RA, Simpson EE. Treating adult marijuana dependence: a test of the relapse 
prevention model. J Consult Clin Psychol. 1994;62(1):92-99. doi:10.1037//0022-006x.62.1.92 
189.  
Welch BM, Marshall E, Qanungo S, et al. Teleconsent: A novel approach to obtain informed consent for 
research. Contemp Clin Trials Commun. 2016;3:74-79. doi:10.1016/j.conctc.2016.03.002 
190.  
Bobb MR, Van Heukelom PG, Faine BA, et al. Telemedicine provides noninferior research informed 
consent for remote study enrollment: A randomized controlled trial. Acad Emerg Med. 2016;23(7):759-765. 
doi:10.1111/acem.12966 
191.  
Weathers FW, Litz BT, Keane TM, et al. The PTSD checklist for DSM-5 (PCL-5). National Center for PTSD; 
2013. 
192.  
Peters EN, Nich C, Carroll KM. Primary outcomes in two randomized controlled trials of treatments for 
cannabis use disorders. Drug Alcohol Depend. 2011;118(2-3):408-416. doi:10.1016/j.drugalcdep.2011.04.021 
193.  
International Conference on Harmonisation Good. ICH harmonised guideline integrated addendum to 
ICH E6(R1): Guideline for Good Clinical Practice ICH E6(R2) ICH Consensus Guideline. Good Clinical 
Practice Network. https://ichgcp.net/. Accessed May 19, 2021. 
194.  
UNC Office of Human Research Ethics (OHRE). SOP 1401: Reporting New Safety Information . July 2018.