Meet me Where I am: A Multilevel Strategy to Increase PrEP Uptake and Persistence in Rural NC
Phase: NA
Conditions: HIV Pre-Exposure Prophylaxis
Sponsor: University of North Carolina, Chapel Hill

Meet me where I am: A multilevel strategy to increase PrEP uptake 
and persistence in rural NC (“STARR-NC”) 
NCT05984030 
DATE: SEPTEMBER 30TH, 2024 

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Meet me where I am: A multilevel strategy to increase PrEP uptake and persistence in 
rural NC (“STARR-NC”)         
PHASE 1 Study  
 
 
 
PROTOCOL NUMBER: UNC IGHID 12221 
 
 
VERSION 4.0 
DATE: SEPTEMBER 30TH, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
List of Abbreviations and Acronyms ................................................................................................................................... 4 
Protocol Team Roster ......................................................................................................................................................... 6 
Study Synopsis .................................................................................................................................................................... 8 
Intervention Trial Study Schema ...................................................................................................................................... 11 
1.0 BACKGROUND AND RATIONALE ................................................................................................................................. 11 
2.0 STUDY OBJECTIVES ..................................................................................................................................................... 13 
3.0 STUDY DESIGN ............................................................................................................................................................ 14 
3.1 Collaborating STI Clinics .......................................................................................................................................... 14 
3.2 Randomization and Conditions .............................................................................................................................. 15 
3.2.1 Intervention Arm Condition ................................................................................................................................ 15 
3.2.2 Control Arm Condition......................................................................................................................................... 17 
4.0 TRAINING .................................................................................................................................................................... 17 
4.1 Research Staff Trainings ......................................................................................................................................... 17 
4.2 Clinic Training ......................................................................................................................................................... 17 
4.3 PrEP Navigator Trainings ........................................................................................................................................ 18 
5.0 SELECTION AND ENROLLMENT OF STUDY PARTICIPANTS .......................................................................................... 19 
5.1 Participant Inclusion Criteria .................................................................................................................................. 19 
5.2 Participant Recruitment ......................................................................................................................................... 19 
5.3 Procedures to Minimize Fraudulent Participation .................................................................................................. 19 
5.4 Screening for Eligibility ........................................................................................................................................... 20 
5.5 Informational Video ................................................................................................................................................ 20 
5.6 Informed Consent ................................................................................................................................................... 20 
5.7 HIPAA Authorization ............................................................................................................................................... 20 
5.8 Participant Randomization ..................................................................................................................................... 20 
6.0 RCT STUDY PROCEDURES (AIM 1, R61) ....................................................................................................................... 21 
6.1 Study onboarding appointment and baseline assessment .................................................................................... 21 
6.2 Participant Enrollment and Onboarding................................................................................................................. 22 
6.3 Intervention Procedures ......................................................................................................................................... 23 
6.4 Follow-up study assessments ................................................................................................................................. 23 
6.5 Self-collected blood sample ................................................................................................................................... 24 

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6.6 Clinic assessments .................................................................................................................................................. 24 
6.7 Qualitative in-depth interviews .............................................................................................................................. 24 
7.0 OUTCOME MEASURES AND DATA SOURCES .............................................................................................................. 25 
8.0 PARTICIPANT MANAGEMENT ..................................................................................................................................... 28 
8.1 Participant Retention ............................................................................................................................................. 28 
8.2 Participant Remuneration ...................................................................................................................................... 29 
8.3 Suspected or Confirmed HIV/STI Infection at Screening, or While on Study ......................................................... 29 
8.4 Participant Withdrawal ........................................................................................................................................... 30 
9.0 STATISTICAL/ANALYTIC CONSIDERATIONS ................................................................................................................. 30 
9.1 Sample Size and Power Estimate ............................................................................................................................ 30 
9.2 Outcome Analysis ................................................................................................................................................... 31 
9.2.1 Primary Outcome Analyses ................................................................................................................................. 32 
9.2.2 Secondary Outcomes Analyses ............................................................................................................................ 32 
9.2.3 Additional Outcome Analyses ............................................................................................................................. 32 
10.0 COST-EFFECTIVENESS STUDY PROCEDURES (AIM 2, R61) ........................................................................................ 34 
10.1 Overall Approach .................................................................................................................................................. 34 
10.2 Cost Measurement ............................................................................................................................................... 34 
10.3 Model Design and Analytical Perspective ............................................................................................................ 35 
10.4 Outcomes and Analysis ........................................................................................................................................ 35 
10.5 Dissemination ....................................................................................................................................................... 36 
11.0 MILESTONES ............................................................................................................................................................. 36 
12.0 REFINING INTERVENTION (AIM 3, R33) .................................................................................................................... 39 
12.1 Objectives ............................................................................................................................................................. 39 
12.2 Approach .............................................................................................................................................................. 40 
12.3 Data Collection and Analysis ................................................................................................................................ 40 
13.0 DETERMINE EFFECTIVENESS OF REFINED INTERVENTION (AIM 4, R33) .................................................................. 40 
13.1 Objectives ............................................................................................................................................................. 40 
13.2 Data Sources ......................................................................................................................................................... 41 
13.3 PrEP Outcome Analysis ......................................................................................................................................... 41 
13.4 Power and Sample Size ......................................................................................................................................... 41 
13.5 Implementation Outcomes .................................................................................................................................. 42 
13.6 Cost Analysis ......................................................................................................................................................... 42 

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14.0 DATA COLLECTION, MANAGEMENT AND MONITORING .......................................................................................... 42 
14.1 Development of Protocol and Case Report Forms ............................................................................................... 42 
14.2 Data Records......................................................................................................................................................... 42 
14.3 Record Availability ................................................................................................................................................ 42 
14.4 Data Collection Across all Aims ............................................................................................................................ 42 
14.5 Data Storage and Security .................................................................................................................................... 43 
14.6 Data Quality Assurance ........................................................................................................................................ 44 
14.7 Role of Data Management ................................................................................................................................... 44 
14.8 Data and Safety Monitoring Plan ......................................................................................................................... 44 
14.9 Study Monitoring Committee ............................................................................................................................... 44 
15.0 HUMAN SUBJECTS CONSIDERATIONS ...................................................................................................................... 45 
15.1 Participant Confidentiality .................................................................................................................................... 45 
15.2 Risks and Benefits ................................................................................................................................................. 45 
15.2.1 Risks ................................................................................................................................................................... 45 
15.2.2 Benefits .............................................................................................................................................................. 46 
15.3 Intervention Monitoring ....................................................................................................................................... 46 
15.3.1 Adverse Events: ................................................................................................................................................. 46 
15.3.2 Social Harms ...................................................................................................................................................... 47 
15.3.3 Unanticipated Problems .................................................................................................................................... 48 
15.4 Ethical review ....................................................................................................................................................... 48 
15.5 Informed consent ................................................................................................................................................. 48 
15.6 Participant Remuneration .................................................................................................................................... 49 
16.0 LABORATORY SPECIMENS ......................................................................................................................................... 49 
16.1 Dried blood spots ................................................................................................................................................. 49 
17.0 STUDY TIMELINE ....................................................................................................................................................... 50 
18.0 PROTOCOL COMPLIANCE .......................................................................................................................................... 52 
REFERENCES ...................................................................................................................................................................... 53 
Appendix ........................................................................................................................................................................... 58 
 
 
 
 
 

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List of Abbreviations and Acronyms 
 
 
AE  
Adverse Events  
AIDS  
Acquired Immunodeficiency Syndrome  
BL 
Baseline  
CAB (CAB LA)  
Long-Acting Injectable Cabotegravir  
CASI  
Computer assisted self-interview  
CDC  
Center for Disease Control and Prevention  
CELR 
Clinical and Environmental Lab Result 
CRF  
Case Report Form  
Co-I 
Co-Investigator  
CQMP 
Clinical Quality Monitoring Plan  
DBS  
Dried Blood Spots  
NC DHHS 
North Carolina Department of Health and Human 
Services  
DHIs  
Digital Health Interventions  
EHR  
Electronic Health Records  
FTC 
Emtricitabine 
GCP  
Good Clinical Practices  
HD  
Health Department 
HCD  
Human-centered design  
HIPAA  
Health Insurance Portability and Accountability Act  
HIV  
Human Immunodeficiency Virus  
HMP  
HealthMPowerment  
HSP  
Human Subjects Protection  
IDI  
In-Depth Interview  
IGHID 
Institute for Global Health and Infectious Diseases 
IRB  
Institutional Review Board  
IT  
Information Technology  
MSM  
Men who have Sex with Men  
NC  
North Carolina  
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD  
National Institute of Child Health and Development  
NIDA  
National Institute on Drug Abuse  
NIH 
National Institutes of Health 
PI  
Principal Investigator  
PrEP  
Pre-exposure prophylaxis  
OHRP  
Office of Human Research Protection  
QA  
Quality Assurance  
RCT  
Randomized Control Trial  

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SID  
Study ID Number  
STI 
Sexually Transmitted Infection 
SOC  
Standard of Care  
STARR-NC 
Supporting Tailored And Responsive PrEP in Rural North 
Carolina 
TFV 
Tenofovir 
UNC  
University of North Carolina  
UNC-CH  
University of North Carolina at Chapel Hill  
UP  
Unanticipated Problem  
YGSM 
Young Gender and Sexuality Minority  
YAB  
Youth Advisory Board  
YMSM  
Young Men Who Have Sex with Men  
 
 
 

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Protocol Team Roster 
 
Principal investigators/protocol co-chairs 
Kate Muessig, PhD 
Professor, College of Nursing 
Florida State University 
98 Varsity Way 
Tallahassee, FL 32306-4310 
Email: kmuessig@fsu.edu  
Sarah Rutstein, MD, PhD 
Assistant Professor, Division of Infectious 
Diseases 
School of Medicine 
UNC-Chapel Hill 
130 Mason Farm Road, 27599 
Chapel Hill, NC 27599 
Email: sarah_rutstein@med.unc.edu 
Co-investigators 
Brian Pence, PhD 
Co-Investigator 
Professor, Department of Epidemiology 
McGavran-Greenberg UNC-Chapel Hill 
Chapel Hill, NC 27599-7435 
Email: bpence@unc.edu 
Christopher Hurt, MD 
Co-Investigator 
Associate Professor, Division of Infectious 
Disease 
UNC-Chapel Hill Department of Medicine 
CB# 7030, Bioinformatics Building 
130 Mason Farm Road, 2nd Floor 
Chapel Hill, NC 27599-7030 
Email: churt@med.unc.edu 
Dale Burwen, MD, MPH 
Medical Officer 
Clinical Prevention Research Branch 
Prevention Sciences Program 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
5601 Fishers Lane 9B38 
Rockville, MD 20892-9831 
United States 
Email: dale.burwen@nih.gov 
Jessie Edwards, PhD 
Co-Investigator 
Research Assistant Professor, Department of 
Epidemiology 
UNC-Chapel Hill McGavran-Greenberg Hall 
Chapel Hill, NC 27599 USA 
Email: jkedwar@email.unc.edu 
Lisa Hightow-Weidman, MD, MPH 
Co-Investigator 
Professor, College of Nursing 
Florida State University 
98 Varsity Way 
Tallahassee, FL 32306-4310 
Email: lhightowweidman@fsu.edu 
Jamal Dejli, PhD, MPH 
Program Officer 
Clinical Prevention Research Branch 
Prevention Sciences Program 
Division of AIDS 
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane 
Rockville, MD 20892-9831 
United States 
Email: jamal.dejli@nih.gov  

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Study staff 
Ella Ferguson, MPH 
Study Coordinator 
Institute for Global Health & Infectious Diseases, 
UNC-Chapel Hill 
Bioinformatics Building, 2nd floor 
130 Mason Farm Road 
Chapel Hill, NC 27599 
Email: ella_ferguson@med.unc.edu 
 
 
 

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Study Synopsis 
 
SPONSOR: 
National Institute of Allergy and Infectious Diseases (NIAID) 
TITLE OF STUDY: 
Meet me where I am: A multilevel strategy to increase pre-exposure 
prophylaxis (PrEP) uptake and persistence in rural North Carolina (NC).  
PROTOCOL NUMBER: 
UNC IRB: 22-3058, IGHID 12221 
NIH Grant: R61AI174285 
STUDY DESIGN AND 
CONDITIONS:  
This project consists of two phases to be completed over five years. Phase 1 
(Aims 1 and 2) will be completed during Years 1-3 (R61). The Phase 1 study 
is a randomized trial of a multilevel PrEP intervention strategy in rural NC 
sexually transmitted infection (STI) clinics, with primary outcome of PrEP 
uptake within 3 months of an index STI clinic visit.  
 
Participants will be randomized 1:1 to an intervention or control condition. 
Participants enrolled in the intervention arm will receive a multilevel 
intervention with three components: a PrEP Navigator to facilitate linkage 
to PrEP services and completion of applications for health insurance/drug 
assistance; a Digital Health Intervention (DHI) platform 
(HealthMpowerment) – a HIPAA-compliant evidence-based DHI that 
provides interactive educational resources, social support, and tools for 
developing PrEP behavioral skills and self-efficacy; and referral to 
Telehealth PrEP services as an option for linking to PrEP care.  
 
Control arm participants will receive the standard PrEP referral services 
available in a given clinic setting. They will also receive linkage to a limited 
version of the DHI, with basic PrEP resources and information. 
 
The current protocol is for the Phase 1 study.   
DURATION: 
The navigation intervention period is 3-6 months (dependent on enrollment 
date), enrolled study participants are followed for up to 12 months.  
SAMPLE SIZE: 
Phase 1 
Intervention trial: 336 STI clinic patients across all participating clinics. 
Implementation evaluation: up to 50 clinic staff, providers and other key 
stakeholders.  
POPULATION:  
Intervention trial participants enrolled who will contribute to final study 
outcomes will be HIV-negative individuals who were assigned male sex at 
birth or cisgender women, are not currently using PrEP at enrollment, have 
regular access to a smartphone, aged 18 to 39 years who report sexual 
activity with a male in the past 12 months and are presenting for STI testing 
or care to participating clinics and/or clinic events in North Carolina. 

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RECRUITMENT SITES: 
 Rural and peri-urban NC STI clinics. 
STRATIFICATION:  
Intervention trial participants will be randomized 1:1 to the control or 
intervention condition at enrollment using blocked randomization stratified 
by county, with randomly ordered blocks of sizes 4 and 6.  
DATA 
COLLECTION: 
Data sources:  
- Computer assisted self-interviewing (CASI) biobehavioral surveys  
- STI/HIV test results  
- Dried Blood Spots (DBS) to detect PrEP use  
- Medical records related to PrEP initiation and care 
- Daily app use data collected automatically by the DHI app’s analytic 
system and as entered by participants  
- Process data measures collected from study implementation records 
- Qualitative in-depth interviews (IDI) with a subsample of up to 50 
intervention trial participants and up to 50 clinic staff/providers/key 
stakeholders 
- Direct observations (time-and-motion) and relevant invoices/receipts for 
costing 
 
Data collection points:  
Baseline, 3-months, 6-months (subset), 12-months (subset).  
 
Participants enrolled in approximately the final quarter of enrollment will 
only complete baseline and 3-month data collection points.  
 
Daily app use, PrEP adherence tracking, and behavioral tracking.  
Costing data collection will be embedded into daily study activities.  
OBJECTIVES 
Aim 1: Conduct a randomized trial of a multilevel PrEP intervention 
strategy in rural and peri-urban NC STI clinics. 
 
Primary Objective: To use episodic STI service encounters to increase 
linkage to convenient, continuous PrEP care.  
Primary outcome:  
PrEP uptake within 3 months of an index STI clinic visit. 
 
Secondary outcomes:  
PrEP uptake within 6 months of an index STI clinic visit, PrEP care 
engagement, PrEP use, PrEP adherence, incident STI/HIV, and PrEP stigma.  
 
Aim 2: Conduct cost-effectiveness analysis, including budget impact 
analysis 
 
Cost-effectiveness analysis: 
Intervention effectiveness and prospectively collected cost data will be used 
to model cost per new PrEP initiation. Budget impact analyses will identify 

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drivers of cost, informing strategy refinement for STI clinic staffing and 
scale-up. 
 
Go/No-Go criteria 
If pre-determined milestones are met, Phase 2 of the project will refine and 
scale up the intervention to all persons who enroll from a participating clinic 
in a subsequent implementation trial.   
A revised protocol will be submitted as an amendment for Phase 2 (R33), 
which includes the following aims: 
 
Aim 3: Engage state and local stakeholders to refine PrEP intervention, 
tailored to unique contextual needs.  
 
Aim 4: Determine effectiveness and cost-effectiveness of refined PrEP 
implementation strategy, expanded to all participants. 

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Intervention Trial Study Schema 
 
 
1.0 BACKGROUND AND RATIONALE 
To end HIV, the United States (US) needs integrated, scalable, and cost-effective prevention strategies. Despite 
the high efficacy of PrEP, less than 20% of PrEP eligible people have received a prescription, with noted regional 
and racial disparities1–4.  In 2018, the US South accounted for 51% of new HIV diagnoses but only 33% of PrEP 
users5. In North Carolina (NC), where 1 in 93 residents will acquire HIV in their lifetime 6,7, PrEP use is half of the 
US average. The PrEP-to-Need ratio, which is a metric of PrEP equity that measures PrEP uptake relative to new 
HIV diagnoses highlights disparities in PrEP uptake among specific demographic groups such as Black, Hispanic, 
Southern people, and women, indicating these groups are underserved relative to their epidemic need 8. 
For newly diagnosed adolescents and adults in North Carolina in 2022, the most likely route of HIV transmission 
reported was male-male sex (reported by 57.8%), followed by heterosexual sex (18.7%) 9. PrEP uptake is lowest 
among young sexual and gender minority populations (YSGM) who account for 63% of new HIV infections in NC 
5,7. In 2022, 17.1% of newly diagnosed HIV cases in North Carolina in were among women aged 20 – 64 9. Among 

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women, 2022 preliminary data indicated that only 15% of women in the United States who could benefit from 
PrEP were prescribed PrEP 10.  
Among NC counties with the most HIV diagnoses in 2019, four have rural designation and nine are small or 
medium metropolitan areas 7,11. The lack of robust healthcare infrastructure in these areas presents challenges 
for HIV prevention services.  NC’s HIV epidemic tracks alongside rising sexually transmitted infections (STI)12  with 
disproportionately high burden among rural YSGM. Despite behavioral risk overlap of incident STIs/HIV, in NC, 
PrEP is only offered at a few, primarily urban health department (HD) affiliated STI clinics13,14. As of November 
2022, we have identified 15 HD-affiliated STI clinics in relatively high-HIV burden, rural (n=13) or peri-urban 
(n=2) counties across NC who are interested in participating in this study.  As of January 2024, the study is 
expanding to additional rural and peri-urban STI clinics in NC. All patients who are seeking STI testing at the 
participating clinics are offered HIV testing on-site. Per NC standard of care, all patients who are diagnosed with 
HIV are referred to immediate ART care, which may be offered onsite or through other HIV providers. However, 
linkage to PrEP services is not well-established: at the initial 15 participating HD STI clinics, as of May 2023, 
one clinic (Wilson County, rural) offers referral to a co-located primary care clinic that can prescribe PrEP. The 
remaining 14 HD clinics do not provide any PrEP services to patients beyond passive referral to services in the 
community (e.g. patient is provided private practice provider name(s) that may offer PrEP services. None of 
these 15 clinics have providers “in-house” prescribing PrEP and none have PrEP navigation services. STI clinics 
are a logical entrée to PrEP, but ineffective integration in rural HDs reflects heterogeneity in clinic structure and 
staffing: STI clinics are designed to provide episodic care, whereas PrEP services require additional human 
resources and longitudinal engagement to be effective 15. Leveraging STI clinics as an on-ramp to PrEP is a 
compelling opportunity to capitalize on STI service encounters and address disparities in PrEP access for YSGM16–
18  
Multilevel impediments to PrEP scale-up in NC include provider shortages, overburdened STI clinics, 
intersectional stigmas, and lack of PrEP knowledge among providers, rural YSGM19–22 and cisgender women23.  
These challenges are compounded by poverty and lack of insurance. Building on collaborations with state and 
local partners, we will implement a multilevel intervention within county STI clinics that links PrEP and STI 
services, addressing barriers at policy, clinic, provider, and user levels while working within clinic operational 
limits and competing demands on physical and human resources. This intervention is intended to build PrEP 
capacity and confidence through clinic training; provides pathways to PrEP using PrEP navigators for linkage to 
available financial support and services; supports linkage to telehealth PrEP; and uses an evidence-based digital 
health platform (HealthMpowerment [HMP]) 24–27 to connect users to tailored social and informational support 
for PrEP initiation and persistence28,29.   
Despite behavioral risk overlap of incident STIs and HIV, incorporating PrEP services into STI clinics presents 
unique implementation challenges. Barriers at the provider (self-efficacy, scarcity of HIV practitioners), clinic 
(budget constraints, understaffing), and structural level (lack of billing 3rd party payers), complicate PrEP scale-
up in rural HD STI clinics 30. One of the most significant barriers to combining effective PrEP services with existing 
STI care is the fact that, by design, STI care is episodic: persons with recent risk, exposure, or symptoms present 
for diagnosis and management, and then are discharged until such need arises again. However, per CDC 
recommendations, screening for bacterial STIs should occur at least every 6 months for all sexually active 
patients and every 3 months among MSM or among patients with ongoing risk behaviors 31,32. 
Effective PrEP care requires ongoing engagement, with adherence support and follow-up visits29. Some persons 
are not ready to initiate PrEP, while others may be ready but require assistance with finances and insurance15. 
One-off referrals from STI clinics to external PrEP providers rarely result in PrEP initiation 30,31, with uptake 
particularly poor among youth30 and non-Hispanic Blacks32. Even urban programs that successfully link STI clinic 
patients to PrEP lack the capacity to longitudinally manage financial needs of PrEP patients without additional 

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individualized navigation17. The diverse needs of potential PrEP recipients likely exceed what can be reasonably 
provided by STI clinic staff in standalone clinics. Developing a pathway to PrEP, such as this intervention, that 
complements clinic resources and workflow, including linking to PrEP navigation and offering high quality STI 
testing services/monitoring for PrEP users, is an appealing strategy to leverage STI clinics as an on-ramp to 
sustained PrEP services. This study will demonstrate an effective, feasible model to co-locate STI services and 
PrEP access in rural and peri-urban settings and provide critical information about ways to tailor this service 
delivery model for differences at small vs. larger clinics and under different types of staffing scenarios (e.g., 
using remote PrEP navigators, telePrEP providers, onsite PrEP providers, etc.).  As established, trusted service 
providers, STI clinics can play an important role in providing individualized services to optimize PrEP uptake and 
retention and ensure ongoing access to PrEP. The HMP DHI was first found effective in a North Carolina-wide 
RCT 23,33 which found that greater HMP engagement was significantly associated with lower condomless anal 
sex, stigma reduction, and greater provider communication, HIV status disclosure to partners, and HIV care 
outcomes (e.g., engagement in care, adherence) 23,34. HMP is currently being employed in multiple 
interventional and cohort trials, including a national sample of Black and Latinx YMSM and transgender women 
(TGW)33, a cohort study focusing on understanding factors associated with the risk of STI and HIV diagnosis and 
predictors of PrEP use among Black cis and transgender women in Alabama, and a national interventional trial 
aiming to improve ART and PrEP adherence over time for sexual and gender minority youth ages 13-34. HMP has 
also been used in RCTs in Nigeria and South Africa, focusing on medication adherence among adolescent men, 
and women.  
This study also includes budget impact and cost-effectiveness analyses (Aim 2) which are critical for program 
planning and for demonstrating the feasibility and sustainability of our proposed intervention strategy for co-
located service access. As payers and providers endeavor to increase PrEP uptake, understanding the 
comparative value of alternative strategies particularly in populations with high HIV risk and low PrEP use, is 
urgently needed. Successful implementation and scale-up of the proposed intervention relies on effectively 
focusing scarce resources and understanding the main drivers of clinic-level costs. Decision models can 
demonstrate and explore tradeoffs in value between upfront intervention costs, potential cost savings, and 
health benefits from averting future illness. 
2.0 STUDY OBJECTIVES  
Primary Objective: Our overarching objective is to parlay episodic STI service encounters into linkage to 
convenient, continuous PrEP care. Our primary effectiveness outcome of interest is PrEP uptake within 3 months 
of an eligible clinic visit. 
In the R61, we will determine effectiveness and cost in 2 aims: 
Aim 1 (R61): Conduct a randomized trial of a multilevel PrEP intervention strategy in rural and peri-urban NC 
STI clinics. Participants will be randomized to intervention or control conditions. Our primary outcome is PrEP 
uptake within 3 months of an STI clinic visit. We will also examine implementation outcomes, capturing process 
indicators including intervention costs, fidelity and acceptability, to inform future refinement.  
Aim 2 (R61): Conduct cost-effectiveness analysis, including budget impact analysis. Using Aim 1 effectiveness 
and prospectively collected costs, we will model cost per new PrEP initiation. We will conduct budget impact 
analyses to identify drivers of cost, informing strategy refinement for clinic staffing and scale-up. 
Upon meeting predefined effectiveness, implementation, and development milestones, we will pursue Phase 2 
R33. An updated protocol will be submitted as an amendment for Phase 2.  

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Aim 3 (R33): Engage state and local stakeholders to refine PrEP intervention, tailored to unique contextual 
needs. We will examine individual-, structural- and organizational-level determinants of success, including 
assessing implementation fidelity. Using an Intervention Mapping framework, we will identify modifiable 
barriers and build stakeholder consensus to refine our multilevel PrEP intervention. 
Aim 4 (R33): Determine effectiveness and cost-effectiveness of refined PrEP implementation strategy, 
expanded to all participants. We will expand implementation of the refined implementation strategy to all 
persons who enroll at a participating clinic. Primary effectiveness and implementation outcomes are the same as 
in Aim 1, comparing PrEP uptake to control condition from R61 phase (Aim 1). We will update our cost-
effectiveness model using parameters generated in this final implementation phase, generating an interactive 
decision-support tool. 
3.0 STUDY DESIGN 
The Phase 1 study is a randomized trial of a multilevel intervention to increase access to, uptake of, and 
maintenance on PrEP for HIV prevention. Participants will be randomized to an intervention or control condition 
(Section 3.2). The primary outcome is PrEP uptake within 3 months of an index STI clinic visit, assessed using 
drug metabolite presence, chart review, and self-report. All study participants will have access to study 
management functions as a DHI platform (HMP).  Participants randomized to the intervention condition will 
receive the multilevel intervention (Section 3.2.1) while those randomized to the control condition will receive 
the informational resources component of the DHI (Section 3.2.2). Participants will complete study measures and 
activities at baseline and 3- and 6-month follow-up timepoints, with a subset of participants also completing  12-
month follow-up (refer to Table 2.2) Participants enrolled in approximately the last 3 months of enrollment, will be 
followed for 3 months (refer to Table 2.3). We will assess implementation and process outcomes and 
organization-level determinants of success to inform future refinement.  
 
3.1 Collaborating STI Clinics  
In coordination with North Carolina DHHS partners, we utilized county-level 2019-2021 HIV/STI data (reported 
to the State Laboratory of Public Health [SLPH]), to identify local Health Department STI clinics for participation. 
Specifically, we examined testing volume and test positivity rates by reported race/ethnicity among men <40 
years of age. We also used National Center for Health Statistics urban-rural classification scheme, limiting to 
counties designated as small (<250,000) or medium (<1,000,000) metropolitan counties, and nonmetropolitan 
(rural) counties including micropolitan counties (counties associated with at least one urban cluster ≥10,000 but 
≤50,000 population) and non-core counties (nonmetropolitan counties that are not in a micropolitan statistical 
area)34. Starting in 2024, additional organizations that offer STI services and which are located in urban and peri-
urban designated counties in NC will be identified as part of the recruitment expansion strategy. Throughout the 
protocol, locations where STI services are offered are referred to as “clinics” or “STI clinics”, however these 
locations may also include non-traditional modes of delivering STI services, for example, mobile van clinics, 
services housed within community-based organizations, and clinic-affiliated health fairs or other events.  
All eligible clinics are contacted with information about the study and an invitation to participate. The study 
team meets with clinics to assess interest and appropriate fit.  Clinics that decide to participate provide signed 
Letters of Support indicating commitment to collaborate, as well as roles and responsibilities.  
 
Of the 15 participating counties participating in the study as of December 2023, 13 are designated as rural34.  

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3.2 Randomization and Conditions 
Arms will be assigned using blocked randomization stratified by county, with randomly ordered blocks of sizes 4 
and 6 to ensure that staff are not able to predict what the next randomization assignment will be. 
Participants may complete baseline, 3, 6, and 12-month assessments, with the duration of follow-up predicated 
on the period in which they were enrolled. Participants who are enrolled into the study with sufficient follow-up 
time remaining in the Phase 1 R61 will be asked to complete a 12-month assessment, while those enrolled in 
approximately the final quarter of study enrollment will only be followed for 3 months. All participants’ 
condition-specific HMP app access will remain the same throughout their study participation, regardless of 
length of participation.  
After month 6, intervention arm participants will not receive additional intervention components, such as PrEP 
navigation.  
3.2.1 Intervention Arm Condition 
All intervention arm activities may be conducted virtually.  
Participants randomized to the intervention arm will receive: 
PrEP Navigator: PrEP navigators will connect with participants following study onboarding. Navigators will serve 
participants across multiple clinics, primarily operating remotely, adapting workflow to participant and clinic 
needs. Primary navigator responsibilities include helping participants engage in PrEP care, assisting with 
completing necessary paperwork for insurance, referral to PrEP care, and application for drug assistance 
programs, as needed. All navigators will undergo study- and navigator-specific trainings (Sections 4.1 and 4.3). 
Navigation services will be available to all participants randomized to the intervention for up to 6 months – 
participants who are only followed for 3 months will by necessity only receive 3 months of navigation services.  
Digital Health Intervention: HMP is an 
HIV status-neutral, theory-informed DHI 
to support sexual health and risk 
reduction among YSGM35–37. HMP is 
guided by the Integrated Behavioral 
Model (IBM)38 facilitating examination 
of the individual and structural 
determinants of health (e.g., stigma and 
discrimination, health literacy, poverty) 
and psychological distress (e.g., 
depression, anxiety, loneliness) which 
hinder adoption of HIV preventive 
behaviors. The app provides critical 
resources for persons regardless of 
readiness to initiate PrEP as well as 
ongoing support and resources for 
those who do initiate PrEP. The features 
of HMP are described in Table 1 and 
example screenshots included in Figure 1. As part of PrEP monitoring features, participants can indicate how 
PrEP was prescribed (i.e. daily oral, event-driven oral, or injectable), as well as indicate dates PrEP was taken or, 
in the case of injectable, received.  

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Telehealth PrEP referral: PrEP Navigators can link interested participants to telehealth PrEP via self-referral.  The 
study facilitates referral for intervention arm participants to pre-existing telehealth PrEP services. The telehealth 
PrEP services participants receive are not provided, financed, or staffed by the study. Participants will receive 
telehealth PrEP services via the technology platform or service that the provider typically employs. PrEP clinical 
eligibility, visit frequency, monitoring labs, and all other PrEP management will be at the discretion of the 
established PrEP provider. Study staff will access records for participants who have agreed to medical record 
release. PrEP navigators can assist with appointment scheduling, reminders, and other provider-access issues, as 
requested, for the period of navigation service receipt.  
 
 
 
Table 1: The healthMpowerment (HMP 2.0) platform 
Administration Portal and mobile app (research staff-facing) 
Communication  
Allows for participant management (two-way, secure, direct in-app messaging, and push notifications) 
Study Management 
Survey integration and incentive tracking   
Calendar 
View schedule of study visits and activities and send automated reminders  
Analytics 
Analytics dashboard to monitor app engagement and perform engagement analyses 
Security 
HIPAA compliant, encryption of data at rest and in transit 
HMP app (participant-facing)  
Study timeline and 
calendar 
Displays access to upcoming study-related activities and a two-way secure messaging feature for 
communication between participants and research staff (including PrEP navigator) and receive reminders to 
promote completion 
Resource Center 
Expansive library of multi-media content tailored for YGSM populations of varying developmental stages 
Activities 
Information/skills building (quizzes, self-assessments, goal setting, choose-your-own-adventure, etc.) 
Newsfeed 
Social component provides space for user-generated content to include peer-to-peer sharing, exchange of 
health information and narrative discussions on topics of interest 
Ask the Expert 
Allows participants to ask questions to HIV/PrEP care expert provider and receive answers 
Medication Tracker 
Self-monitor PrEP adherence with visual calendar and provision of user feedback 
Health Tracker 
Self-monitor behaviors that impact PrEP adherence with reminders and provision of tailored feedback 
Gamification 
Sophisticated tracking of app use to trigger behavior-specific virtual rewards (e.g. badges)  

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3.2.2 Control Arm Condition 
All control arm activities may be conducted virtually.  
Participants randomized to the control arm will receive: 
Digital Health Intervention Standard-of-Care: The control arm version of the HealthMPowerment DHI platform 
includes Study timeline and Calendar features and all educational content in the Resource Center.  
4.0 TRAINING  
All training will be conducted virtually or in-person.  
4.1 Research Staff Trainings 
Any current or future project staff having study-related contact with participants will be required to complete 
Good Clinical Practice (GCP) and Human Subjects Research training for the responsible conduct of research and 
the requirements of maintaining privacy and confidentiality. Training for all research staff includes (but is not 
limited to): an overview of the study; study procedures and human subjects' issues (informed consent process, 
confidentiality); a demonstration of all technology components (e.g., screening survey, HMP application); 
methods for establishing comfort with the sensitive issues that may arise; quality management; confidentiality; 
and reporting of adverse events. Research staff includes the project manager, PIs, and research assistants.  
 
PrEP navigators are not involved in the assessment of study specific outcomes or patient consent. However, 
given that they are retained by the study and have direct participant interactions, PrEP navigators will complete 
all required Human Subjects Research and GCP trainings as well as PrEP Navigator Training (Section 4.3).  
 
Clinic staff will not be responsible for assessing patient eligibility nor conducting informed consent or 
administering any aspect of data collection or intervention delivery. In general, clinic staff will not have access to 
data other than what they have previously been granted access to through their professional appointment and 
duties. Some clinics may opt to securely upload records from consenting participants enrolled at their clinic, 
rather than providing study staff direct access to these records. In this case, study staff will provide a list of 
consented, enrolled participants from that site to the designated clinic staff via secure, password protected files. 
All clinics will be asked to participate in an introduction to STARR-NC study procedures training and PrEP training 
(Section 4.2).   
 
4.2 Clinic Training  
Prior to study implementation, representatives from participating clinics will have completed two trainings: 
introduction to STARR-NC study procedures and introduction to PrEP.  
STARR-NC Study Procedures Training: Clinics will select staff to attend study procedure trainings including those 
who interact with clinic patients who might be eligible for the study (e.g. clinical personnel, clinic leadership, 
laboratory, front-desk staff). Study procedure trainings will focus on building capacity to ensure that clinic staff 
can: 
• 
Answer basic patient questions about study objectives and refer patients to the STARR-NC study staff. 
• 
Understand the study timeline and the timeline for when standard of care HIV/STI testing should occur 
in line with current CDC clinical guidelines 31.  

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• 
Know when and how to contact STARR-NC study staff with questions or concerns related to study 
implementation or participant follow-up. 
PrEP Training:  As described in Section 1.0, there are currently no PrEP services offered at any of the 
participating clinics. While all participating clinics have expressed interest in expanding access to PrEP for their 
patients, the timing and resource capacity of each clinic to begin offering PrEP on-site is outside of the scope of 
this project. PrEP capacity includes everything from on-site provision of PrEP, robust PrEP referral strategies, or 
PrEP provider knowledge to help answering basic questions regarding PrEP effectiveness and eligibility for 
patients who express interest in PrEP. As a first step in building PrEP capacity at the clinic level, the North 
Carolina HIV Training & Education Center (NC HTEC) will provide PrEP training to all participating clinics.  This 
standardized program will provide all participating clinics the same PrEP awareness and knowledge training 
regardless of each individual clinic’s intention or ability to launch clinic-embedded PrEP clinics. Delivering the 
same training across all clinics provides clinic staff common messaging about PrEP which could help limit this 
potential source of site-level variation in the context of the study. PrEP training content areas will include 
educational and skill building to: 
• 
Explain how PrEP protects against HIV infection.  
• 
Distinguish among PrEP, PEP, and U=U.  
• 
Outline criteria that would make a client eligible for PrEP.  
• 
Describe the components of PrEP service delivery.  
• 
Identify resources to help patients prepare for, initiate, and persist on PrEP. 
4.3 PrEP Navigator Trainings  
PrEP navigators will complete all trainings described in Sections 4.1 and 4.2. In addition, PrEP navigators will 
complete structured and hands-on training using resources developed by PrEP-focused organizations and 
initiatives, including:  
• 
PleasePrEPMe 
• 
AIDS Education & Training Center Program National Coordinating Resource Center 
• 
Centers for Disease Control and Prevention 
• 
National Minority AIDS Council 
• 
U.S. National Library of Medicine 
Centers for Disease Control and Prevention National Prevention Information Network 
Drawing from the above trainings, PrEP navigators will be trained to conduct the following:  
• 
All study staff and clinic competencies as described in Sections 4.1 and 4.2 above.  
• 
Facilitate linkage to PrEP services, including assisting participants with identifying/connecting with a 
PrEP provider and completing appropriate referral paperwork as needed.  
• 
Support completion of Medicaid enrollment assistance and drug assistance programs, as appropriate.  
• 
Recommend and discuss resources and strategies for supporting PrEP medication adherence and 
maintenance.  
• 
Identify and recommend community resources that are culturally sensitive to communities at highest 
need for PrEP.  
• 
Stay informed about current HIV/AIDS trends, prevention efforts, and strategies. 
• 
Demonstrate cultural humility, understanding, awareness, and respect for diversity among study 
participants. 

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5.0 SELECTION AND ENROLLMENT OF STUDY PARTICIPANTS 
5.1 Participant Inclusion Criteria  
RCT eligible participants must: ; (1) report sexual activity with a male in the past 12 months; (2) received HIV 
testing within 90 days pre-enrollment and not known to be HIV-positive at screening/enrollment by self-report 
(3) age 18-39 years; (4) have daily smartphone access; (5) be English speaking; and (6) deny current PrEP use (i.e. 
has not taken oral PrEP or received injectable PrEP within the last 3 months).  
Qualitative interview (clinic patient participants) must be enrolled in the study and complete their Baseline 
study visit activities and at least one follow-up study time point (3 and/or 6-month visit). We will interview up to 
50 patient participants. Participants will be purposively sampled to ensure a diversity in areas such as PrEP 
initiation status, recruitment clinic, age, sex, and race/ethnicity.   
Qualitative interviews (clinic staff/providers/relevant stakeholders): We will conduct qualitative interviews 
with a purposively selected sample of up to 50 clinic staff, providers and other relevant stakeholders for PrEP 
provision. Interviewees will be purposively sampled to ensure a diversity of clinic roles and relationship to PrEP 
provision services and referrals, diversity in leadership level, and representation across all participating clinics.  
 
5.2 Participant Recruitment 
The study team and clinic representatives will meet as needed to troubleshoot any clinic-specific or cross-clinic 
recruitment challenges, as well as share successes.  
Venue-based recruitment at participating STI clinics: Ads (e.g. posters, one-pagers) and business cards/palm 
cards with scannable QR codes will be posted throughout the clinic waiting areas, bulletin boards, patient 
rooms, etc. The study will also be promoted through word of mouth via the clinic health professionals, 
administrative staff, and community outreach personnel. Clinic and study staff may also bring recruitment 
materials to community-based events they attend on behalf of the clinic (e.g. health fairs, blood drive) with 
information about the study and encouraging persons to seek STI services at their local STI clinic. 
Primary recruitment materials: Scannable QR codes will lead to a study landing page and online screener, which 
allows people to learn about the study discretely if they do not wish to carry study-related materials on their 
person. Each county will be assigned an individualized QR code so that study staff can recognize which county each 
completed screener is associated with. If multiple collaborating clinics exist within one county, the participant will 
self-report from which clinic they engaged with recruitment materials. We will work with clinic staff and our 
Community Advisory Board to develop a comprehensive recruitment portfolio, reviewing messages, imagery, tone 
and dissemination modalities. All recruitment materials will be reviewed and approved by the IRB prior to use.  
Social media promotion: In addition to clinic-based recruitment, we will also work with each clinic to establish a 
social media recruitment plan. To maintain consistency across clinics, the intention of the social media 
promotion is to increase visibility of the clinic to the target population and encourage our population of interest 
to seek sexual health services through the collaborating clinics.  
5.3 Procedures to Minimize Fraudulent Participation  
Study ads and the initial screener will not indicate full, explicit eligibility criteria and will de-emphasize incentives as 
to minimize fraudulent responses.  UNC study staff will verify eligibility prior to full study enrollment.  
 

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5.4 Screening for Eligibility  
County-specific QR codes are used to link potential participants to a study pre-screening assessment. Patients 
will be asked for consent to screen and then complete the pre-screening questionnaire independently of study 
or clinic staff. Prospective participants that complete the eligibility assessment questions will receive a small 
incentive valued at approximately $5. The pre-screening assessment will explain the name, sponsor, funder, and 
the purpose of the study and assess key eligibility criteria (Section 5.1) and collect basic demographics. 
Participants who are not eligible based on screening criteria, duplicate entries, or choosing not to proceed, will 
be thanked, and rerouted to a public webpage (e.g., Google). Prospective participants will be asked permission 
for study staff to contact them and to provide preferred contact information (preferred name, pronouns, phone 
number, email, preferred time for phone, text or email contact).  
5.5 Informational Video 
After providing contact information, prospective participants who are found to be eligible thus far, will be 
routed to a brief online video outlining the purpose of the study, participant activities, data collection, and 
timeline of participation. Participants may view the video immediately after pre-screening or at a time most 
convenient to them.  
5.6 Informed Consent  
Participants have the choice to complete a self-guided electronic informed consent following the informational 
video prior to enrollment, or to complete a staff-guided electronic informed consent (via HIPAA-compliant 
videoconferencing platform or phone call) prior to enrollment. All participants will be asked to complete 
comprehension questions to ensure they adequately understand the research, risks, and benefits prior to 
providing an electronic signature (Section 15.5).  
5.7 HIPAA Authorization  
All prospective participants who complete Informed Consent will be required to review and sign a HIPAA release 
form, approved by the UNC IRB, to facilitate study access to test results specific to study outcomes and PrEP 
eligibility and medical records related to receipt of PrEP-related services. The release form specifies the scope of 
results/records that will be accessed and the timeframe over which research staff would be able to access this 
information. 
5.8 Participant Randomization 
Participants will be randomized 1:1. Randomization procedures are automated through the study database. 
Randomization is completed after a participant has completed informed consent and their Baseline survey. 
Participants will be informed by study staff of their study condition assignment during their onboarding 
appointment.  The study onboarding appointment is tailored to the study arm condition they are assigned 
(Figure 2).  
Study staff are trained to follow similar protocol for scheduling, enrollment, and follow-up regardless of arm 
which includes the use of IRB-approved guides for participant communications and specified standard operating 
procedures for participant outreach mode, timing, and frequency. Communication attempts will be tracked in a 
communication log for prospective and enrolled persons. PIs and the study monitor will be able to see the 
records for all those who complete screening and could assess whether there is differential communication 
efforts or enrollment by randomization condition. 

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6.0 RCT STUDY PROCEDURES (AIM 1, R61) 
All study activities and interactions may be completed remotely/virtually through a combination of email, phone 
call, SMS, study app, online assessments, and videoconference. There is no required in-person contact with 
study staff.  
6.1 Study onboarding appointment and baseline assessment  
All participants will complete an onboarding appointment via phone or HIPAA-compliant videoconferencing 
platform. Participants will be considered enrolled and be eligible for the enrollment completion incentive once 
the below activities are complete:  
• 
Informed consent and HIPAA authorization. Receipt of a unique access link to complete their Baseline 
CASI survey capturing PrEP use history, sexual behaviors, demographics, and determinants of PrEP use 
(access to care, perceived HIV risk, social support, perceived discrimination, mental health, substance 
use, and PrEP decision making). The CASI survey is self-administered via secure HIPAA-compliant 
platform (e.g. RedCap) and participants can complete the survey on their personal device with internet, 
wi-fi or mobile data. The survey saves after every page thus participants can return to complete the 
survey if their connection is disrupted or for any other reason.   
• 
Randomized to study condition.  
• 
Receipt of a unique access code and directions to download their free designated version (intervention 
or control) of the HMP study app from either the Google Play or Apple store. 
• 
Creating their unique HMP account profile and log-in; touring the app features. 
The onboarding appointment for intervention participants will also include being connected to their 
assigned PrEP navigator.  
 
 
 
 
 
 
 
 
 
 
 
 

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6.2 Participant Enrollment and Onboarding 
 
 

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6.3 Intervention Procedures 
Intervention arm participants will have access 
to the three primary intervention components 
(PrEP Navigation, Digital Health Intervention, 
and Telehealth PrEP Referral) for the full 
duration of the 6-month follow-up period, 
limited to 3-months for a subset of 
participants enrolled in approximately the final 
quarter of enrollment. Participants will be 
encouraged to use the intervention features 
through a combination of study staff 
reminders, PrEP navigator interactions, 
automated in-app notifications, and 
automated SMS and push notifications.  
6.4 Follow-up study assessments  
Follow-up study assessments will be 
conducted for all participants, including 
standard of care repeat HIV/STI testing 31 and 
repeat self-administered CASI survey 
assessments, with the number of follow-up 
assessments dictated by timing of enrollment. 
The baseline questionnaire is distributed after 
a participant completes informed consent and 
before they are randomized. If the participant 
does not complete Informed Consent, HIPAA 
Authorization, the baseline questionnaire and 
baseline HIV status verification within 45 days 
of completing the screening questionnaire, the 
participant must re-screen to assess eligibility.  
The follow-up period (described as the post-
randomization phase) begins once participants 
have been randomized to a study condition. 
Randomization will occur once participants 
have connected with study staff for their 
onboarding appointment. An overview of the 
pre and post randomization assessments 
conducted in each study phase are described 
in Tables 2.1 – 2.3.  
A subset of participants will be asked to 
complete a brief CASI survey pertaining to 
PrEP uptake and/or persistent use and self-
reported STI or HIV testing outcomes at 12-
months if this follow-up interval falls within 
the allowable data collection timeframe 
based on when a person was enrolled (see Section 17.0 Timeline). The study windows for each follow-up time 

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Version 4.0, Dated September 30th, 2024  
point are intentionally broad to maximize data completeness and accommodate variation in HIV follow-up 
testing that may occur as part of standard clinical care, PrEP initiation and monitoring, and event-driven HIV 
testing following a potential exposure event. The target dates for follow-up assessments are at the completion 
of the 3-month, 6-month, and 12-month mark, with windows before and after these dates to accommodate 
variation in HIV/STI testing schedules.   
For participants that initiate PrEP while on study, study staff will update the timeline for their HIV/STI 
assessments according to their PrEP initiation date. As HIV/STI testing is expected to be collected as part of their 
standard PrEP management, we will not ask participants to duplicate this testing at their STI clinic if they can 
demonstrate having been tested within the acceptable window for their expected 3- or 6-month testing interval. 
The timeframe in which participants are asked to complete DBS kits and CASI assessments will remain the same, 
defined by the date participants are randomized.  
6.5 Self-collected blood sample 
Dependent on their enrollment date, participants will be asked to complete one to two self-collection whole 
blood sample kits corresponding to a 3- and 6-month follow-up to assess for PrEP uptake by measuring for the 
presence and levels of tenofovir diphosphate and emtricitabine triphosphate (TFV-DP/FTC-TP) or Cabotegravir 
(CAB) levels.  Participants may have the specimen collection kits sent to their current residence or any mailing 
address of their choice. Kits will contain detailed instructions for use of the blood collection device as well as all 
packaging materials needed to return the kit to the lab. See Section 16.1 for laboratory details.  
6.6 Clinic assessments 
We will conduct assessments of all participating clinics to evaluate staffing, patient volume, hours of operation, 
and available services. These assessments may be conducted using a combination of in-person and 
remote/virtual interactions and will occur within 3-months before or after initiating patient participant 
recruitment at each site, and again within 3-months before or after the end of the study follow-up period (see 
Section 17.0). Additionally, we will track how clinics are engaging with technical assistance services as offered 
through NC HTEC.  
Alongside in-depth interviews (Section 6.7), we will also ask relevant stakeholders about intervention 
acceptability and organizational factors that may influence PrEP provision and integration of services, including 
organizational readiness for change, support climate, and intervention-values fit 39–41. As part of anticipated 
biannual convening of study leadership, state policymakers, and members of our Community Advisory Board, we will 
monitor relevant policy changes such as those pertaining to insurance, PrEP coverage, or recommendations for use 
that may serve as external influences relevant to our observed outcomes. This information will be documented in 
study minutes and circulated to all attendees.  
6.7 Qualitative in-depth interviews 
A sub-set of up to 50 participants will complete an in-depth interview following their 3 or 6-month study visit to 
provide contextualized data about: experience with the study participation, perceived accessibility of PrEP 
before and after study enrollment, evaluation of the acceptability of this PrEP-access model, unmet PrEP-related 
health service needs/barriers, experience initiating PrEP (if relevant), experience using the study-related 
intervention components (app, PrEP navigator, telehealth for PrEP) (if relevant), and other emergent topics as 
raised by participants. Participant interviews may be conducted remotely by phone or videoconference 
platform.  
Up to 50 relevant stakeholders, including STI clinic staff, healthcare providers, and other stakeholders relevant 
for PrEP services will also complete in-depth interviews covering topics such as: experiences and challenges with 

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Version 4.0, Dated September 30th, 2024  
being part of a participating clinic for this study, perceived accessibility of PrEP to target patient population 
before and after study implementation, perceived strengths and drawbacks of this PrEP-access model, 
suggested changes to this PrEP-access model, unmet PrEP-related health service needs/barriers among target 
patient population, and other emergent topics as raised by participants. Stakeholder interviews may be 
conducted in-person or remotely by phone or videoconference platform.  
Interviews will be conducted by trained research staff experienced in qualitative research. Interviews will be 
guided by the use of an SOP and a semi-structured interview guide which will include open-ended questions 
corresponding to each qualitative endpoint. Interviewers will be allowed the flexibility to probe patient 
responses and pursue discussion diverging from the initial interview questions if it is relevant to the endpoints of 
interest. Each interview will be digitally recorded and transcribed to text for analysis.  
7.0 OUTCOME MEASURES AND DATA SOURCES 
For interventions that address systems-level challenges or utilize patient navigation as an intervention 
component, PrEP uptake is an appropriate primary outcome as it is an indication of the success of the 
intervention to overcome the barriers to access to the health service/treatment42,43. Given the current lack of 
PrEP availability in the proposed study settings, an intervention that can overcome the multi-level barriers to 
PrEP access and uptake is a critical first-step.    
With PrEP uptake as the primary outcome and the primary objective to increase PrEP uptake, this study will follow a 
similar operational definition as another large-scale mHealth RCT intervention for PrEP uptake among MSM in the 
southern United States44: self-report taking any PrEP (oral or injection) on a follow-up survey or in the app, AND 
verified by at least one of the following: (1) an uploaded photo or image demonstrating a PrEP prescription; OR (2) 
any indication of the presence of tenofovir diphosphate or cabotegravir in DBS; OR (3) staff-abstracted electronic 
medical record of PrEP prescription issued or physician notation of PrEP initiated.  
Table 3 presents the study Outcome Measures and their data sources.  
Table 3: Study Outcome Measures and Data Sources 
Name 
Time Frame 
Brief Description  
Data sources 
Primary outcome 
PrEP uptake 
3-month follow-
up 
Verified self-reported PrEP use (first 
dose, oral or injectable)1 
CASI, in-app 
report, EHR 
abstraction, 
self-collected 
lab sample 
Secondary outcomes 
PrEP uptake 
6-month follow-
up4 
Verified self-reported PrEP use (first 
dose, oral or injectable)1 
CASI, in-app 
report, EHR 
abstraction, 
self-collected 
lab sample 
PrEP care 
engagement 
3- and 6-month4 
follow-up 
Daily oral or event driven PrEP: after 
PrEP uptake, number and dates of any 
subsequent PrEP visits or new/refilled 
CASI, EHR 

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PrEP prescriptions   
Injectable PrEP: after initial injection, 
number and dates of any subsequent 
PrEP visits/injections  
PrEP use 
3- and 6-month4 
follow-up 
Number of consecutive months PrEP 
used, based on date of first and last 
dose2 
CASI, EHR 
PrEP adherence 
(self-report) 
3- and 6-month4 
follow-up 
Daily oral PrEP: reported PrEP use 
(past 30 days)  
Event-driven PrEP: reported PrEP use 
corresponding to reported sexual 
activity (past 30 days)  
Injectable PrEP: based on date of 
injections  
CASI 
PrEP adherence 
(injection history & 
drug measurement) 
3- and 6-month4 
follow-up 
Daily oral PrEP: PrEP concentrations 
detected at designated study follow-
up visits, based on intraerythrocytic 
TFV-DP collected as DBS;  
Injectable PrEP: based on dates of 
injections  
Self-collected lab 
sample, EHR  
Incident STI/HIV 
3- and 6-month4 
follow-up 
Clinical test result (yes / no / 
indeterminate / missing) for each STI 
and HIV that participant is tested for.  
CASI; State, 
clinic, 
commercial lab 
results3 
PrEP Stigma 
3- and 6-month4 
follow-up 
Self-reported scored PrEP Stigma scale  CASI 
Implementation measures (intervention arm and stakeholders) 
Fidelity-Engaged by 
PrEP navigator 
First two weeks 
following 
enrollment 
Proportion of Intervention Arm 
enrolled participants that are engaged 
by the PrEP navigator within two 
weeks of enrollment 
Intervention CRF 
Intervention 
satisfaction - 
Quantitative 
3- and 6-month4 
follow-up 
Average score on participant-
completed System Usability Scale (10 
item universal measure of usability 
and acceptability).  
CASI 
Intervention 
satisfaction – 
Qualitative 
3- or 6-month4 
follow-up 
Description of participant experiences 
and satisfaction, usefulness and 
attribution to PrEP use while on study 
and with each intervention 
component.  
In-depth 
interviews with 
participants 
Acceptability 
Within 3-months 
before or after 
baseline and 
Description of stakeholder experiences 
and acceptability of intervention, 
readiness for change, implementation 
In-depth 
interviews and 
surveys with 

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within 3 months 
before or after 
study close-out 
climate, and intervention values 
stakeholders  
Clinic measures 
STI service delivery Baseline, 3- and 
6-month4 follow-
up 
Proportion of enrolled participants 
receiving STI screening (urogenital, 
rectal, pharyngeal)  at baseline (pre-
enrollment) and follow-up timepoints  
State, clinic, 
commercial lab 
results3 
Sexual health 
service delivery 
Within 3-months 
before or after 
baseline and 
within 3 months 
before or after 
study close-out 
New or modified sexual health 
programs or offerings at participating 
clinic, including PrEP (on-site or 
integrated into clinic), point-of-care 
testing, and other initiatives  
In-depth 
interviews and 
surveys with 
stakeholders  
Exploratory measures 
PrEP uptake 
12-month 
follow-up5 
Verified self-reported PrEP use (first 
dose, oral or injectable)6 
CASI, in-app 
report, EHR 
abstraction  
PrEP care 
engagement 
12-month 
follow-up5 
Daily oral or event driven PrEP: after 
PrEP uptake, number and dates of any 
subsequent PrEP visits or new/refilled 
PrEP prescriptions  
Injectable PrEP: after initial injection, 
number and dates of any subsequent 
PrEP visits/injections  
CASI, EHR 
PrEP use 
12-month 
follow-up5 
Number of consecutive months PrEP 
used, based on date of first and last 
dose2 
CASI, EHR 
PrEP adherence 
(self-report) 
12-month 
follow-up5 
Daily oral PrEP: reported PrEP use 
(past 30 days) 
Event-driven PrEP: reported PrEP use 
corresponding to reported sexual 
activity (past 30 days) 
Injectable PrEP: based on date of 
injections  
CASI 
Incident STI/HIV 
12-month 
follow-up5 
Clinical test result (yes / no / 
indeterminate / missing) for each STI 
and HIV that participant is tested for.  
CASI; State, 
clinic, 
commercial lab 
results3 
Effective HIV 
protection 
First 3 months of 
trial 
Proportion of days out of the first 3 
months of the trial that participant 
was "effectively" protected from HIV 
transmission based on their self-
reported PrEP use and self-reported 
CASI, in-app 
reported 
behaviors7 

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sexual behavior. 
Effective HIV 
protection 
 6-month study 
period4 
Proportion of total days of the trial 
that participant was "effectively" 
protected from HIV transmission based 
on their self-reported daily PrEP use 
and self-reported sexual behavior. 
 CASI, in-app 
reported 
behaviors7 
1 Persons who self-report taking any PrEP (oral or injection) during a follow-up survey OR in their app will meet 
this endpoint if this self-report is verified by at least one of the following: (1) an uploaded photo or image 
demonstrating a PrEP prescription; OR (2) any indication of the presence of tenofovir diphosphate or 
cabotegravir in DBS; OR (3) staff-abstracted electronic health record of PrEP prescription issued or physician 
notation of PrEP initiated.  
2  First dose and last dose determined based on self-report for oral PrEP and medical record (or self-report if 
record not available) for injectable PrEP. Respondents endorsing any PrEP dose will have uploaded current PrEP 
prescription as described in PrEP uptake outcome as above. 
3 State, clinic and commercial labs: We will collect HIV/STI test results directly from laboratory portals or via 
secure upload of results from participants or participating clinics’ medical records. 
4 Participants who reach 6-months of study follow-up prior to study end will contribute to 6-month outcome 
measures.  
5 Participants who reach 12-months of follow-up prior to study end (see 17.0 Timeline) will complete a brief CASI 
survey inquiring about PrEP use, including PrEP uptake and any interruptions or discontinuations of PrEP. They 
will also maintain ability to self-report PrEP start within the app through month 12. Self-reported STI and HIV 
results will also be captured at this time point, as well as preferences for provision of extended PrEP navigation 
resources.  
6 Persons who self-report taking any PrEP (oral or injection) during a follow-up survey OR in their app will meet 
this endpoint if this self-report is verified by at least one of the following: (1) an uploaded photo or image 
demonstrating a PrEP prescription; OR (2) staff-abstracted electronic health record of PrEP prescription issued or 
physician notation of PrEP initiated. DBS samples will not be collected at month 12.  
7 All participants (intervention and control) will be asked questions on CASI about PrEP use, medication 
adherence and sexual behavior; CASI data will be used to calculate an estimate of effective protection for all 
participants. In-app daily medication adherence self-report and daily sexual behavior self-report are only 
available for intervention arm participants; in-app data will be used to calculate an app-based estimate of 
effective protection for any intervention arm participants who used the app to record these behaviors.  
8.0 PARTICIPANT MANAGEMENT 
8.1 Participant Retention  
We will collect multiple forms of participant contact information and study-related communication preferences 
(e.g. email, phone/text, social media handles) as part of study enrollment.  The HMP app supports participant 
retention through a timeline that displays upcoming study activities and a two-way secure messaging feature for 
participants and study staff. The study staff-facing web-based administrative portal also facilitates retention via 
prompts to reach out to participants who have missed specified study activities and by providing a secure 
platform to communicate with participants and deliver participant incentives. The study team will meet weekly 

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and review retention reports and proactively identify barriers to retention. 
  
8.2 Participant Remuneration 
Participants will receive remuneration throughout the course of their participation. Intervention and control arm 
participants are eligible to receive the same level of remuneration.     
o Participant enrollment activities: $60 
o Participant follow-up 3-month survey: $40 
o Participant follow-up 6-month survey: $40 
o Participant follow-up 12-month survey: $40 
o Participant return of 3-month whole blood self-collection kit: $50  
o Participant return of 6-month whole blood self-collection kit: $50  
o Participant qualitative exit interview (sub-sample of participants): $50 
o Clinician/Stakeholder/Staff qualitative interview and brief survey: $50 
8.3 Suspected or Confirmed HIV/STI Infection at Screening, or While on Study  
Individuals who self-report a prior HIV diagnosis or reactive HIV test at screening will not be eligible for the 
study. Once participants have completed informed consent and a HIPAA waiver, HIV status can be confirmed by 
study staff (access to lab results via state or clinic portals). If lab results are not available, participants/clinics 
may use a secure link to self-report a recent (<90 days) test result to confirm HIV negative status. 
Individuals who are found to be HIV seropositive at time of eligibility verification will not complete enrollment. 
Participants who test positive for HIV or other STIs at any point during study follow-up will be appropriately 
connected to care through the North Carolina State Health Department’s standard notification procedures and 
Disease Intervention Specialists. 45 All participants are encouraged to adhere to CDC recommended frequency of 
testing which includes screening for bacterial STIs every 3 months among MSM or among patients with ongoing 
risk behaviors 31. Therefore, HIV/STI testing will be completed as part of patients’ routine care at established STI 
clinics (not administered through the study). The HMP app and study staff will help facilitate participants’ return 
to STI clinics for HIV/STI testing by providing in-app appointment reminders, text messages and phone calls, as 
needed. Test results will be communicated to participants by clinic staff following their standard of care and 
established notification procedures. Study staff will not communicate HIV/STI test results to participants 
directly. The conduct of HIV/STI testing at 3 & 6 months is considered routine clinical care. 
For patients who initiate PrEP, quarterly HIV and STI testing will be ordered by the prescribing PrEP provider, at 
their clinical discretion. These participants may not require additional HIV or STI testing (see Section 6.3). Post-
hoc abstraction of HIV/STI test results by research staff is considered a research activity and is covered by the 
HIPAA authorization form participants sign at study enrollment. Participants who initiate PrEP will have HIV/STI 
testing results abstracted from HD (if HD-based PrEP) or external PrEP providers’ records, or, if access to such 
records is not feasible, participants will be asked to upload the results of said testing within the app portal.  
Participants who receive an HIV diagnosis while enrolled in the study will be study stopped. Following an HIV 
seroconversion SOP, study staff will document that the participant has been notified and received appropriate 
counseling as described above. Participants will have an opportunity to complete an end-of-study survey to 
capture any interim PrEP use and referral for or initiation of HIV treatment. A seroconversion CRF will be 
completed for any such participants and indication noted in the HMP study staff-facing administrative portal for 
study staff and PrEP navigators. Participants who test positive for other STIs will continue to be eligible for study 
participation. 

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8.4 Participant Withdrawal  
Enrolled participants are free to withdraw from participation in the study at any time and for any reason upon 
request. A study stop CRF will be completed for participants who request withdraw from the study. No further 
data collection will occur following completion of the study stop CRF. 
 
An investigator may withdraw a participant from the study for the following reasons: 
 
a) If any clinical adverse event (AE), serious adverse event (SAE), laboratory abnormality, or 
other medical condition or situation – related or unrelated to the study – develops after 
enrollment such that continued participation in the study would not be in the best interest 
of the participant. 
b) If a patient presents a safety risk to the research staff.  
c) If their participation in the study is disruptive to the study or the clinic.  
d) If the participant receives an HIV diagnosis (see section 8.3).  
e) They intentionally violate study procedures, including fraudulent engagement with study 
screening or DHI-based survey completion. 
 
The reason for any participant’s discontinuation or withdrawal from the study will be recorded on the study stop 
CRF. 
 
Furthermore, study staff may use their professional discretion not to enroll a prospective participant for reasons 
b through e, listed above. 
9.0 STATISTICAL/ANALYTIC CONSIDERATIONS 
9.1 Sample Size and Power Estimate  
We expect > 7,400 patients will present for care in the 21-month enrollment period, with 20-35% study eligible. 
Aim 1 analysis includes eligible, consenting patients who successfully download the HMP app. The study will 
enroll for 21 months with a target sample size of 336. We expect approximately half of participants will be 
randomly assigned to the intervention arm and the remaining half to the control arm (see Randomization, 
Section 3.2). 
We calculated statistical power for the effect of intervention upon PrEP uptake by 3-month follow-up using SAS 
9.4 (Cary, NC) with a 5% type I error rate and a two-sided Chi-square test. Assuming 2.5% of eligible patients 
start PrEP within 3 months in the control arm, we calculated statistical power to detect a range of small to large 
effect sizes from 5% to 15% percentage point increases in PrEP uptake under a range of possible sample sizes 
and assuming 10% missing data (Table 4). At a total sample size of 336, given our design and assumptions, we 
will have >88% statistical power to detect medium (10%) and large (15%) effect sizes, and 80% statistical power 
to detect a moderate (7.5%) effect size.  
Effect size rationale: As there is currently limited-to-no infrastructure or existing programing providing PrEP in 
rural North Carolina STI clinics, no prior studies that we are aware of have measured PrEP uptake in these 
settings. Overall, U.S. PrEP coverage of those assigned male sex at birth with PrEP indications was reported by 
CDC as 18.4% in January – March 2021, but only 5.6% among Black/African American46, who will constitute a 
large portion of our sample. Among the CDC-designated End-the-Epidemic jurisdictions, recent PrEP coverage 
estimates of those with PrEP indications range from a low of 4.5.% in San Bernardino to a high of 42.3% in San 
Francisco; North Carolina’s state level PrEP coverage estimate is 13.3%, which belies the wide variability from 

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urban to rural areas47. Looking to other settings with some comparable characteristics, the THRIVE national CDC 
demonstration project (n=9538 PrEP-eligible MSM) found a range across study sites of 10.7% to 95.9% (mean 
53.8%) of eligible screened participants linked to PrEP services (defined as attending an initial PrEP 
appointment), with substantially fewer being prescribed PrEP (37.2%). At sites where PrEP navigation was 
provided, 48.5% of MSM who used navigation were linked to PrEP as compared to 2.8% being linked among 
those who did not use navigation 42.  In a pilot RCT mHealth app (without navigation), overall PrEP uptake 
among a primarily urban MSM population was 12.8% overall (n=6/58) with no difference between intervention 
and control arms48. Among an urban sample of 2106 PrEP-priority eligible MSM attending sexual health clinics in 
New York City who were offered PrEP navigation services, 288 (13.6%) linked to a PrEP provider and 235 (11.2%) 
received a PrEP prescription49. Looking at these data together and considering the added barriers posed by our 
rural setting and PrEP stigma, we anticipate being able to see a moderate effect size and have conservatively 
selected a preliminary intervention efficacy milestone of an observed difference in PrEP uptake of at least 7.5% 
(see Table 6).  This conservative, but still clinically meaningful, effect size will be used as part of the overall 
determination of whether the intervention approach should be explored further in Phase 2 (see 11.0 Milestones 
for further discussion).  
Based on historical testing data, we expect <2% of all persons who are undergoing HIV screening on day of 
enrollment to be seropositive. Persons with unidentified HIV at time of enrollment should be randomly 
distributed between the intervention and control groups. Given the small proportion we anticipate may be 
enrolled/randomized prior to seropositive results being available, our study remains powered to detect the 
differences as described above. 
Table 4: Statistical power as a function of the observed difference in effect (PrEP uptake) and sample size* 
 
TOTAL SAMPLE SIZE – R61 PHASE 
OBSERVED 
DIFFERENCE 
IN PREP 
UPTAKE 
n=200 
n=300 
n=400 
n=500 
n=600 
5% 
33% 
47% 
58% 
68% 
76% 
7.5% 
59% 
77% 
87% 
93% 
96% 
10% 
72% 
88% 
95% 
98% 
99% 
15% 
92% 
98% 
99% 
>99% 
>99% 
*Assuming PrEP uptake of 2.5% in the control arm, 10% missing data at month 3, and 5% type I error 
9.2 Outcome Analysis 
Eligible participants will enter the study within 45 days of screening as eligible and will be followed longitudinally 
for PrEP uptake for up to 12 months. Analyses will be conducted for all primary and secondary outcomes defined 
in Table 3 (Section 7.0) using the following general procedures for analysis.   
Basic descriptive statistics will be calculated. Frequency tables will be presented for the categorical variables and 
means, standard deviations, and percentiles (25th, 50th, 75th) will be given for the continuous variables. For each 
binary outcome, we will estimate the proportion of patients achieving the event (e.g., PrEP uptake) in each arm 
and a probability difference (PD) and a corresponding 95% confidence interval (CI) to compare the intervention 
vs. control arms at each timepoint (3-month, 6-month, and 12-month follow-up). For continuous endpoints, we 
will use a non-parametric Wilcoxon Rank-Sum Test to compare the intervention and control arms. For count 

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data variables (e.g., number of unprotected sex acts), we will use small analysis methods for count data (e.g. 
exact Poisson regression). 
To address missing data, we will review the frequency of missing and non-missing values for all variables at 
baseline, 3-month, 6-month, and 12-month follow-up. We will conduct missing value analyses to determine 
whether persons with missing values are systematically different from those without missing values and if the 
probability of having missing values differs by arm. If this assessment of the frequency and imbalance of missing 
data suggests that bias may be introduced, we will employ inverse probability of observation weights or multiple 
imputation to address the missing data. 
If there is chance imbalance in the measured baseline covariates, we will conduct sensitivity analyses applying 
stabilized inverse probability treatment weights (IPTW). 
9.2.1 Primary Outcome Analyses 
The primary outcome of PrEP uptake is measured at the 3-month follow-up. The effectiveness of the 
intervention will be estimated as the difference in proportion of participants starting PrEP within 3 months of an 
index STI clinic visit, comparing patients randomized to the intervention and control groups. For participants 
enrolled through clinic-collaborating outreach events, the date of clinic outreach serves as the index visit. 
9.2.2 Secondary Outcomes Analyses 
Secondary effectiveness outcomes are listed in Table 3 (Section 7.0) including PrEP uptake at 6-months, and 
PrEP care engagement, PrEP use, PrEP adherence, incident STI/HIV, and PrEP stigma (at both 3- and 6-months, 
determined by when they are enrolled in the course of study enrollment). All analyses will follow the 
specifications described above in 9.2.  
PrEP adherence at 3 and 6 months will be assessed using PrEP metabolite levels and self-report (3-month only 
for persons enrolled in approximately the final quarter of enrollment). We will use standard of care quarterly 
STI/HIV testing results to examine differential rates of incident STIs, adjusting for testing frequency given 
potential increased frequency among PrEP initiators.  
9.2.3 Exploratory Outcomes Analyses  
As exploratory analyses, we will also report the effectiveness of the intervention as measured by PrEP uptake at 
the 3-month follow-up stratified by sex. The effectiveness of the intervention will be estimated as the difference 
in proportion of women starting PrEP within 3 months of an index STI clinic visit, comparing randomized to the 
intervention and control groups. For participants enrolled through clinic-collaborating outreach events, the date 
of clinic outreach serves as the index visit.  
9.2.4 Additional Outcome Analyses  
Additional analyses will compare self-reported PrEP use among patients who complete the self-administered 
screening questions (Section 5.4) but who do not enroll in the study (ineligible or eligible but decline). 
Specifically, we will examine the proportion of respondents endorsing recent or current PrEP use and trends 
throughout the enrollment period to evaluate “background” PrEP use in the community of patients seeking STI 
services at participating clinics. We will estimate the proportion reporting PrEP use in each month as the number 
of patients reporting current PrEP use divided by the number of patients completing the screening 
questionnaire. We will compute trends in PrEP use by regressing these estimated monthly proportions on time 
using logistic regression and interpreting the regression coefficient on time.   

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We will also explore effective-PrEP use, namely PrEP use that aligns with periods of HIV risk 50,51 using daily app 
data of tracked sexual behaviors, incident STIs, and PrEP use for persons in the intervention arm. As the daily 
tracking feature is only in the intervention arm app, this outcome will be exploratory for use in future work. 
Additional exploratory analyses will examine PrEP uptake, persistent use, HIV or STI incidence, and intervention 
satisfaction/preferences at 12-months. All measures will be self-reported and captured using CASI. Only persons 
who reach the 12-month follow-up visit within the allowable data collection window will have these 
assessments completed.  
We will examine whether there are subgroups (of clients and/or clinics) for which the intervention may be more or 
less effective (see Section 11.0). 
We will also examine the proportion starting PrEP separately for patients enrolled in each calendar year quarter 
of the study to explore trends over time.  
This assessment describes process indicators to inform intervention implementation, optimization, and scale-up. 
We will measure acceptability of the implementation strategies to providers and clinic directors, feasibility of 
the intervention, and intervention satisfaction among patients and providers.  
To measure acceptability of the intervention and to explore clinic-level influences on implementation feasibility 
at each clinic, we will interview providers and clinic directors. We will assess factors such as provider burden of 
intervention, adequacy and timing of training, supervision/support structure, organizational readiness for 
change (quantitative scale and qualitative interviews),39 management support (qualitative interviews), 
implementation climate (quantitative scale and qualitative interviews), 40 and intervention-values fit 
(quantitative scale and qualitative interviews) 41. We will use facility audit data, including county population, 
patient panel size and demographics, number and training level of clinic staff, clinic staff-to-patient ratio, daily 
patient volume, open hours and local access to PrEP to contextualize determinants. 
Feasibility measures will assess patient engagement with the intervention, including uptake of elements (i.e. 
linkage to insurance if not durably insured at enrollment, use of telehealth PrEP, interactions with PrEP 
navigators). We will examine the percent of enrolled participants in the intervention arm who are engaged by 
the PrEP navigator within two weeks of enrollment. We will also examine app-specific engagement, including 
successful app installation, account creation and log-in, total number of log ins, and time spent in the app.  
Measurement of patient satisfaction with intervention includes qualitative (IDI data) and quantitative (e.g. System 
Usability Scale) assessments. We will conduct interviews with a subset of patients regarding their experiences 
with the intervention. This sample will include a mix of persons with variable HMP engagement and PrEP uptake. 
We will ask about satisfaction with clinician interactions, time and financial cost, and perceived quality of PrEP 
care. As a quantitative assessment, all participants will complete a satisfaction scale at quarterly follow-up visits 
52. 
Analysis of implementation outcome measures will include qualitative analysis. Interviews will be recorded and 
transcribed. Transcripts from participants and providers/clinic staff will be analyzed separately and reviewed for 
quality. 
Interview transcripts will be thematically analyzed following a combination of deductive and inductive analytic 
approaches. An initial codebook will be developed based on a priori concepts driven by the theoretical 
underpinnings used to develop the interview guide. All textual data will then be read thoroughly to summarize 
first impressions. Emerging themes will be incorporated into the codebook. Pre-existing codes may be modified 
based on interview transcripts. Transcripts will be coded iteratively using qualitative analysis software. Two 

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researchers will code interviews separately to assess inter-coder reliability. The codebook will be revised and 
updated. Analysis of the coded data will include investigation of relationships between codes, coding matrices, 
and mapping of codes and themes. Data from qualitative interviews will be triangulated with the quantitative 
data to gain a more complete understanding of the factors underlying implementation. For example, if our 
survey data show that clinics with lower fidelity tended to score low on the implementation climate scale, we 
will examine our qualitative data for indications about what aspects of the leadership or climate may have 
contributed. 
10.0 COST-EFFECTIVENESS STUDY PROCEDURES (AIM 2, R61) 
10.1 Overall Approach 
We will build a decision model to estimate and compare the budget impact, cost- effectiveness, and population 
outcomes of our multilevel PrEP intervention. We will model the value of each component (PrEP navigator, HMP 
app, telehealth provider) as assessed in Aim 1, separately and in combination. We will examine the impact of 
alternative combinations via sensitivity analyses, varying assumptions about the costs and combined 
effectiveness of the interventions. We will further parameterize the model and conduct sensitivity analyses using 
published PrEP cost and effectiveness data 53–56. 
We will directly measure costs and a surrogate marker of HIV prevention effectiveness (PrEP uptake) in our RCT. 
Our analysis presumes that increasing uptake of PrEP is a desired outcome, focusing our assessment on 
incremental STI clinic related intervention costs. Following established methods, we will measure non-research 
related costs associated with the intervention and control arms to estimate incremental cost per additional 
person starting PrEP. Analyses will take the perspective of the STI clinics and public payers. 
10.2 Cost Measurement 
We will embed an empirical costing study into Aim 1 
activities. Costs will be collected prospectively in two ways: 
micro costing and time-and-motion logs. Micro-costing 
involves “direct enumeration” for consumed inputs57, an 
ingredients-based approach. We will quantify resources 
associated with the development and implementation of our 
intervention (Table 5).
We will not assess fixed costs common to both arms (e.g., 
clinic operations overhead), or costs related to the conduct 
of the study alone (e.g., consent). Cost data will be available 
through contractual information with developers, clinic and 
project receipts, and NC DHHS supply chain partners. We will also extract data from project expenditure and 
management records, including purchase logs and human resource records. Time-and-motion assessments 
record how involved parties (navigators, providers, etc) divide time among PrEP-related tasks, reliably 
apportioning effort relevant to implementing the intervention. This includes time for: health worker trainings, 
PrEP navigators, and PrEP providers. Notably, PrEP provider costs will be estimated to inform clinics of the 
potential expenses (and possibly revenue) regardless of if a given clinic opts to implement PrEP programming 
during the study period. As such, costs of PrEP provision and monitoring may be extrapolated from available 
data even if these programs or activities are not uniformly implemented in participating STI clinics. 
Table 5: Cost elements and data source 
Cost 
Source 
Trainings 
Project receipts 
HMP app updates 
Project receipts 
Telecommunications 
Project receipts 
Test supplies* 
EHR 
Healthcare 
utilization** 
App paradata, EHR 
Personnel 
Time-and-motion, NC 
DHHS salary, project 
expenses 
*HIV, STI, renal function, **clinic visits 

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Costs will be calculated by multiplying total time spent with the average hourly salary of the respective roles for 
those who are only partially committed to PrEP services; persons whose roles are entirely PrEP-related (i.e. PrEP 
navigator) will be based on their 100% full time equivalent salary, with more in-depth exploration of distribution 
of time/tasks to examine opportunities to split service provision across multiple lower-volume health 
departments and other STI clinics. We will record this information in spreadsheets that document resource, 
category, quantity, and unit cost. We will follow international conventions for comprehensive costing (i.e. 
including equipment, consumables, and overhead that is not common to both arms); discounting future costs; 
and reporting based on accepted practices  and guidelines from the Panel on Cost-Effectiveness in Health and 
Medicine 58. We will conduct sensitivity analyses that consider costs related to sustainability and intervention 
fidelity (e.g., monitoring and evaluation), varying intervention effectiveness with fidelity changes. Incorporating 
downstream costs is critical to adequately estimate costs of scale-up 59.  
10.3 Model Design and Analytical Perspective  
 We will a conduct decision analysis following 
best practices 57, moving a cohort through a 
decision tree (left-to-right), with the left-most 
decision node controlled by the randomized 
experiment in the trial (Fig 3). “Event nodes”, or 
probabilistic events that happen by chance, will 
be derived from trial data. Terminal node is PrEP 
uptake. We will assess cost-effectiveness 
outcomes from two perspectives: 1) the STI clinic; 
and 2) Medicaid or the state, grouped together 
because state governments cover a larger portion 
of Medicaid expenses and make decisions about 
Medicaid administration and public health 
programmatic offerings. We will assume that if 
Medicaid launched a version of our multilevel 
PrEP intervention, the materials, equipment, and 
personnel costs would be borne by Medicaid or 
its care coordination entity.  
 
10.4 Outcomes and Analysis 
We will conduct a budget impact analysis of the cost in dollars of the intervention overall and each of its 
components, answering the question of whether the intervention is affordable for an organization. We will also 
conduct a cost-effectiveness analysis estimating the incremental cost per additional person started on PrEP (the 
primary study outcome). We will run simulations to estimate additional costs and additional PrEP uptake 
compared to the status quo to assess whether the intervention provides value relative to the status quo. We will 
also assess cost per QALY gained, based on HIV infections averted, applying our estimates to accepted 
transmission models 56,60. 
We will report incremental cost-effectiveness ratios (ICERs). Interventions that cost less and result in more PrEP 
starts, QALYs gained, or infections averted are cost-saving options. Interventions that cost more and result in 
more PrEP starts or more QALYs will be evaluated against standard willingness-to-pay thresholds ($50,000, 
$100,000, $150,000 per QALY gained) contextualizing willingness to absorb costs per added QALY 61,62. For our 
primary outcome, for which willingness- to-pay thresholds are unavailable, we will plot outcomes on an 
efficiency frontier and cost-effectiveness acceptability curve to help decision makers visualize benefits gained at 

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different willingness-to-pay levels 63,64. 
The budget impact analysis will provide decision makers with estimates of the financial feasibility of the 
intervention64. We will examine the budget impact over 1- and 3-year time horizons. Budget impact analysis 
results will be particularly important for decision makers in healthcare systems, as they may not see the long- 
term benefits modeled in cost-effectiveness analyses due to individuals moving between clinics and insurance 
plans over the life course. For our primary analysis (incremental cost per person started on PrEP, comparing 
intervention to control arms), we will use a 1-year time horizon, aligning analyses with primary RCT effectiveness 
outcome (Aim 1). 
Sensitivity analyses examine the potential impact of varying cost and effectiveness assumptions. We will employ 
deterministic sensitivity analyses to examine model assumptions and key parameter uncertainties. We will 
assume that intervention effects would be additive unless cost components are redundant. We will conduct 
probabilistic sensitivity analyses (using Monte Carlo simulation x5000) to account for parameter uncertainty65, 
capturing input uncertainty (e.g., PrEP effectiveness, intervention cost and effectiveness). Upper and lower 
bounds will be based on trial data, literature, and/or expert opinion. Results represent an average across 
simulated model runs with an estimated uncertainty range. We will depict sensitivity results graphically and 
with relevant descriptive statistics. We will estimate net monetary benefits over a range of willingness-to-pay 
thresholds155–159, depicting the probability that each intervention is preferred given the decision maker is willing 
to pay at least the threshold value for each additional person started on PrEP or each QALY gained 63,64,66,67. 
 
10.5 Dissemination 
We will generate an interactive interface with data customized for each HD, to be used by decision makers to 
guide scale-up of the multilevel PrEP intervention. Such an interface augments conventional population health 
modeling data, allowing stakeholders to make informed decisions specific to their population and setting. By 
integrating cost-effectiveness and budget impact results from each intervention component (PrEP navigator, 
telehealth PrEP, and digital health platform) into a single interactive tool, decision makers will be able to access 
a side-by-side comparison of cost and impact estimates specific to their context. Examples of modifiable 
parameters include: population size, HIV incidence, budget and intervention effectiveness. Decision support tool 
outputs will include estimated: cost of each component of study intervention implementation (PrEP navigator, 
telehealth PrEP, digital health platform), cost per person starting PrEP and impact of implementation on number 
of people starting PrEP. We will work with local partners to make the customizable platform widely available. 
11.0 MILESTONES  
Milestones are summarized and defined in Table 6. Specific Go/No-Go criteria for proceeding to the R33 phase 
include the study meets or exceeds the two effectiveness outcome milestones (milestones #5 and 6 in Table 6), 
and at least four of the six R61 milestones, overall. Due to changes in the study design since initial Notice of Award, 
including expanding the number of involved sites and revising study design from a cluster randomized trial at the 
clinic level to a participant-randomized trial, some milestones have been adjusted or adapted to accommodate these 
differences. Revisions have been incorporated where the original wording is no longer applicable or aligned with the 
current design. Functionally, these still represent criteria that capture critical administrative, implementation, and 
effectiveness outcomes which inform decisions regarding proceeding to the next proposed phase of study (R33).  
As noted in section 9.0, the study is designed to have adequate statistical power to detect an improvement in 
PrEP initiation at 3 months of 7.5 percentage points between the intervention arm and control arm.  A 
statistically significant improvement would meet milestone 5.  Any other scenarios would be at the discretion of 
NIH.  For milestone 6 (see Table 6), the milestone will be met if at least 50% of those who initiate PrEP sustain 

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PrEP use for ≥3 months as manifest by follow-up PrEP prescription or ongoing engagement in PrEP care.  Any 
other scenario would be at the discretion of NIH.  
For milestone 5, if a statistically significant improvement is not achieved, we will explore whether the intervention is 
still worth pursuing at the R33 phase with further refinement and development by examining whether there are 
subgroups (of clients and/or clinics) for which the intervention may be effective. We propose examining the following 
as part of this assessment, and exploring whether there are revisions that would be worthwhile and feasible to 
pursue:  
Race/ethnicity: U.S. HIV epidemiologic monitoring data documents continued inequities reflected in HIV risk and 
infection by race/ethnicity with Black/African American and Latinx individuals at higher risk as compared to 
White individuals. If we find that this intervention is effective for people of color, it would be worth pursuing 
both from an equity perspective and a cost-effectiveness perspective. For example, a recent modeling study 
found that PrEP use among Black MSM was substantially more cost-effective as compared to among white MSM 
($33,064 vs $427,788 per QALY saved)56,68.  In contrast, if we find differences by race/ethnicity indicating a 
stronger effect for white individuals, this may suggest that the intervention succeeded in overcoming some – but 
not all – structural-level PrEP barriers. In this case, we would explore in the R61 phase whether the barriers 
seem feasible to address, and if so, focus R33 refinements and intervention mapping more in these areas.    
Age: U.S. HIV epidemiologic monitoring data from 2019 showed a decrease in new infections among those in the 
youngest and oldest age ranges, with no change for those in middle age categories. The document rates are 
highest among those aged 25-34 (30.1 per 100,000 people) and those aged 35-44 (16.5 per 100,000 people). 
Literature has also documented greater structural barriers to PrEP access among younger individuals. The 
components of our intervention aim to address some of these structural barriers (e.g. limited transportation, 
navigating health insurance, societal stigma)68.   
Intervention use: Our prior studies using technology-based interventions among MSM and transwomen (including a 
national sample inclusive of both and North Carolina statewide sample of MSM), have shown that those who use the 
digital health intervention platform experience a greater intervention benefit than those who do not (i.e. “non-
compliant” participants”)27,69.  Furthermore, while results from our study using HMP among South African adolescent 
girls and young women are not yet published, preliminary data reflects similarly promising findings 70. Based on 
results from the North Carolina study, the U.S. Centers for Disease Control and Prevention (CDC) has identified 
HMP as a good evidence-based intervention (EBI) for HIV risk reduction 71. 
 
Clinic characteristics: Contextual analyses will be conducted using quantitative and qualitative measures, including 
intervention engagement (i.e., training attendance, participant enrollment, etc) and interview data from stakeholder 
interviews to identify possible characteristics and conditions that may facilitate or hinder intervention success, for 
example, clinic population, on-site PrEP champions, and PrEP delivery model adopted by the clinic. (See Section 6.6) 
 Progress on all Milestones will be tracked and reported on each annual progress report.  
Table 6: Study Milestones 
Year (Quarter)  Milestone  
Definition  
R61  
Administrative  

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Y1a (Q2)  
(1) Established data use 
agreement facilitating access 
to clinic data to assess 
patient PrEP eligibility and 
referral  
Signed (by clinic-selected designee) letter of 
support for clinics to participate in STARR-NC; 
prior to clinic initiating enrollment.   
Y1 (Q4)  
(2) Finalized standard operating 
manual to cover training, study 
management and implementation  
Written SOPs for study staff, clinic and PrEP 
navigator training; study specific procedures; 
and study implementation.   
Study Implementation  
Y1 (Q4)  
(3) Trial enrollment begins by month 
12a.   
At least 1 clinic prepared to initiate participant 
screening  
Y3 (end of trial) (4) ≥50% of participants complete 6-
month survey and return DBSb  
  
Among participants who a) received a DBS kit 
and b) completed their 6-month study period, 
≥50% have completed the 6-month survey; 
≥50% have returned ≥1 DBS  
Effectiveness Outcomes  
 Y3 (end of trial)  (5) A statistically significant 
difference in PrEP uptake 
comparing intervention to controlc 
  
The proportion of participants who initiated 
PrEPd, is at least 7.5 percentage points higher 
in the intervention arm than the control arm. 
This milestone will be met if a statistically 
significant increase in PrEP initiation is found 
at 3 months in the intervention arm compared 
to the control arm. Any other scenarios would 
be at the discretion of NIH.   
 Y3 (end of trial) (6) Among intervention arm PrEP 
initiators, ≥50% sustain use ≥3 
months  
Among participants in the intervention arm 
who have initiated PrEP and for whom 3-
months of study follow-up time has elapsed 
since PrEP initiation, at least 50% will sustain 
PrEP use for ≥3 months as indicated by 
engagement in PrEP care (on-time 
visits/refills/injections) and self-reported PrEP 
use. Any other scenarios would be at the 
discretion of NIH.  
We will also report the number 
of participants who initiate PrEP after their 3-
month study visit and thus have less than 3-
months of available PrEP sustainment data at 
their 6-month follow-up visit.   
R33  
  
Established relationship with HD 
stakeholders and letters of 
support   
  
  
Refined strategy approved by key 
stakeholders for implementation  
  

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Interactive costing interface 
platform finalized  
  
  
Refined strategy ≥75% effective 
(PrEP uptake) vs R61 intervention  
 
a Year 1 refers to the RCT pre-implementation phase aligning with the grant timeline (Budget Period 1: June 13, 
2022 – May 31, 2023). 
b Because participants for whom intended follow-up is limited to 3-month outcomes are scheduled to have only 1 
DBS, criteria for these participants is as follows:  ≥50% have completed the 3-month survey, and ≥50% have returned 
1 DBS.  Any other scenarios would be at the discretion of NIH.   
c  The original grant proposal specified this milestone as pertaining to PrEP uptake at a clinic level compared to 
"pre-intervention baseline". However, this is not applicable because revisions to the study now specify 
randomization will be at the individual (rather than clinic) level with comparison of intervention versus a 
concurrent control arm. This change describes the effect of the intervention above background uptake in the 
control arm during the same time (e.g., to control for secular trend). Power analysis suggests that this milestone 
will reach statistical significance at a 7.5% difference, as clarified in the definition.   
d Persons who self-report taking any PrEP (oral or injection) during a follow-up survey OR in their app will meet 
this endpoint if this self-report is verified by at least one of the following: (1) an uploaded photo or image 
demonstrating a PrEP prescription; OR (2) any indication of the presence of tenofovir diphosphate or 
cabotegravir in DBS; OR (3) staff-abstracted electronic health record of PrEP prescription issued or physician 
notation of PrEP initiated.  
12.0 REFINING INTERVENTION (AIM 3, R33) 
12.1 Objectives 
Aim 3: Engage state and local stakeholders to refine PrEP intervention, tailored to unique contextual needs using 
Intervention Mapping. 
We will examine individual-, structural- and organizational-level determinants of success, including assessing 
implementation fidelity . Using an Intervention Mapping framework, we will identify modifiable barriers and 
build stakeholder consensus to refine our multilevel PrEP intervention. 

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12.2 Approach  
We will use Intervention Mapping (IM) to refine our 
PrEP intervention. Grounded in community 
participatory research, IM emphasizes matching an 
intervention with population needs and 
intervention contexts72–74; as such, it is well-suited 
for translating the effectiveness, implementation, 
and cost-effectiveness outcomes collected in Aims 1 
& 2 to the proposed expansion in Aim 4. As in Aim 
1, an ecological approach will be applied to 
understand PrEP use from the individual (PrEP 
user), provider, clinic, and policy levels. We will 
work with providers and leaders from local HDs, NC 
DHHS, and additional STI clinics, being mindful of 
interval changes to the PrEP landscape in our 
intervention refinement. YSGM stakeholder 
engagement is a critical aspect of the process 
evaluation and refinement: we will engage an 
established Community Advisory Board overseen by 
mPI Muessig, which includes racially and ethnically diverse YSGM including five members recruited from 
participating NC counties (see PHS). The IM process unfolds in six major steps (Fig 4)74. Step 1 focuses on 
identifying the problem and context for intervention. We will leverage Aim 1 data (Section 6.4-6.6), 
contextualized by cost-effectiveness outcomes in Aim 2, to provide a comprehensive assessment of the needs 
and determinants of PrEP use from the critical vantage points of user, provider, and policy-influencer. In Step 2 
we will state our agreed-on performance outcomes and objectives, creating matrices (how, who, result) of the 
change objectives and examining the determinants (barriers/facilitators) for outcomes. We will explore these 
determinants guided by the Consolidated Framework for Implementation Research (CFIR)75, explicitly assessing 
relevant constructs (i.e., intervention complexity) in terms of their impact on implementation. In Steps 3 - 5 we 
move planning through design, production, and implementation – refining our multilevel PrEP intervention 
based on user (provider and patient) feedback. The final step is preparing the program evaluation– developing 
measures for assessment to be used in Aim 4. Our established collaboration and support from NC DHHS 
policymakers will aid progression through IM steps, returning to the Aim 1 and 2 data as a touchstone. 
12.3 Data Collection and Analysis 
Each IM step includes processes for documentation. The steps are iterative, and matrices, objectives, and 
outcomes are revisited, revised, and expanded as involved parties gain new knowledge about the population, 
determinants, and context. As such, record-keeping at each step is detailed and includes decision logs and 
formal reports following each step and the conclusion of the process. At the conclusion of Aim 3, the refined 
PrEP intervention will be ready for use in all clinics, as outlined in Aim 4 (Section 13.0). 
13.0 DETERMINE EFFECTIVENESS OF REFINED INTERVENTION 
(AIM 4, R33)  
13.1 Objectives 
Aim 4: Determine effectiveness and cost-effectiveness of refined PrEP implementation strategy. 

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We will redeploy the refined intervention at all participating clinics from the R61- phase (sections 6.0 – 11.0). 
Enrollment criteria and recruitment will follow that of Aim 1 (Sections 5.1, 5.2), though some intervention 
adaptations may occur as part of the Aim 3 refining process. There will be no randomization in this phase. 
Effectiveness, as described below, will be determined via comparison to R61 control condition PrEP uptake 
outcomes.  
13.2 Data Sources 
We will use the same data sources as Aim 1 (Sections 6.4 – 6.6). 
13.3 PrEP Outcome Analysis 
Our primary effectiveness outcome of interest is the probability of PrEP uptake within 3 months of an eligible 
clinic visit or outreach encounter. For the R33 phase, we will evaluate this outcome among all participants, 
comparing uptake to the control condition rates observed in our R61 phase. Similar to Aim 1, we will evaluate 
secondary outcomes, including relevant HIV prevention cascade components, programmatic, and clinical 
outcomes. We will also examine the relative effectiveness of the refined vs original strategy by comparing PrEP 
uptake in the first 6 months of implementation for each phase. That is, the PrEP uptake in months 0-6 during the 
R61 among the intervention arm participants compared to the PrEP uptake in months 0-6 during the R33 using 
the refined intervention. Temporal trends and changes in PrEP awareness (both patient and provider) and 
prescribing capacity may influence these differences, so we will also capture the relative effectiveness by looking 
at differences in the PrEP uptake by time. 
13.4 Power and Sample Size 
Assuming stable clinic volume, we use the same assumptions for patient PrEP/study eligibility. Again, our 
primary analysis includes eligible patients who consent to the study and download the app, though all 
participants will receive the full app in this expansion phase. We anticipate enrolling 300 persons across all 
clinics during the R33. 
 
We calculated statistical power for the effect of intervention upon PrEP uptake by 3-month follow-up using SAS 
9.4 (Cary, NC) with a 5% type I error rate and a two-sided Chi-square test. Assuming 2.5% of eligible patients 
started PrEP within 3 months in the control arm during the R61 Phase 1, we calculated statistical power to 
detect a range of small to large effect sizes from 5% to 10% percentage point increases in PrEP uptake under a 
range of possible sample sizes and assuming 10% missing data (Table 4b). Given our design and assumptions, 
with a sample size of 300 receiving the intervention compared to 168 historic controls, we will have >84% 
statistical power to detect a medium effect size (7.5%) and >97% power to detect a large effect size (10%).  
Table 4b: Statistical power as a function of the observed difference in effect (PrEP uptake) and sample size* 
SAMPLE SIZE IN R33 INTERVENTION ARM 
OBSERVED 
DIFFERENCE 
IN PREP 
UPTAKE 
n=250 
n=300 
n=350 
n=400 
n=450 
5% 
54% 
55% 
56% 
57% 
59% 
7.5% 
83% 
84% 
86% 
87% 
88% 
10% 
96% 
97% 
98% 
98% 
98% 
 
*Assuming PrEP uptake of 2.5% among the historical control arm, 10% missing data at month 3, and 5% type 1 
error 

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13.5 Implementation Outcomes 
Implementation outcomes focus on intervention fidelity at all clinics. Measures are assessed via chart review, 
mirroring Aim 1 (Table 3). We will also evaluate acceptability of the refined strategy, engaging clinic stakeholders 
in in-depth interviews (n=15) to assess provider burden of intervention, adequacy of training, support structure, 
and other organizational-level success determinants. Sampling, data collection and analysis for all methods will 
follow those of Aim 1. 
 
13.6 Cost Analysis 
We will update our cost-effectiveness (Aim 2, Section 10.0) model using parameters generated in this final 
implementation phase, adapting cost inputs to account for refinements in intervention components. The need 
for prospective costing will be determined based on the scope of intervention refinement/revision from Aim 3. If 
costing is pursued, we will utilize the methods previously described. Primary cost-effectiveness outcomes and 
methods follow those described in Aim 2, including updated budget impact analyses and sensitivity analyses, 
including evaluation over a range of potential effectiveness outcomes. 
14.0 DATA COLLECTION, MANAGEMENT AND MONITORING 
14.1 Development of Protocol and Case Report Forms  
The study team is responsible for the development of this protocol as well as the Case Report Forms (CRFs) 
needed to collect the information required to implement this protocol.  
14.2 Data Records 
Participant-related study information will be identified through a study ID number (SID) and participant code on 
all participant CRFs, audio files, transcripts, and CASI files. Participant names or other personally identifying 
information will not be used on any study documents and will be redacted from interview transcripts.  
14.3 Record Availability 
Study PIs will ensure the availability of all study-related records for audit by NIH, UNC Regulatory, and the Study 
Monitor including participant records, consent forms, CRFs and supporting source documentation for the 
purpose of ensuring the protection of study participants, compliance with the protocol and regulatory policies, 
and accuracy and completeness of records.   
14.4 Data Collection Across all Aims 
Data collection for the purposes of each aim will occur from sources as follows (Table 7). Study screeners, 
assessments, and in-depth interviews may all be completed virtually/remotely via secure HIPAA-compliant 
platforms for survey administration, phone, or videoconferencing:  
Table 7 
Data source 
Collection method 
Aim 1 
Aim 2 
Aim 3 
Aim 4 
CASI surveys 
In-clinic or online 
 
x 
 
 
 
x 
Whole blood samples 
Self-collected blood sample  
 
x 
 
 
 
x 
Qualitative notes and transcripts 
 
 
 
 

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14.5 Data Storage and Security 
We will secure study data with all appropriate physical, electronic and operational protections. All data files will 
have encryption and strong password protection. Any identifiable data will either be stored on secure servers or 
will be on fully encrypted laptops. Participant names and their SID and participant code will be stored in 
separate tabs in REDCap accessible only to designated study staff, and site monitors. Original source documents 
for individual participants will be maintained at the UNC study site and will be accessible only to the study staff. 
We use 256-bit SSL encryption for transfers of information online. UNC uses Transport Layer Security (TLS) 
encryption (also known as Hypertext Transfer Protocol Secure (HTTPS) for all transmitted data. Survey data are 
protected with passwords and HTTPS referrer checking. Secure, encrypted file transfer is also available via FTPS 
(FTP-ssl) for uploading and downloading data and documents. The database is hosted on secure servers at UNC 
which reside physically in the dedicated Institute for Global Health and Infectious Diseases (IGHID) server rooms 
and are maintained by UNC IGHID IT staff. The server rooms are locked, and access can only be obtained by 
authorized personnel. Electronically, the servers are protected by multiple layers of firewalls and the data 
systems use 256-bit SSL data encryption, the secure socket layer technology used for transmission of 
confidential information over the internet. To ensure no loss of data, an automated backup process is 
implemented with integrity checks and incremental backup performed daily and full back-up monthly for both 
the web and data servers. Encrypted copies of the monthly full back-up images are also sent to an offsite 
storage facility. 
CASI surveys: We will use RedCap, a HIPAA-compliant web-based platform for CASI data transmission and 
storage. 
Self-collection blood sample kits: Self-collection blood sample kit materials will be identified with a study ID 
number only. The kit includes return packaging and a self-addressed, pre-paid return mailer that participants will 
use to send completed samples directly to the study’s CLIA-certified lab for storage and subsequently to UNC’s 
lab for processing (see section 16.1). Samples will be received by the labs and logged into password-protected 
manifest on HIPAA-compliant secure servers using study ID only (no participant identifying information). 
Samples will be securely stored at the lab until processed following standard lab procedures and destroyed 
following testing. Test results will be added to the sample manifest. Study staff will abstract results from the 
sample manifest into a Blood sample CRF in RedCap. After analysis, no samples will be stored for subsequent 
use.   
Interviews, intervention mapping 
x 
x 
x 
x 
Digital Health Intervention paradata 
Entered in app by participants, study staff, PrEP 
navigators 
 
x 
 
 
 
x 
Clinic Observations 
 Project receipts, personnel salary  
 
 
x 
 
 
HIV/STI test results 
Electronic Health Record 
data/LapCorp/Quest/CELR/participant-provided records 
 
x 
 
 
 
x 
PrEP care history 
 Electronic Health Record data/participant-provided   
records 
x 
x 
 
x 

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Qualitative notes and transcripts: We will use a qualitative data analysis software (e.g. Atlas.ti, Dedoose) to 
perform all qualitative analyses. These programs employ HIPAA-compliant data encryption and allow for 
password-protected, project specific access. Only approved study staff will have access to these data. 
Digital Health Intervention paradata: We use 256-bit SSL encryption for transfers of information online. UNC 
uses Transport Layer Security (TLS) encryption (also known as Hypertext Transfer Protocol Secure (HTTPS) for all 
transmitted data. Secure, SSL file transfer is used for downloading of data and documents. The database is 
hosted on secure servers at Florida State University. 
Access to data will be on a role-based standard; only those study staff who require access to each type of data to 
complete their study-related roles will be allowed access. Study staff will be assigned an individual login and 
password for use to access the system, linked to their name and e-mail address. Hierarchical permission settings 
are associated with each password, giving the user the level of access appropriate to their role in the study.  
 
Medical Records: Data abstracted from medical records will be recorded by study staff on electronic CRFs stored 
in RedCap.  
CRFs: Study monitoring data, including information about eligibility, demographic data and monitoring 
untoward effects, will be collected on CRFs. All CRFs for this study will be entered into REDCap. Hard copies will 
be made available via download from a UNC-run secure cloud management platform, to be used if needed.  
14.6 Data Quality Assurance 
Quality assurance checks will be implemented throughout the data collection process to quickly identify and 
rectify potential problems. Survey instruments will employ skip patterns and built-in checks to minimize 
discrepant and unrealistic answers. Standard data cleaning procedures will be used prior to analyses, including 
outlier detection and graphical representation of the data.  
14.7 Role of Data Management 
All data will be entered, managed and retained by the UNC study staff until analyses are complete and for up to 
three years following study closure.  
14.8 Data and Safety Monitoring Plan 
The purpose for study monitoring is to verify that the rights and well-being of human participants are protected; 
the reported trial data are accurate, complete, and verifiable from source documents; and the trial is conducted 
in compliance with the currently approved protocol and amendment(s), with good clinical practice (GCP), and 
with all applicable regulatory requirements. The Clinical Quality Monitoring Plan (CQMP) specifies the frequency 
and types of data that will be reviewed (CRFs, regulatory documents, study staff training records, and medical 
and laboratory records) to accomplish these monitoring activities. Monitoring for this study will be conducted 
through the North Carolina Translational and Clinical Sciences Institute monitoring service, including quality 
assurance and study monitoring such as regulatory file review, informed consent review, patient eligibility 
confirmation, protocol compliance review, assessment of safety reporting requirements, and review of training 
records. 
 
Mechanisms to ensure the security and integrity of the study data are also described above in Section 14.5. 
14.9 Study Monitoring Committee 
A study monitoring committee (SMC) will be constituted prior to initiation of the study. This committee will 
include 2 HIV clinicians or research investigators not directly involved in the study, and a community 
representative.  At least one DAIDS representative will attend the meetings. Cumulative study reports including 

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reports of adverse events, social harms, and unanticipated problems, as well as ad hoc reports of unanticipated 
problems will be shared with the SMC and reviewed on a bi-annual basis. The SMC will assess study conduct, 
adequate delivery of the behavioral intervention package, ascertainment of PrEP uptake outcomes, and other 
related data to ensure adequate collection of primary and key secondary outcome data. Recommendations from 
the SMC will be provided to the study investigators and DAIDS.  
In addition, the University of North Carolina IRB (as prime IRB) will conduct regular reviews of the study 
protocol, changes in the study protocol, and adherence to the protocol during implementation The PIs are 
required to report any unexpected study-related adverse events following UNC IRB protocol.  
15.0 HUMAN SUBJECTS CONSIDERATIONS 
This study will be conducted in compliance with the protocol, ICH Good Clinical Practice guidelines, and 45 CFR 
Part 46. 
15.1 Participant Confidentiality 
We will take the utmost caution to protect the confidentiality of participants’ involvement in the study and all 
participant provided information/data throughout all research procedures and data management and analysis. 
Participants may be concerned about the security of their data, particularly since it is collected and stored 
electronically. Every effort will be made to ensure that study participants are protected from the risk of breach 
of confidentiality using a variety of steps to ensure participant data security across all sources (Section 14.5).  
The results of the research will be disseminated but no participant names or other identifying information will 
be used in any dissemination materials (published or otherwise).  
15.2 Risks and Benefits 
15.2.1 Risks 
To minimize the risk of participants feeling uncomfortable about answering personal questions, we will use CASI 
methods for the study's assessments. Participants will be able to decline to answer any question that makes 
them uncomfortable during in-depth interviews as well as on the study assessments.  
To minimize risks to confidentiality, we will secure study data with all appropriate physical, electronic and 
operational protections (Section 14.5). Access to data will be on a role-based standard; only those study staff 
who require access to each type of data to complete their study-related roles will be allowed access. All study 
staff will be trained in security and confidentiality procedures (Section 4.1) and will sign a confidentiality 
agreement before receiving access to any participant data.  
For each mode of participant contact information, we will ask specifically whether anyone else potentially has 
access to that mode of communication, and if it is acceptable to leave a non-specific message about 
participation in a health study. Additionally, all scripts for email, text message, and telephone contact with 
participants will be reviewed and approved by the IRB before being used for contact with participants.  
As per NIH policy, this study is automatically issued a Certificate of Confidentiality (CoC): “Per Section 2012 of 
the 21st Century Cures Act as implemented in the 2017 NIH Certificates of Confidentiality Policy, all ongoing or 
new research funded by NIH as of December 13, 2016 that is collecting or using identifiable, sensitive 
information is automatically issued a CoC. Compliance requirements are outlined in the NIH Grants Policy 
Statement, which is a term and condition of all NIH awards.” 

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15.2.2 Benefits   
The main potential benefit of the proposed study for both Intervention and Control Arm participants is the 
provision of resources and referrals for PrEP among SGM men and 6/18/2025der women at risk for HIV. If the 
study intervention arm is shown to be effective, the potential societal benefit is an increase in affordable PrEP 
access, use, and maintenance among populations at heightened risk for HIV.  
The risk-benefit assessment is considered acceptable given the modest level of participant risk and potential for 
individual and societal benefit.  
15.3 Intervention Monitoring  
This study involves a behavioral intervention using PrEP navigators, an interactive digital platform for 
information and support, and linkage of participants to PrEP providers. The PrEP providers are not part of the 
study.  They include clinicians in the community, telehealth providers in the community, or clinicians working at 
STI clinics.  PrEP drugs are not provided by the study. Aggregate reporting of the harms and events outlined in 
Sections 15.3.1 – 15.3.3 will be completed quarterly.  Quarterly reports will be reviewed by representatives from 
the investigator team and DAIDS.  Cumulative reports will be made available to the SMC for their biannual 
reviews (see Section 14.9). 
15.3.1 Adverse Events:  
As STARR is a behavioral intervention that does not include investigational product, standard adverse event (AE) 
reporting will not be undertaken. The study team will monitor for and track serious adverse events (SAEs) and 
non-serious adverse events related or possibly related to study procedures and/or to participation in the study. 
Such events will be reported to the NIH NIAID Division of AIDS (DAIDS) Program Officer and Medical Officer for 
this protocol at the same time as they are reported to IRB/ECs following the UNC IRB’s reporting requirements 
for Promptly Reportable Information (UNC Office of Human Research Ethics SOP 1401: Promptly Reportable 
Information available at https://policies.unc.edu/TDClient/2833/Portal/KB/ArticleDet?ID=132230) and DAIDS 
Expedited Adverse Event (EAE) Manual (in the case of SAEs, as specified below).  Study site staff must document 
in source documents all of these AEs reported or observed in STARR-NC participants, regardless of seriousness 
or severity. Source documentation for all AEs will minimally include the following:  
• 
AE term/diagnosis  
• 
Severity grade  
• 
Onset date  
• 
Outcome  
• 
Outcome date  
• 
Treatment for the AE (if any) 
Study participants will be instructed how to contact the study staff to report any AEs they may experience at any 
time between enrollment and follow-up assessments. AEs will also be actively assessed in all follow up CASI  
assessments. Should a participant report experiencing an AE that they perceive to be related to their study 
participation, research staff will contact the participant to assess the severity and appropriate resolution action.  
The most current Division of AIDS Table for Grading the Severity of Adult Adverse Events (DAIDS AE Grading 
Table) is used and is available on the RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
Serious adverse events (SAEs) are those AEs that result in one or more of the following outcomes:  
• 
Death  
• 
A life-threatening (i.e., an immediate threat to life) event  

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• 
Requires in-patient hospitalization or prolongation of an existing hospitalization  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
• 
A medically important event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above 
Based on the low-risk nature of the study procedures, we do not anticipate the occurrence of any SAEs.  
Expedited Reporting:  All SAEs will be entered into the study database, with appropriate levels of documentation 
(including a brief narrative description) and notification of the IRB.  SAEs will be reported to the DAIDS Medical 
Officer within 3 reporting days of the staff becoming aware of the SAE and will include study staff assessment 
(per section 15.3.3) of SAE expectedness, relatedness, and whether it is an unanticipated problem. If actions are 
taken to address the event, these will also be reported. Reporting days are Monday through Friday, as defined in 
Version 2.0 of the DAIDS Expedited Adverse Event (EAE) Manual, which is available on the RSC website at 
http://rsc.tech-res.com/safetyandpharmacovigilance.  
If additional significant information becomes available subsequently, the report will be updated.  A study 
physician investigator or sub-investigator listed on the DAIDS Investigator of Record (IoR) Agreement must 
review and verify the completed expedited adverse event report for accuracy and completeness. This physician 
also makes the investigators’ final assessment of relatedness. 
 
The expedited AE reporting period for this study is through the end of follow-up for each participant.  After this, 
SAEs will be reported to the DAIDS Medical Officer if the study staff become aware of the events on a passive 
basis (from publicly available information) until database lock. 
15.3.2 Social Harms 
In addition to AEs, participants may experience social harms — nonmedical adverse consequences — as a result 
of their participation in the study. For example, participants could experience difficulties in their personal 
relationships with partners, family members, and friends. They also could experience stigma or discrimination 
from family members and members of their community. In the event that any social harms occur, study staff will 
document the issues or problems and make every effort to facilitate their resolution. 
 
The potential for social harms will be described in the informed consent form (ICF, Section 15.5) and assessed 
both actively and passively during study participation. At 3-, 6-and 12-month study assessment points, 
participants will complete a questionnaire probing for social harms that are perceived to have occurred as a 
result of study participation (For example, “Since your last visit, has anyone treated you poorly as a result of your 
participation in this study?”). In addition to responding to this standardized assessment at the specified visits, 
participants also may spontaneously passively report study-related issues and problems to study staff at any 
time. All reported Social Harms (actively and passively captured) will be recorded on a Social Harms CRF for 
aggregate reporting.  
 
Study staff will follow all social harms to resolution (until they no longer exist) or stabilization (they exist but at a 
manageable level) or until study exit. Study staff will provide referrals as needed/appropriate to other 
organizations, agencies, and service providers that may be able to help address the problem. 
 
If the reported social harm is associated with an AE, the AE will be recorded on an AE Log.  

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15.3.3 Unanticipated Problems 
An unanticipated problem is any incident, experience, or outcome that meets all of the following criteria, as 
defined by the OHRP76:  
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population being studied;  
• 
Related or possibly related to participation in the research (possibly related means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved 
in the research); and 
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
Unanticipated problems will be collected by passive ascertainment. All unanticipated problems that meet the 
three criteria above will be reported to DAIDS (Medical Officer and Program Officer), the IRB, and to the SMC as 
described in Section 14.9 and in accordance with the UNC IRB’s reporting requirements for Promptly Reportable 
Information (UNC Office of Human Research Ethics SOP 1401: Promptly Reportable Information available at 
https://policies.unc.edu/TDClient/2833/Portal/KB/ArticleDet?ID=132230), and may warrant consideration for 
alterations to the research protocol or informed consent process or documentation to more accurately reflect 
and communicate expected risks. 
15.4 Ethical review 
This protocol, the informed consent documents and any subsequent modifications will be reviewed and 
approved by the UNC IRB responsible for the oversight of the study.  Annual IRB reporting and review is required 
for the duration of the study.  
15.5 Informed consent 
Informed consent procedures will be conducted virtually/remotely and signed electronically following the 
informed consent SOP.   
The informed consent will follow the UNC required consent template including describing the purpose of the 
study, the procedures to be followed, and the risks and benefits of participation.  The consent forms will use 
language that is sufficiently simple for lay persons to comprehend. Patients will not be coerced into 
participating. Children under the age of 18 years, decisionally impaired adults and non-English speakers will not 
be enrolled in this study. As specified in the consent form, participants’ co-enrollment in additional PrEP related 
studies will not be permitted.  
Following initial screening (Section 5.4) participants may opt to complete a self-guided electronic informed 
consent process and/or to request an appointment to review the informed consent with a study staff via phone 
or videoconference. Study staff will review consent forms with potential participants (each in a confidential 
setting) and explaining all risks and benefits associated with participation of the study, soliciting questions, 
allowing the potential participant time to review the form, soliciting questions again, and then offering the 
opportunity to electronically sign the consent form. At the study enrollment/onboarding visit, the investigators 
will verify that informed consent has been completed for each participant before starting any study procedures 
according to the standards set forth in the ICH Good Clinical Practice guidelines.  
 
The informed consent process will cover all elements of informed consent required by research regulations. In 
addition, the process specifically will address the following topics of importance to this study: 

49 
Version 4.0, Dated September 30th, 2024  
 
1. The unknown safety and unproven efficacy of the study interventions 
2. The potential medical risks of study participation (and what to do if such risks are experienced) 
3. The potential social harms associated with study participation (and what to do if such harms are experienced) 
and examples of possible adverse outcomes of these social harms.  
4. The limited benefits of study participation  
5. The distinction between research and clinical care  
6. The right to withdraw from the study at any time  
 
The informed consent process will include an assessment, through a series of questions, of each potential 
participant's understanding prior to enrollment. Patients who are not able to demonstrate adequate 
understanding of key concepts after exhaustive educational efforts will not be enrolled in the study.   
 
The e-signed original consent form will be securely stored on HIPAA-compliant servers at UNC. All prospective 
study candidates will be offered a copy of the informed consent(s) by email and offered a hard copy sent by mail 
to the address of their choice. In addition, a copy of the informed consent text is available within the password 
protected HMP app (both intervention and control arm versions) for participants’ reference.  
15.6 Participant Remuneration 
Participants will receive financial compensation throughout the course of their participation. See section 8.2 for 
specific financial compensation amounts.   
16.0 LABORATORY SPECIMENS  
This study is abstracting STI/HIV laboratory results from established standard-of-care HIV/STI testing done by 
local STI clinics specimen collection procedures. All collaborating STI clinics will be responsible for specimen 
collection, processing, or handling are deemed accredited by the North Carolina Local Health Department 
Accreditation Board (NCLHD) 77.  The NCLHD Accreditation Program provides an efficient way to ensure local STI 
clinics meet minimum requirements by linking basic standards to current state statutes, administrative code and 
the contractual and program monitoring requirements that are already in place through the N.C. Division of 
Public Health. 
Any lab from which we are abstracting results will be appropriately licensed/certified under the Clinical 
Laboratory Improvement Amendments of 1988 (CLIA 88)78 
16.1 Dried blood spots 
Dried blood spot (DBS) kits for measuring PrEP will be sent to participants at an address of their choice at study 
months 3 and 6 for self-collection (See Section 6.5). Following an illustrated step-by-step instruction card, 
participants use a single use lancet to prick the side of their finger and collect a few drops of blood to saturate 
the designated areas on the DBS card. After allowing the card to dry for at least 15 minutes, participants re-
package the sample as directed and return the sample using the pre-addressed, pre-paid shipping envelope.   
DBS kits will be assembled, shipped out, received back, stored and processed using two laboratories: Molecular 
Testing Labs (MTL https://moleculartestinglabs.com/) and the UNC CFAR Clinical Pharmacology and Analytical 
Chemistry (CPAC) Core following previously established protocols from the NICHD-funded study protocol of the 
Adolescent Medicine Trials Network (ATN 142 P3 study)79.  

50 
Version 4.0, Dated September 30th, 2024  
MTL is Clinical Laboratory Improvement Act (CLIA) certified and College of American Pathologists (CAP) 
accredited, and all testing is run in compliance with FDA requirements. MTL will assemble, ship, receive and 
store DBS kits and then batch ship samples to UNC for processing following their standard SOPs.   
The UNC CFAR Clinical Pharmacology and Analytical Chemistry (CPAC) Core provides Comprehensive Study 
Design, Bioanalytical, and Data Analyses Support to Animal and Human Clinical Pharmacology Investigations in 
the HIV/AIDS arena. The CPAC Core applies the principles of Good Laboratory Practices, Good Clinical Laboratory 
Practices, and FDA guidelines to provide quality assurance and scientific support.  
CPAC specimen collection instructions, shipping, and receipt procedures are dictated by CPAC SOP 0360 
(Available upon request). Bioanalytical assays are developed and utilized according to SOPs: CPAC SOP 0342, 
0343, and 0344. All Lab SOPs are available upon request. In brief, stock solutions are prepared from reference 
materials corrected for purity according to their respective Certificates of Analyses or supporting data, and the 
equivalency of two independent stock solution preparations is confirmed and should not differ by more than 
5%. These reference materials are obtained from reputable commercial sources such as but not limited to the 
following: Aptochem, Toronto Research Chemicals, MedChemExpress, Alsachim, Moravek, and TriLink. Source, 
lot number, expiration date, storage conditions and certificates of analysis for all reference material is procured 
and documented. Calibration standards and quality control samples (QCs) are prepared from stock solutions in a 
matched matrix when available or surrogate matrix when not available. A calibration standard curve is 
generated for each analytical run to calculate the concentration of the analyte in the unknown samples. 
Estimation of concentration in unknown samples by extrapolation of standard curves below the lower limit of 
quantification (LLOQ) or above the upper limit of quantification (ULOQ) is not performed. Dilution QCs are 
included in the run to verify the unknown samples that are diluted due to exceeding the calibration range are 
accurate and precise. An analytical run generally begins with a system suitability sample, blank matrix samples 
to verify the lack of matrix interferences from both the analyte and internal standard, followed by a set of 
calibration standards, continuing with QCs and study samples intermixed.  At least one blank sample is injected 
following the ULOQ standard to mitigate possible carryover. If two sets of calibration standards are used, the 
second set follows the last study sample and QCs showing minimal or no instrument fluctuation from the start 
to the end of the analytical run. Passing criteria for individual standards and QCs as well as the analytical run, in 
general, are predefined in accordance with CPAC SOP 0344.  
The CPAC Core participates in domestic and international proficiency testing through the Clinical Pharmacology 
Quality Assurance (CPQA) and K.K.G.T. Programs to ensure the highest level of scientific rigor and 
reproducibility. The Laboratory employs a full time QA/QC officer who maintains and reviews SOPs on an annual 
basis. All data are reviewed against source to ensure accuracy of reporting and reviewed for pharmacologic 
plausibility before being released to investigators. Preventive Maintenance of instruments in the CPAC Core is 
conducted on an annual or semi-annual schedule, dependent on the instrument. Detailed descriptions of 
experimental procedures, including sample storage and processing, are documented electronically and in 
notebooks. Instruments and settings used for all experiments are detailed with the associated experiment 
electronically and in laboratory notebooks. 
17.0 STUDY TIMELINE 
The study is divided into two phases, with the Phase 2 R33 contingent on Go/No-go criteria Study Milestones 
(Section 11.0) which reflect critical effectiveness and implementation outcomes, indicating readiness to 
implement the intervention strategy on a wider scale. 
 

51 
Version 4.0, Dated September 30th, 2024  
Table 8: Study Timeline  
R61 
R33 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
1 2 3 4 1 2 3 4 1 2 3 4 
1 2 3 4 1 2 3 4 
Finalize data use agreements 
HMP customization/SOP finalization 
IRB Review 
PrEP navigator training 
Aim 1: clinic-randomized trial of multilevel intervention 
Clinic trainings (NC ATEC) 
Patient enrollment 
Patient follow-up 
Patient and provider interviews 
Clinic surveys 
Implementation & effectiveness outcome
analysis
Aim 2: Cost-effectiveness 
Prospective cost collection 
Model construction & analysis 
Interactive interface development 
Submit progress report 
Aim 3: Refine intervention 
Stakeholder engagement & intervention
mapping
Aim 4: Expand intervention  
Clinic trainings/on-boarding 
Patient enrollment 
Patient follow-up 
Patient and provider interviews 
Update cost-effectiveness 
model/analysis & finalize interactive 
platform 
Dissemination 
Aim 1 and 2 manuscript 
preparation/submission 
Aim 3 and 4 manuscript 
preparation/submission 
Presentation to national Youth 
Advisory Board 
Project website and social media 
updates 
 

52 
Version 4.0, Dated September 30th, 2024  
18.0 PROTOCOL COMPLIANCE 
The study will be conducted in full compliance with the protocol. The protocol will not be amended without prior 
written approval by the Protocol Chair and DAIDS Medical Officer. All protocol amendments must be submitted to 
and approved by the relevant IRB(s) prior to implementing the amendment.

53 
 
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Appendix 
The appendix will include the following documents: 
• 
Enrollment Informed Consent Forms